bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPID-26. SEX-SPECIFIC GLIOMA MOLECULAR SIGNATURES
Authors: Claus Elizabeth , Cannataro Vincent , Gaffney Stephen , Townsend Jeffrey 
Published: November 2019

Abstract
Many genetic and environmental factors have been explored in epidemiological studies of glioma risk but the magnitude of effect of these factors on gliomagenesis is uncertain. A number of constitutional genes associated with glioma risk, many noted to be related to telomere function, have been identified. High-dose ionizing radiation has consistently been associated with an increased glioma risk while a history of allergies and atopy is inversely associated with risk. Results have been inconsistent for most other factors studied but whether this lack of evidence is due to study limitations or a true lack of risk factors is unclear. Using 901 glioma exomes from The Cancer Genome Atlas (TCGA) we estimate the intensity of positive selection on gene variants, and order them by their cancer effect size, quantifying the contribution of gene variants to the somatic evolution of glioma. Examination of subsets of tumor exomes from males and females showed similar patterns in genes mutated but some differences in variant profile for a given gene including PIK3CA suggesting a possible differential response to treatment. Furthermore, these cancer effect sizes enable quantification of the degree to which COSMIC-defined processes associated with genetic pathways and environmental environmental factors within the somatic evolution of tumors contribute mutations that are highly selected, driving gliomagenesis. The results confirm the major roles of previously reported mutations in IDH1, TP53, EGFR, and PIK3CA, but also suggest a large cancer effect for low-prevalence genes including BRAF. Age-related mutagenesis was the primary molecular signature identified for all glioma while homologous recombination disfunction was an important signature for males but not females. Although additional signatures remain to be identified and less common exposures difficult to access, these data suggest a profile of glioma mutations that are caused primarily from endogenous rather than exogenous factors.
EPID-29. THE INFLUENCE OF SOCIOECONOMIC FACTORS AND CANCER CARE RECEIVED AT DIFFERENT FACILITIES ON OUTCOME IN PATIENTS WITH GLIOBLASTOMA
Authors: Li Terry , Patel Palak , Chou Janice , Patel Amie , Crispo Sylvia , Utate Minerva , Kurz Sylvia 
Published: November 2019

Abstract

BACKGROUND
Younger age and higher performance status are strong positive predictors of longer survival in patients with high-grade gliomas. In many cancers, disparities in race, gender, socioeconomic background, and immigration status were shown to influence outcome. Only few studies have investigated the impact of healthcare disparities in patients with glioblastoma, with conflicting results. We hypothesized that patient-specific and healthcare system-related factors influence the utilization of healthcare and impact outcome in glioblastoma patients.

METHODS
This is a retrospective observational study in glioblastoma patients receiving care at a NCI-designated Comprehensive Cancer Center (CCC) or a City Hospital (CH). Patient information including demographics, insurance status, molecular characteristics, treatment details, and survival was retrieved from the medical record.

RESULTS
59 patients were included (CCC n=47, PCH n=12). There were 22 females and 37 males. Median age was 63.0 years at CCC, 54.0 years at CH (p = 0.023). The two groups significantly differed by race (p=0.004), insurance status (p< 0.001), median income by zip code (p=0.015), extent of resection (p=0.001), receiving radiotherapy (p=0.014), and receiving chemotherapy (p< 0.001). Median overall survival (mOS) was longer at CCC (17.9 months) versus at CH (4.4 months) (p=0.021). Univariate Cox regression analyses found significantly better survival for insured vs. uninsured patients (HR 0.035, 95% CI 0.002–0.611, p=0.022) and for married/domestic partnership (M/DP) vs. non-M/DP patients (HR 0.352, 95% CI 0.141–0.879, p=0.025). Care facility, race, income, and treatment received did not emerge as significant predictors. Multivariate analysis controlling for facility and age at diagnosis showed improved survival for M/DP versus non-M/DP patients (HR 0.267, 95% CI 0.103–0.691, p=0.006). CONCLUSION(S): Insurance status and marital status emerged as significant contributors to survival. They may serve as surrogate markers for socioeconomic class and social support. Differences in Cancer Care received at different facilities may influence outcome as well.
EPID-33. GENDER-SPECIFIC PROBABILISTIC ATLASES OF GLIOBLASTOMA REVEAL IMPACT OF TUMOR LOCATION ON PROGRESSION FREE SURVIVAL
Authors: Beig Niha , Ismail Marwa , Saeed Bamashmos Anas , Statsevych Volodymyr , Hill Virginia , Madabhushi Anant , Ahluwalia Manmeet , Tiwari Pallavi 
Published: November 2019

Abstract

BACKGROUND
Recent epidemiological studies suggest that gender differences in Glioblastoma (GBM) influence the prognostic outcome of patients, and thus should be considered for patient management. In this feasibility study, we developed population atlases of pre-treatment MRI lesions to evaluate whether progression free survival (PFS) in gender-specific GBM patients have a spatial proclivity to hemispheric or lobe-specific locations.

METHODS
203 pre-operative MRI sequences (1.5T/3T T1w, T2w, FLAIR scans, multi-center) of GBM (125 males [m] & 78 females [f]) from TCIA (n=130), Ivy-GAP (n=32) and participating institution (n=41), along with PFS (median cut-off =189 days [m], 78 days [f]) were analysed. Frequency atlases (improved PFS [i-PFS] & worse PFS [ω-PFS]) of tumor occurrence in T2/FLAIR hyperintense regions were developed for each gender, by averaging voxel intensities across all patients. To compute significant differences (p-value< 0.05), voxel-based analysis of differential involvement (ADIFFI) based on two-tailed Fisher’s exact test was performed on (a) m: i-PFS (n= 61) vs m: ω-PFS (n= 62), and (b) f: i-PFS (n= 39) vs f: ω-PFS (n= 39) atlases. Prominent clusters were identified and mapped to LONI Probabilistic Brain Atlas (LPBA40) parcellations to provide anatomic localization for each gender’s PFS.

RESULTS
ADIFFI analysis revealed that m: i-PFS tumors were more often localized to the inferior frontal gyrus of left hemisphere with a frequency of 20% whereas m: ω-PFS were more often localized to the right insular cortex (p< 0.005). f: i-PFS tumors were more often localized to the right hemisphere in the parietal and temporal lobe, while f: ω-PFS had 15.7% occurrence in the superior and middle frontal gyri of the right hemisphere (p< 0.03).

CONCLUSION
Our analysis suggests spatial proclivity of gender-specific PFS to hemispheric and lobe-specific locations in the brain. Gender-specific prognostic models and nomograms may be more accurate than unisex models and nomograms for GBM patients.
EXTH-06. DOWN-REGULATION OF PD-L1 VIA FKBP5 LOWERED BY A CYCLOOXYGENASE-2 INHIBITOR IN GSCs AND GBM CELLS MAY BE ATTRIBUTABLE TO ENHANCE ANTITUMOR EFFECTS OF IMMUNOTHERAPY
Authors: Yamaguchi Izumi , Nakajima Kohei , Shono Kenji , Mizobuchi Yoshifumi , Fujihara Toshitaka , Kitazato Keiko , Takagi Yasushi 
Published: November 2019

Abstract

BACKGROUND
Antitumor therapies targeting programmed cell death-1 (PD-1)/its ligand-1 (PD-L1) are influential at present stage. However, in glioblastoma (GBM), the expression of PD-L1 is variable and the role of anti-PD-1 antibody therapy is still unclear. The high expression of PD-L1 affects cell proliferation and invasion in GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested our hypothesis that a COX-2 inhibitor, celecoxib may play a role on anti-PD-1 antibody treatment via down-regulation of PD-L1.

METHODS
Six weeks old male C57BL/6 mice subjected to intracranial injection of mice glioma stem cells (GSCs) were randomly divided into four treatment groups; vehicle control (VC), celecoxib, anti PD-1 antibody or the combination of celecoxib and anti-PD-1 antibody groups and examined antitumor effects. To verify the mechanisms underlying antitumor effects, mice GSCs and human GBM cells were used.

RESULTS
Compared to each single treatment in the glioma model, the combination therapy of anti PD-1 antibody and celecoxib significantly decreased the tumor volume and improved the survival period. Importantly, the high expression of PD-L1 in the glioma model, mice GSCs and human GBM cells was decreased by celecoxib. Interestingly, the reduction of PD-L1 was associated with post-transcriptional regulation of co-chaperone FK506-binding protein 5 (FKBP5) by celecoxib. The combination therapy of anti PD-1 antibody with celecoxib could be a promising therapeutic strategy targeting PD-L1 in GSCs and GBM.

CONCLUSIONS
Down-regulation of PD-L1 via FKBP5 by celecoxib may play a role on the antitumor effects under the overwhelmed expression of PD-L1.
EXTH-10. THE ACTIVATION AND SENSITIZATION OF GLIOBLASTOMA CELLS VIA COLD ATMOSPHERIC PLASMA TREATMENT
Authors: Sherman Jonathan , Yan Dayun , Gjika Eda , Keidar Michael 
Published: November 2019

Abstract

BACKGROUND
Treatment of glioblastoma multiforme (GBM) continues to remain a challenge using conventional treatment. Through an in vitro study we assessed the efficacy of our novel cold atmospheric plasma technology (CAP) to sensitize GBM cells to temozolomide (TMZ).

METHODS
The CAP jet is formed through the discharge (Pk-Pk: 5.8 kV) between a ring grounded cathode and a central anode and with He flow through a glass tube. The discharge process is driven by an AC high voltage (3.16 kV) with a frequency of 12.5 kHz. Human glioblastoma (U87MG) cells were cultured in DMEM supplemented by 1% (v/v) penicillin and streptomycin solution and 10% (v/v) FBS. CAP was delivered to U87 cells in a 96-well plate for 1 min in combination with 10 and 15 μM H2O2. The cell viability was measured by using the MTT assay. We then tested TMZ concentrations of 10 and 50 uM. Cell viability was monitored with the Cell Titer Glo 2.0. luminescent assay. All experiments were performed in triplicate and were independently repeated at least 3 times.

RESULTS
We identified an activation state of U87MG cells after the plasma treatment. This activation state resulted in GBM cells sensitized to reactive species identified by decreased cell viability after treatment with H2O2 as compared to the H2O2 treatment alone (p< 0.005). In addition, the plasma-activated cells were sensitized to TMZ. Cells treated with CAP in combination with TMZ displayed decreased cell viability at TMZ concentrations of (10 uM) (p< 0.05) and (50 uM) (p< 0.005) as compared to TMZ alone.

CONCLUSIONS
This study demonstrates the activation phenomenon on GBM cells via direct CAP treatment. Due to this activation, the GBM cells were sensitized to both H2O2 and TMZ identified via decreased cell viability. Future work looks to assess this effect of cell activation/sensitization with chemotherapy plus radiation treatment.
EXTH-27. ACTIVATING THE IMMUNITY WITHIN THE TUMOR USING VIROIMMUNOTHERAPY: DELTA-24-RGD ONCOLYTIC ADENOVIRUS ARMED WITH THE IMMUNOPOSITIVE REGULATOR GITRL
Authors: Rivera-Molina Yisel , Fueyo Juan , Jiang Hong , Nguyen Teresa , Ho Shin Dong , Youssef Gilbert , Fan Xuejun , Gumin Joy , Alonso Marta M , Phadnis Sheetal , Lang Frederick , Gomez-Manzano Candelaria 
Published: November 2019

Abstract
Based on promising results of recent clinical trials using oncolytic viruses, virotherapy is evolving as an alternative to treat patients with malignant glioma. Our group developed the oncolytic adenovirus Delta-24-RGD (DNX-2401) that is being tested, alone or in combination with anti-PD1, in clinical trials for recurrent glioblastoma (NCT00805376; NCT01956734; NCT02798406). The results suggest that, besides the expected oncolytic effect, the injection of the pathogen initiated, in a subset of patients, an anti-tumoral immunity that led to 20% of long-term survivors (3.5–5 years). To further enhance this effect, we have armed Delta-24-RGD to express the co-stimulatory ligand GITRL, and generated Delta-24-GREAT. The intracranial injection of Delta-24-GREAT prolonged the survival of GL261 glioma-bearing immunocompetent mice when compared to Delta-24-RGD treatment (P=0.002, log-rank test). Delta-24-GREAT treatment resulted in enhanced frequency of tumor-infiltrating lymphocytes: T lymphocytes (CD45+/CD3+) and cytotoxic T lymphocytes (CD45+CD3+CD8+). Functional studies performed by culturing splenocytes from Delta-24-GREAT-treated mice with glioma cells and analyzing secretion of Th1 cytokines, such as IL2 and IFN-γ, showed that lymphocytes recognized not only viral antigens but also tumoral antigens, suggesting the triggering of anti-tumoral immunity. Of interest, Delta-24-GREAT treatment resulted in an antigen-restricted anti-tumor memory effect and in the generation of central immune memory. Thus, rechallenging the survivor mice from the first experiment with a second implantation of glioma cells did not lead to tumor growth, and we detected an increased frequency of central memory CD8+ T cells (CD45+CD62L+). However, survivor mice developed lethal tumors when implanted intracranially with B16/F10 melanoma cells, strongly indicating that the developed immune response was specific for GL261 glioma antigens. This is a novel approach using an oncolytic adenovirus expressing GITRL to target cancer and to stimulate the immunity within the tumor. Our data strongly indicate that this type of strategy may be further developed to treat patients with malignant glioblastoma.
EXTH-46. ALISERTIB POTENTIATES THE EFFECT OF CABOZANTINIB AND VANDETANIB AGAINST GLIOBLASTOMA CELLS
Authors: Williams Brian , Zumbar Cory , Mifsud Caroline , Smith Kendall , Sak Muge , Lehman Norman 
Published: November 2019

Abstract
Glioblastoma is the most common primary malignant brain tumor in adults and has a poor prognosis with current standard of care. Aurora-A (AURKA) is a serine-threonine kinase critical for mitotic progression through its role in centrosome maturation and mitotic spindle assembly. Vascular endothelial growth factor (VEGF) is a regulator of tumor angiogenesis and vasculogenesis. Both AURKA and VEGF are commonly over-expressed in glioblastoma. The AURKA inhibitor alisertib and inhibitors of VEGF have been shown to inhibit glioblastoma cell proliferation in vitro and in vivo, and both have been used in clinical trials for glioblastoma. Here we tested the ability of alisertib to potentiate the effects of the VEGF receptor (VEGFR) inhibitors cabozantinib and vandetanib using colony formation assays in U1242 and U87 glioblastoma cell lines. Chou-Talalay and Bliss independence models demonstrated synergistic growth inhibition in some cases. Annexin V binding assays were performed to assess the extent that apoptosis could account for the inhibitory effects in U87 cells, and a concentration of alisertib that did not cause apoptosis as a single agent was found to increase the induction of apoptosis caused by cabozantinib. These results support the rationale for further in vitro and in vivo studies of the combined use of alisertib and VEGFR inhibitors, including possible future clinical trials.
EXTH-54. MULTIVALENT TARGETED PROTEINS FOR GLIOBLASTOMA TREATMENT
Authors: Sharma Puja , Herpai Denise , Rossmeisl John , Tatter Stephen , Debinski Waldemar 
Published: November 2019

Abstract
A heterogeneous and infiltrating tumor like glioblastoma (GBM) cannot be effectively treated with a single-targeted therapy. Hence, targeting several GBM-associated factors that are responsible for the disease progression and/or recurrence at once is a way to address the issue of tumor heterogeneity. Building on a Phase I clinical trial of a cytotoxic cocktail targeting IL-13-RA2 and EphA2 receptors showing dramatic anti-tumor responses in dogs with spontaneous gliomas, we have developed multivalent single pharmaceutical agents that target four specific to GBM receptors: IL-13RA2, EphA2, EphA3, and EphB2. The combined expression of these receptors spans almost 100% of the tumor microenvironment of pathobiological importance, such as tumor initiating cells, infiltrating cells, neo-vasculature, and GBM-infiltrating cells of monocytic origin like macrophages. Variants of this multivalent protein termed QUAD 2.0 and 3.0 contain an IgG1 scaffold, ephrinA5, which is a ligand for the EphA2, EphA3, and EphB2 receptors, and IL-13.E13K, a mutated version of interleukin 13 (IL-13) binding preferentially to IL-13RA2. In QUAD 3.0, a cysteine was added to the C-terminal end of QUAD 2.0 to allow effective conjugation to cytotoxic agents/labels. All QUAD variants bound effectively to the four receptors using ELISA with KD values of 100–200 pM for EphA2, EphA3, and IL-13RA2, and 700 pM-4 nM for EphB2, and downregulated the EphA2 and EphA3 receptors in GBM cells. QUAD 2.0 and 3.0 were conjugated to a modified form of Pseudomonas Exotoxin A and a modified doxorubicin. The conjugates were highly cytotoxic to established and primary GBM cells with IC50s < 1.0 nM. Intracranial injections (1.3 mM, 5µL) of the conjugates were well tolerated in mice. Thus, targeting multiple receptors with a single multivalent protein is possible. One additional advantage in using these targeted cytotoxins is that they produce immunogenic cell death and can be combined with other approaches activating the immune system.
EXTH-58. INHIBITION OF DNA TOPOISOMERASE 1 AND POLY(ADP-RIBOSE) POLYMERASE SYNERGISTICALLY INDUCES CELL DEATH IN GLIOBLASTOMA WITH PTEN LOSS
Authors: Butler Madison , Su Yu-Ting , Hwang Lee , Marzi Laetitia , Gilbert Mark , Pommier Yves , Wu Jing 
Published: November 2019

Abstract

BACKGROUND
Glioblastoma is known for its aggressive behavior and resistance to most available treatments. Topoisomerase 1 (Top1) functions by relaxing DNA supercoiling to facilitate replication. The novel Top1 inhibitor, LMP400, traps the enzyme and prevents its normal function, particularly in highly proliferative cells, resulting in DNA damage. Poly(ADP-ribose) polymerase (PARP) is involved in DNA repair responses triggered by Top1 inhibition. Phosphatase and tensin homolog (PTEN) loss, a frequent occurrence in glioblastoma, promotes DNA damage repair deficiency. We hypothesize that PTEN loss presents a vulnerability to combined induction of DNA damage and inhibition of repair mechanisms.

METHODS
Human glioblastoma cells were treated with LMP400 and/or Olaparib, a PARP inhibitor. Effects on cell proliferation and cell death were determined using a Beckman Coulter cell viability analyzer and colony formation assays. Synergism was calculated using COMPUSYN software. Cell cycle analysis was performed by FACS with EdU/DAPI staining, and Western blotting of lysate from drug-treated cells was performed to explore mechanisms of cytotoxicity.

RESULTS
LMP400 inhibited cell proliferation with an EC50 of 8.0 nM in U251 cells, and combination of LMP400 and Olaparib had a synergistic cytotoxic effect. Combination treatment enhanced activation of ATM-Chk2 and ATR-Chk1 pathways involved in DNA damage response signaling and increased S phase arrest. Increased protein expression of gamma-H2AX, cleaved caspase 3, and cleaved PARP was observed in combination-treated cells compared to single agents. Cell viability assays using isogenic glioblastoma cell lines with and without PTEN indicate that PTEN loss increases sensitivity to combination treatment.

CONCLUSION
Our results suggest that LMP400 and Olaparib combined treatment synergistically induces glioblastoma cell death, partially through inducing DNA damage, cell cycle arrest, and apoptosis. Mechanistic studies to investigate this vulnerability in glioblastoma with PTEN loss are ongoing. These results may lead to an effective personalized therapy for a molecularly defined subset of glioblastoma patients.
EXTH-61. CELECOXIB IMPROVES OUTCOME OF PATIENTS TREATED WITH TUMOR TREATING FIELDS
Authors: Wong Eric , Xu Oliver , Riley Mercedes , Swanson Kenneth 
Published: November 2019

Abstract
Tumor Treating Fields (TTFields) are known to cause mitotic catastrophe resulting in aberrant mitotic exit. However, there is accumulating evidence that the clinical effectiveness of TTFields requires immune competence. Exposure of cells to TTFields induced signs of cellular stress including cytoskeletal changes, surface expression of calreticulin and secretion of HMGB1 suggesting that TTFields may promote anti-tumor immunity that leads to subsequent tumor regression. Many tumor-protective mechanisms require immunosuppressive cell types within the tumor microenvironment whose development and suppressive functions are supported by prostaglandin E2 (PGE2). The rate limiting enzyme for PGE2 production is Cyclooxygenases-2 (COX-2) whose upregulation has been correlated with poor survival in glioma patients. Therefore, we reasoned that reduction of PGE2 production within the tumor microenvironment might improve response to TTFields therapy. Previous data from our group indicated that dexamethasone use interfered with TTFields-efficacy. When our population having low dexamethasone usage (n=42) was dichotomized according to celecoxib use, those without celecoxib (n = 14) had a median overall survival (OS) of 8.1 months while those receiving celecoxib had a median OS of 12.9 months (chi-square 5.42, p=0.002, HR = 2.1, 95% CI = 1.19–5.59). Patients not receiving celecoxib were treated with TTFields for a median of 3.8 months while those receiving celecoxib were treated for a median of 8.2 months (Chi-square = 6.75, p = 0.01, HR = 2.3, CI = 1.33–6.47). These data suggest that the addition of celecoxib improved the efficacy of TTFields against glioblastoma in this cohort. However, celecoxib did not sensitize TTFields-induced killing of cells in vitro suggesting an indirect mechanism of action. Together with our in vitro data, the results support an immune mechanism of action underlying TTFields’ anti-tumor efficacy. These findings concerning the effects of celecoxib on patient outcomes need to be confirmed in a prospective clinical trial.
EXTH-64. EVALUATION THE COMBINATION EFFECT OF RADIATION AND FOCUSED ULTRASOUND IN TREATMENT OF BRAIN TUMOR MODEL ANIMALS
Authors: Huang Chiungyin , Wei Kuochen 
Published: November 2019

Abstract
The standard treatment of malignant brain tumor is surgical resection followed by adjuvant chemo/radiotherapy. However, in spite of these aggressive treatments, tumor may still recur and resulting in poor survival. In solid tumors, the hypoxia condition presented in most of tumor area may contribute to treatment failure in both adjuvant therapies. It had been proven that systemic delivered oxygen may not sufficient for ionizing radiation to produce cytotoxic effect. A recent study reported using focused ultrasound combined with oxygen-contained microbubbles prior to radiation significantly increased the oxygen content in breast cancers and statistically improved animal survival. Therefore, providing sufficient oxygen in tumor area may be beneficial for radiation therapy. To study the potential role of such strategy for brain tumor treatment, we used focused ultrasound to treat brain tumor bearing animals before radiation therapy. As compared with non-ultrasound treatment groups, the tumor growth rate was significantly inhibited, and the animal survival is prolonged. Furthermore, we found focused ultrasound combined with non-oxygen-containing microbubbles also represented similar results, demonstrate the focused ultrasound induced cerebral vascular permeability increment may also contribute to the radiation therapy effect for brain tumor treatment.