tbuckley/cabot-search huggingface dataset:
EXTH-24. EXPOSURE TO TUMOR TREATING FIELDS INHIBITS DNA REPAIR, INDUCES REPLICATION STRESS AND RENDERS TUMOR CELLS SENSITIVE TO AGENTS THAT IMPINGE UPON THESE PATHWAYS
Authors: Michael Story, Narasimha Karanam, Lianghao Ding, Brock Sishc, Debabrata Saha
Journal: Neuro-Oncology (2018)

Tumor treating fields (TTFields) are low-intensity, intermediate frequency, alternating electric fields applied non-invasively across a tumor. Optune (NovoCure), a TTFields delivery device, has been approved for recurrent and newly diagnosed glioblastoma and clinical trials are ongoing for other cancers. To further understand the molecular mechanisms underlying TTFields sensitivity beyond the anti-mitotic effects already described, we monitored temporal gene expression changes in 5 non-small cell lung cancer (NSCLC) cell lines whose response to TTFields is variable. We found the expression of the BRCA1 DNA damage repair pathway, as well as other DNA repair/checkpoint pathways were significantly downregulated (P<0.05). Quantitative measurement of DNA double strand break repair revealed that TTFields treatment slowed the repair of ionizing radiation (IR)-induced DNA damage and interestingly, TTFields alone increased the number of γH2AX foci and the incidence of chromatid aberrations. Furthermore, as a function of TTFields exposure time, the length of newly replicated DNA was shorter and R-loop formation increased, suggesting that TTFields induce replication stress. Based on these newly identified mechanisms of TTFields action in DNA damage and replication stress pathways we hypothesized that by applying TTFields first, a conditional vulnerability environment would develop rendering cells more susceptible to agents such as radiation, cisplatin, or PARP inhibition. In agreement with our hypothesis, NSCLC cell susceptibility to radiation increased when cells were exposed to TTFields prior to IR treatment compared to IR treatment followed by TTFields. Furthermore, we found that the effect of TTFields exposure concomitant with the PARP inhibitor Olaparib followed by radiation was synergistic compared to radiation or Olaparib alone or in combination, although the degree of sensitization and synergy varied across the different cell lines. Based upon these results we suggest the clinical use of TTFields as neoadjuvant therapy prior to radiation treatment and either prior to or concomitant with chemotherapy agents.
CMET-46. INITIAL CLINICAL AND ADVANCED IMAGING OUTCOMES FROM A MULTI-INSTITUTIONAL PHASE I DOSE-ESCALATION TRIAL OF RRX-001 PLUS WHOLE BRAIN RADIATION FOR PATIENTS WITH BRAIN METASTASES
Authors: Michelle Kim, Hemant Parmar, Madhava Aryal, Matthew Schipper, Theresa Devasia, Santosh Kesari, Aki Morikawa, Daniel Spratt, Larry Junck, James Hayman, Theodore Lawrence, Christina Tsien, Robert Aiken, Sharad Goyal, Susan Knox, Scott Caroen, Corey Carter, Bryan Oronsky, Yue Cao, Christopher Lao
Journal: Neuro-Oncology (2018)

RRx-001, a novel redox modulator was evaluated as a potential radiosensitizer with WBRT in a multicenter phase I trial for adults with brain metastases. The primary endpoint was to determine MTD. Secondary endpoints included intracranial response rate (IRR), survival and correlation of DCE-MRI parameters with outcome. Dose-escalation was managed by a TITE-CRM design to establish MTD at a 20% estimated DLT rate with four planned dose levels (5, 8.4, 16.5, 27.5 mg/m2). RRx-001 was given pre-WBRT (30 Gy/10 fractions) then twice weekly during WBRT. Target accrual was 30 patients. Correlative DCE-MRI was performed in a subset of patients at baseline, 24 hours post-RRx pre-WBRT, 1 and 4 months. Linear mixed models were used to correlate baseline and change in 24-hour Vp (plasma volume) with change in tumor volume. Between 2/2015-2/2017, 31 patients were enrolled across 5 centers. Two patients dropped out at baseline, and seven were treated with RRx/concurrent temozolomide to be reported separately, for a total of 22 evaluable patients. Median age was 60 years (range 35–85), 13 were male, 55% had melanoma and 23% had NSCLC. No DLTs were observed within 28 days of treatment and 5 patients were treated at the highest dose level. IRR was 50%, five patients survived > 12 months, 3 were alive at last follow-up. Among 10 evaluable patients undergoing DCE-MRI with 64 total lesions at baseline, lower baseline Vp (p=0.002) and reduction in Vp at 24 hours (p=0.001) were associated with reduced tumor volume at 1 and 4 months. RRx-001+WBRT appears well-tolerated in adults with brain metastases, with several long-term survivors and IRR of 50%. Following a single dose of RRx, a reduction in Vp is associated with tumor response at 1 and 4 months, suggesting activity within tumor vasculature and utility as a biomarker of longer-term response.
EXTH-03. LOCAL ONCOLYTIC ADENOVIRUS TREATMENT AFFECTS BOTH THE INNATE AND ADAPTIVE ARMS OF THE IMMUNE SYSTEM AND PROVIDES AN AVENUE FOR ENHANCING IMMUNOTHERAPIES FOR GBM
Authors: Martine Lamfers, Zineb Belcaid, Wouter van, den Bossche, Anne Kleijn, Cor Berrevoets, Cor Lamers, Charlotte Teunissen, David Noske, Michael Lim, Stefan Sleijfer, Reno Debets, Jacques van Dongen, Clemens Dirven
Journal: Neuro-Oncology (2018)

The oncolytic adenovirus (OV) Delta24-RGD, also known as DNX-2401, is currently under clinical investigation for GBM. We studied multiple components of the immune system in response to local treatment with this agent using both in vitro and in vivo models and patient-derived materials. C57BL/6 mice bearing orthotopic GL261 tumors were treated with Delta24-RGD virus. Tumors were analyzed for cytokine levels, influx of immune cells, and Tcell expression of a panel of co-signaling molecules by flowcytometry. Combination virotherapy with checkpoint inhibitors was tested in vitro and in vivo. Effects of Delta24-RGD infection on tumor macrophages was studied in co-cultures of human monocyte-derived macrophages analyzed for immunophenotype and cytokine secretion. CSF from Delta24-RGD-treated patients was analyzed for immune cell infiltrates and cytokine levels. Tumor macrophages in resected material from one patient were immunophenotyped. Analysis of OV-treated GL261 tumors revealed a rapid increase in inflammatory cytokines followed by an influx of macrophages, CD4+ and CD8+ Tcells. Analysis of co-signaling molecules on intratumoral Tcells revealed marked changes in ICOS and PD-1 expression. Ex vivo functional assays identified PD-1 blocking antibodies as an effective enhancer of OV-mediated anti-tumor immunity, which was confirmed in vivo. Macrophages co-cultured with OV-infected GBM cells displayed a shift from M2 to M1 phenotype and pro-inflammatory cytokine production. This shift was dependent on the presence of large secreted molecules from OV-infected tumor cells. CSF from Delta24-RGD-treated GBM patients contained increased levels of all Tcell subsets and cytokine levels indicative of a pro-inflammatory microenvironment. Macrophages in resected tumor from one patient showed significantly greater M1 characteristics than from control GBM tissue. Together, these in vitro, in vivo and patient studies contribute to our understanding of the complex interactions that occur between the tumor and the different arms of the immune system in local oncolytic virus treatment.
OP0069 The relationship between estimated bone strength by finite element analysis at the peripheral skeleton to areal bmd and tbs at lumbar spine in adults
Authors: J.C. Alvarenga, S. Boyd, R. Pereira
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Bone strength, estimated by finite element (FE) analysis based on high resolution peripheral quantitative computed tomography (HR-pQCT) images is an important contributor to understanding risk of fracture. However, it is a peripheral device and cannot be evaluated <i>in vivo</i> at lumbar spine L1-L4. <h3>Objectives</h3> The aim of this study was to investigate if the axial bone quality can be predicted by strength measurements of peripheral bone. <h3>Methods</h3> Peripheral bone microarchitecture, areal bone mineral density (aBMD) and trabecular bone score (TBS) were measured in adults individuals (n=262, 60 years and older; 63% women). Stiffness and failure load were estimated by FE analysis at HR-pQCT images at radius and tibia. Areal BMD and TBS were measured by dual energy X-ray absorptiometry (DXA) at L1-L4. Correlations between peripheral and axial data were estimated for each gender adjusted by age, weight, and height. <h3>Results</h3> Areal BMD L1-L4 resulted in weak to moderate significant correlations with stiffness and failure load at radius (women: R²=0.178, p&lt;0.05 and R²=0.187, p&lt;0.001, respectively; men: R²=0.454 and R²=0.451, p&lt;0.001, respectively) and at tibia (women: R²=0.211 and R²=0.216, p&lt;0.001, respectively; men: R²=0.488 and R²=0.502, p&lt;0.001, respectively). TBS showed a very weak or no correlation with stiffness and failure load at radius (women: R²=0.148 and R²=0.150, p&lt;0.05, respectively; men: R²=0.108 and R²=0.106, p&lt;0.05, respectively) and at tibia (women: R²=0.146 and R²=0.150, p&lt;0.05, respectively; men: R²=0.072 and R²=0.078, respectively). <h3>Conclusions</h3> These data suggest that aBMD L1-L4 was better explained by peripheral bone strength characteristics than the TBS, mainly in men and tibia is generally the site with a better relationship. <h3>Disclosure of Interest</h3> None declared
CADD-16. DUAL PI3K/Akt INHIBITION TO OVERCOME THE P-gp/BCRP DRUG EFFLUX SYSTEM FOR IMPROVED DRUG DELIVERY IN GLIOBLASTOMA THERAPY
Authors: Anika Hartz, Julia Schulz, Brent Sokola, Bjoern Bauer
Journal: Neuro-Oncology (2018)

The blood-brain barrier is a primary obstacle for effective anticancer drug therapy of patients with glioblastoma multiforme (GBM). On a molecular level, failure of anticancer drug treatment is largely due to the blood-brain barrier efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). P-gp and BCRP (P-gp/BCRP) work together to restrict anticancer drugs from crossing the barrier and from entering the brain to reach tumor targets. We found that PI3K/Akt regulates P-gp/BCRP in brain capillaries of the rodent and human blood-brain barrier. Our in vivo data show that combination treatment with LY294002 (PI3K inhibitor) and triciribine (Akt inhibitor) downregulates P-gp and BCRP protein expression and transport activity in brain capillaries. We also have evidence from brain capillaries isolated from GBM mice and GBM patients showing that GBM induces P-gp/BCRP overexpression in capillaries in the brain hemisphere that is contralateral to the primary tumor. These findings indicate that P-gp/BCRP overexpression in brain capillaries protects invasive tumor cells that are scattered throughout the brain from being targeted by anticancer drugs. To overcome this obstacle, we are currently developing a novel therapeutic strategy by targeting PI3K/Akt to transiently decrease P-gp/BCRP expression and activity, thus, creating a “window-in-time” during which anticancer drugs can enter the brain.
Neuromodulatory treatment of recalcitrant plaque psoriasis with onabotulinumtoxinA
Authors: Kelly A. Aschenbeck, Maria K. Hordinsky, William R. Kennedy, Gwen Wendelschafer-Crabb, Marna E. Ericson, Sima Kavand, Ana Bertin, Dennis D. Dykstra, Ioanna G. Panoutsopoulou
Journal: Journal of the American Academy of Dermatology (2018)
GENE-34. MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA HARBORING Acvr1 G328V
Authors: Flor Mendez, Felipe Nunez, Carl Koschmann, Ramya Ravindran, Marta Dzaman, Pedro Lowenstein, Maria Castro
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is pediatric brain tumor that occurs in the pons and for which there is no treatment. Mutations in Activin-A Receptor Type 1 (ACVR1), a bone morphogenetic protein (BMP) receptor, are highly recurrent and specific for DIPG. We used the Sleeping Beauty Transposase (SB) system to deliver plasmids encoding NRASV12 and a short hair pin for TP53 (shp53) with or without ACVR1-G328V, the most frequent of the six ACVR1 mutations found in DIPG, into the brainstem of neonatal mice, to generate endogenous tumors with DIPG mutations. Tumor development was monitored by measuring luciferase activity in vivo. Moribund stage animals were perfused and processed for histology. H&E staining demonstrated that the tumors developed in the brainstem and cerebellum. Tumors induced with NRAS/shp53/ACVR1 G328V had an increased median survival, MS = 129 dpi, compared to control group NRAS/shp53, MS = 65 dpi (p=0.0002). In vitro and in vivo, tumors or tumor neruospheres (NS) harboring ACVR1-G328V exhibit elevated phospho-Smad1/5, transducer of the BMP pathway. RNA-seq analysis confirms that the TGF-Beta pathway is upregulated in tumor NS harboring ACVR1 G328V. From this data we also identified that signaling pathways involved in regulating pluripotency of stem cells and focal adhesion are differentially regulated. In summary, we used the SB transposase system to develop a mouse model that accurately represents the molecular biology of DIPGs with ACVR1 G328V mutations. Tumors arise in the brainstem and ACVR1 G328V prolongs survival through upregulation of the BMP-Smad1/5 pathways. In the future, we aim to elucidate the mechanisms by which ACVR1 contributes to tumor development to develop novel therapies for ACVR1 mutant DIPGs.
EXTH-70. EFFICIENT DELIVERY OF SIRNAS TO GLIOMA VIA FUNCTIONALIZED EXTRACELLULAR VESICLES PRIMED BY RADIATION
Authors: Bakhos Tannous, Tian Tian, Pierre Obeid
Journal: Neuro-Oncology (2018)

Efficient delivery is a major obstacle in oligonucleotide therapeutics for the treatment of gliomas. Endogenous small vesicles known as extracellular vesicles (EVs) hold potential to act as oligonucleotide delivery vehicles given their unique properties, such as low immunogenicity, innate stability, and ability to cross the blood-brain barrier (BBB). However, their insufficient targeting ability upon intravenous administration limits the clinical advancement. In this study, neural stem cell line ReNcell was cultured to release EVs. The cyclo(Arg-Gly-Asp-D-Tyr-Lys) peptide [c(RGDyK)], which exhibits high affinity to integrin αvβ3 on tumor vascular endothelial cells, was conjugated on the isolated EVs via bio-orthogonal click chemistry. In the syngeneic graft glioma mice model, the c(RGDyK)-conjugated EVs (cRGD-EV) targeted glioma after intravenous administration. Then, priming with radiation enhanced cRGD-EV accumulation in the tumor and decreased their entrapment in the liver and spleen significantly. Furthermore, small interfering RNAs (siRNAs) for immune checkpoint molecules programmed death-ligand 1 (anti-PD-L1) and CD47 (anti-CD47) were conjugated with cholesterol, and loaded into EV membrane by hydrophobic interaction simultaneously. After intravenous injection, the knockdown of target proteins in the tumor was found. Also, the number of infiltrated CD4+ and CD8+ T cells and M1/M2 rate of macrophages were increased, showing the up-regulated immune response in tumor. The injection of siRNAs-loaded cRGD-EV induced the regression of tumor growth in immuno-competent mice and significantly prolonged survival. In addition, no obvious liver and lung toxicity or tissue damage was observed in the treated mice. These results suggest a targeting delivery strategy for glioma based on EVs, and have implications for cancer immunotherapy.
Abstract P222: Consumption of Sugar-Sweetened Beverages, but Not 100% Fruit Juice, is Associated With Fasting High-density Lipoprotein and Triglyceride Concentrations in U.S. Adults
Authors: Danielle E Haslam, Mark A Herman, Josée Dupuis, Alice H Lichtenstein, Gina M Peloso, Caren E Smith, Nicola M McKeown
Journal: Circulation (2018)

Introduction: Dyslipidemia, characterized by high triglyceride (TG) and low HDL concentrations, is a risk factor for cardiovascular disease (CVD). Decreasing dietary sugar consumption is one dietary modification that may influence dyslipidemia risk to reduce the risk for CVD. Two major sources of dietary sugar in the US are sugar-sweetened beverages (SSB) and 100% fruit juices, and both can contribute to excess caloric intake. Based on current observational data, there is limited evidence linking these dietary exposures to lipid levels in population-based studies. Hypothesis: We hypothesize that SSB and 100% fruit juices may differentially associate with TG and HDL concentrations in adults due to differences in both beverage consumption patterns and nutrient content. Methods: We conducted a cross-sectional analysis of data from the Framingham Heart Study (1998-2005; n=6,802). Fasting plasma TG and HDL concentrations were measured using standard assays. Consumption of SSB (sodas and fruit drinks; 1 serving = 12 oz.) and 100% fruit juice (1 serving = 8 oz.) was estimated using the Harvard-Food Frequency Questionnaire. Participants were grouped by category of intake. Using mixed-effect linear regression models accounting for family structure, we examined the associations between SSB intake and 100% fruit juice intake with TG and HDL concentrations, adjusting for potential confounding factors related to demographics, lifestyle, and diet. Results: After multivariate adjustment for potential confounding factors, SSB intake was positively associated with TG concentrations [ &amp;#946; ± SE: 0.12 ± 0.03 [ln] mg/dl comparing the highest category of intake (median = 8.5 servings/week) with the lowest category (median = 0 servings/day); p for trend &lt; 0.0001] and inversely associated with HDL concentrations ( &amp;#946; ± SE: -2.90 ± 0.69 mg/dl comparing the highest category of intake with the lowest category; p for trend &lt; 0.0001). Fruit juice intake was not significantly associated with TG concentrations [ &amp;#946; ± SE: 0.04 ± 0.02 [ln] mg/dl comparing highest category of intake (median = 11 servings/week) with the lowest category (median = 0 servings/day); p for trend = 0.15] or HDL concentrations ( &amp;#946; ± SE: -0.18 ± 0.60 mg/dl comparing the highest category of intake with the lowest category; p for trend = 0.73). Conclusions: Higher intakes of SSB are significantly associated with lower HDL and higher TG concentrations, which supports dietary recommendations to limit SSB intake. Fruit juice consumption patterns, up to 1.5 servings/day, were not significantly associated with TG and HDL concentrations in this study.
ACTR-29. KETOGENIC DIETS AS AN ADJUVANT THERAPY IN GLIOBLASTOMA (KEATING): A MIXED METHOD APPROACH TO ASSESSING TRIAL FEASIBILITY.
Authors: Kirsty Martin-McGill, Gemma Cherry, Anthony Marson, Catrin Tudur Smith, Michael Jenkinson
Journal: Neuro-Oncology (2018)

There is increasing interest in the use of ketogenic diets (KD) as adjuvant therapy for glioblastoma (GBM). This trial aimed to: (i) investigate protocol feasibility, (ii) measure patient/carer acceptability and (iii) inform phase III trial design. A prospective, randomised, feasibility study, with an embedded qualitative design. Twelve newly diagnosed GBM patients were randomised to the modified ketogenic diet (MKD) or the medium chain triglyceride ketogenic diet (MCTKD). Primary outcome was retention; secondary outcomes included recruitment rate, side effects, extent of ketosis and dietary acceptability, assessed at 12 weeks and 12 months. Semi-structured interviews were conducted with a representative sample of patients and relatives (n=15). Recruitment was achieved within the defined timeframe of 12 months; 42 patients were eligible, of which 12 were recruited (29% recruitment rate). Retention was poor; of the 12 patients randomised, 4 completed the 12-week dietary trial (3 on MCTKD; 1 on MKD). Median duration on diet was 36.5 days (range 0–49) for those who discontinued prior to 12 weeks (n=8). Those who completed the 12-week intervention (n=4) achieved ketosis (1.65mmol/L 1.3mmol/L). No dietary related serious adverse events occurred. Qualitative interviews revealed patients who completed the 12-week diet consented without hesitation. Those who declined participation pre-empted the issues experienced by those who withdrew prior to 12-weeks; namely high levels relative/carer burden and social exclusion. Retainers had a positive experience and reported the diet became the new normal. Patients stated that the 3-month diet duration was too long, but 6 weeks would be more attainable. CONCLUSION: Recruitment to a GBM ketogenic trial is feasible. Retention at 3 months was poor due to the diet negatively impacting patient lifestyle and causing burden for relatives. To assess efficacy in a phase III trial, a 6-week dietary intervention would be advantageous.
Myocardial Ischemia Suppresses Ketone Body Utilization
Authors: Yuichiro Arima, Yasuhiro Izumiya, Toshifumi Ishida, Seiji Takashio, Masanobu Ishii, Daisuke Sueta, Koichiro Fujisue, Kenji Sakamoto, Koichi Kaikita, Kenichi Tsujita
Journal: Journal of the American College of Cardiology (2018)
PATH-42. EGFR-AMPLIFIED IDH-WILDTYPE GLIOBLASTOMAS SELDOM TRANSFORM INTO A HYPERMUTATED PHENOTYPE
Authors: Kaspar Draaisma, Aikaterini Chatzipli, Martin Taphoorn, Melissa Kerkhof, Astrid Weyerbrock, Marc Sanson, Ann Hoeben, Slavka Lukacova, Giuseppe Lombardi, Monique Hanse, Ruth Fleisscheuer, Sieger Leenstra, Colin Watts, Thierry Gorlia, Vassilis Golfinopoulos, Johan Kros, Ultan McDermott, Martin van den Bent, Pierre Robe, Pim French
Journal: Neuro-Oncology (2018)

Current efforts to improve patient survival in recurrent glioblastomas (GBMs) are often based on targeting the tumors acquired genetic changes. However, most molecular data is derived from the initial tumor: resections of recurrent GBMs are seldom performed. This study aims to assess whether genetic traits of initial GBMs are still present at recurrence. DNA/RNA was isolated from pairs of initial and recurrent Stupp-treated GBM tumor samples (FFPE) and sequenced on a panel of 365 cancer genes. MGMT promotor methylation was determined by MS-PCR, EGFRvIII by RT-PCR and TERT-promotor mutations by SNaPshot. 276 patients from ten medical centers in six countries were identified with median age of 54.1 years. Median survival was 23.7 months, and median time to second surgery 13.0 months. Only 10 of 186 sequenced matched tumor pairs were IDH-mutated (5.4%). Overall, genetic traits of initial GBMs were stable with a median retention rate of coding mutations of 81.8%. Similarly, copy number changes (CNVkit/GISTIC) generally were retained at tumor recurrence. However, the retention rate was also ~80% in all of the major GBM driver pathways (TP53 signaling, RAS-RAF-MEK-ERK, RTK signaling). This is important as decreases 20% of loss of a marker requires a doubling of the number of included patients to achieve a similar power (assuming an objective response rate of 40% as a positive outcome). One noticeable change was a loss of TERT-promoter mutations in 7.5% of recurrent samples. Only four tumors were hypermutated (> 100 coding mutations) at recurrence, though more samples (n=12) acquired mutations in MSH2 and MSH6. Only one EGFR-amplified tumor was hypermutated. EGFR-amplified GBMs seldom transform into hypermutated tumors which suggests immune-checkpoint inhibitors have limited clinical use in recurrent GBMs. Re-sampling should be considered prior to inclusion in targeted therapy trials to ensure proper patient selection.