bluuebunny/crossref_metadata_2025 huggingface dataset:
EPCO-27. REVEALING TUMOR HETEROGENEITY AND IMMUNE MICROENVIRONMENT IN NF-1 GLIOMA BY SINGLE-CELL GENE EXPRESSION PROFILING
Authors: D'Angelo Fulvio , Garofano Luciano , Oh Young Taek , Najac Ryan , Ceccarelli Michele , Eoli Marica , Sanson Marc , Lasorella Anna , Iavarone Antonio
Published: November 2022

Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1), the most common human genetic cancer predisposition syndrome. NF1 patients are prone to develop peripheral and central nervous system tumors, with glioma occurring in 15-20% of patients. The molecular profiles of glioma from patients with NF-1 have been previously explored by large scale DNA and RNA bulk analyses, providing the first comprehensive genetic landscape of NF-1 glioma. However, the intra-tumoral architecture and the microenvironment organization remained largely concealed within the global bulk profile. Here, to characterize the complexity of molecular states of both malignant and non-malignant cells, we profiled NF-1 glioma gene expression at individual cell resolution. We performed single-nuclei RNA sequencing (Nucseq) on frozen NF-1 glioma specimens, including high-grade and low-grade tumors. The functional classification of the transcriptional programs activated in the individual tumor cells identified three main molecular states that partially overlapped with the cellular subtypes of sporadic glioblastoma. Tumor cells of low-grade NF-1 glioma exhibited marked enrichment of neuronal functions, suggesting that the gliomagenesis process in the context of NF1 inactivation might be supported by specialized neuronal activities. Conversely, the proliferative state characterized high-grade NF-1 glioma, indicating that cell cycle-associated pathways are drivers of tumor progression. The single-cell deconvolution of immune microenvironment in NF-1 low grade glioma revealed infiltration of CD8+ T lymphocytes and the active crosstalk of these cells with pro-inflammatory macrophages and mature dendritic cells, supporting a possible anti-tumor cell-mediated response. The identification of divergent tumor cell states as well as the characterization of the immune infiltrates provide new insights for accurate stratification of NF-1 glioma patients and to inform personalized therapeutics.
EPCO-29. KLF5 IS REQUIRED FOR THE SEX-DIFFERENCES ACROSS MULTIPLE TUMORIGENIC PHENOTYPES IN PEDIATRIC GLIOBLASTOMA (GBM)
Authors: Abou-Antoun Tamara , Rubin Joshua , Mitra Rob , Kfoury Najla , Chen Xuhua , Warrington Nicole , Reiss India
Published: November 2022

High-grade glioblastoma (GBM) is a highly heterogeneous, malignant cancer with no cure to date. A sex-biased incidence and therapeutic response is reported (1) for GBM with a male to female incidence ratio of 1.6:1 and female patients having a 4-6 month survival advantage (2) compared to male patients. In our current work, we sought to determine the molecular basis for the sex-bias in incidence and therapeutic response using an isogenic murine model of GBM with dual loss of neurofibromin 1 (NF1) and P53 (DNP53) in astrocytes. Our model yielded GBM from the murine astrocytes in a sex-biased manner, with male GBM cells exhibiting a highly significant proliferative, migratory, in-vivo tumorigenicity, stem-cell enrichment rate and therapeutic resistance compared to female GBM cells. Using transposon calling cards, we mapped Brd4 enhancer usage across the genome in male, compared to female GBM cells and identified key transcription factors that differentially enriched at male-biased, compared to female-biased Brd4 bound enhancers. Interestingly, female-biased Brd4-bound enhancers were enriched for transcription factors with tumor suppressor roles including P53 and SMAD4, whereas male-biased Brd4-bound enhancers were enriched for transcription factors with oncogenic roles, including Oct4, MYC and KLF5. Genetic or chemical silencing of KLF5 reduced the tumorigenic potential in male GBM with rates of cellular proliferation, survival, migration and stem-cell frequency significantly reduced to levels that resemble female GBM. Using transposon calling cards, we mapped KLF5 genomic localization in male and female GBM cells and identified significant peaks that affiliated with differentially expressed genes between the sexes. Interestingly, genes induced by KLF5 in the male cells were affiliated with poor survival in patients with various cancers, whereas those induced by KLF5 in the female cells were affiliated with favorable prognosis. This signifies the need to explore molecular mechanisms by which KLF5 drives these sex differences in GBM.
EPCO-30. IDENTIFICATION OF PRECANCEROUS CELLS LEADING TO INTRATUMORAL HETEROGENEITY IN GLIOBLASTOMA
Authors: Kim Hyun Jung , Cha Do Hyeon , Kim Keon Woo , Kim Myeong Heui , Park Jung Won , Kim Ja Hye , Yoon Seon Jin , Kang Seok-Gu , Lee Jeong Ho
Published: November 2022

Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. Although multiple oncogenic mutations have been identified in neural stem cells of the subventricular zone (SVZ) in humans, the dynamic process of how tumor initiation begins with a mutation-harboring stem cells remains elusive. To better understand how GBM evolves, we analyzed longitudinal transcriptomic changes of mutation-harboring stem cells using a spontaneous, somatic GBM animal model with EGFRvIII, TP53, PTEN mutations. Using single-cell RNA sequencing, we have identified precancerous cell populations originating from oligodendrocyte precursor cells, with increased proliferation and decreased capacity to differentiate into oligodendrocytes. The precancerous cell populations undergo malignant transformation to become heterogeneous cancer cells characterized by immune evasion, mesenchymal transition, and cell cycle. We further identified the precancerous populations in the SVZ of human GBM patients with chromosomal aberrations. Our findings suggest that GBM evolution is closely related to oligodendrocyte precursor cell specification, and the time-dependent transcriptomic changes in precancerous cells is a novel therapeutic target for tumor evolution.
EPCO-33. DIFFERENTIAL EXPRESSION OF AN ENDOGENOUS RETROVIRAL ELEMENT [HERV-K(HML-6)] IS ASSOCIATED WITH REDUCED SURVIVAL IN GLIOBLASTOMA PATIENTS
Authors: Shah Ashish , Govindarajan Vaidya , Doucet-O'Hare Tara , Rivas Sarah , Ampie Leo , DeMarino Catherine , Banasavadi-Siddegowda Yeshavanath , Zhang Yong , Johnson Kory , Almsned Fahad , Gilbert Mark , Heiss John , Nath Avindra
Published: November 2022

INTRODUCTION

Comprising approximately 8% of our genome, Human Endogenous RetroViruses (HERVs) represent a class of germline retroviral infections that are regulated through epigenetic modifications. In cancer cells, which often have epigenetic dysregulation, HERVs have been implicated as potential oncogenic drivers. However, their role in gliomas is not known.Given the link between HERV expression in cancer cell lines and the distinct epigenetic dysregulation in gliomas, we utilized a tailored bioinformatic pipeline to characterize and validate the glioma retrotranscriptome and correlate HERV expression with locus-specific epigenetic modifications.Method:A custom workflow was used to quantify HERV expression in our cell lines of interest. Cell-line methylation was quantified using a custom script. We generated primers specific for the Human endogenous Mouse mammary tumor (MMTV)-Like virus 6 (HML-6). Visualization of RNA transcripts was performed using RNA-scope. Clinical data was obtained using the R package, TCGABiolinks.

RESULTS

The A172 cell line had significantly higher mean overall HERV expression relative to the M059J and H4 cell lines (p< 0.0001 for both). A172 cells had significantly lower mean number of CpG islands relative to M059J cells and H4 cells (p< 0.0001 for both). There was a significant inverse correlation between mean beta value and FC HERV expression (R=-0.57, p=0.01). qPCR confirmed robust expression of the HML-6 locus in cell culture and neurospheres. Elevated ERVK3-1 expression was associated reduced survival among IDHwt GBM patients (18.3 vs. 15.1 months, p=0.039). This was preserved among IDH mutant (IDHm) GBM as well (17.9 months vs. 14.0 months, p=0.0088).

CONCLUSION

In gliomas, HERV expression correlates with loss of DNA methylation at HERV loci. HML-6 is overexpressed in highly invasive glioblastoma cell lines and patient-derived neurospheres. We have demonstrated a potential survival detriment associated with elevated expression of the HML-6 product, ERVK3-1.
EPCO-39. ADAPTIVE CONVERGENCE OF METHYLOMES REVEALS EPIGENETIC DRIVERS AND BOOSTERS OF REPEATED RELAPSES IN PATIENT-MATCHED CHILDHOOD EPENDYMOMAS AND IDENTIFIES TARGETS FOR ANTI-RECURRENCE THERAPIES
Authors: Zhao Sibo , Li Jia Li , Zhang Huiyuan , Qi Lin , Du Yuchen , Kogiso Mari , Braun Frank K , Teo Wan-Yee , Lindsay Holly , Baxter Patricia A , Su Jack M , Adesina Adekunle , Xiao Sophie , Stephan Clifford , Goldman Stewart G , Davies Peter J A , Man Tsz-Kwong , Huang Yun , Song Yongcheng , Sun Deqiang , Li Xiao-Nan
Published: November 2022

Ependymoma (EPN) is the third most common brain tumor in children and frequently recurs. Here, we report an integrated longitudinal analysis of epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses obtained from 10 pediatric patients to understand the mechanism of recurrences. Genome-wide DNA methylation analysis revealed stable molecular subtypes and convergent epigenetic reprogramming during serial relapses of the 5 RELA and 5 PFA EPNs that paralleled with elevated patient-derived orthotopic xenograft (PDOX) (13/27) formation in the late relapses. Differentially methylated CpGs (DMCs) preexisted in the primary tumors and persisted in the relapses (driver DMCs) were detected, ranging from 51 hypo-methylated in RELA to 148 hyper-methylated DMCs in PFA tumors; while newly acquired DMCs sustained in all the relapses but was absent in the primary tumors (booster DMCs) ranged from 38- 323 hyper-methylated DMCs in RELA and PFA EPNs, respectively. Integrated analysis of these DMC associated DNA methylation regions (DMRs) and RNAseq in both patient and PDOX tumors identified a small fraction of the differentially expressed genes (4.6±4.4% in RELA and 4.5±1.1% in PFA) as regulated by driver DMRs (e.g., up-regulated CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and booster DMRs (including the sole upregulated PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). Most these genes were novel to EPN relapses. Seven DMCs in RELA and 22 in PFA tumors were also identified as potential relapse predictors. Finally, integrating DNA methylation with histone modification identified LSD1 as a relapse driver gene. Combined treatment of a novel inhibitor SYC-836 with radiation significantly prolonged survival times in two PDOX models of recurrent PFA. This high-resolution epigenetic and genetic roadmap of EPN relapse and our 13 new PDOX models should significantly facilitate biological and preclinical studies of pediatric EPN recurrences.
EPCO-40. INFRATENTORIAL NF2 MUTANT SPORADIC MENINGIOMAS DIFFER FROM THOSE IN SUPRATENTORIAL LOCATIONS AND ARE MORE BENIGN
Authors: Vasandani Sagar , Vetsa Shaurey , Jalal Muhammad , Yalcin Kanat , Marianayagam Neelan , Nadar Arushii , Jin Lan , Fulbright Robert , Erson-Omay E Zeynep , Günel Murat , Moliterno Jennifer
Published: November 2022

INTRODUCTION

Approximately 50% of sporadic meningiomas, which originate throughout the neuroaxis, harbor bi-alleic NF2 loss. We sought to determine whether NF2 mutant meningiomas originating from different intracranial locations relative to the tentorium differ with regards to their genomic profile and clinical behavior.

METHODS

Clinical and whole exome sequencing data (WES) for all patients who underwent resection of NF2 mutant meningiomas and consented to WES were reviewed and analyzed.

RESULTS

258 NF2 mutant meningiomas were included and subdivided into supra- (sNF2) versus infra-tentorial (iNF2) groups (230 versus 28, respectively). Supratentorial location was significantly associated with genomically unstable tumors (percent genome altered median 12% vs. 1%, p< 0.001) and were more likely to harbor the more aggressive feature of chromosome 1p deletion (31.4% vs. 8.3%, p= 0.036). These malignant genomic features correlated with an increased incidence of high risk clinical features, including higher-grade (i.e. WHO Grade II/III) (48.9% vs. 7.14%, p < 0.001) and elevated Ki-67 (58.9% vs. 16.6%, p< 0.01), as well as larger volume (median 26.21 cm3 vs. 9.84 cm3, p< 0.001) and edema (65.8% vs. 25.9%, p= 0.001) in sNF2 meningiomas as compared with iNF2 tumors, respectively. Not surprisingly, although there was no difference in extent of resection between the groups (gross total resection (GTR), 96.26% vs. 96.15%, p= 0.45), patients with sNF2 tumors had more associated deaths (14.6% vs. 0%, p= 0.03) and a marginally shorter overall survival (p= 0.061). GTR was associated with longer progression-free survival (p= 0.037).

CONCLUSION

Within the homogeneous group of somatic NF2 mutated meningiomas, infratentorial tumors are seemingly more benign in their genomic make-up and clinical manifestation as compared to ones located in the supratentorial location. While GTR is useful to both groups in preventing recurrence, this benefit may be especially important in the clinically and genomically higher risk sNF2 tumors.
EPCO-44. HOXD13 GENE PLAYS A ROLE AS A PUTATIVE MASTER EPIGENETIC REGULATOR IN GLIOMA RECURRENCE AND PROGRESSION
Authors: Morosini Natalia , Sabedot Thais , Cazacu Simona , de Carvalho Ana , Iavarone Antonio , Noushmehr Houtan
Published: November 2022

BACKGROUND

Adult diffuse glioma is a heterogenous brain tumor group that has malignant potential and recurring properties. Glioma CpG island methylator phenotype (G-CIMP) associated with chromatin remodeling encompasses two different methylation degrees: G-CIMP-high and G-CIMP-low that have high levels of DNA methylation and loss of DNA methylation, respectively. G-CIMP-high confers a more favorable prognosis and better predictive values by altering transcriptional dynamics and the gene expression.

METHODS

We have performed Chromatin Immunoprecipitation Sequencing (ChIP-Seq) on DNA extracted from fresh frozen primary tumor tissues (G-CIMP-high and G-CIMP-low). We have processed the sequencing data by using FastQC (v.:0.11.5), bwa-mem (v.:0.7.15) and picard tool (v.:2.7.1). The ChIP-seq peaks and the differentially bound peaks were obtained using MACS2 (v.:2.1.1) and DiffBind (v.:3.4.11), respectively. We have also integrated transcriptomic, epigenomic and genomic data.

RESULTS

Initial results showed that the differentially bound H3K27ac and H3K4me3 peak gains and losses are located mainly in intronic and intergenic regions. The integration between epigenetic and transcriptomic data revealed that the promoter of the HOXD13 gene upregulated in GCIMP-low presents an active regulatory region and is enriched by H3K27ac and H3K4me3 sites. We were able to identify that GCIMP-low, in addition to presenting more downregulated genes than GCIMP-high, also has greater affinity to the H3K27ac peaks. In GCIMP-low, we identified that regions enriched by H3K27ac are highly associated with the presence H3K4me3 marks.

CONCLUSION

We mapped the enrichment of histone modifications in the TSS of differentially expressed genes in G-CIMP-high and G-CIMP-low identifying both the susceptibility of GIMP-low to interact with H3K27ac and the fact that the progression of GCIMP-high to G-CIMP-low can be explained by the association between H3K27ac gain and gene downregulation. Also, we predicted the HOXD13 gene as a putative master epigenetic regulator of the G-CIMP demethylation process and, consequently, of tumor recurrence and progression, over time.
EPCO-45. EXTRACHROMOSOMAL DNA PROMOTES ONCOGENE AMPLIFICATION ACROSS MULTIPLE PEDIATRIC CANCER TYPES
Authors: Sridhar Sunita , Chapman Owen , Dutta Aditi , Wang Shanqing , Chavez Lukas
Published: November 2022

Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive cancers. Its frequency and impact on pediatric cancers has yet to be fully described. To determine the ecDNA prevalence in various pediatric cancer types, we accessed whole genome sequencing (WGS) data in the Children’s Brain Tumor Network (CBTN) and St. Jude cancer cloud genomics platforms and utilized the bioinformatics tools Amplicon Architect (AA) and Amplicon Classifier (AC) to reconstruct ecDNA sequence structures. We then identified which genes were amplified on the ecDNA and how ecDNA correlated with survival, using Kaplan Meier curves. Different cancer types were noted to have varying prevalence of ecDNA with the highest detection in pediatric high-grade gliomas (30% of cases). In analyzing matched diagnostic/relapse and relapse/progression pairs, ecDNA was noted to evolve over time with progression of disease. Our preliminary results demonstrate that ecDNA is prevalent in pediatric cancer, can contain known and potential novel oncogenes and can be associated with poorer outcomes across many different pediatric cancer types.
EPCO-46. EPIGENETIC STEMNESS PREDICTION ACROSS CENTRAL NERVOUS SYSTEM TUMORS MOLECULAR SUBTYPES
Authors: Malta Tathiane , Simões Renan , Marção Maycon
Published: November 2022

Tumor progression and therapeutic resistance in cancer have been strongly associated with stemness. Rather than focus on a discrete subpopulation for stemness and tumor maintenance, we might explore stemness as a continuous variable through machine learning algorithms. We chose One Class Logistic Regression algorithm to define an epigenetic signature to assess stemness in brain tumors using induced Neural Stem Cell (iNSC) through public DNA methylation data. In order to keep DNA methylation features most related to iNSC, we perform Wilcoxon test between 9 iNSC and 128 non-tumor brain tissue (methylation difference |0.3|, FDR < 0.01) and mapped the resultant features to genome regions. Our model revealed a positive correlation (r2 = 0.86 p < 0.001) with the pluripotent model from Malta et al. (2018) applied on TCGA gliomas. More remarkable, the iNSC model stratified IDHwt glioma survival by the median of stemness both on TCGA and GLASS cohorts (TCGA: p < 0.001, GLASS: p = 0.086; Likelihood ratio test). Having shown its potential, we next applied the iNSC model in other Central Nervous System (CNS) tumors using cohorts studied by Capper et al. (2016). The iNSC model stratified distinct DNA methylation-based subtypes, such as: i) ependymoma-RELA presented a very distinct and lowest stemness among all ependymal subtypes; ii) low stemness in lymphoma and high stemness in plasmacytoma; iii) low stemness pituitary-ACTH and high stemness pituitary-STH-DNS-B. Interestingly, gliomas IDHmutant have the lowest stemness. Additionally, among putative new entities identified by Capper, our iNSC model stratified high-grade-neuroepithelial-BCOR with the lowest stemness among embryonal tumors and infantile-hemispheric-glioma, high-grade-neuroepithelial-MN1, and anaplastic-pilocytic-astrocytoma showing differences among each other in “Other glioma” group. Our results indicate prognosis prediction for gliomas and recapitulate CNS tumors subgroups, which might suggest the iNSC model as a surrogate strategy to explore the stemness in brain tumors from an epigenetic perspective.
EPCO-48. STEMNESS SIGNATURE STRATIFIES GLIOMAS WITH CLINICAL IMPORTANCE AND REVEALS A PROLIFERATIVE PHENOTYPE IN SINGLE CELL DATA
Authors: Simões Renan , Marção Maycon , Malta Tathiane
Published: November 2022

Gliomas are the most common central nervous system neoplasm and despite the past significant progress, its diagnostics faces suboptimal classification which impacts patient management. The stem cell-like phenotype of various cancers is correlated with the worst overall prognosis. We propose a Stemness prediction model based on gene expression signatures of neural progenitors that can be used to measure the dedifferentiation state (or Stemness) of glioma samples. To built the model, publicly available single-cell RNA sequencing data was used to identify gene expression from the fetal astrocyte (AST) population. Subpopulations of interest were identified through the expression of marker genes. We applied a one-class logistic regression to built the prediction model using the AST population. The model was applied to glioma bulk transcriptomic data to generate an fetal astrocyte stemness index (ASTsi). The ASTsi was able to stratify gliomas based on grade, histology, and molecular subtypes. Grade 4, glioblastoma, IDHwt, and the mitochondrial and proliferative functional subtypes had the highest stemness. When applied to longitudinal samples we observed an increase of ASTsi in IDHmut recurrent and a decrease in IDHwt recurrent tumors, compared to primary samples. Additionally, we applied the model to single-cell RNAseq of adult IDHwt glioblastomas and found clusters of high-stemness cells (ASTsi > 0.8). A differential gene expression combined with pathway analysis between high- and low-stemness cells revealed cell cycle, DNA repair mechanisms and histone modifications upregulated in the high-stemness population. The balance between histone methylation and demethylation may be directly related to the phenotype of these cells. More in-depth analysis of these genes and pathways are being carried out and may provide important information about the oncogenesis and phenotypic characterization of glioma stemness. Our stemness prediction model stratified glioma samples by pathological and molecular features and revealed tumor subpopulations with distinct stemness degree in gliomas IDHwt.
DISP-01. IMMUNOTHERAPY ADMINISTRATION RATES IN PATIENTS WITH BRAIN METASTASES: IMPACT OF END STAGE RENAL DISEASE AND DIALYSIS
Authors: Baroz Angel , Bhanja Debarati , Stahl Caleb , Wilding Hannah , Mansouri Alireza
Published: November 2022

INTRODUCTION

Comorbid conditions such as end-stage renal disease (ESRD) are common in patients with a diagnosis of brain metastasis (BM). Renal replacement therapy for ESRD patients typically includes hemodialysis or peritoneal dialysis. However, the efficacy of immunotherapy (IT) delivery in dialyzed patients is not well understood. Therefore, treatment modalities for BM and ESRD must be considered during clinical decision-making. This study aimed to determine the rate of IT administration in ESRD patients on dialysis using a network of real-world data.

METHODS

Data were collected from TriNetX (TriNetX, Inc., Cambridge, MA), a research network that provides clinical data access from 92 healthcare organizations globally. The independent variables included ‘secondary malignant neoplasm of brain’, ‘introduction of antineoplastic, monoclonal antibody’, ‘pembrolizumab’, ‘nivolumab’, ‘ipilimumab’, ‘ESRD’, ‘dependence on renal dialysis’ and ‘dialysis services and procedures’. Dialyzed patients were identified as having received dialysis within 3 months before to 5 years after their brain metastases diagnoses. Rates of immunotherapy administration were measured from BM diagnosis and concomitant dialysis use, or the lack thereof.

RESULTS

Two patient cohorts with malignant neoplasms of the brain were identified: a dialyzed cohort of 3,593 patients and a non-dialyzed cohort of 525,831 patients. The dialyzed cohorts’ mean age at index was 64.7 years; 43% were female. Of those, 81 patients received concomitant IT (2.25%). The non-dialyzed cohorts’ mean age at index was 60.7 years; 52% were female. From this cohort, 19,347 patients with BM received IT (3.68%). Patients with BM on dialysis were less likely to receive IT than those not on dialysis (odds ratio: 0.604, 95% confidence interval: 0.484-0.753, P < 0.0001).

CONCLUSION

Patients on dialysis may be selected against as candidates for IT. Given the relative scarcity of patient size and the potential implications of dialysis, prospective studies will be vital to improving IT efficacy in patients with BM.
DISP-02. CENTRAL NERVOUS SYSTEM METASTASES FROM EXOCRINE GLANDS CARCINOMA: CASE MANAGEMENT IN LOW RESOURCE SETTING AND REVIEW OF LITERATURE
Authors: Golidtum Jared Paul , Navarro Joseph Erroll , Seng Kenny , Alcazaren Jose Carlos , Ferraris Kevin Paul
Published: November 2022

INTRODUCTION

Head and neck exocrine gland tumors metastases to central nervous system (CNS) account for less than 1% with median survival of less than 6 months. Unlike brain metastases from lung, breast, melanoma, and colon, there is no established consensus or published clinical guidelines in the management from excorine glands. Filipino patients are manage individually but experienced delays due to limited access to a tertiary level health care and with scarcity of treatment protocols. Methods and

RESULTS

We present two cases with exocrine glands carcinoma with CNS metastases. First case is a 51/F with a known case of left parotid cystic adenocarcinoma s/p parotidectomy and radiation therapy 2 years prior to the development of neurological deficits and COVID-19 infection, neuroimaging noted extra-axial 7.5 x 5 x 4.5 cm contrast enhancing tumor at bilateral frontal convexity. She underwent bifrontal craniotomy, gross total excision of tumor and anterior sagittal sinus, histopathology results cystic adenocarcinoma. She was discharged GOS 2, planned for chemoradiotherapy but lost to follow up and expired after 2 months post op. Second case is a 28/M known case of lacrimal gland pleomorphic adenocarcinoma OD s/p excision biopsy 2 years prior to the development of multiple right frontal lobe, right orbital wall and right pterion metastases. He underwent gross excision of extracranial and intracranial tumors and a right orbital exenteration. He was discharged GOS 2 and underwent chemoradiation as outpatient with good tumor control and no tumor recurrence after 1 year of treatment.

DISCUSSION

CNS metastases from exocrine glands are rare and difficult to manage since no approved protocol was established. Patients in low resource setting were then manage on individual basis since molecular and genomic studies are not available. The delays in the management are multifactorial such as geographic disadvantages, COVID-19 pandemic, and government's inadequate support for health system.
DISP-05. SOCIAL DETERMINANTS OF HEALTH AND INPATIENT SPINE TUMOR OUTCOMES: A NATIONWIDE ANALYSIS OF DISPARITIES FROM 2002-2019
Authors: Tang Oliver , Ayala Cameron , Feler Joshua , Perla Krissia Rivera , Bajaj Ankush , Ganga Arjun , Fridley Jared , Toms Steven , Gokaslan Ziya , Sullivan Patricia Zadnik
Published: November 2022

BACKGROUND

Earlier research has demonstrated that social determinants of health (SDoH) impact neuro-oncology access and outcomes, influencing patient disparities. This study aimed to elucidate the association between SDoH and inpatient spine tumor outcomes.

METHODS

All admissions with a spine tumor diagnosis in the National Inpatient Sample from 2002-2019 were identified. Four SDoH were analyzed: race and ethnicity, insurance, household income, and safety-net hospital (SNH) treatment. Hospitals in the top quartile of safety-net burden (percentage of patients receiving Medicaid or uninsured) were categorized as SNHs. Multivariable regression queried the association between 22 variables (patient, hospital, tumor, and severity characteristics) and six inpatient outcomes: mortality, discharge disposition, complications, length of stay (LOS), and hospitalization costs. Relative importance of predictors for discharge disposition were assessed using random forest models.

RESULTS

Of 6,593,391 total admissions with spine tumors, 219,380 (3.3%) underwent surgical intervention. Non-white race (odds ratio [OR] = 0.80–0.91, P = 0.001) and non-private insurance (OR = 0.76–0.83, P = 0.001) were associated with lower odds of surgery. Among surgical admissions, presenting severity, including myelopathy and plegia, was elevated among nonwhite, non-private insurance, and low-income admissions (all P = 0.001). Black race (OR = 0.70, P = 0.001), Medicare (OR = 0.70, P = 0.001), Medicaid (OR = 0.90, P=0.001), and lower income (OR = 0.88–0.93, all P = 0.001) were associated with decreased odds of favorable discharge disposition. Elevated LOS and costs were observed among non-white (LOS: +6-10%, costs: +5-9%, both P = 0.001) and Medicaid (LOS: +16%, costs: +6%, both P = 0.001) admissions. SNH treatment was also associated with higher mortality (OR = 1.49, P = 0.001) and complications (OR = 1.20, P = 0.001). From 2002-2019, disposition improved annually for Medicaid patients (OR = 1.03 per year, P = 0.022) but worsened for Black patients (OR = 0.98 per year, P = 0.046). Random forest models identified household income as the most important disposition predictor.

CONCLUSION

For spine tumor admissions, SDoH predicted surgical intervention, presenting severity, and perioperative outcomes. Over two decades, disparities improved for Medicaid patients but worsened for Black patients.
DISP-10. A SYSTEMATIC REVIEW OF SEX DIFFERENCES OF INCIDENCE AND OVERALL SURVIVAL IN 15 NON-REPRODUCTIVE CANCERS
Authors: Dmukauskas Mantas , Waite Kristin , Livinski Alicia , Edelson Jacob , Cioffi Gino , Hunter Chyren , Brown Jalen , Jackson Sarah , Song Minkyo , Day Chi-Ping , Schaffer Alejandro , Barnholtz-Sloan Jill
Published: November 2022

Sex is an important factor that influences disease development, progression, and treatment. In multiple non-reproductive cancers, sex differences in incidence, progression, treatment response, survival, and other clinical outcomes are observed. Overall, males have a 20% higher chance of developing cancer over their lifetime, and experience worse clinical outcomes when compared with females. The NIH recognizes the importance of sex as a biologic variable and addressing sex as a biological variable is now required for all researchers submitting NIH grants. While more researchers are investigating the role of sex differences in cancer, a systematic review that examines the patterns of sex differences in incidence and survival across 15 non-reproductive cancers has not yet been published. We performed a systematic review by searching five databases using keywords and controlled vocabulary terms for each concept of interest and limited to English language. Records were included if it reported sex differences in human adults (18+), addressed incidence, mortality, or survival, at least one of the 15 cancers of interest, and were a cohort, cross-sectional, RCT, or case control study. Covidence was used for screening and two reviewers independently screened each record at title/abstract and then full text. Two reviewers independently completed data extraction using Microsoft Excel and the Cochrane RoB 2.0, and JBI tools were used for risk of bias assessment. The searches and pilot of the methods are underway. Understanding the role sex-differences play on incidence and survival are important for adding to our understanding of advances in diagnosis and treatment of individuals with cancer.
DISP-13. FEMALE MICE HAVE GREATER SUSTAINED ACTIVITY SUPPRESSION AND HYPERSOMNOLENCE AFTER RADIATION THERAPY: EXPLORATION OF SEX DIFFERENCES IN A MODEL OF CRANIAL-RADIATION-INDUCED HYPERSOMNOLENCE (C-RIH)
Authors: Adegbesan Kendra , Ardori Francesco Tomassoni , Yanpallewar Sudhirkumar , Bradley Sean , Chudasama Yogita , Briceno Nicole , King Amanda , Tessarollo Lino , Gilbert Mark , Smart DeeDee , Armstrong Terri , Shuboni-Mulligan Dorela
Published: November 2022

Female cancer patients have a better prognosis but more adverse events with chemotherapy; less is known with other cancer treatments like radiation therapy. Previous literature has demonstrated sex-dependent effects on the hippocampi and behavioral tasks within post-natal mice after radiotherapy. We explored the differences in activity and sleep in adult male and female mice within our previously established mouse model of cranial-irradiation-induced hypersomnolence (C-RIH). Ten mice of each sex (B6 x B6D2 backcrossed with C57/b6NCr) were observed for general activity and sleep continuously over 10 days before and after therapeutic irradiation (whole brain, 15Gy, single fraction). Behavioral assessments aimed at measuring anxiety (Light Dark Box, Elevated Zero Maze) and depression (Sucrose Preference Test) related behaviors, and working memory (Y Maze) were then used to assess any radiation-induced changes in mood or cognition. Independent samples t-tests compared male and female cohorts before and after radiation. At baseline, females had significantly higher peak activity (p < 0.001), as well as day (p < 0.001), and night (p = 0.004) activity. Females also showed less anxiety in the Elevated Zero Maze (p < 0.001) and Light-Dark Box (p = 0.012). In the Y-Maze, females had significantly more alternations (entry into each arm without repeat) (p = 0.004). Males and females consumed the same proportion of sucrose solution in respect to water (p = 0.124). After radiation, males and females showed a significant decrease in activity, with females displaying a higher suppression of night activity both 1-3 days (t(18) = 2.162, p = 0.045) and 7-9 days (t(18) = 2.266, p = 0.037). Female mice also showed increased night hypersomnolence at 1-3 days (t(18) = 4.474, < p = 0.001) and 7-9 days (t(18) = 2.920, p = 0.01). Further analysis is underway on post-radiation sex differences in sleep and activity. Here we used a mouse model of C-RIH to assess the behavioral outcomes between the sexes and found marked effects on sleep and activity.
DISP-14. DEFINING INTERVENTIONS AND METRICS TO IMPROVE DIVERSITY IN CNS CLINICAL TRIAL PARTICIPATION: A SNO AND RANO EFFORT
Authors: Budhu Joshua , Porter Alyx , Jackson Sadhana , Lee Eudocia , McFaline-Figueroa J Ricardo , Willmarth Nicole , Dalmage Mahalia , Kawachi Ichiro , Arons David , Chang Susan M , Wen Patrick Y , Hervey-Jumper Shawn L , Chukwueke Ugonma
Published: November 2022

Despite major strides in cancer research, care, and therapy, these advances have not been equitable across race and ethnicity. Groups underrepresented in medicine (URM) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black and Latino Americans represent 29% of the population but only reflect 8% of oncology clinical trial participants. Recent studies have shown that this disparity is also present in neuro-oncology as women, Black, and Latino Americans remain under-accrued in clinical trials. Brain tumor patients already face unique barriers to clinical trial enrollment and completion due to disease-specific conditions–such as impaired motor function, cognition, language deficits, and caregiver dependency–which pose additional difficulties in clinical trial consent, enrollment, and adherence. As part of this collaborative initiative, we evaluated the impact of how a lack of diversity in cancer research is detrimental to scientific discovery and propose interventions focused on improving URM engagement with clinical research. Recommendations include the creation of inclusive trial design at the onset, decreasing barriers to care, expanding trial eligibility, and equitable access to tumor profiling for personalized medical trials. Additionally, setting reasonable metrics and goals for accrual and engagement with patient and community stakeholders will ultimately help to diversify trial participants. Lastly, diversification and inclusion practices within the neuro-oncology workforce, including all personnel involved in clinical research, will help to minimize bias, promote concordant care, and assist with developing sustainable solutions. The diversification of participation in neuro-oncology clinical trials is imperative. The lack of diversity in clinical trials can contribute to improper generalizability of treatment efficacy, resulting in potentially harmful practices. Equitable access and inclusion of URM brain tumor patients will not only enhance research discoveries but will also result in improved patient care for all cancer patients.
IMMU-04. SINGLE-CELL RNA-SEQUENCING IDENTIFIES FUNCTIONAL MACROPHAGE SUBSETS THAT ARE ENRICHED IN RESPONSE TO DIFFERENTIAL PHAGOCYTOSIS INDUCTION AGAINST GLIOMA
Authors: Chetty Senthil Lakshmana , Riemondy Kent , Donson Andrew , Balaakrishnan Ilango , Venkataraman Sujatha , Vibhakar Rajeev , Foreman Nicholas , Mitra Siddhartha
Published: November 2022

Pediatric diffuse midline gliomas (DMGs), are fatal brain tumors of childhood arising in the ventral pons. Currently, radiation therapy (RT) is the mainstay treatment for DIPG. However, RT is not a curative treatment and provides only temporary relief for most patients. Recent advances in immunotherapy have yielded some fantastic opportunities to effectively treat patients with high-grade pediatric brain tumors. In this study, we demonstrate that fractionated RT (4Gy X 3) induces immunogenic cell death and activates multiple damage-associated molecular patterns (DAMPs) on DMG/DIPG cells. Furthermore, combining 4Gy X 3 with anti-CD47 therapy enhances the in vitro phagocytosis of DIPG/DMG cells by peripheral blood mononuclear cell-derived macrophages. Next, using single-cell RNA sequencing (scRNA-seq), we investigated the transcriptomic profile of macrophages that were co-cultured with irradiated or non-irradiated DMG cells in the presence of either phosphate-buffered solution (PBS) or anti-CD47 monoclonal antibody for 24 hours. Our findings identified eleven distinct macrophage clusters displaying different gene expression patterns in all the treatment conditions. However, PBS treatment led to a marked increase in macrophages expressing antigen-presentation genes (HLA-DR and HLA-DQB1). 4Gy X 3 treatment led to the enrichment of macrophages expressing genes related to the oxidative phosphorylation pathway, whereas anti-CD47 treatment led to the enrichment of macrophages expressing genes related to interferon-gamma response and ERK-signaling pathway. Lastly, mice intracranially transplanted with DMG/DIPG that received 4Gy X 3 and anti-CD47 therapy showed a significant decrease in tumor growth and an increase in survival rate than those receiving either monotherapy alone. We are currently performing scRNA-seq validation studies on tumors obtained from orthotopic and syngeneic models of DMG. In summary, our results highlight the functional heterogeneity of macrophages and suggest that combining fractionated RT with anti-CD47 therapy has potent anti-tumor effects and may be used as a novel therapeutic approach for treating Glioma patients.
IMMU-05. THE INFLUENCE OF THE KETOGENIC DIET ON THE IMMUNE TOLERANT MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Kesarwani Pravin , Zhao Yi , Kant Shiva , Miller C Ryan , Chinnaiyan Prakash
Published: November 2022

Glioblastoma (GBM) represents a particularly aggressive and immune-resistant cancer. Preclinical investigations have identified the anti-tumor activity of a ketogenic diet (KD) in GBM, potentially being used as a tool to target its glycolytic phenotype. Since immune cells in the tumor have a similar reliance upon nutrients to perform their individual functions, we sought to determine if the KD influenced the immune landscape of GBM. Utilizing genetically-engineered murine GBM tumor cells orthotopically implanted in immune-competent mice, we demonstrate that KD improved survival in GBM. Immunophenotyping of tumors identified a novel role KD plays in macrophage polarization, with a paradoxical 50% increase in immune-suppressive M2-macrophages and a decrease in pro-inflammatory M1-macrophages. We recapitulated KD in vitro using a modified cell culture based on comprehensive metabolomic profiling of serum in KD-fed mice. Consistent with in vivo studies, murine macrophages cultured in these conditions skewed polarization towards the M2-phenotype with immune-suppressive properties. We went on to mechanistically link these findings to the activation of transcription factor PPARg. Although anti-tumor activity was observed in mice fed a KD, we hypothesized this parallel increase in M2 macrophage polarization tempered its potential therapeutic benefit. Colony-stimulating factor 1 (CSF-1) plays a central role in macrophage differentiation, and CSF-1R inhibition is actively being investigated as a strategy to skew their polarization towards an M1-phenotype. Therefore, we tested a combination of KD with the brain-penetrant CSF-1R inhibitor BLZ945. Consistent with our hypothesis, this combination demonstrated a striking improvement in survival (p = 0.0004), with 50% of mice achieving long-term survival ( > 50 days). Correlative studies confirmed the capacity of BLZ945 to normalize KD-induced increases in M2s, and the combination induced an increase of anti-tumor iNOS+M1s. Combinatorial strategies using agents designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM.
IMMU-08. RAGE ABLATION ATTENUATES GLIOMA PROGRESSION AND ENHANCES TUMOR IMMUNE RESPONSES BY SUPPRESSING GALECTIN-3 EXPRESSION
Authors: Dayyani Mojtaba , Zhang Ian , Liu Shunan , Zhang Leying , Liang Rongrui , Fang Qinxiao , Zhao Jie , Ren Lyuzhi , Medina Eric , Filippov Aleksandr , Bonjoc Kimberley-Jane , Chaudhry Ammar , Bild Andrea , Badie Behnam
Published: November 2022

INTRODUCTION

Malignant gliomas consist of heterogenous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment (TME). Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth, invasion, and immune escape.

OBJECTIVE

We aimed to demonstrate that blockade of RAGE expression may tackle resistance pathways by inhibiting GBM progression, invasion, and immune evasion.

METHODS

We evaluated genetic ablation of RAGE on the tumorigenicity of two syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by immunohistochemistry, qPCR, ELISA, western blotting, NanoString, flow cytometry, and in vivo survival analysis.

RESULTS

Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition also enhanced tumor inflammatory responses by downregulating the expression of galectin-3, rendered the immunotherapy resistant K-Luc gliomas responsive to immune checkpoint blockade therapy, and significantly increased survival.

CONCLUSION

This study is the first to link RAGE expression with galactin-3 as an immune modulator in glioblastoma and revealed that the effect of glioma RAGE expression on TME was mediated through downregulation of Gal-3 and subsequent polarization of Tumor-associated macrophages. The therapeutic significance of RAGE downregulation was demonstrated by sensitizing a highly invasive and immune-resistant glioma model to immune checkpoint blockade and strongly supports the development of RAGE ablation as a complementary treatment strategy for malignant gliomas.
IMMU-12. ABERRANT EGFR SIGNALING IS ASSOCIATED WITH DIMINISHED CYTOTOXIC T-CELL INFILTRATION IN GLIOBLASTOMA PATIENTS
Authors: Pioso Marissa , Sun Lu , Bayley Nicholas , Anil Amanda , Lee Alexander , Nathanson David , Prins Robert
Published: November 2022

Glioblastoma (GBM) has not benefitted from recent advances in immunotherapy compared to other solid malignancies, which suggests that a deeper understanding of the immunobiology of GBM is necessary to develop better therapeutic options. Both oncogenic signaling and evasion of immune destruction are hallmarks of cancer, contributing to tumor growth and reduced survival, respectively. Despite recent evidence in non-CNS malignancies demonstrating the importance of aberrant oncogenic signaling on shaping the tumor immune microenvironment, the impact of aberrant epidermal growth factor (EGFR) signaling – genetically altered in 60% of GBM patients - on the tumor immune microenvironment is not well characterized in GBM. To evaluate the importance of altered EGFR signaling in GBM patient samples, we performed single-cell transcriptomic analysis of primary tumor infiltrating leukocytes (TILs) from twenty-five patients which revealed aberrant EGFR signaling is associated with a unique tumor immune microenvironment in both primary and recurrent disease. Specifically, in the primary disease setting, higher infiltration of macrophages and dendritic cells, and significantly lower infiltration of T-regulatory cells was observed in EGFR altered patients compared to non-altered patients. In recurrent disease, EGFR alterations were associated with significantly diminished infiltration of activated and activated exhausted cytotoxic T-cells compared to unaltered disease. Intriguingly, differential gene expression analysis revealed that EGFR altered patients display significantly increased expression of interferon stimulated genes (ISGs) in both myeloid and lymphoid lineages, while analysis of the tumor compartment unexpectedly revealed greater expression of MHCI genes. Collectively, these data emphasize the impact of aberrant EGFR signaling on the tumor immune microenvironment composition and suggest further characterization of EGFR-immune crosstalk and mechanism is warranted in GBM.
IMMU-17. LEVERAGING CORE EPIGENETIC PROGRAMMING OF IMMUNOSUPPRESSIVE MYELOID CELLS FOR THERAPEUTIC TARGETING OF GLIOBLASTOMA
Authors: Bayik Defne , Bartels Cynthia , Lovrenert Katreya , Zhang Duo , Watson Dionysios , Kay Kristen , Lee Juyeun , Vogelbaum Michael , Fan Yi , Scacheri Peter , Lathia Justin
Published: November 2022

Accumulation of various immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), facilitates progression and treatment resistance of glioblastoma (GBM). We previous demonstrated that monocytic MDSCs (mMDSCs) but not granulocytic MDSCs (gMDSCs) infiltrate tumors in mouse models and patients, and that nonspecific targeting of mMDSCs with chemotherapies provided therapeutic benefit in preclinical models of GBM. To investigate the differential role and trafficking of mMDSCs versus gMDSCs in GBM, we adoptively transferred these cells into tumor-bearing mice. Mice that received mMDSCs succumbed to disease at an earlier point compared to control mice or mice that received gMDSCs. To delineate the cellular basis of this distinct behavior of MDSC subsets, we performed assay for transposase-accessible chromatin using sequencing (ATAC-seq) and observed that cell adhesion-related genes were significantly enriched in open chromatin regions of mMDSCs as opposed to gMDSCs. Aligned with this epigenetic profile, mMDSCs from blood and tumors had significantly higher surface integrin β1 expression compared to gMDSCs in both mouse models and GBM patients. To evaluate the functional role of these integrins, we pre-treated mMDSCs with anti-integrin β1 prior to adoptive transfer. Blockade of surface integrin β1 interfered with the pro-tumorigenic role of mMDSCs, as the survival span of mice receiving these cells was similar to that of vehicle controls. Further analysis of the ATAC-Seq data revealed that dipeptidyl peptidase-4 (Dpp4), an interacting partner of integrin β1, was more accessible in mMDSCs compared to gMDSC. Consistently, bone marrow-derived mMDSCs in mouse and tumor-infiltrating mMDSCs in GBM patients expressed high levels of Dpp4. Pharmacological inhibition of Dpp4 reduced chemotaxis of mMDSCs in vitro and extended survival duration of mice with tumors. The findings from this study have broad implications across cancer types to modulate immunosuppressive myeloid cells by leveraging these novel insights into their adhesion mechanisms.