tbuckley/cabot-search huggingface dataset:
SURG-22. SUPRATOTAL RESECTION IN GLIOMA: A SYSTEMATIC REVIEW
Authors: Charles de Leeuw, Michael Vogelbaum
Journal: Neuro-Oncology (2018)

PURPOSE: To evaluate the published evidence addressing supratotal resection in glioma, where supratotal is defined as resection beyond all MRI abnormalities present on T1 enhanced and FLAIR modalities. EMBASE, MEDLINE, Scopus, and Web of Science were queried using search terms designed to identify published works on supratotal resection. Records that were case studies, reviews or editorials, non-English, abstract-only, brain metastases, or only descriptive, were excluded. All others were included. 309 unique references yielded 41 studies for full-text review, with 7 included in the final analysis. Five originated from research in France, one from Germany, and one from Italy. All five French studies focused on low-grade glioma, whereas the remaining two focused on glioblastoma. A total of 88 patients had undergone supratotal resection in a combined cohort of 492 patients (214 males and 278 females, age 18 to 82 years). Fifty-one supratotal resections were conducted on high-grade gliomas, and 37 on low-grade gliomas. Surgical resection technologies included intraoperative MRI, cortical and subcortical functional testing, and 5-aminolevulinic acid. Studies were mostly of Oxford Center for Evidence-Based Medicine Level 4 quality. Karnofsky Performance Status, overall survival, progression-free survival, neurological deficits post-operatively, and anaplastic transformation were the main measured outcomes. No randomized controlled trials were identified. Preliminary low quality support was found for supratotal resection in increasing overall survival and progression-free survival for both low-grade and high-grade glioma. The literature suggests insufficient evidence for carte blanche application of supratotal resection, particularly in lower grade gliomas where neurological deficits can result in long-term disability. Current evidence consists of data from only a few centers without independent validation. There is a definite need for further research with larger patient populations, clearly defined metrics and comparisons to evaluate improvements by, and the involvement of multi-national/multi-center research groups.
ATIM-23. ANTI-CD27 AGONIST ANTIBODY VARLILUMAB IN COMBINATION WITH NIVOLUMAB FOR RECURRENT GLIOBLASTOMA (rGBM): PHASE 2 CLINICAL TRIAL RESULTS
Authors: David Reardon, Thomas Kaley, Fabio Iwamoto, Joachim Baehring, Deepa Subramaniam, Tracey Rawls, Yi He, Tibor Keler, Michael Yellin
Journal: Neuro-Oncology (2018)

CD27 is a key immunostimulatory molecule that enhances T cell survival, activation and effector function, as well as proliferation and cytotoxic activity of NK cells. Preclinical studies demonstrate synergistic activity of PD-(L)1 blockade and varlilumab, an anti-CD27 agonist monoclonal antibody. In an open-label Phase 2 study (NCT02335918), patients with bevacizumab-naïve, rGBM following first line chemoradiation received varlilumab (3 mg/kg, up to 16 doses) and nivolumab (240 mg) Q2W. Objectives were to determine preliminary antitumor activity based on 12-month survival rate (OS12; primary), objective response rate (ORR; iRANO), progression-free survival (PFS), as well as tolerability. 22 patients were enrolled: 23% methylated MGMT (mMGMT), 68% unmethylated MGMT (uMGMT), 9% unknown; median age 58 years; 68% male; 36% ECOG performance status 0, 64% ECOG 1; 4/18 (22%) PD-L1+ tumor. Safety profile was consistent with that of each agent alone and generally grade 1–2, without dose-limiting toxicity or drug-related deaths. The most common toxicities were lymphopenia, pruritus, headache, and rash. Two patients experienced treatment-related serious events (grade 2 gait disturbance, headache and personality changes; and grade 4 thrombocytopenia). OS12 was 38.5% (95% CI; 18.6, 58.2) overall and 43.6% (95% CI; 18.2–66.7) for the uMGMT subgroup. Median OS (months) was 9.7 (95% CI; 6.7–14.8) overall and 11.3 (95% CI; 5.3, -) for the uMGMT subgroup. Eight patients (6 uMGMT, 1 mMGMT, 1 unknown) survived 12 months (range: 13.7 - 23+). Two patients (9%; both uMGMT) experienced Partial Responses (63% and 92% shrinkage) continuing at 19 and 16 months. Nine patients experienced stable disease, including 5 for 6 months (range: 7.3 - 20.3). Varlilumab with nivolumab was generally well tolerated in patients with rGBM and achieved durable therapeutic benefit in a subset of patients, although overall ORR and OS12 were similar to historical nivolumab monotherapy data. Outcome among uMGMT rGBM patients may be encouraging.
ACTR-14. PHASE I STUDY OF AZD1775 WITH RADIATION THERAPY (RT) AND TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM) AND EVALUATION OF INTRATUMORAL DRUG DISTRIBUTION (IDD) IN PATIENTS WITH RECURRENT GBM
Authors: Brian Alexander, Jeffrey Supko, Nathalie Agar, Manmeet Ahluwalia, Arati Desai, Jorg Dietrich, Thomas Kaley, David Peereboom, Naoko Takebe, Serena Desideri, Joy Fisher, Megan Sims, Xiaobu Ye, Keith Ligon, L Burt Nabors, Stuart Grossman, Patrick Wen
Journal: Neuro-Oncology (2018)

AZD1775 is an oral small molecular inhibitor of the G2/M checkpoint regulator Wee1. The Adult Brain Tumor Consortium 1202 trial (NCT01849146) is a phase I, open label, multicenter dose-finding study of AZD1775 in combination with standard RT and TMZ followed by an IDD study for patients undergoing surgery for recurrent GBM. Dose of AZD1775 was increased in a 3 + 3 design M-F during concurrent RT/TMZ and x 5d/28d cycle with adjuvant TMZ in separate cohorts. A combination cohort with both concurrent and adjuvant AZD1775 at MTD and analysis of PK/PD and IDD at MTD in patients undergoing surgery for recurrent GBM followed. MTD was 200 mg for concurrent with 2/6 patients experiencing DLTs (grade 4 neutropenia, grade 3 ALT elevation). MTD for the adjuvant cohort was 425 mg with 1/6 patients experiencing DLT (grade 4 decrease in ANC). 6/12 patients experienced DLTs when cohorts were combined, however, five during the concurrent phase. Three patients had grade ≥3 ALT/AST elevation, one had grade 3 afib, and one had grade 4 neutropenia/thrombocytopenia, grade 3 dehydration/fatigue/muscle weakness. A sixth patient had grade 4 neutropenia in the first adjuvant cycle. Following amendment, an additional 6 patients were enrolled with 150 mg (concurrent) and 425 mg (adjuvant) combination and are in the observation period with one DLT currently. Drug concentration in contrast enhancing and non-enhancing brain tumor was 4–8 x and 0.5–2.6 x greater than plasma, respectively for patients on IDD portion. AZD1775 in combination with RT/TMZ at 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ had unacceptable DLT rate in the concurrent phase. A cohort with 150 mg concurrent/425 mg adjuvant has competed accrual with acceptable rates of toxicity currently in observation. AZD1775 has good penetration to non-enhancing and enhancing tumor areas.
HOUT-14. HOMOLOGOUS RECOMBINATION DEFICIENCY IN PATIENTS WITH HIGH GRADE GLIOMAS
Authors: Matthew Krutz, Austin Mcginnis, Kelley Osborn, Sara Vesely, Gabriel Vidal, Sarah Sung, Shakti Ramkissoon, James Battiste
Journal: Neuro-Oncology (2018)

Patients with Homologous Recombination Deficits (HRD) have shown increased survival in many cancers. With PARP inhibitors surfacing as a potential therapy for Glioma patients, we aim to explore the existence of HRD and its prognostic value in High-Grade Glioma patients. We conducted a chart review of patients with Gliomas who received Foundation One testing at The University of Oklahoma from 2013 to 2018. We used Foundation Ones Loss of Heterozygosity (LOH) score as a measure for HRD. We analyzed the correlation between the existence of mutated IDH and the LOH score. We then analyzed the significance of receiving Foundation One testing prior to any treatment on LOH score. Finally, we separated the patient population into two groups, High-HRD (>5% LOH or >3% LOH) and Low-HRD (<5% LOH or <3% LOH), and used the Kaplan-Meier method to assess OS and PFS. 39 patients were included in the final analysis. The relationship between IDH status and LOH score approached significance (P=.09). The relationship between time of foundation testing and LOH score was statistically significant (P=.05). In analyzing survival, we were only able to find significance in patients who received genetic testing post-treatment. Interestingly, the average OS of the Low-HRD group was 19 months, compared to 52 months for the High-HRD population which was statistically significant (p=.02). There appears to be a relationship between IDH status and HRD and although it was not yet statistically significant, it approached significance. Patients tested in a recurrent setting were more likely to possess higher HRD. We found no statistically significant difference in PFS or OS between the low-HRD and high-HRD populations, except in the later stage patient population. Due to the difference in the average PFS and OS this should be studied further in a larger population.
Abstract 12785: In Patients Supported by a Left Ventricular Assist Device, Bi-Ventricular Pacing does not Offer Hemodynamic Improvement over Right Ventricular Pacing
Authors: Chakradhari Inampudi, Frances Johnson, Rizwan Tahir, Rudhir Tandon, Omer J Iqbal, Uzodinma Emerenini, Michael C Giudici, Vlad Cotarlan
Journal: Circulation (2015)

Hypothesis: The benefit of biventricular (BiV) pacing in patients supported by a left ventricular assist device (LVAD) is unknown. This pilot study aimed to assess the acute hemodynamic effects of biventricular pacing compared to right ventricular (RV) pacing in patients supported by LVADs and to determine appropriate pacing rate. Methods: We studied 7 patients (age 65±7, 100% males) supported by Heartmate II (HM2) LVAD who underwent biventricular (BiV) pacemaker (PM) implant prior to LVAD. All patients underwent a ramp echo study for speed optimization prior to enrollment. Two patients were in sinus rhythm and 5 were in chronic atrial fibrillation (AF) and pacemaker dependent due to complete atrioventricular block (AVB). Results: A total of 42 complete sets of hemodynamics were obtained during BiV and RV pacing at various pacing rates ranging from 50 to 110 bpm. There were no significant differences in right atrial(RA) pressure, mean pulmonary artery(mPA) pressure, cardiac index(CI), PA saturation(PASat) and right ventricular stroke work index(RVSWI) between BiV and RV pacing (table). There was a trend for higher stroke volume index (SVI) and RVSWI at lower heart rates for each individual patient. Conclusion: BiV pacing does not appear to have any acute hemodynamic benefit compared to RV pacing in patients supported by HM2-LVAD. At lower heart rate, whether BiV or RV, may confer better RV efficiency.
Abstract 20625: False Activation of the Emergency Department for Triaged Patients With Presumed STEMI is Associated With Worse Long Mortality
Authors: Anushree Agarwal, Frank V Aguirre, Mohammad Al-akchar, Hadi Mahmaljy, Stephanie Besser, Jenny Chambers, Atman Shah, James Liao
Journal: Circulation (2017)

Introduction: The onus of facilitating timely reperfusion therapy among STEMI patients ultimately depends on the clinical evaluation and electrocardiographic (ECG) interpretation. False activation ...
Abstract 15559: Comparison of Cardiac Output Assessment With Two Different Minimally-invasive Pulse Contour Analysis-monitoring Devices and Echocardiography During Mild Therapeutic Hypothermia and Normothermia
Authors: Henrik Staer-Jensen, Kjetil Sunde, Espen R Nakstad, Jan Eritsland, Geir Ø Andersen
Journal: Circulation (2016)

Background: Post-cardiac arrest myocardial dysfunction and hemodynamic instability characterize survivors of out-of-hospital cardiac arrest (OHCA). There is a need for optimal hemodynamic monitorin...
IMMU-22. PHARMACOLOGICALLY TARGETING EXTRACELLULAR VESICLE-IMMUNE CELL INTERACTIONS IN GLIOBLASTOMA
Authors: Benjamin Himes, Cori Fain, Zachariah Tritz, Ian Parney
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most aggressive type of primary brain cancer and carries a dire prognosis. Increasing evidence points to extracellular vesicles (EVs) as a means by which GBM tumor cells modulate the tumor microenvironment, leading to immunosuppression and disease progression. Several pharmacologic agents may inhibit EV release (fasudil, a ROCK1 inhibitor; GW4869, a Rab27B inhibitor) or block EV interactions with target cells via heparin sulfate proteoglycan (heparin, an HSPG competitive inhibitor). We sought to characterize the effects of these drugs on EVs release from GBM cells and binding to target cells. EVs released by the human GBM cell line BT116 were quantified by nanoparticle tracking in with the presence or absence of the putative release inhibitors fasudil and GW489. Compared to untreated cells, pharmacologically treated BT116 cells demonstrated modest reductions in EV release with 50uM fasudil (17%) and 10uM GW4869 (31%). We have previously demonstrated that BT116 EVs can induce immunosuppressive monocyte development including myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). Under confocal microscopy, monocytes conditioned with GBM-derived EVs demonstrated markedly reduced EV uptake in the presence of heparin than untreated cells in a dose-dependent manner (1uM-50uM heparin). In the presence of heparin, BT116 EVs induced reduced NCM formation when cocultured with normal donor-derived monocytes, but did not appear to affect MDSC differentiation. Taken together, these findings point to druggable targets in the interaction between glioblastoma-derived EVs and host immune cells. This may prove important in treating GBM-mediated immunosuppression and optimizing GBM immunotherapy.
RDNA-06. A NOVEL ROLE OF SGEF IN MEDIATING GBM CELL SURVIVAL BY MODULATING THE DNA DAMAGE REPAIR MECHANISM
Authors: Serdar Tuncali, Christopher Sereduk, Shannon Fortin Ensign, Jean Kloss, Jann Sarkaria, Joseph Loftus, Nhan Tran
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is among the most genetically heterogeneous, treatment resistant, and lethal of all human cancers. A significant hurdle to effective treatment of GBM is the aggressive invasion of tumor cells into surrounding healthy brain tissue that invariably leads to tumor recurrence, brain injury, and patient death. These invasive cells preclude complete surgical resection and exhibit marked resistance to chemotherapeutics. As invasion is a universal property of GBM, studies focused on the invasive cell population and on the development of therapies that target them are greatly needed in order to significantly improve the survival of GBM patients. We have previously showed that SGEF (ARHGEF26), a RhoG-specific guanine exchange factor is overexpressed in high-grade brain tumors and correlates with poor patient survival. Here we report that SGEF is critical for promoting GBM invasion and survival by modulation of the DNA repair mechanism. Upon TMZ treatment, SGEF accumulated in the nucleus and mediated BRCA1 binding to γH2AX, and knockdown of SGEF expression in GBM cells impaired the phosphorylation of BRCA1 and CHK1. In addition, GBM cells with stable knockdown of SGEF expression showed enhanced susceptibility to TMZ induced cell death. Re-expression of SGEF in these cells rescued BRCA1 phosphorylation and glioma cell resistance to TMZ. Thus, our data showed an important role for SGEF in mediating GBM cell survival.
DDIS-18. THE PROTEASOME: TARGETING THE NF-κB PATHWAY IN THE TREATMENT OF GLIOBLASTOMA MULTIFORME
Authors: Jamal Mohamud
Journal: Neuro-Oncology (2018)

Glioblastoma Multiforme is a rare neoplastic disease of the brain that is known for its rapid aggressive growth and its poor clinical outcomes secondary to limitations in treatment efficacy. As such, the discovery of new agents to hinder and slow the proliferation of GBM is paramount for the eventual eradication of the disease. One such pathway of targeting is the proteasome, as it provides a unique and novel means of targeting the growth and metastasis of aggressive forms of GBM. Expression of the proteasome is integral for the canonical NF-kB pathway, an inflammation pathway heavily associated with the progression of numerous cancers. One means of activation of the stress induced pathway is via increase pressure. As neoplasias of the brain grow within the confined space of the skull, they press against their stroma and experience higher interstitial pressure, further activating an NFkB mediated positive feedback cascade. By inhibiting the proteasome with novel imodazoline complexes, maintenance of the NFkB pathway is blocked and pressure stimulated growth should be halted. Stimulation of cultured U87 glioblastoma cells with 15mgHg for various periods of time induced a pressure activated increase in cell population, as well as activation of the NFkB pathway as well as in HEK293 embryonic kidney cells. Using our TCH-013 proteasomal inhibitor, pressure induced proliferation of these U87 cells appeared to be inhibited. Furthermore, using our TCH-01 compound pressure induced activation of the NFkB pathway was greatly in the HEK cells, indicating our imadazoline complexes target the pressure induced pathway at a downstream site enough to occlude the effect. Further screening of these compounds effects on pressure stimulated activation of NFkB and proteasomal activity is necessary in further brain cancer cell types.
Response assessment of novoTTF-100A versus best physician’s choice chemotherapy in recurrent glioblastoma.
Authors: Eric Wong, Edwin Lok, Kenneth D. Swanson, Shiva Gautam, Herbert H. Engelhard, Frank S. Lieberman, Sophie Taillibert, Zvi Ram, John L. Villano
Journal: Journal of Clinical Oncology (2013)

2080 Background: The NovoTTF-100A device emits tumor treating electric fields and was tested against Best Physician’s Choice (BPC) chemotherapy in a randomized phase III trial. We analyzed post hoc the characteristics of responders and non-responders in both cohorts. Methods: Macdonald criteria were used to determine tumor response and progression. Kaplan-Meier and Chi-squared statistics were computed for time to response, response duration, progression-free survival (PFS) with and without Simon-Makuch correction, and overall survival (OS). Prognostic factors were compared using the Wilconox rank sum test. Relative hazard rates for responders and non-responders were plotted. Results: The median response duration was 7.3 versus 5.6 months for NovoTTF-100A and BPC chemotherapy respectively (p=0.0009). Five of 14 NovoTTF-100A responders but none of 7 BPC responders had prior low-grade histology. The mean cumulative dexamethasone dose was 35.9 mg for responders versus 485.6 mg for non-responders in the NovoTTF-100A cohort (p&lt;0.0001) as compared to 525.6 mg for responders and 431.0 mg for non-responders in the BPC cohort (p=0.9520). Hazard rate analysis showed delayed tumor progression in responders compared to non-responders. The Simon-Makuch conditional plot, which adjusted for unequal progression-free states, still showed longer PFS in responders than non-responders treated with NovoTTF-100A (χ 2 =11.5, P=0.0007) or BPC chemotherapy (χ 2 =5.2, P=0.0222). The median OS was 24.8 months for responders that is longer than 6.2 months for non-responders treated with NovoTTF-100A (χ 2 =25.7, P&lt;0.0001). In the BPC chemotherapy cohort, the median OS was 20.0 months for responders and 6.8 months for non-responders (χ 2 =5.1, P=0.0235). There was strong Pearson correlation between response and OS in NovoTTF-100A (P&lt;0.0002) but not in BPC cohort (P=0.2952). Conclusions: Response duration, adjusted Simon-Makuch PFS and OS favor NovoTTF-100A over BPC chemotherapy. Data on prior low-grade histology and dexamethasone dose suggest potential genetic and epigenetic determinants of NovoTTF-100A response. Clinical trial information: NCT00379470.
Abstract 14285: Rapamycin Nanoparticles Potently Induce Cardiac Autophagy and Improve Ventricular Function in 18-month Old mdx Mice, The Animal Model of Duchenne Muscular Dystrophy
Authors: Ya-Jian Cheng, James Ching, Jon Marsh, Huiying Zhang, Junjie Chen, Chris Weihl, Samuel A Wickline
Journal: Circulation (2013)

INTRODUCTION: Autophagy, or “self-eating”, is a cellular process responsible for recycling metabolites and eliminating toxic byproducts. We have shown previously that rapamycin-loaded nanoparticles...
NIMG-16. IMPACT OF SEX DIFFERENCES AND TUMOR LOCATION ON SURVIVAL OUTCOMES IN GLIOBLASTOMA PATIENTS
Authors: Julia Lorence, Susan Christine Massey, Sandra Johnston, Sara Ranjbar, Paula Whitmire, Cassandra Rickertsen, Gustavo De Leon, Barrett Anderies, Haylye White, Kyle Singleton, Leland Hu, Joseph Mitchell, Alyx Porter, Maciej Mrugala, Bernard Bendok, Joshua Rubin, Kristin Swanson
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults with a median survival of 14–16 months. Patient sex plays an important role in GBM as there is a difference in incidence rates and outcome between males and females, which may be attributable to differences in genetic makeup and physiology. Investigate the impact of tumor location and sex differences on survival outcomes based on tumor location, laterality, age, handedness, and extent of resection. Patients (129 males and 87 females) who received standard-of-care were included. Analyses were performed using Cox proportional hazard modeling and Kaplan-Meier analysis (log-rank test) to determine which variables impacted patient survival. Overall survival was significantly longer in females in comparison to males (197 days, p = 0.0391). Investigating specific tumor locations, females with a tumor in the left frontal lobe (n = 12) showed a survival advantage compared to females with a right frontal (n = 15) GBM (2853 days, p = 0.0160). Significant differences in median OS were also associated with age. Female patients below the age of fifty showed significantly longer survival (2602 days, n = 84, p<0.001). Interestingly, 70% of IDH1 mutant tumors (n = 10) and 76% of MGMT methylated tumors (n = 26) were found in the frontal lobe and were found in the right hemisphere. Together, our results demonstrate that age, sex, and specific brain locations are associated with differences in genetics and survival in GBM.