bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDDR-23. COMBINATION THERAPY WITH PACLITAXEL, CARBOPLATIN, AND LOW-INTENSITY ULTRASOUND FOR RECURRENT GLIOBLASTOMA: RATIONALE FOR ONGOING PHASE II CLINICAL TRIAL
Authors: Habashy Karl , Dmello Crismita , Chen Li , Arrieta Victor , Kim Kwang-Soo , Gould Andrew , Bouchoux Guillaume , Canney Michael , Stupp Roger , Sonabend Adam 
Published: November 2023

Abstract
We recently participated in phase 1/2 clinical trials where patients with recurrent glioblastoma received surgery for tumor resection followed by implantation of an ultrasound device into a skull window for subsequent repeated blood-brain barrier opening and concomitant delivery of chemotherapy (Sonabend et al., Lancet Oncology). Intraoperative experiments demonstrated a 3.7 to 5.9-fold increase in the brain concentration of paclitaxel (NCT04528680) and carboplatin (NCT03744026). Building on the pharmacokinetics and safety of these trial results, and the historical use of paclitaxel and carboplatin as a combination in other cancers, we investigated the efficacy of this combination in glioblastoma models. First, we analyzed the cytotoxicity of both drugs in vitro against five human cell lines and six patient-derived xenografts as monotherapy and in combination at concentrations derived from our human intraoperative pharmacokinetic studies. Cell lines exhibited little overlap in susceptibility to the drugs, with 27% being exclusively susceptible to one of the two drugs tested. The combination covered 81% of cell lines, compared to 54% covered with monotherapy. We also assessed for synergy using the Loewe model and recorded synergy in 55% of cells. We then evaluated the benefit of this combination in vivo in two xenograft models (MES83 and GBM6) where drugs were administered with ultrasound. Combination therapy proved more effective than monotherapy with either of the drugs, led to distinct effects on cell cycle progression and enhanced DNA damage and apoptosis. We conclude that the addition of carboplatin to paclitaxel may be more effective than monotherapy with paclitaxel, which we performed in our phase 1 trial. This combination is supported by its efficacy in other cancers, and the synergy and independent susceptibility to each drug in glioma models. The safety and efficacy of this approach are currently under investigation in an ongoing phase II trial for patients with recurrent GBM (NCT04528680).
DDDR-24. SINGLE-CELL FUNCTIONAL TISSUE PROFILING IDENTIFIES PROMISING CANDIDATES FOR DRUG REPURPOSING AGAINST GLIOBLASTOMA
Authors: Weiss Tobias , Lee Sohyon , Buehler Marcel , Mena Julien , Lottenbach Zuzanna , Wegmann Rebekka , Bihl Michael , Sun Miaomiao , Goetze Sandra , van Drogen Audrey , Vasella Flavio , Wollscheid Bernd , Snijder Berend , Weller Michael 
Published: November 2023

Abstract
There remains an unmet need for novel treatment strategies against glioblastoma that are more effective than the current standard of care. However, the complex tumor microenvironment and genetic heterogeneity of these tumors require novel technologies enabling high-throughput assessment of cellular responses to treatments on a functional level in complex tumor samples with an intact cellular microenvironment. Here, we used a novel single-cell functional tissue profiling platform based on high—throughput microscopy followed by computer vision and machine learning algorithms to screen 70 clinically-approved drugs with good blood-brain-barrier penetration in 35 glioblastoma patient samples that were freshly obtained from surgery. This revealed prognostically relevant subtypes of glioma cell morphologies and promising candidates for drug repurposing. Among the drugs with potent anti-glioma activity, we identified the antidepressant Vortioxetine, that had strong anti-glioma activity across patients independent of the promoter methylation status of O6-methylguanine-DNA methyltransferase (MGMT). Complementrary in vitro studies using patient-derived glioma cell lines and orthotopic glioma xenograft mouse models confirmed the strong anti-glioma activity of Vortioxetine, leading to a notable fraction of long-term surviving mice. Mechanistically, multiplexed transcriptomics and proteomics unveiled that Vortioxetine induced an upregulation of the Activator protein 1 (AP-1) transcription factor family, along with the B-cell translocation gene (BTG) tumor suppressor genes. These findings serve as the cornerstone for future clinical applications of the single-cell functional tissue profiling platform and the potential clinical translation of Vortioxetine as a promising drug-repurposing candidate for glioblastoma patients.
DDDR-26. INHIBITION OF RAD52 ACTIVITY ENHANCES THE RADIOSENSITIVITY IN DIPG
Authors: Uchida Eita , Ishi Yukitomo , Watanabe Jun , Wang Lu , Abdala-Valencia Hiam , Gadd Samantha , Hashizume Rintaro 
Published: November 2023

Abstract
Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating childhood cancers that limited response to radiation therapy, resulting in median overall survival of approximately 10 months. There is a critical need for new therapeutics that enhance the radiation effect while enabling the use of lower doses of radiation to limit long-term side effects in young patients. We, therefore, tested the hypothesis that targeting RAD52 activity sensitizes the radiation response of DIPG. Genome-wide CRISPR/Cas9 screening identified RAD52 as potential therapeutic target in DIPG cells. RAD52 inhibition, using shRNA mediated RAD52 depletion and treatment with RAD52 inhibitor, D-I03, suppressed DIPG cell proliferation. Importantly, RAD52 inhibition in combination with radiation therapy further increased radiosensitivity of DIPG cells. Immunocytochemistry of DNA double-strand breaks (DSB) marker γH2AX and repair marker 53BP1 showed that RAD52 inhibition sustained DNA damage with high levels of γH2AX at 24 hours following radiation while the level of 53BPI was decreased, thereby inhibiting DNA DSB repair. Western blotting also revealed that RAD52 inhibition causes a sustained level of phosphorylated Rad50 and γH2AX in irradiated DIPG cells. DNA repair assay showed that RAD52 inhibition suppressed DNA DSB repair through a homologous recombination pathway. RNA sequencing showed that RAD52 inhibition downregulated genes associated with the DNA repair pathway. Finally, the combination therapy of D-I03 RAD52 inhibitor and radiation inhibited tumor growth and significantly increased survival of mice bearing DIPG patient-derived xenografts, outperforming either monotherapy. Together, these results highlight RAD52 inhibitor as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.
EPID-09. ASSOCIATION BETWEEN VIRAL INFECTIONS AND GLIOMA RISK: A TWO-SAMPLE BI-DIRECTIONAL MENDELIAN RANDOMIZATION ANALYSIS
Authors: Yang Wenzhuo , Zhong Sheng , Xie Haoqun , Zhang Zhiyun , Sai Ke , Mou Yonggao 
Published: November 2023

Abstract

BACKGROUND
Glioma is one of the leading causes of brain tumors, but few etiologic factors of primary gliomas were identified. Previous observational research has shown an association between viral infection and glioma risk. Here, we sought to use Mendelian Randomization (MR) analysis to explore the direction and magnitude of the causal relationship between viral infections and glioma.

METHODS
We conducted a two-sample bi-directional MR analysis using Genome-Wide Association Study (GWAS) data. Summary statistics data of glioma were collected from the most extensive meta-analysis GWAS involving 12,488 cases and 18,169 controls. Single Nucleotide Polymorphisms (SNPs) associated with the exposures were used as instrumental variables to estimate the causal relationship between glioma and twelve types of viral infections from corresponding GWAS data. In addition, sensitivity analyses were performed.

RESULTS
After correcting for multiple tests and sensitivity analysis, we detected that genetically predicted VZV infection significantly decreased the risk of lower-grade glioma (LGG) development (OR=0.85, 95% CI: 0.76-0.96, P=0.0066, FDR=0.0396). No causal effects of the other eleven viral infections on glioma and reverse causality were detected.

CONCLUSIONS
Our research is one of this field's first and most significant studies. We showed robust evidence supporting that genetically predicted VZV infection reduces the risk of LGG. The findings from our research are a big step forward in understanding the etiology of glioma.
EPID-13. DATA-DRIVEN MACHINE LEARNING MODELS AS PROGNOSTIC TOOL FOR PREDICTING SURVIVAL OUTCOMES IN PEDIATRIC PATIENTS WITH GLIOMA OF THE OPTIC APPARATUS
Authors: Brown Nolan , Kuo Cathleen , Gendreau Julian 
Published: November 2023

Abstract
Optic pathway gliomas (OPG) are low-grade lesions arising from the astrocytes of the visual pathway and diencephalon. For most patients, observation appears to be the treatment of choice, but it remains unclear how frequently serial imaging should be obtained and at what point lesions can be deemed to have become quiescent. There is therefore an ongoing need for prognostication tools that can accurately predict the behavior of OPG to help identify those lesions meriting therapeutic intervention. In the present study, we leverage population-level data from the Surveillance, Epidemiology, and End. RESULTS: program (SEER) database to develop a predictive calculator for overall survival (OS) in pediatric OPG. Accordingly, we extracted all available patient-level data from the SEER database. Training and testing datasets were established. Cox proportional hazards regressions were then used to identify independent predictors of survival, and model validation was performed. A total of 1,052 pediatric patients met inclusion criteria. Most were between 5 to 9 years old (45.7%), males (51.6%), white (85.6%), non-Hispanic (82.1%), and 232 patients (22.1%) came from houses with a median income less than $54,999, while 111 patients (10.6%) lived in a rural county. Nearly 90% of patients did not undergo surgical debulking. Twenty-three patients (2.2%) received radiotherapy and 294 (27.9%) received chemotherapy. Additionally, univariate and multivariate analyses were performed to identify variables associated with OS. Median household income and subtotal resection were found to be predictors of OS on univariate analysis. Furthermore, on multivariate analysis, median household income greater than $55,000 and subtotal resection were predictive of higher OS. Age at diagnosis, sex, rural versus urban setting, benign versus malignant behavior, and use of chemotherapy or radiotherapy did not appear to affect OS. Finally, we created a calculator (https://spine.shinyapps.io/optic_glioma/) using our model to estimate 5-,10-, and 1-year OS probability and other survival outcomes.
EPID-30. DYSPHAGIA-RELATED HEALTHCARE UTILIZATION AMONG OLDER PATIENTS WITH PRIMARY AND METASTATIC BRAIN TUMORS: A NATIONAL STUDY OF MEDICARE BENEFICIARIES
Authors: Leiman David A , Parish Alice , Cohen Seth M , Niedzwiecki Donna , Johnson Margaret O 
Published: November 2023

Abstract

BACKGROUND
Swallowing dysfunction is common among older adults and the presence of a malignant brain tumor (primary or metastatic) may compound the existing burden of dysphagia in this population. We aimed to characterize the dysphagia-specific healthcare utilization among Medicare beneficiaries with malignant brain tumors.

METHODS
Using a Medicare 5% limited dataset (2013-2018) and ICD-9/10 codes, we identified beneficiaries (≥ 65 years) with primary malignant brain tumors (PMBTs) as well as the five most common solid tumors metastasizing to the brain (lung, breast, melanoma, renal, and colorectal). Those with disorders predisposing to dysphagia were excluded. Healthcare utilization was quantified using CPT codes for hospitalizations, gastroenterology services (endoscopy [EGD]), nutrition consultation, speech language management, radiographic testing, and enteral feeding access, occurring after cancer diagnosis. Comparisons of utilization by dysphagia status were made using chi-square and Wilcoxon rank-sum tests.

RESULTS
Among 79,926 beneficiaries, we identified 3,184 (4.0%) with malignant PBTs and 1,033 (1.3%) with brain metastases. Of the total cohort, 4.7% (n=3,777) experienced dysphagia. Whereas, 11.0% (n=349) of those with PMBTs and 7.9% (n=82) with brain metastases experienced dysphagia. Those with PMBTs were diagnosed with dysphagia significantly earlier in their disease course compared to other groups (median 20 vs. 36 vs. 58 days for PMBTs, brain metastases, and no brain metastases, respectively; p&lt; 0.01). Speech pathology services use was highest among PMBT patients compared other groups (36.1%; n=126; p&lt; 0.001). Gastroenterology services utilization overall was high among all groups and enteral feeding tube placement was significantly higher among PMBTs (p&lt; 0.001).

CONCLUSIONS
Dysphagia increases with age and older patients with brain malignancies are at particularly high risk. Those with PMBTs experience dysphagia earlier in their disease course and dysphagia-related healthcare utilization is higher when compared to other cancers. Our findings have important implications as the number of Medicare beneficiaries is expected to increase.
EPCO-13. CNMF-SNS, A FRAMEWORK FOR UNSUPERVISED INTEGRATION OF MULTIOMICS DATA, IDENTIFIES INVASION AND RECURRENCE ASSOCIATED PROGRAMS IN GBM
Authors: Verhey Theodore , Seo Heewon , Morrissy Sorana 
Published: November 2023

Abstract
Glioblastoma (GBM) is an aggressive cancer of the brain for which novel therapies are urgently needed. Heterogeneity in GBM underlies tumor evolution and resistance to therapy and involves genetic diversity of tumor cells, spatially distinct niches harbouring stem-like cells, and immune cells spanning anti- and pro-tumor states. No single profiling methodology can capture all these facets of tumor biology in the same space and time, necessitating multi-omics data collection and computational methods suited for multi-omic integration across and within cohorts. We therefore set out to develop a generalizable framework for integration that can bridge across cohorts and data types. Using consensus non-negative matrix factorization (cNMF), we discover gene expression programs (GEPs) corresponding to cell types and/or states in an unsupervised fashion. Rather than choosing a single rank (number of programs), we identify both high and low-resolution programs for each dataset, and then integrate programs from all datasets and ranks into a solution network space (SNS) on which graph algorithms identify communities of highly similar GEPs identified in all or some datasets. These communities are characterized by gene set enrichment analyses and association with sample metadata. SNS communities can be used to transfer sample metadata across datasets, enabling multi-omics and multi-cohort integration, even in the absence of shared samples or cells. We showcase the utility of cNMF-SNS in integrating multiomics datasets of GBM from single-cell to bulk RNA-Seq and mass spectrometry proteomics. We further demonstrate the power of cNMF-SNS to define and cross-annotate programs identified in 5 complementary mass spectrometry datasets of GBM, layering on survival, driver gene mutation status, clinical features, and imaging features. We demonstrate robust mapping of biologically and clinically relevant processes, highlighting how programs for tumor cell invasion and therapy resistance can be mined for novel therapeutic targets. cNMF-SNS is available at https://github.com/MorrissyLab/cNMF-SNS.
EPCO-14. IDENTIFYING EPIGENETIC VULNERABILITIES OF MINIMAL RESIDUAL DISEASE IN GLIOBLASTOMA USING IN VIVO CRISPR SCREENS
Authors: Mitchell Kelly , Mihalas Anca , Arora Sonali , Paddison Patrick , Patel Anoop 
Published: November 2023

Abstract
Therapy for glioblastoma (GBM) includes surgical resection, radiation, and chemotherapy, which functionally reduces tumor burden to a state of minimal residual disease (MRD). However, recurrence over time is universal. Large-scale longitudinal studies of GBM patient samples did not identify selection pressure for specific DNA mutations in recurrent disease, highlighting the importance of epigenetic mechanisms during relapse. In this study, we aim to model MRD and the functional and transcriptional effects of epigenetic perturbations in GBM patient derived xenografts (PDXs). We developed an in vivo inducible genome editing system by engineering 827 GBM stem cells to express doxycycline inducible Cas9 and a pool of 14 CRISPR sgRNAs targeting 5 epigenetic factors (readers/erasers of H3K27me3 and H4 acetyltransferase KAT5) and controls. Tumor cells are implanted orthotopically and mice are followed by serial MRIs until tumor volumes reach 2mm3, after which in vivo editing is induced by administration of doxycycline. Cells are harvested for scRNA-sequencing and targeted amplification of sgRNA libraries, allowing for assignment of sgRNAs to individual cells. Genome editing efficiencies ranged from 50-90% in vivo. Knockout of core Polycomb (PcG) complex members led to dysregulated expression of genes involved in therapeutic resistance and altered cell state distributions. Current directions include optimization of sgRNA targeting and recovery of CRISPR-edited cells from tumors for scaling up screens. In addition, we have developed a “standard of care” treatment regimen in GBM PDX models whereby temozolomide and radiation therapy is dose optimized to achieve a latent state that mimics MRD followed by eventual tumor recurrence. Future experiments will combine MRD modeling in PDXs with in vivo CRISPR screening to characterize functional dependencies of MRD in GBM. This data provides proof of concept for utilizing these tools for studying genotype to phenotype connections in a complex GBM model system.
EPCO-15. DETECTING HISTOLOGIC & CLINICAL GLIOBLASTOMA PATTERNS OF PROGNOSTIC RELEVANCE
Authors: Baheti Bhakti , Rai Sunny , Innani Shubham , Mehdiratta Garv , Guntuku Sharath Chandra , Nasrallah MacLean P , Bakas Spyridon 
Published: November 2023

Abstract

BACKGROUND
Glioblastoma is the most common adult primary brain tumor. Limited improvement in patient prospects over the last 20 years reflects our limited disease understanding. Robust prognostic patient stratification from whole slide images (WSI) & clinical data using interpretable computational methods could improve disease understanding and patient management.

MATERIAL AND METHODS
The TCGA-GBM and TCGA-LGG data collections were reclassified according to the 2021 WHO classification criteria, identifying 188 glioblastoma (IDH-wt, Gr.4) cases and stratifying them to short- (&lt; 9 months) and long-survivors ( &gt; 13 months). H&E-stained WSI were comprehensively curated to remove artifactual content. An interpretability mechanism based on weakly-supervised attention-based multiple-instance-learning was employed. The prognostic relevance of associated clinical data was also evaluated both independently and integratively, using XGBoost and ‘SHapely Additive exPlanations’. Late fusion amalgamates the advantage of WSI patterns with clinical features by averaging the output probabilities of two distinct models at the decision level. Quantitative performance evaluation was based on a 10-fold monte carlo cross-validation, with training (80%), validation (10%), and test (10%) sets.

RESULTS
Our imaging, clinical, and integrative multi-modal models revealed AUCTest of 0.68/0.72/0.75 respectively. The imaging analysis revealed correctly predicted long-survivors associated with histologically malignant areas, including necrosis, hypercellularity, atypia, infiltration, and proliferation. Correctly classified short survivors highlighted influence by aggressive infiltrative features, including leptomeningeal involvement. The clinical analysis revealed age, mutation count, and TERT promoter status as the top three features contributing to stratification, in the XGBoost model.

CONCLUSION
Our findings support data-driven histology & data interpretation of algorithmic decisions contribute to further understanding of glioblastoma by identifying morphology patterns & clinical patterns of prognostic relevance. Integration of multiple modalities can be a powerful approach for improving the performance of AI models.
EPCO-50. THE TRANSCRIPTIONAL LANDSCAPE OF KEY INNATE DNA SENSORS WITHIN PRIMARY BRAIN TUMORS
Authors: Mangoli Avani , Bowie Michelle , Ashley David , Low Justin , Stevenson Kevin , Chandramohan Vidya , Hariharan Seetha 
Published: November 2023

Abstract
Primary brain tumors are notoriously resistant to immunotherapy. The efficacy of these treatments potentially requires normal expression of DNA innate sensors within both the immune and tumor compartments. Recently, we found that STING1, involved in the CGAS/STING pathway, is epigenetically silenced in the neoplastic cells of primary brain tumors. This silencing can be traced back to the normal brain. We and others have shown that rescue of STING1 expression can be modulated with epigenetic treatments. The mechanism by which DNA damage in cancer leads to an inflammatory response sheds light on the significance of other DNA sensors. We hypothesize that innate immune silencing within the tumor contributes to immunotherapy resistance and the addition of epigenetic treatments could increase efficacy. We evaluated the transcriptional landscape of DNA innate sensors within normal adult brain and in patient derived tumors including glioblastoma, pilocytic astrocytoma, and diffuse midline gliomas, H3K27M mutant. We found low expression of additional cytosolic DNA sensors including cGAS, AIM2, ZBP1 in normal neuronal as well as tumor cells. Since epigenetic silencing is modulated during normal development, we compared the transcriptional innate profiles from normal cortex brain development to primary brain cancers. DNA innate immune sensor expression correlates with pre-oligodendrocyte progenitor cells and oligodendrocyte progenitor cells. These results suggest the innate immune suppression of these key cytosolic DNA sensors is established early in fetal brain development and retained in the context of primary brain tumors. We are currently exploring the epigenetic profiles of fetal brain and brain tumors to determine how these innate immune expression patterns affect tumorigenesis and response to immunotherapy treatment.