bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCO-43. STING EPIGENETIC SILENCING IN GBM: IMPLICATIONS FOR INFLAMING THE IMMUNE MICROENVIRONMENT AND DESIGNING COMBINATION THERAPIES
Authors: Low Justin , Bowie Michelle , Wertman Virginia , Baker Eric , Mangoli Avani , Gibson Emiley , Gomar Rodrigo de La Vega , Stevenson Kevin , Fuller Rebecca , Hostettler Janell , Brown Michael , Waitkus Matthew , Reitman Zachary , Ashley David 
Published: November 2023

Abstract
Primary brain tumors including glioblastoma (GBM) are notoriously resistant to immunotherapy due in part to disrupted innate immunity. The stimulator of interferon genes (STING) pathway is a key component of innate immunity and senses pathogenic cytosolic DNA, stimulating the production of type I interferons (IFN) and pro-inflammatory cytokines. We have recently shown that STING signaling is silenced in the neoplastic compartment of the GBM tumor microenvironment, but remains intact in vascular and immune cells. Methylation analysis of bulk GBM tumor samples revealed a STING promoter region that is highly methylated and strongly correlates inversely with STING RNA expression, suggesting epigenetic control of STING expression. Methylation array analysis of patient specimens demonstrates that such promoter hypermethylation is unique amongst innate immune genes, and STING RNA expression correlates strongly with markers of immune inflammation. STING epigenetic silencing is also present in normal fetal and adult brains, suggesting that STING silencing occurs early in neural development and may provide an immunosuppressive environment conducive to tumorigenesis. Treatment with the blood brain barrier-penetrant DNA methyltransferase inhibitor Decitabine demethylates the STING promoter and activates interferon stimulated genes (ISG). STING knockout experiments and treatment with the DNMT1-selective inhibitor GSK-3685032 suggest that STING expression is necessary but not sufficient for ISG activation. These results suggest that innate immune silencing is a fundamental characteristic of GBM that underlies its intrinsic therapy resistance, yet may also represent a vulnerability that can be exploited by epigenetic therapies to inflame the GBM tumor microenvironment. However, epigenetic therapies that de-represses STING may need to be coupled with DNA damaging agents, immunotherapy, or STING agonists for optimal immune inflammation.
EPCO-46. CHARACTERIZING ATYPICAL TERATOID RHABDOID TUMOR SUBTYPE ENHANCER INTERACTION LANDSCAPE
Authors: Ho Ben , Fan Xiaolian , Xu Liming , Huang Annie 
Published: November 2023

Abstract
Atypical Teratoid Rhabdoid Tumor (ATRT) is one of the most aggressive pediatric tumors of the central nervous system (CNS). The majority of ATRTs are characterized by the recurrent bi-allelic loss of the SWI/SNF nucleosome remodeling complex core component gene, SMARCB1, or SMARCA4 in rare cases. Despite its bland genome, three ATRT subgroups “SHH”, “TYR”, and “MYC” were discovered with unique molecular profiles. Also, distinct activating histone mark H3K27ac profiles between molecular subgroups were identified, suggesting subgroup-specific regulatory networks through enhancers. However, comprehensive cis-regulatory network descriptions in ATRT are lacking. Here, we aim to elucidate ATRT subgroup pathogenesis through its dysregulated enhancer-promoter interactions. We have created a regulatory mutational profile of the three ATRT subgroups using whole-genome sequencing method of 60 ATRT tumors and matching genome-wide H3K27ac profiles on 16 tumors. To investigate mutation burden on cis-regulations, we have employed high-throughput Hi-C chromatin immunoprecipitation (HiChIP) technique to directly map enhancer sequences involved in DNA-looping with high specificity and sensitivity. Recent findings from our lab suggest that activating interaction PDGFRB confer to therapeutics venerability in the MYC subgroup. Here, our preliminary analysis shows a hub of interactions near PDGFRB reveals an extensive interaction hub with long-range enhancer interactions extending as far as 1500Kb, suggesting a much more complicated regulatory picture than previously expected. Interestingly, we have identified long-range DNA interactions between PDGFRB and H3K27ac marks upstream of its gene body and overstretching into other gene elements. This result suggests a potential alternative activation mechanism for MYC cell lines. Our next steps are to perform performing additional HiChIP assays on other ATRT cell lines from other subgroups to capture the full range of ATRT’s heterogeneity. Comprehensive mapping of the non-coding genome and enhancer regulatory network would help identify critical pathogenic elements underlying ATRT biology and provide insights into therapeutic targets.
EPCO-54. GENETIC PROFILE OF SKULL BASE CHONDROSARCOMAS AND RESPONSE TO TREATMENT IN PATIENTS WITH IDH1 MUTATED TUMORS
Authors: Eaton Jessica , Parada Carolina Da Silva , Parrish Oscar , Tucker Mallory , Zhao Tina , Delegard Jennifer , Lassiter Eric , Ruzevick Jacob , Cranmer Lee , Ferreira Manuel 
Published: November 2023

Abstract
Chondrosarcomas are uncommon tumors, with an incidence of 0.1-0.3 cases per 100,000 people. Current treatment consists of maximal safe surgical resection. The addition of adjuvant radiation reduces 5-year mortality by about 50%, but recurrence rates at 5 years are still over 30%. Targeted treatment options are needed to improve outcomes for patients with these tumors. IDH catalyzes the oxidative carboxylation of isocitrate to produce a-ketoglutarate. IDH1 mutations been identified across multiple cancers, included gliomas, AML, cholangiocarcinomas, and chondrosarcomas. These mutations are thought to impair cell differentiation and lead to tumorigenesis. OBJECTIVES: We present 2 cases of IDH1 mutant skull base chondrosarcomas that were treated with an IDH inhibitor. Both patients had radiographic involution of their tumors with no progression 2 years later. We describe the genetic profile of chondrosarcomas, elucidate associations between tumor mutations and clinical course, and investigate the mechanism of treatment response. METHODS: We performed a retrospective cohort analysis of 38 patients with skull base chondrosarcomas. Cox proportional hazards models were performed. Whole exome sequencing (WES) was performed on tumor samples, including multiple samples taken at various time points during the clinical course in 3 patients. RESULTS: A total of 38 patients with skullbase chondrosarcomas underwent surgery between 2000 and 2020. Mean follow-up time was 83.3 ± 107.7 months. Mean progression free survival time was 54.4 ± 71.5 months. Mortality was 15.8%. WES was available for 29 patients. Of these, 22 patients had IDH1 mutations (75.9%). Of these 22, the most common amino acid change was at the R132C position (45.5%). There was a trend towards increased mortality in patients that were IDH1 wildtype (42.8%) vs IDH1 mutant (13.6%). CONCLUSION: While IDH1 mutations are possible therapeutic targets with exciting preliminary responses, treatment response is likely complex and dependent on multiple mutations. Further analyses and validation studies are underway.
DISP-02. PATTERNS IN THE INCIDENCE OF BRAIN METASTASIS BY RACE AND ETHNICITY: A SYSTEMATIC REVIEW
Authors: Gomez David , Feng Jeffrey , Dicharry Holly , Cheok Stephanie , Musabelliu Erion , Zada Gabriel 
Published: November 2023

Abstract

INTRODUCTION
Despite advancements in cancer treatment, the incidence of brain metastases (BM) continues to rise which necessitates risk factor analyses. Although current literature indicates racial variance in BM incidence, there exists a major knowledge gap in understanding associations between race/ethnicity, BM incidence, and subtypes which emphasizes the need for a systematic review. We aimed to analyze the relationship between BM incidence, race/ethnicity, and primary cancer type.

METHODS
Using PRISMA guidelines, a systematic review of PubMed and Ovid databases from January 2000 to January 2023 for terms related to BM, ethnicity and race, in conjunction with incidence was conducted. Inclusion criteria comprised peer-reviewed journals with ages &gt; 18, sample size &gt; 100, primary malignancy diagnosis with evidence of BM, and descriptions of patient race or ethnicity.

RESULTS
Of 806 identified studies, 11 articles primarily utilizing US data were included for final analysis. Lung and bronchus cancers, revealed the highest incidence of BM in Asian patients, followed by Black, White, and American Indian/Alaska Natives (P&lt; .001), despite overall increased incidence of primary cancer in Black patients. Breast cancer revealed highest BM incidence in American Indian/Alaska Natives (5.9%), followed by Black (5.0%), White (3.6%), and Asian/Pacific Islanders (3.5%) (P&lt; .001). When compared to White and Hispanics only, Black patients had greater incidences of BM (OR: 2.26, 95% CI: 1.57–3.25). Lower incidence of BM for esophageal cancer was observed in Black patients compared to White patients (OR=0.38; 95% CI: (0.16–0.89); P= 0.026). No significant differences were observed in BM incidence for bladder, prostate, or non-small cell and small cell lung cancers.

CONCLUSIONS
Our review suggests that BM incidence does vary amongst racial/ethnic groups dependent on primary cancer type. Differences may be due to numerous factors, underscoring the need for more work with inclusive, diverse cohorts to tackle BM disparities.
DISP-05. UNDERSTANDING THE INDIVIDUAL CHALLENGES AND EXPERIENCES OF YOUNG ADULTS WITH A DIAGNOSIS OF GLIOBLASTOMA AND HIGH-GRADE ASTROCYTOMA
Authors: Devaraja Kaviya , Avery Jonathan , Daniels Maureen , Edelstein Kim , Gupta Abha , Tsang Derek 
Published: November 2023

Abstract
High-grade gliomas are highly aggressive and fatal primary malignant brain tumors in adults with ineffective existing treatment methods. Older adults are greatly impacted by high-grade gliomas as they are more common among this population. Young adults (individuals aged 18-39) are uniquely impacted by high-grade glioma. However, there are few resources and information available to address these unique needs. The purpose of this study is to explore the lived experience of this population to inform the development of resources to help address their specific needs. A qualitative descriptive design drawing on thematic analysis was chosen to conduct and analyze interviews with young adult high-grade glioma patients at the Princess Margaret Cancer Center. Interviews focused on patient experiences as a high-grade glioma patient at Princess Margaret Cancer Center, the challenges they face and changes they would like implemented. A coding framework was created to determine emerging themes using qualitative data analysis software NVivo 10. To date, 5 interviews (1 men; 4 women; age range 19-37) have been completed. Interviews described the challenges living with high-grade glioma as a young adult and the changes in resources and support services patients would like implemented. Experiences highlighted 1) difficulty accepting this change in life and disruptions brought upon life goals and plans at the young adult age; 2) an overall lack of young adult high-grade glioma specific education, advocacy and support resources 3) A call for more community building and connecting so patients do not feel alone through this diagnosis. These patient interviews highlight a connection between the young adult age and high-grade glioma diagnosis and the challenges experienced and the services required. These results will serve as the foundation to advocate for the creation of tools that cater to patient needs of young adult high-grade glioma patients.
DISP-11. PROMINENT FRONTAL BOSSING AND BLINDNESS FOLLOWING SUBTOTAL RESECTION OF LOW-GRADE MENINGIOMA: HIGHLIGHTING HEALTH DISPARITIES
Authors: White Jessica , Lim Sanghee , Neth Bryan , Carabenciov Ivan , Stitt Derek , Mustafa Rafid 
Published: November 2023

Abstract
Low-grade meningiomas with subtotal resection carry significantly shorter recurrence-free survival rates than those with gross total resection. We report the natural history of a case of low-grade meningioma after subtotal resection and review the literature. We aim to highlight known global health disparities in oncology treatment by describing a case of meningioma progression following subtotal resection. A 40-year-old Kenyan woman presented locally with headache, nausea, and vision loss over approximately a six month time period. A 5 cm olfactory groove meningioma was discovered, and she subsequently underwent subtotal resection that was likely limited due to hemorrhagic complications. Over the following two years, she developed progressive dizziness, nausea, gait instability, difficulty performing tasks, and visual loss prompting medical evaluation at our institution. Physical examination demonstrated blindness, bilateral proptosis with severe vertical gaze palsy, and prominent frontal bossing. MRI Brain revealed a 9 cm enhancing mass arising from the cribriform plate with elevation of an ununited overlying frontal craniotomy flap and apparent meningoceles extending through the presumed osteotomy bilaterally. She underwent successful resection with pathology demonstrating CNS WHO Grade 1 meningioma. Her postoperative neurologic exam showed subtle improvement, specifically in regards to orientation questions. In this patient, bone flap displacement from prior craniotomy allowed significant interval tumor growth while minimizing mass effect on brain parenchyma. This case highlights global health disparities in low-grade meningioma management related to appropriate healthcare access in underserved patients.
DISP-15. DISPARITIES IN THE AVAILABILITY OF NEURO-ONCOLOGY CLINICAL TRIAL SUPPORTING INFRASTRUCTURE IN THE UNITED STATES
Authors: Kim Yeonju , Armstrong Terri , Gilbert Mark , Celiku Orieta 
Published: November 2023

Abstract

BACKGROUND
Barriers to clinical trial access have significant implications for patient care and disproportionally impact rural and socioeconomically disadvantaged populations. Expanding on reported disparities in neuro-oncology trial availability, we assessed whether existing networks of clinical providers and collaboratives, including NCI’s National Clinical Trials Network (NCTN) and Community Oncology Research Program (NCORP), can effectively bridge these disparities.

METHODS
Locations of adult neuro-oncology trial sites, UCNS-certified neuro-oncologists, NCTN Main Members, NCORP Community Affiliates, and general oncologists reporting to Centers for Medicare/Medicaid Services were obtained, mapped to zip code tabulation areas (ZCTAs), and annotated with US Census population and geography data and the Neighborhood Atlas Area Deprivation Index (ADI). Regression and spatial analyses were conducted assessing the role of geography, socioeconomic disadvantage, and population on infrastructure accessibility.

RESULTS
We identified 1976 neuro-oncology trials, 586 NCTN institutions, 962 NCORP sites, 306 neuro-oncologists, and 863 general oncologists located in just 8% of all ZCTAs, inhabited by 19% of the US population. All trial-supporting infrastructure components were more likely to exist in more populated, geographically neighboring regions (OR &gt;1, p&lt; 0.00001). Trial sites, NCTN institutions, and neuro-oncologists served ZCTAs with less disadvantage (OR=0.99, p=0.03958; OR=0.99, p&lt; 0.00001; OR=0.98, p&lt; 0.00001), while NCORP served more disadvantaged areas (OR=1.01, p=0.00102) and general oncologists were distributed similarly across ADI (OR=1.00, p=0.94317). Investigating potentially underutilized infrastructure, 2 neuro-oncologists, 8 NCTN institutions, 10 NCORP sites, and 107 general oncologists were located more than 25 miles from utilized trial sites.

CONCLUSION
The identified disparities in neuro-oncologists and trial-supporting institutions reflect disparities in trial-site access and point to broader disparities in neuro-oncology care access. NCORP sites reach more socioeconomically disadvantaged populations, but the overall sparsity of trial-supporting networks indicates that the existing infrastructure cannot effectively bridge trial-access barriers and novel approaches including telehealth and decentralized trial designs may be necessary to promote equity.
DISP-16. RACIAL/ETHNIC DIFFERENCES OF PEDIATRIC BRAIN TUMORS IN PATIENT DERIVED ORTHOTOPIC XENOGRAFT (PDOX) MODEL DEVELOPMENT AND DRUG RESPONSES DETECTED BY HIGH-THROUGHPUT DRUG SCREENING
Authors: Abdallah Aalaa , Du Yuchen , Li Xiao-Nan , Qi Lin , Kogiso Mari , Braun Frank 
Published: November 2023

Abstract
Brain tumors are the leading cause of cancer-related death in children. While the last decade has ushered in significant advances in molecular subtyping of pediatric brain tumors, little is known about the biological differences among racial/ethnic populations. We previously completed high-throughput Screening (HTS) in 12 malignant glioma and 13 medulloblastoma models. For each model, cultured xenograft cells (primary or cell line) were maintained both as a classic monolayer and as 3D neurospheres then treated for 3-7 days with a library of ~8,000 drugs/investigational agents, each at 4 different doses (0.01~ 10 µM). The antitumor activities were evaluated by the level of suppressed cell proliferation that was determined by the area under the curve (AUC) for which our cutoff value was set at 0.75. In the current study, we performed a retrospective analysis to determine the race/ethnicity of these completed PDOX models. Our cohort of medulloblastoma models included 3 models from children who self-identified as Hispanic and 5 models from children who self-identified as, that allowed for a statistical analysis (t-test) to compare the differences between these two racial/ethnic groups. From the 8,000 drugs, we identified 11 drugs (mostly NSC compounds) that were equally active in both Hispanic and White children (i.e. commonly shared drugs), and 442 drugs that showed significantly different (P&lt; 0.05) activities between the Hispanic and the White medulloblastomas grown as neurospheres and treated for 7 days. The difference of active drugs (AUC &gt;0.75) was even more prominent. Compared with 38 active drugs in White children (i.e., privately active drugs, including Bortezomib, YM155, Carfilzomib, Daporinad, GMX-1778, Dalanzomib, Cucurbitacin, Bafilomycin, Vincristin and Mitoxantrone), the number was 0 for Hispanic children. Our data indicates a significant difference in drug response across different racial/ethnic groups and provides a strong rationale for additional examination of those differences with broader coverage of tumors.
IMMU-02. IS DUAL AGENT IMMUNOTHERAPY SHIFTING THE EPIDEMIOLOGY OF MELANOMA BRAIN METASTASES? A REAL-WORLD ANALYSIS AND SINGLE-INSTITUTION VALIDATION
Authors: Bhanja Debarati , Wilding Hannah , Moeckel Camille , Hong Jinpyo , Baroz Angel , Stahl Caleb , Ozair Ahmad , Dao Joseph , Sivik Jeff , Drabick Joseph , Pameijer Colette , Ahluwalia Manmeet , Mansouri Alireza 
Published: November 2023

Abstract

INTRODUCTION
Dual agent immunotherapy (dIT) has been paradigm changing in melanoma brain metastasis (MBM). Recent clinical trials have supported the role of dIT for upfront management of small, asymptomatic MBM. Yet, its potential role in extending brain metastasis free survival and decreasing MBM incidence overall has been inadequately explored. Objective: To compare new brain metastasis incidence, median overall survival (OS), and brain metastasis free survival (BMFS) in melanoma patients treated with dIT versus single immunotherapy (sIT).

METHODS
A real-world deidentified database collating clinical information from 92 organizations (TriNetX, Inc) was queried. Melanoma patients without brain metastases prior to immunotherapy were stratified by treatment (anti-CTLA4 [sIT] and combination anti-CTLA4/ anti-PD1 [dIT]) and propensity score matched. A complementary single-institution retrospective cohort study analyzed melanoma patients treated from 2012-2019. The incidence of new asynchronous MBMs after immunotherapy initiation was compared. Median OS and BMFS were compared via log-rank tests and Cox proportional-hazards model.

RESULTS
TriNetX identified 8,686 melanoma patients who received immunotherapy (4,585 dIT; 4,101 sIT). MBM prevalence was 9.6%, and 15.6%, for the dIT and sIT cohorts, respectively (p &lt; 0.0001). DIT was associated with a lower likelihood of developing MBM compared to sIT (OR [95%CI], 0.64 [0.61-0.77]). After propensity score matching on demographics and significant comorbidities, OS was not statistically different between treatment groups. On single-institution analysis, 222 melanoma patients were included (89 dIT; 45 anti-CTLA4; 88 anti-PD1). Patients were predominantly stage III at diagnosis (43%) with PD-L1 expression (51%) and BRAF (43%), and NRAS wildtype (50%) mutational status. BMFS was significantly extended in the dIT cohort compared to the anti-CTLA4 or anti-PD1 alone cohorts (406, 217, 139 days, respectively; p&lt; 0.0001). On Cox-proportional hazards model, no covariates significantly contributed to the BMFS difference.

CONCLUSION
These data highlight the impact of combination anti-CTL4/ anti-PD1 immunotherapy in decreasing BM incidence in melanoma.
IMMU-09. IDENTIFICATION OF A NEW THERAPEUTIC ANTIGEN FOR GLIOBLASTOMA USING A MONOCLONAL ANTIBODY LIBRARY FROM PATIENT-DERIVED TUMOR SPHERES
Authors: Kuroda Hideki , Kijima Noriyuki , Tachi Tetsuro , Murakami Koki , Hirayama Ryuichi , Okita Yoshiko , Kagawa Naoki , Hosen Naoki , Kishima Haruhiko 
Published: November 2023

Abstract
Glioblastoma (GBM) has a poor prognosis despite intensive treatment by surgery, radiation, and chemotherapy, thus new treatment strategies are urgently needed. Various innovative cancer therapies targeting cancer-specific cell surface antigens, such as chimeric antigen receptor T cell therapy, are developed and more cell surface antigens that is highly specific for GBM cells are needed. Although extensive transcriptome analyses or proteomic analysis of GBM cells were performed, few transcripts specific for GBM cells have been identified. However, GBM cell-specific antigen epitopes formed by post-translational modifications of proteins may have been missed by transcriptome or proteomic analysis, and could still be discovered by thoroughly searching for cancer-specific monoclonal antibodies. In this study, we aim to identify GBM-specific antigens using a monoclonal antibody library from patient-derived tumor spheres. Approximately 25,000 monoclonal antibody-producing hybridomas were establishment using Balb/c mice and patient derived tumor spheres. Among them, two antibodies that bind to glioblastomas and not to normal brain cells were selected and we identified the antigen by the expression cloning method. The antigen is a cell adhesion molecule and has been reported to be involved in the progression of solid tumors and is expected to be a tumor-specific antigen. These results indicate that the strategy shown in this study is useful for identifying antigens that are potentially useful as targets for GBM therapy.