bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPID-10. VENOUS THROMBOEMBOLIC EVENTS IN GLIOBLASTOMA PATIENTS: AN EPIDEMIOLOGICAL VIEW
Authors: Gramatzki Dorothee , Roth Patrick , Le Rhun Emilie , Rushing Elisabeth , Rohrmann Sabine , Stahel Rolf , Weller Michael 
Published: November 2019

Abstract

BACKGROUND
Venous thromboembolic events (VTE) are a common complication in cancer patients. Anticoagulant use is the appropriate treatment for acute VTE in cancer, although assumed to be associated with increased risk for bleeding. The population-based relationship of VTE and anticoagulant therapy to survival in glioblastoma patients remains unclear.

METHODS
Frequency, risk factors, treatment and complications of VTE were assessed in a glioblastoma cohort in the Canton of Zurich, Switzerland (2010 to 2014). Survival data were retrospectively analyzed using the log rank test.

RESULTS
248 glioblastoma patients with known isocitrate dehydrogenase (IDH) wildtype status were identified in a 5-year time-frame. Median overall survival (OS) was 12.8 months (95% CI 11.0–14.6), with a median follow up of 60.7 months (95% CI 51.4–70.0). VTE were diagnosed in 35 patients (14.4%; 5 out of 248 patients with no follow-up data on VTE). Median time from diagnosis to VTE was 2.23 months (95% CI 0.6–3.9); 3 patients (8.6%) had a history of VTE. Most patients were on steroids at time of diagnosis of VTE (68.6%), and a Karnofsky Performance Score of less than 70% was documented in 21 patients (60%). Most patients with VTE (88.6%) received therapeutic anticoagulation. Complications, resulting in the cessation of therapeutic anticoagulation, occurred in 11 patients (35.5%), mainly (9 patients, 81.8%) due to intracranial hemorrhage. OS did not differ between patients diagnosed with VTE and those without VTE (p=0.103). Tumor progression was the major cause of death (91.3%); 1.4% of patients died from VTE; 1.9% of the patients suffered unexpected sudden death.

CONCLUSION
Although VTE were identified in 14.4% of glioblastoma patients, VTE were not the major reason for death. These data do not support the implementation of primary thromboprophylaxis in glioblastoma patients. Prospective clinical trials are needed to examine the association of anticoagulant use with survival in glioblastoma patients.
EPID-19. SHARED GENOMIC ARCHITECTURE OF GLIOMA AND NEURO-COGNITIVE AND NEURO-PSYCHIATRIC TRAITS REVEALED BY LD-SCORE REGRESSION
Authors: Walsh Kyle , Ostrom Quinn , Zhang Chenan , Edelson Jacob , Shen Erica , Byun Jinyoung , Han Younghun ,   Collaborators GICC, Amos Christopher , Bondy Melissa 
Published: November 2019

Abstract

BACKGROUND
Genome-wide analyses estimate glioma heritability at 25%, yet known risk loci account for just one-third of this risk and suggest that sporadic glioma is a highly polygenic disease with hitherto unaccounted for genomic architecture. LD-score regression leverages results from genome-wide association studies (GWAS) and known patterns of linkage disequilibrium (LD) to estimate correlation between the genetic architecture of multiple phenotypes. We applied LD-score regression to identify associations with neuro-cognitive and neuro-psychiatric traits not amenable to study in prior glioma case-control analyses.

METHODS
GWAS summary statistics were obtained from the Glioma International Case-Control Consortium (GICC) meta-analysis (Melin, et al. 2017) and for 64 neuro-cognitive and neuro-psychiatric traits primarily from the UK Biobank. Included SNPs had quality scores ≥0.70 and minor allele frequency ≥0.01. Pairwise genetic correlations between traits were estimated using the LDSC package. P-values < 7.8x10-4 (i.e. 0.05/64) were considered significant.

RESULTS
Significant negative correlations were identified between the genetic architectures of glioma and bipolar disorder (Rg=-0.41, P=1.4x10-9) and schizophrenia (Rg=-0.29, P=7.1x10-9), consistent in both GBM and LGG. Significant positive correlations were identified with measures of educational attainment, including age at educational completion (Rg=0.11, P=2.0x10-4), obtaining a college degree (Rg=0.086, P=4.9x10-4), college attendance (Rg=0.086, P=5.9x10-4), and years of education (Rg=0.081, P=7.7x10-4). These associations were notably stronger with LGG. A number of additional nominal associations were observed, including with anorexia (anti-correlated) and performance on a pair-matching cognitive test (positively correlated). Importantly, LD-score regression did not identify an association between glioma risk in GICC data and Townsend deprivation index in UK Biobank data.

CONCLUSIONS
These results implicate a shared genetic basis for glioma and several psychiatric and cognitive traits. Further research is needed to understand these associations and to explore underlying mechanisms, including the mediating effects of neuro-inflammation, developmental differences in neural‒glial cell circuitry, and inter-individual variation in myelination.
EPID-23. PURSUIT OF AN INTERNATIONAL LANGUAGE OF GLIOMA RESEARCH: COMMON DATA ELEMENTS FOR THE LONGITUDINAL STUDY OF ADULT MALIGNANT GLIOMA
Authors: Poisson Laila , Kouwenhoven M C M , Snyder James , Alfaro-Munoz Kristin , Kaur Manpreet , Bates Amanda , Verhaak Roel , Watts Colin , Zadeh Gelareh , Ryan Ormond D , Claus Elizabeth , Khasraw Mustafa 
Published: November 2019

Abstract
As an uncommon cancer, clinical and translational studies of glioma rely on multi-center collaborations, confirmatory studies, and meta-analyses. Unfortunately, interpretation of results across studies is hampered by the absence of uniformly coded clinical data. Common Data Elements (CDE) represent a set of clinical features for which the language has been standardized for consistent data capture across studies, institutions and registries. We constructed CDE for the longitudinal study of adult malignant glioma. To identify the minimum set of CDE needed to describe the clinical course of glioma, we surveyed clinical standards, ongoing trials, published studies, and data repositories for frequently used data elements. We harmonized the identified clinical variables, filled in gaps, and structured them in a modular schema, defining CDE for patient demographics, medical history, diagnosis, surgery, chemotherapy, radiotherapy, other treatments, and outcomes. Multidisciplinary experts from the Glioma Longitudinal AnalySiS (GLASS) consortium, representing clinical, molecular, and data research perspectives, were consulted regarding CDE. The validity and capture feasibility of the CDE were assessed through harmonization across published studies, then validated with single institution retrospective chart abstraction. The refined CDE library is implemented in the Research Electronic Data Capture (REDCap) System, a secure web application for building and managing online surveys and databases. The work was motivated by the GLASS consortium, which supports the aggregation and analysis of complex genetic datasets used to define molecular trajectories for glioma. The goal is that modular REDCap implementation of CDE allows broad adoption in glioma research. To accommodate novel aspects, the CDE sets can be expanded through additional modules. In contrast, for efficient initiation of focused studies, subsets of CDE can be selected. Broad adoption of CDE will improve the ability to compare results and share data between studies, thereby maximizing the value of existing data sources and small patient populations.
EXTH-07. OPTIMIZATION OF TARGETING ELTD1 IN GLIOBLASTOMA USING A MOLECULAR TARGETING APPROACH
Authors: Smith Nataliya , Sauders Debra , Towner Rheal , Zalles Michelle 
Published: November 2019

Abstract
The standard of care for glioblastoma multiform (GBM), an aggressive form of cancer, has not significantly increased the prognosis for patients. ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain containing protein 1), a biomarker for angiogenesis, was found to be highly expressed in human high-grade gliomas. Novel treatments targeting ELTD1 with polyclonal (pAb) and monoclonal (mAb) antibodies were effective as a potential cancer therapy in a G55-xenograft mouse model. While our studies have demonstrated that the blood brain barrier (BBB) was leaky around the tumor region, other studies have shown that the BBB is not equally disrupted in GBM patients, therefore suggesting that the mAb may have difficulty crossing the BBB and infiltrating the tumor due to its size. To overcome these limitations, this study focused on the optimization of targeting ELTD1 by using an optimized svFc antibody fragment derived from our mAb against ELTD1. Immunocompromised mice were intracerebrally injected with human-G55 cells. Morphological MRI was used to monitor and calculate tumor volumes. Treatments using IgG, anti-ELDT1 mAb or fragment upon tumor detection. Vascular perfusion images were obtained to examine vascular alterations. Molecular targeting imaging (mtMRI) was conducted to assess the binding specificity of our antibodies against the tumor region. Targeting ELTD1 with varying antibodies (anti-ELTD1 mAb and scFv fragment) resulted in increased survival and decreased tumor volumes in a G55 xenograft GBM mouse model. Additionally, through the use of mtMRI, we determined altered levels of binding specificity against the tumor region using three different anti-ELTD1 attached probes (monoclonal and scFv fragment antibodies). Our data suggest that the optimization of an anti-ELTD1 therapy could be used to better target angiogenesis in glioblastomas.
EXTH-11. TREATMENT WITH DELTA-24-RGDOX OF SUBCUTANEOUS TUMORS RESULTS IN ABSCOPAL EFFECT ERADICATING INTRACRANIAL MELANOMAS
Authors: Jiang Hong , Ho Shin Dong , Nguyen Teresa , Alonso Marta M , Lang Frederick , Gomez-Manzano Candelaria , Fueyo Juan 
Published: November 2019

Abstract
Immune checkpoint blockade has revolutionized cancer therapy; however the therapeutic benefit is limited to only a subset of patients with immunogenic (“hot”) tumors and is compromised by immune-related adverse events. We have reported the efficacy of oncolytic adenovirus Delta-24-RGDOX (DNX-2440) in syngeneic glioma mouse models. We hypothesized that localized treatment with the virus is effective against disseminated melanomas, including intracranial melanomas. We tested the hypothesis in the subcutaneous (s.c.)/s.c. and s.c./intracranial (i.c.) melanoma models derived from luciferase-expressing B16-Red-FLuc cells in C57BL/6 mice. First, through monitoring tumor growth with bioluminescence imaging, we found that, in both s.c./s.c. and s.c./i.c. models, three injections of Delta-24-RGDOX significantly inhibited the growth of both the virus-injected s.c. tumor and untreated distant s.c. or i.c. tumor, thereby prolonging survival. Next, through cell profiling with flow cytometry, we observed that the virus increased the presence of T cells and effector T cell frequency in the virus-injected tumor and mediated the same changes in T cells from peripheral blood, tumor-draining lymph nodes (TDLNs), spleens, and brain hemispheres with untreated tumor. Moreover, Delta-24-RGDOX decreased the frequency of exhausted T cells and regulatory T cells in the virus-injected and untreated i.c. tumors. Consequently, the virus promoted recruitment and/or in situ expansion of antigen-specific T cells in tumors expressing the target antigen. Therefore, we concluded that local intratumoral injection of Delta-24-RGDOX resulted in systemic immune activity against the disseminated tumors. Furthermore, we speculate that given the immunogenicity, cancer-selectivity and intratumoral administration of the virus, Delta-24-RGDOX is expected to have an improved safety profile when compared to immune checkpoint blockade treatment strategies. This is the first report demonstrating that local administration of oncolytic adenovirus results in eradication of intracranial tumors, suggesting Delta-24-RGDOX could be used to manage brain metastases of melanoma.
EXTH-14. PULSED ELECTRIC FIELDS FOR THE TREATMENT OF BRAIN TUMORS
Authors: Sharabi Shirley , Last David , Daniels Dianne , Cooper Itzik , Bresler Yael , Mardor Yael 
Published: November 2019

Abstract
When high pulsed electric fields (PEFs) are applied to the brain electroporation occurs. Depending on the electric fields strength, irreversible electroporation, inducing necrotic cell death or reversible electroporation, inducing BBB disruption may occur. We have developed a unique minimally-invasive setup for treating brain tumors employing a single insulated intracranial electrode with an exposed tip placed within the tumor and an external surface electrode. This unique setup, termed point-source electroporation, provides intratumoral irreversible-electroporation (inducing necrosis) with surrounding reversible BBB disruption, enabling efficient delivery of systemically administered drugs into the infiltrating zone. Treatment duration is 1–2 min. An efficacy study conducted with 120 glioma-bearing rats resulted in suppressed tumor growth rates in the electroporation+Cisplatin group (1.1±0.1) relative to growth rates in the control group (5.2±1.0), p< 0.047, and in the Cisplatin-only group p< 0.012 (3.92±1.0) (Welch’s F(2,12.73)=10.84; p< 0.002; ω2=0.28). Kaplan-Meir analysis revealed that electroporation+Cisplatin prolonged survival significantly (χ2=7.54; p< 0.006). Immunofluorescence analysis revealed significant infiltration of peripheral macrophages and CD8+ cells in the residual tumor. A finite elements simulation demonstrated the feasibility for obtaining clinically-relevant treatment volumes (~6cm diameter) using a single 3mm (diameter) intracranial catheter. Additionally, we discovered that low PEFs, an order of magnitude lower than electroporation threshold, can also transiently disrupt the BBB by a different mechanism, enabling penetration of both small (Gd/NaF) and large (Evans blue bound to serum albumin) molecules and immune cells, non-invasively. The extent of BBB disruption, measured in mice using delayed-contrast MRI, was found to be linearly dependent both on the electric field strength (r2=0.9,p< 0.03) and on the number of applied pulses (r2=0.94,p< 0.003). These results demonstrate the feasibly of applying combined systemic chemotherapy with point-source electroporation, a minimal-invasive/rapid treatment of PEFs, for obtaining significant antineoplastic effects. Furthermore, low PEFs may be applied non-invasively, rapidly and repeatedly for obtaining reversible BBB disruption.
EXTH-19. IBRUTINIB MODULATES BLOOD-BRAIN BARRIER INTEGRITY TO ENHANCE CHEMOTHERAPY PERMEABILITY
Authors: Meeks Caitlin , Vezina Amelie , Robey Robert , Gottesman Michael , Jackson Sadhana 
Published: November 2019

Abstract

BACKGROUND
The blood-brain barrier (BBB) poses a major treatment challenge for malignant brain tumors. Ibrutinib is an FDA approved Bruton’s tyrosine kinase (BTK) and bone marrow x-linked tyrosine kinase (BMX) inhibitor indicated for the treatment of B-cell lymphomas. BMX is highly expressed in endothelial cells and is suggested to regulate cytoskeletal organization and barrier function in epithelial cells. We hypothesize that inhibition of BMX by ibrutinib in brain endothelial cells will disrupt the integrity of the BBB to increase drug permeability.

METHODS
Protein expression and phosphorylation of BMX was confirmed in immortalized mouse brain endothelial cells (bEnd.3). Endothelial barrier integrity was evaluated with increasing doses of ibrutinib (1–30μM) for 24hrs via the ACEA xCELLigence system (impedance) and the ECIS TEER24 system (resistance). Paracellular permeability of doxorubicin was measured by fluorescent spectrophotometry. Junctional protein expression of VE-Cadherin and F-actin cytoskeletal organization were detected by fluorescent staining. Ibrutinib’s effect on efflux pumps, ABCB1 and ABCG2, was performed by flow cytometry using specific substrates, valspodar and FTC, respectively.

RESULTS
Ibrutinib decreased endothelial cell impedance in a dose-dependent manner over 24hrs, with transient decrease by 46% at 30min with an optimal dose of 1μM, and partial recovery by 4hrs. TEER was decreased by 60% at 3hrs. Ibrutinib enhanced doxorubicin permeability by 30%; attributed to the transient disorganized nature of actin cytoskeletal filaments 2hrs post treatment. No effects on VE-cadherin expression or localization were observed. Ibrutinib successfully inhibited activity of ABCB1 and ABCG2 in a dose-dependent manner.

CONCLUSION
Our results suggest ibrutinib causes transient disruption of the brain endothelial monolayer due to cytoskeletal disorganization and ABC transporter inhibition to enhance permeability of doxorubicin. Further studies using ibrutinib and cytotoxic agents are warranted in glioma bearing animals. We propose that using ibrutinib as an adjunctive therapy may enhance drug delivery to patients with malignant brain tumors.
EXTH-30. PRECEDING p53 STABILIZATION USING DOXORUBICIN AUGMENTS PRIMA-1-MEDIATED p53 REFOLDING AND INCREASED CELLULAR APOPTOSIS: EVALUATION OF A SEQUENTIAL COMBINATION THERAPY AGAINST GLIOBLASTOMA
Authors: Babikir Husam , Afjei Rayhaneh , Paulmurugan Ramasamy , Massoud Tarik 
Published: November 2019

Abstract

INTRODUCTION
Mutant p53 cancer cells are poorly responsive to chemotherapy. A small molecule drug, PRIMA-1, can bind to wildtype and mutant p53 to induce structural conformation that enhances p53 DNA binding. In a quest for new effective combination chemotherapies, we hypothesized that sequential treatment of GBM cells with doxorubicin then PRIMA-1 could stabilize and refold p53 to enhance chemotherapy-induced cellular apoptosis. We evaluated this combination in GBM cells engineered to express different p53 mutants and exhibiting different phenotypes.

METHODS
We constructed split reporter biosensors incorporating different structural mutants of p53 (p53Y220C, p53G245S, and p53R282W) all within p53-null Ln308 GBM cells, to evaluate PRIMA-1-mediated refolding of p53 using bioluminescence imaging. We used these cells, and other GBM cells endogenously dissimilar for p53 phenotypes (U87MG with wt-p53, and Ln229 with mutant p53 [mt-p53P98L/p14ARFdel/p16del]), to investigate the anticancer activity of doxorubicin plus PRIMA-1 by using immunoblot analysis of p53 downstream pathway proteins. We also evaluated treatment by imaging mice implanted with GBMs of different p53 phenotypes.

RESULTS
PRIMA-1 induced reporter complementation at > 80 mM in all GBM cells regardless of p53 status. Doxorubicin stabilized p53 and increased its levels significantly more than in control cells. Significant changes in apoptotic index occurred in GBM cells treated with doxorubicin (1mM) followed by PRIMA-1 (40 mM), compared to cells treated with each drug independently, or with PRIMA-1 followed by doxorubicin. There was upregulation of p53, p21, and Bax, but downregulation of Bcl2 after combination therapy. PRIMA-1 and doxorubicin acted synergistically in GBM cells, but not significantly compared to using doxorubicin followed by PRIMA-1.

CONCLUSION
Our molecular imaging biosensor is useful to detect drug-induced restoration of p53 wildtype conformation. Doxorubicin stabilizes and increases p53 levels in GBM cells for subsequent enhanced PRIMA-1-mediated p53 refolding and increased levels of cellular apoptosis—an effective anti-GBM combination treatment.
EXTH-31. COMBINATION OF TUMOR TREATING FIELDS (TTFIELDS) AND PACLITAXEL PRODUCES ADDITIVE REDUCTIONS IN PROLIFERATION AND CLONOGENICITY IN PATIENT-DERIVED METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) CELLS
Authors: Michelhaugh Sharon , Mittal Sandeep 
Published: November 2019

Abstract
Clinical trials are underway to test the efficacy of TTFields in patients with progressive NSCLC or NSCLC brain metastases following standard-of-care or radiosurgery, respectively. Our study utilized patient-derived cells isolated from NSCLC brain metastases from a patient previously treated with standard-of-care chemo-radiation prior to progression to brain metastasis. These patient-derived cells underwent TTFields application in vitro with and without paclitaxel to determine if the response to the combination of TTFields with paclitaxel would be different from either treatment alone. Use of patient tissues was approved by the Institutional Review Board. Written informed consent was obtained from the patient, who was 60 years-old and female. She received concurrent carboplatin/paclitaxel and radiotherapy to the upper lobe of her left lung prior to discovery and resection of a solitary brain lesion. Cells isolated from the metastatic brain tumor were cultured for 3 passages prior to plating on coverslips (4×104 each) in DMEM/F12 media with 10% fetal bovine serum. TTFields were applied at ~1.6 V/cm at 150 kHz. Paclitaxel was added to the media to a final concentration of 5 nM. After 14 days, cell lysates were assayed for lactase dehydrogenase (LDH) to represent cell number (n=5) or were harvested and replated in triplicate for the clonogenic assay (n=3). Groups were compared with one-way ANOVA. Mean ± SD of LDH for the control, TTFields-alone, paclitaxel-alone, and the combination were 1.83 ± 0.09, 1.34 ± 0.15, 0.81 ± 0.04, and 0.46 ± 0.21, respectively (ANOVA p< 0.0001). Clonogenic assay counts for the same groups were 26641 ± 4625, 17399 ± 5998, 8697 ± 1617, and 1598 ± 598 (ANOVA p= 0.0003). The additive effects of TTFields and paclitaxel suggest that they target different cell populations within a heterogeneous tumor, and that patients previously treated with standard-of-care may benefit from TTFields therapy.
EXTH-32. DEVELOPMENT OF EPHA3 DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME
Authors: Ruff Michael , Sakemura Reona , Cox Michelle , Hefazi Torghabeh Mehrdad , Roman Moreno Paulina , Schick Kendall , Sarkaria Jann , Kenderian Saad 
Published: November 2019

Abstract

BACKGROUND
Efficacy of chimeric antigen receptor T cell (CART) therapy remains limited in solid tumors. Given the heterogeneity of surface receptor expression and immunosuppressive stromal microenvironment, strategies to target tumor neovasculature and tumor stromal cells are needed to help overcome CART inhibition by GBM. Eph receptors are the largest family of receptor tyrosine kinases and are integral to cell adhesion, migration, and axon guidance, during development and homeostasis. EphA3 is a receptor tyrosine kinase which is lowly expressed in adult tissues but is highly expressed in tumor neovasculature and tumor stromal cells in GBM and other solid tumors. EphA3 is over-expressed in up to 40% of GBM samples. We aimed to develop CART cells directed against EphA3 to use in targeting tumor neovasculature and tumor stromal cells in GBM.

METHODS
we developed a second generation CD28 co-stimulated CAR construct in a third generation lentivirus backbone to generate EphA3 CART cells using the single chain variable fragment of ifabotuzumab, a monoclonal antibody directed against EphA3. Patient derived GBM xenograft cell lines were used in these experiments.

RESULTS
EphA3 directed CART cells exhibited specific and potent antitumor activity against EphA3+ GBM cell lines with variable transcriptome EphA3 expression indicating its broader applicability in patients with GBM. Killing over 24-hour incubation was significant at low effector: target ratio: 52.5% killing at 1.25:1 against cell lines with 25.05% EphA3 expression and 37.1% killing at 1.25:1and 90% killing at 5:1 ratio against a cell line with 19.28% expression. Conversely, when co-cultured with UTD controls there was significantly lower killing, or growth of tumor cells.

CONCLUSION
We demonstrate for the first time that targeting EphA3 with CART cells is feasible, efficacious and represents a novel therapeutics strategy to target GBM. Data from in vivo and combinatorial CART experiments will be reported at the meeting.