bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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&lt; 0.0001 for both). A172 cells had significantly lower mean number of CpG islands relative to M059J cells and H4 cells (p&lt; 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

Abstract
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

Abstract

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&lt; 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 &lt; 0.001) and elevated Ki-67 (58.9% vs. 16.6%, p&lt; 0.01), as well as larger volume (median 26.21 cm3 vs. 9.84 cm3, p&lt; 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

Abstract

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

Abstract
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

Abstract
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 &lt; 0.01) and mapped the resultant features to genome regions. Our model revealed a positive correlation (r2 = 0.86 p &lt; 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 &lt; 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

Abstract
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 &gt; 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

Abstract

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 &lt; 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

Abstract

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

Abstract

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.