bluuebunny/crossref_metadata_2025_split huggingface dataset:
DISP-10. RACIAL AND SOCIOECONOMIC DIFFERENCES IN CLINICAL AND ACCESS TO CARE OUTCOMES IN NEUROSURGICAL-ONCOLOGY PATIENTS
Authors: Prabhu Ashna , Perryman Travis , Harper Stuart , Carson Amani , Dudley Lindsey , Delgadillo Alondra , Gor Aidan , Patel Kunal 
Published: November 2024

Abstract

BACKGROUND
Large database studies have identified racial and socioeconomic differences in neurosurgical-oncologic outcomes. For clearer insights and understanding, more detailed and prospective evaluation is needed.

METHODS
We retrospectively analyzed a database of 1475 patients undergoing surgery for CNS tumors over 5 years. Multivariate analysis, specific to various pathologies, was conducted to identify demographic and socioeconomic factors (including age, sex, racial identity, primary language, insurance status, and income estimate) associated with access to care and clinical outcomes. Additionally, prospective patient-centered interviews were conducted on neuro- oncology patients to qualitatively explore reasons for disparities in healthcare.

RESULTS
Significant associations were found between racial identities (White n=911; Hispanic n=285; Asian n=206; Black n=74) and sex (ANOVA p 0.0043), age (p&lt;0.0001), income estimate (p&lt;0.0001), primary language (p&lt;0.0001), and insurance status (p&lt;0.0001). Among different pathologies, presentation to the ED, rather than outpatient setting, was consistently associated with a non- English primary language (p=0.0312) and Medi-Cal insurance (p=0.0029). Time from imaging diagnosis to neurosurgical consultation was associated with non- English primary language (p=0.0262) and Medi-Cal (p=0.0030). Delay between recommendation for surgery and date of surgery was significant in Black patients (p=0.0112). A non- English primary language was negatively associated with having a gross total resection (p=0.0087). Notably, adjuvant treatments were less likely for those with non-English primary language (p=0.0203), Black race (p=0.0049), and Medi-Cal coverage (p=0.0014). Cox regression analysis identified only age (p&lt;0.0001) as a predictor of poorer overall survival in oncologic cases. Prospective interviews identified cultural, economic (work- related), and healthcare navigation issues as reasons for differences in access to care.

CONCLUSIONS
Across the spectrum of neurosurgical oncology diagnoses, racial and socioeconomic factors independently associate with access to care but not clinical outcome variables. Further investigation is needed, particularly in patients with non- English primary languages and cultural attitudes towards chemotherapy and radiation therapy.
DISP-17. OUTCOMES, CLINICAL AND MOLECULAR CHARACTERISTICS OF HISPANIC PATIENTS WITH IDH WILDTYPE GLIOBLASTOMA
Authors: Blaquier Juan , D’Angelo Fulvio , Tejera Dalissa , Nasany Ruham , Kushnirsky Marina , Hill Colin , Iavarone Antonio , de la Fuente Macarena 
Published: November 2024

Abstract

BACKGROUND
Knowledge about outcomes in Hispanic patients with gliomas is scant and mainly derived from tumor registries. IDH wild-type glioblastomas (GBM) are the most common and aggressive malignant primary brain tumor. Hispanics account for 19% of US population, reaching 29% in Florida and 65% in Miami-Dade County. As a reference center for GBM serving the community of South Florida we provide care for many Hispanic patients. Herein, we aim to describe the clinical and molecular features, including RNA seq analysis of Hispanic vs non-Hispanic patients with IDH wild-type GBM.

METHODS
Retrospective study of adult patients with diagnosis of IDH Wild-type Glioblastoma, who had NGS testing, treated at University of Miami.

RESULTS
179 patients were included, 63 (35%) were Hispanic. 41 (65%) of Hispanic patients were males as compared to 65 (56%) of the non-Hispanics. Median age at diagnosis was 54 years (45-67) for the Hispanic vs 62 (54-72) years for non-Hispanic, p=.002. With a median follow up of 17 months (CI 95% 14-19), median overall survival for Hispanic patients was 22 months (18-25) and 23 months (18-28) for non-Hispanics, p=.99. 42 (23%) patients were enrolled in clinical trials, of whom 21 (50%) were Hispanic, meaning 33% of Hispanic patients enrolled. The molecular characteristics from these patients by next-generation sequencing, including RNA seq, are being analyzed.

CONCLUSIONS
In our series of IDH wild-type Glioblastomas, Hispanic patients were significantly younger at diagnosis compared to non-Hispanic patients, but there were no differences in overall survival. 33% of Hispanic patients were enrolled in clinical trials. As the latest growing ethnic group in the USA, major efforts have to be made to better understand the disease characteristics and outcomes of this particular population. To our knowledge this will be the first report of the molecular characteristics by NGS from Hispanic patients with GBM.
IMMU-04. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES IN AN IMMUNE-DEPENDENT MANNER
Authors: Pathak Asmita , Palavalasa Sravya , Ciervo Erika , Van Den Knott Maxon Berg , Susic Nikola , Shah Khushi Hemendra , Colon Bruno , Chin Diana , Zhou Yadi , Cheng Feixiong , Lyssiotis Costas , Watson Dionysios C , Wahl Daniel , Ceccarelli Michele , Shah Ashish , Lathia Justin D , Bayik Defne 
Published: November 2024

Abstract
Communication with a neuronal network and accumulation of myeloid-derived suppressive cells (MDSCs) support GBM growth and therapeutic resistance. GBM incidence and outcomes differ between males and females. We previously demonstrated that granulocytic (gMDSCs) drive GBM in females. However, a lack of understanding of the host factors regulating distinct MDSC subset function remains to be a major obstacle for therapeutically targeting these cells in GBM. In this study, we identified γ-aminobutyric acid (GABA) pathway as a modulator of gMDSC activity. gMDSCs from both healthy adults and glioma patients, expressed significantly higher levels of GABA receptor B1 (GABBR1) and GABA receptor B2 (GABBR2) compared to monocytic MDSCs (mMDSCs). On contrary, GABA receptor A (GABAAR) subunits were not expressed in either MDSC subtype. Given these differences, we investigated the effect of GABA on MDSC metabolism and found an increase in L-arginine metabolism specifically in female gMDSCs following GABA treatment while no significant metabolic changes were observed in any other groups. In MDSCs, L-arginine can be metabolized via nitric oxide synthase (NOS2) or Arginase-1 (Arg-1). While treatment with GABA or the GABBR agonist baclofen increased NOS2 production in specifically in female gMDSCs, Arg-1 was not affected. Mechanistically, baclofen enhanced gMDSC-mediated T cell suppression in females. In preclinical models of GBM, baclofen treatment resulted in a truncated survival only in immunocompetent female mice, which was reversed by pharmaceutical inhibition of NOS2. Clinically, female patients on GABA analogs (pregabalin, gabapentin) had significantly lower 12-month survival probabilities compared to control population. This effect was not observed in male patients. Conversely, inhibition of GABBR with CGP35348 prolonged survival in female GBM models and reprogramed the immunosuppressive tumor microenvironment. Collectively, these results highlight that GABA alters anti-tumor immune response in a sex-specific manner. These results support the future assessment of GABA pathway inhibitors as potential immunotherapy agents in GBM.
IMMU-05. TNFR2 IS A NOVEL MARKER OF EXHAUSTION AND TNFR2 BLOCKADE IMPROVES SUBCUTANEOUS TUMOR CONTROL
Authors: Hoyt-Miggelbrink Alexandra , Polania Jessica Waibl , Mohan Aditya , Wachsmuth Lucas , Lorrey Selena , Lerner Emily , Wilkinson Daniel , Hardigan Andrew , Blandford Emily , Hotchkiss Kelly , Hemmers Saskia , Quackenbush Sarah Cook , Ayasoufi Katayoun , Fecci Peter 
Published: November 2024

Abstract
Checkpoint inhibitors have been successful in various tumors. However, these treatments have failed in glioblastoma. Approaches harnessing the immune response are hindered by multiple factors, including T cell exhaustion. TOX is particularly important for the transcriptional and epigenetic reprogramming of exhausted T cells. While it is known that NFAT is upstream of TOX, our understanding of the upregulation of TOX remains incomplete. We hypothesized that tumor necrosis factor (TNF) could be involved in the upregulation of TOX as TNF can lead to the translocation of NFAT into the nucleus. We observed significant upregulation of the anti-inflammatory TNF receptor type II (TNFR2) in tumor-infiltrating T cells. This local upregulation mimics expression patterns of canonical exhaustion markers. TNFR2 expression is correlated with markers of exhaustion, including PD1, TIM3, and TOX. Furthermore, TNFR2 knock out (KO) CD8 T cells have significantly lower TOX expression, without the concomitant decrease of TIM3. Whereas previous studies have linked TIM3 and TOX expression, these data suggest that TIM3 and TOX are regulated independently. We utilized bulk RNA-sequencing to assess transcriptional regulation of WT and KO T cells and detected a significant reduction of T cell exhaustion and immune checkpoint pathways in TNFR2 KO T cells. Various exhaustion-related transcription factors and coinhibitory markers were significantly reduced. In contrast, a significant increase in AP1 transcription factors, commonly associated with T cell effector functions, was detected. Given this reduced exhaustion profile, we subsequently investigated the influence of TNFR2 on tumor burden. TNFR2 KO mice had significantly lower tumor burdens following subcutaneous tumor challenges. We subsequently treated mice with a TNFR2 antagonist. While the antagonist alone was not sufficient to improve tumor control, combination with anti-PD1 significantly reduced tumor volumes. These data provide evidence for a novel marker of exhaustion that could result in a unique therapeutic strategy.
IMMU-07. THE IMMUNE LANDSCAPE OF PEDIATRIC BRAIN TUMORS: A TRANSCRIPTOMIC ANALYSIS
Authors: Frederico Stephen , Raphael Itay , Nisnboym Michal , Huq Sakibul , Shlegel Brent , Sneiderman Chaim , Jackson Sydney , Jain Anya , Rood Brian , Pollack Ian , Hwang Eugene , Rajasundaram Dhivyaa , Kohanbash Gary 
Published: November 2024

Abstract
Despite standard-of-care therapy, pediatric brain tumors are now the leading cause of cancer-related death in children, highlighting an urgent need for the development of new treatments. Immunotherapy is actively being evaluated as a therapeutic approach to pediatric brain tumors, however, more research is needed to reveal additional antigenic targets that exist in these malignancies. In this study, our team performed a transcriptomic analysis of pediatric brain tumor RNA sequencing data within the Children’s Brain Tumor Network (CBTN) to identify intra and extracellular antigens that are highly expressed across major tumor types. Interestingly, our team observed that most tumors had high gene expression of a group of antigens that were unique to that specific tumor type. Specifically, our analysis revealed that diffuse midline gliomas (DMGs) highly expressed the extracellular antigens CA9, CTCFL, and ST8SIA1, whereas atypical rhabdoid tumors (ATRTs) highly expressed MUC1 and TEK. Other tumors that displayed high gene expression for a variety of antigenic targets included H3-wildtype high-grade gliomas (HGGs), and ependymomas (EPNs). Strikingly, we observed minimal difference in antigen expression in primary tumors when compared to patient-matched recurrences. Beyond antigen expression, we evaluated the expression of antigen processing machinery (APM) which includes major histocompatibility complexes (MHCs). Our findings revealed that DMGs had the lowest level of APM expression, however, these tumors uniquely expressed high levels of the immune checkpoints ADORA2A, CD276, and KLRC1. Contrarily, ATRTs showed a high expression of immune checkpoints CD274 (PD-L1), PVR, and CD80. Other tumors included in our analysis had unique expression patterns of antigen, as well as APM and immune checkpoints. Our findings illustrate that pediatric brain tumors have distinct expression patterns of antigens, APM, and immune checkpoints that are specific to tumor type, emphasizing diverse, rather than general, immunotherapeutic approaches must be considered for childhood brain tumors.
IMMU-36. MULTI-OMIC CHARACTERIZATION OF A SYNGENEIC MOUSE CANCER STEM CELL MODEL OF GBM FOR PRECLINICAL APPLICATIONS
Authors: Heemskerk Kyle , Assaf Samir , Hao Xiaguang , Meode Mathieu , Kala Smriti , Pemberton James , Mirzaei Reza , Cairncross J Gregory , Forsyth Peter , Yong V Wee , Weiss Samuel , Zemp Franz , Artee Luchman H 
Published: November 2024

Abstract
Glioblastoma (GBM) is resistant to many therapies including immunotherapies. There is an urgent need to explore the role of the microenvironment in resistance to therapy with tailored pre-clinical models. Using multi-omic approaches we describe a syngeneic cancer stem cell mouse model of GBM, with a spontaneous amplification of Igf2. We investigate whether Igf2 influences tumour and microenvironment cells to promote immunosuppression in GBM. Three cell lines were previously established from spontaneous brain tumours in C57Bl/6 Trp53+/-/Nf1+/- mice and maintained under neural stem cell culture conditions. Whole genome sequencing (WGS) was used to determine single nucleotide, copy number, and structural variation, revealing loss of both copies of Trp53 and Nf1 in all three cell lines. However only one cell line, mBT0309, developed tumors when orthotopically allografted. Analysis of genomic alterations and transcriptomics revealed that mBT309 exhibits amplification of the Igf2 loci and overexpression was confirmed at the RNA and protein level. Spatial and single cell transcriptomics showed that Igf2 is overexpressed in mBT0309 allografted tumours and correlated with specific transcriptomic programs. A high-parameter Imaging Mass Cytometry (IMCTM) panel was used for spatial proteomic analysis, to monitor the development of tumours in a time-course experiment. In vitro growth characteristics and stem marker expression in both transcriptomic and spatial IMC data suggest that high levels of Igf2 may regulate GBM stemness features. Analysis of human GBM datasets revealed that Igf2 amplified tumours have reduced CXCL11 expression. These findings suggest that high levels of Igf2 may influence immunosuppression by reducing T-cell recruitment. This syngeneic immunocompetent GBM stem cell model harbouring Igf2 amplification adds to the suite of models to study the GBM microenvironment and its role in immunosuppression and resistance to therapy.
IMMU-40. INVESTIGATING THE ROLE OF MUTATIONAL BURDEN IN TUMOR IMMUNOGENICITY USING A PRE-CLINICALMLH1-DEFICIENT GLIOBLASTOMA MODEL
Authors: Haynes Tuesday , Breen Kevin , Zhang Meili , Song Hua , Davis Dionne , Briceno Nicole , Wong Zalman , Li Aiguo , Watanabe Masashi , Gilbert Mark 
Published: November 2024

Abstract

BACKGROUND
Although there is an established correlation between tumor mutational burden (TMB) and response to immune checkpoint inhibition (ICI) in many cancers, such an association has not been definitively shown in high-grade gliomas. Most studies of ICI therapy in gliomas, including glioblastoma (GBM), have failed to demonstrate efficacy, with the exception of hypermutated cases resulting from rare inherited defects in mismatch repair (MMR) genes. We sought to investigate the association of TMB to immune response using a syngeneic murine model with a spectrum of mutational burdens.

METHODS
We used CRISPR-Cas9 to knockout the MMR gene Mlh1 in the murine glioma model SB28, an ICI-resistant cell line with a very low mutational burden (108 non-synonymous mutations).

RESULTS
Single-cell sorted Mlh1 knockout SB28 clones revealed a two- to six-fold increase in TMB. Importantly, loss of Mlh1 also brought about global changes in immune- and inflammatory-related gene expression in vitro, without correlation to increasing TMB. While all clones had the same rate of in vitro proliferation, flank injection of a high TMB vs a low TMB SB28 Mlh1 knockout clone resulted in similar survival benefits compared to Mlh1 wildtype SB28.

CONCLUSIONS
These preliminary results suggest that, although disruption of the MMR system may result in heightened tumor immunogenicity, elevated TMB may not be the sole significant determinant. We are currently investigating tumor proliferation after flank injection in immunocompromised mice to confirm that slowed growth is immune-related, as well as clone-specific response to ICI treatment. We are also exploring the role of specific cytokines/chemokines in conferring this survival advantage and potential immune response. By generating a GBM model of varied mutational burdens and immune profiles and comparing to the baseline SB28 cell line, we can interrogate the relative significance of TMB in tumor immunogenicity and ICI response.
IMMU-44. EXTRINSIC ELECTRICAL MODULATION OF THE GLIOBLASTOMA TUMOR MICROENVIRONMENT
Authors: Castro Fernandes Gil Nuno , Palacin-Aliana Irina , Dussold Corey M , Tripathi Shashwat , Lesniak Maciej S , Heimberger Amy B , Sita Timothy L 
Published: November 2024

Abstract

BACKGROUND
Approximately 30 to 50% of patients with glioblastoma (GBM) present with glioma-related epilepsy (GRE). Despite morbidity associated with seizures, GRE constitutes an independent positive predictive predictor for survival in GBM. Our prior results showed that repeated seizure induction through extrinsic electrical modulation (EEM, a technique in which an electrical stimulus sufficient to produce a therapeutic seizure is applied) slows intracranial tumor growth and prolongs overall survival in immunocompetent CT-2A glioma-bearing mice. However, the overall survival advantage following EEM treatment was diminished in immunocompromised mice bearing human patient derived xenografts. We hypothesized that EEM induces immune-related tumor microenvironment (TME) changes that prolong survival in mice.

METHODS
C57BL/6J mice were orthotopically implanted with CT-2A xenografts and subjected to EEM of 2.0 millicoulombs or sham treatment. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed at 3 and 24 hours to determine mRNA level of inflammatory cytokines. Immunohistochemistry (IHC) and bulk RNA sequencing analysis were utilized to assess CD3+ T-cell infiltration and identify immune-related secreted genes, respectively. Flow cytometry at 3 and 96 hours was utilized to characterize tumor-infiltrating immune cell populations. Samples were subjected to Percoll gradient enrichment of immune cell populations and stained for extracellular (CD45, CD4, CD8, CD11b, F4/80, CD80, Ly6G, Ly6C, and CX3CR1) and intracellular (TNF-a, Il-1b, CCL2, and Arg1) antigens.

RESULTS
RT-qPCR showed an increase in pro-inflammatory cytokines TNF-α (P = 0.0087) and IL-1β (P = 0.000349). IHC analysis demonstrated an increase in intratumoral CD3+ T-cells in EEM-treated samples (P = 0.0171). From 1855 upregulated genes, 3 immune-related secreted genes (C1QTNF4, FAM19A4, and GREM2) were identified. Flow cytometric analysis showed a significant increase in CD11b+, CX3RC1+ microglia (P = 0.0306) and CD45+, CD11b+ tumor-associated myeloid cells (TAMCs) (P = 0.0192) at 3 hours post-EEM.

CONCLUSIONS
EEM treatment promotes an inflammatory TME with increased intratumoral microglia, TAMCs and T-cell infiltration. These inflammatory changes may prolong survival of CT-2A glioma-bearing mice.
IMMU-60. MYELOID POPULATIONS MODULATE GD2 CAR T CELL ACTIVITY IN DIFFUSE MIDLINE GLIOMA
Authors: Ramakrishna Sneha , Geraghty Anna , Good Zinaida , Desai Moksha , Mancusi Rebecca , Mahdi Jasia , Song Kun Wei , Ehlinger Zachary , Chen Yiyun , Hamilton Mark , Rietberg Skyler , Majzner Robbie , Schultz Liora , Richards Becky , Kamens Jennifer , Barsan Vali , Campen Cynthia , Partap Sonia , Moon Jennifer , Baggott Christina , Kunick Michael , Fujimoto Michelle , Li Amy , Jariwala Sneha , Mavroukakis Sharon , Egeler Emily , Jacobs Ashley , Erickson Courtney , Prabhu Snehit , Davis Kara , Feldman Steven , Sahaf Bita , Mackall Crystal , Monje Michelle 
Published: November 2024

Abstract
H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal cancers in children and young adults. Our team previously demonstrated efficacy of GD2-targeting chimeric antigen receptor T cells (GD2-CAR T-cells) in preclinical models of DMG of the pons (also called diffuse intrinsic pontine glioma (DIPG) and DMG of the spinal cord, and opened a Phase I clinical trial (NCT04196413) treating patients with first intravenous (IV) followed by repeated infusions of intracerebroventricular (ICV) GD2-CAR T-cells. We employed high-dimensional analyses to define immune states contributing to CAR-T activity in patients. Single cell RNA-sequencing (scRNAseq) was conducted on 555,406 single cells from 115 cerebrospinal fluid (CSF) samples of 13 patients before and after CAR-T treatment. This is the largest CSF CAR-T dataset in central nervous system (CNS) tumors and provides insights into the immune biology surrounding CAR-T treatment for CNS malignancies. Patient CSF samples were dominated by T cell and myeloid populations. After CAR-T infusion, patient CSF exhibited an increased fraction of regulatory T cells and myeloid populations from baseline. Myeloid cells in early timepoints after ICV administration demonstrated a unique pro-inflammatory signature, while CSF samples from IV and late ICV timepoints exhibited a suppressive signature. To further explore the immune biology of these myeloid contributors, we developed a patient-derived xenograft model of DMG relapse following low-dose ICV GD2 CAR-T treatment. Using a pharmacological CSF1R-inhibitor, we demonstrate that depletion of microglia/myeloid cells at a specific window following CAR-T administration enhances durability of tumor control. Together, these data display the power of in-depth correlative analyses to identify distinct immune populations that drive durability of response. Key findings from these data will allow for optimization of CAR-T therapies for H3K27M+ DMG patients, providing hope to shift the paradigm of this fatal disease.