bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCO-31. THE GERMLINE POLYMORPHISM RS55705857 IS ASSOCIATED WITH A POOR SURVIVAL IN ASTROCYTOMA, IDH-MUTANT, GRADE 2
Authors: Drucker Kristen L , Kollmeyer Thomas M , Decker Paul A , Kosel Matthew L , Odukoya Lateef A , Sarkar Gobinda , Halder Chandralekha , De Lorenzo Silvana B , Burns Terry C , Giannini Caterina , Ida Cristiane M , Lachance Daniel H , Eckel-Passow Jeanette E , Jenkins Robert B 
Published: November 2024

Abstract
Histologic features, presence of CDKN2A/B homozygous deletion and methylation subtype are strong determinants of outcome and of therapy in IDH-mutant gliomas. We were interested in learning if there are additional markers of outcome in these tumors. To address this question, we assembled a cohort of 963 IDH-mutant gliomas with overall survival data (median follow-up alive 2.7 years, median follow-up deceased 3.9 years). Array-based copy number data, targeted NGS, germline genotyping data and Illumina EPIC array methylation data were available on 872, 226, 542, and 401 patients, respectively. Morphologic type (oligodendroglioma versus astrocytoma, grade (2/3 vs 4) and methylation subtype (A_IDH_LG vs A_IDH_HG) were all significantly associated with survival (p &lt;0.001). There was no significant difference in survival between grade 2 vs 3 IDH-mutant astrocytomas (p=0.53 adjusting for age and sex). However, subjects with the risk allele (G) for rs55705857 had a better overall survival than subjects with the non-risk allele (A) in IDH-mutant oligodendroglioma (AG/GG vs AA, median overall survival 21.6 vs 15.7 years, p=0.048 after adjusting for grade, age, and sex). Conversely, rs55705857 was associated with a markedly worse survival in grade 2 IDH-mutant astrocytomas (AG/GG vs AA, median overall survival 8.6 vs 19.6 years, p=0.007 after adjusting for age and sex). Despite similar sample sizes and number of deaths, there was no significant difference in overall survival by rs55705857 genotype in grade 3 or 4 IDH-mutant astrocytomas. Upon further functional analyses, TLX1 and GALNT17 were found to be differentially methylated in IDH1-mutant astrocytomas and oligodendrogliomas, respectively, when stratified by rs55705857 risk allele. This is the first observation of a germline characteristic (e.g. rs55705857) predicting survival in low-grade IDH-mutant astrocytoma. While this observation requires validation, it suggests that germline genotype may be practice changing and inform results of trials such as CATNON and CODEL.
EPCO-35. GENOMIC CHARACTERIZATION OF GROWTH HORMONE SECRETING PITUITARY ADENOMAS
Authors: Alanya Hasan , Yalcin Kanat , Hilton Brian , Gultekin Batur , Mishra-Gorur Ketu , McGuone Declan , Gunel Murat , Omay Sacit Bulent , Erson-Omay Zeynep 
Published: November 2024

Abstract

BACKGROUND
Pituitary adenomas (PAs) are the second most common brain tumors in adults with prevalence ranging from 80 to 100 per 100,000 individuals. Of these, 9% to 14% are growth hormone (GH)-secreting PAs. While recurrent somatic GNAS mutations are identified in approximately half of sporadic GH-secreting PAs, the remaining cases are not well-characterized. This study aims to expand the genomic profile of GH-secreting PAs and explore correlations between molecular and clinical features.

METHODS
Whole exome sequencing (WES) was performed on 19 tumors with matching blood samples from consenting patients, achieving mean coverages of 262.74X for tumor samples and 112.43X for blood samples. Somatic variants, including single nucleotide variants (SNVs), short insertions/deletions (INDELs), and copy number variations (CNVs), were identified, and analyzed using protocols established by our institution. Genomic instability was assessed by calculating the percentage of the genome displaying loss-of-heterozygosity (LOH). Clinical data were collected and analyzed to establish genomic correlations.

RESULTS
The cohort comprised 19 GH-secreting PAs, with a mean age of 46 years at surgery, and was predominantly female (78.9%). The cohort was enriched for macroadenomas, with a mean tumor size of 18.4 mm. WES revealed a mean somatic mutation count of 20.4 (range 7-79), with 47% of cases harboring recurrent GNAS mutations. The mean alteration by LOH across the cohort was 11.13% (range: 0-44.80%) and did not show a statistically significant difference between cases with GNAS mutations and GNAS-wildtype cases (7.71% vs. 14.21%, respectively). Chromosomes 3, 8, 16, 22q were frequently affected by CNV/LOH events.

CONCLUSION
Comprehensive genomic characterization, including assessment of genomic instability through CNV/LOH analysis, is critical for better understanding the pathogenesis of GH-secreting PAs. This study underscores the importance of detailed genomic profiling in larger cohorts for improving the diagnosis and management of these tumors.
EPCO-49. SEX-SPECIFIC CHROMATIN REMODELING DRIVES TUMORIGENESIS IN GLIOBLASTOMA
Authors: Halaoui Adham , Kfoury-Beaumont Najla , Beaumont Thomas 
Published: November 2024

Abstract
Glioblastoma (GBM) is the most prevalent primary malignant brain cancer and has higher incidence and lower survival in males compared to females. The SWI/SNF chromatin remodeling complexes, including canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), play a critical role in multiple cancers including gliomas. However, their role in gliomagenesis and progression remains largely unknown. We analyzed 18 human glioma specimens for BAF complex mRNA expression by CNS WHO grade and used these data to guide CRISPRi knockdown of BAF components in syngeneic murine male and female GBM astrocytes. BAF complex knockdown revealed marked sex-specific differences in proliferation. Specifically, Smarce1 or Smarcb1 knockdown (cBAF & PBAF) resulted in increased growth in male astrocytes but decreased growth in females. Brd7 (PBAF) knockdown enhanced growth in both sexes, while Brd9 (ncBAF) had minimal impact. We utilized extreme limiting dilution analysis (ELDA) to assess the clonogenic potential of GBM cells with depleted BAF components. Notably, cells with BRD7 knockdown displayed enhanced sphere-forming capacity in both male and female cells. Male cells with Smarce1or Smarcb1 knockdown showed increased clonogenic frequency, whereas females with Smarce1 knockdown had a marked reduction in sphere formation. Brd9 knockdown did not affect the sphere-forming capacity in male or female cells, in part due to compensatory plasticity of an alternate BAF complex. Epitranscriptomic analysis is ongoing and demonstrates sex-specific differences in chromatin accessibility and downstream gene expression programs based on BAF complex knockdown. Immunoprecipitation coupled with mass spectrometry was performed to elucidate the structure and assembly of the BAF complex in GBM cells. Understanding sex-specific mechanisms of BAF chromatin remodeling complex in glioma pathogenesis may yield critical insights for the development of precision therapeutics that have the potential to improve patient outcomes.
BIOM-21. SMALL EXTRACELLULAR VESICLES AS A NOVEL LIQUID BIOPSY APPROACH FOR GLIOBLASTOMA
Authors: He Yangen , Kumar Ashish , Singh Sangeeta , Kim Susy , Su Yixin , Herpai Denise , Fansler Ashley , Whitlow Christopher , Strowd Roy , Debinski Waldemar , Lesser Glenn , Deep Gagan 
Published: November 2024

Abstract
Glioblastoma (GBM) remains the most common and aggressive primary malignant brain tumor, with limited treatment options and poor overall survival. Diagnosis, prognosis, and assessment of treatment effectiveness are hampered by the lack of sensitive, tumor-specific, non-invasive blood-based assays which could be followed serially. Small extracellular vesicles (sEV) are nano-sized (≤200 nm) membrane-bound bodies secreted by all cells, encapsulating cargo reflective of their parent cells. sEVs have emerged as promising molecular disease indicators. Here, we report the feasibility of isolating glioma-specific sEV (sEVglioma) from plasma and characterizing them for GBM-specific molecular biomarkers. Plasma samples were collected from 31 glioma patients (grades 3 and 4 GBM, grades 2 and 3 astrocytoma) and 9 healthy individuals. Total sEVs (TE) were isolated from plasma by a modified precipitation (ExoQuick™) method, followed by immunoprecipitation to isolate sEVglioma employing surface markers targeting the cellular origin of gliomas, including astrocyte (GLAST and EAAT2), oligodendrocyte precursor cell (OSP and MOG), and neural stem cell (CD133). The average size of sEVglioma was less than 200 nm. Importantly, compared to TE, sEVglioma showed significant enrichment for glioma-specific biomarkers such as ephrin type-A receptor 2 (14.7-fold), tenascin-C (22.7-fold), and glial fibrillary acidic protein (8.4-fold). Similarly, sEVglioma demonstrated higher expression of the GBM biomarker EGFRvIII (3.6-fold). These results were confirmed by confocal microscopy. Interestingly, the expression of specific miRNAs (miR-9a-5p, miR-16-5p, miR-21-5p) in sEVglioma was higher in glioma patients with shorter survival (&lt;12 months) compared to longer survival (&gt;20 months). Lastly, we successfully detected the existence of wild-type IDH1 and absence of mutated IDH1 R132H in sEVglioma from GBM patients, validated with cell line experiments. In conclusion, we present a novel liquid biopsy approach for isolating sEVglioma from blood, providing valuable molecular and genetic information. This approach promises early detection, potential to distinguish pseudo-progression, and assessment of treatment effectiveness with remarkable precision.
BIOM-30. NOVEL HISTOLOGIC AND MOLECULAR BIOMARKERS FOR OLIGODENDROGLIOMA
Authors: Smith Vanessa , Stevenson Kevin , Wieden Tia , Anand Monika , Desjardins Annick , McLendon Roger , Ashley David , Gregory Simon , López Giselle 
Published: November 2024

Abstract
Oligodendrogliomas are progressive, infiltrative gliomas. While new molecular criteria were introduced in 2016 for diagnosing oligodendroglioma, the grading criteria remains largely unchanged. We evaluated histologic and molecular features for new biomarkers of aggressive behavior, using a cohort of 184 specimens diagnosed as low grade oligodendroglioma within the Duke Brain Tumor Center Biorepository. To identify tumors meeting current molecular criteria for oligodendroglioma, IDH1/2 status was confirmed by whole exome sequencing and 1p/19q codeletion confirmed using inferred copy number variation. First, we assessed for a histologic feature called hypercellular nodules (HCN), which are foci of increased cellularity in regions of otherwise lower cellularity tumor. In patients with newly diagnosed grade 2 oligodendroglioma, 16% (15/92) had HCN. While the median overall survival (OS) was 24.1 years without HCN, the median OS with HCN was only 13.6 years (p&lt;0.02, Mantel-Cox test). We then assessed for homozygous deletion of CDKN2A. Cases with potential CDKN2A homozygous deletion by inferred copy number variation were validated by fluorescence in situ hybridization. In patients with newly diagnosed grade 2 oligodendroglioma, 2% had homozygous CDKN2A deletion (2/107). While the median OS with intact or hemizygous CDKN2A loss was 21 years, it decreased to 3.8 years with homozygous CDKN2A deletion (p&lt;0.0001, Mantel-Cox test), although interpretation is limited given the rarity of homozygous CDKN2A loss at initial diagnosis. For recurrent grade 2 oligodendroglioma, 6% had homozygous deletion (5/77). While the median OS with intact or hemizygous CDKN2A loss in recurrent oligodendroglioma was 25.4 years, it decreased to 6.7 years with homozygous CDKN2A deletion (p&lt; 0.04, Mantel-Cox test). These studies provide support for using HCN and CDKN2A homozygous deletion as grading criteria for oligodendroglioma. Further studies are ongoing, including covariate analysis, expanded cohorts, and ongoing analysis of whole exome sequencing data to identify additional genetic alterations correlated with overall survival.
BIOM-54. AI-DRIVEN RISK-OF-PROGRESSION (AIRIP) CLASSIFIER FOR DISTINGUISHING RECURRENT BRAIN METASTASES FROM RADIATION TREATMENT EFFECT: A MULTI-INSTITUTIONAL COMPARATIVE STUDY WITH ADVANCED MULTIMODAL IMAGING
Authors: Um Hyemin , Ismail Marwa , Hill Virginia , Puri Sushant , Yu Jennifer , Lu Lan , Nayate Ameya , Rogers Lisa , Prasanna Prateek , Bardhan Mainak , Li Chengnan , Basree Mustafa , Baschnagel Andrew , McMillan Alan , Bhatia Ankush , Ahluwalia Manmeet , Veronesi Michael , Tiwari Pallavi 
Published: November 2024

Abstract
Following radiation therapy, a significant challenge in brain metastases (BM) management is differentiating radiation-induced-treatment effect (TrE) from tumor recurrence (TuR). TrE can be indistinguishable from TuR using conventional MRI. Advanced imaging techniques (e.g., perfusion MRI, PET/MRI) are not consistently used, and the standardized Response Assessment in Neuro-Oncology for brain metastases (RANO-BM) is sensitive to inter-reader variability. The performance of an artificial intelligence (AI)-driven risk-of-progression (AiRiP) classifier, which has been shown to capture pathophysiologic differences between TrE and TuR on routine MRI, was compared to that of clinical assessments and advanced imaging methods, in a multi-institutional setting. A total of n=261 lesions with pathologically-confirmed diagnoses in n=189 patients were analyzed. 115 lesions (73 TuR, 42 TrE) from site 1, 86 lesions (38 TuR, 48 TrE) from site 2, and 60 lesions (33 TuR, 27 TrE) from site 3 were used for training and testing the AiRiP-model. Gd-T1w, T2w, FLAIR MRI were preprocessed, and lesions were segmented by experts. Texture features (n=856) were extracted from each lesion. Random-forest classifier was employed for 3-fold cross-validation. Top-performing AiRiP-features, RANO-BM criteria, perfusion MRI and PET/MRI were evaluated in a sub-group analysis. For n=51 lesions on the test-set (site 3), 14 were classified as stable disease and 37 as TuR using RANO-BM (accuracy=54.1%). AiRiP-model achieved an accuracy of 76.5% on the same test-set and accurately classified 78.6% of the stable lesions as TrE or TuR. For another subset of lesions (n=27) on the same test-set, perfusion MRI and AiRiP-model achieved an accuracy of 59.3% and 70.4%, respectively. Lastly, for a subset of lesions (n=35) on the test-set (site 2), multimodal (perfusion, PET) imaging and AiRiP-model accurately classified 60% and 74.3% of lesions, respectively. 15 lesions were considered indeterminate via multimodal imaging, 73.3% of which AiRiP-model accurately classified as TrE or TuR. Our results suggest AI-driven models on conventional MRI may reliably distinguish TuR from TrE.
BIOM-59. INDIVIDUALIZED TUMOR-SPECIFIC AMPLIFIED DNA JUNCTIONS FOR PLASMA-BASED MONITORING IN PATIENTS WITH HIGH-GRADE GLIOMAS
Authors: Ali Mohamed , Riviere-Cazaux Cecile , Johnson Sarah , Salvatori Rebecca , Penheiter Alan , Smadbeck James , Murphy Stephen , Harris Faye , McCune Alexa , Barrett Michael , Kosari Farhad , Jones Leila , Ida Cristiane , Borad Mitesh , Bendok Bernard , Basil Aleeshba , Quinones-Hinojosa Alfredo , Porter Alyx , Mrugala Maciej , Jaeckle Kurt , Anastasiadis Panos , Kizilbash Sani , Cheville John , Routman David , Burns Terry , Vasmatzis George 
Published: November 2024

Abstract
Accurate response assessment in patients with high-grade gliomas (HGGs) is complicated by post-treatment radiographic changes that are equivocal for treatment effect versus progression. Plasma-based liquid biopsy assays for circulating tumor DNA (ctDNA) have had limited sensitivity to date, due in part to the presence of the blood-brain barrier that limits the diffusion of tumor-derived analytes out of the central nervous system. To address this challenge, we developed a ctDNA plasma-based assay to detect individualized tumor-derived amplified junctions in patients with HGGs. These junctions occur due to large-scale chromosomal rearrangements, such as those associated with epidermal growth factor receptor (EGFR) or cyclin-dependent kinase 4 (CDK4) amplification. To identify these amplified junctions, whole genome sequencing was performed on resected tissue. Primers were designed to flank junction breakpoints and were then utilized on each patient’s plasma samples to detect the amplified junction via qPCR. Tumor-specific amplified junctions were robustly detected in plasma from 14/14 (100%) patients with IDH-mutant or wild-type grade 4 astrocytomas whose tumor genomes demonstrated amplification-related junctions, located at chromosomes 7, 11, or 12. In comparison, ctDNA could not be detected in three control cases that did not have an amplification or did not have high copy number junctions. Importantly, serial plasma samples obtained prior to and at disease recurrence in 4 patients demonstrated an increasing abundance of amplified junctions that accurately correlated with disease progression in 4/4 patients (100%). In two of these patients, increasing abundance of amplified junctions preceded radiographic changes compatible with disease progression by approximately 2 or 4 months, respectively. In conclusion, tumor-specific amplified junctions could reliably be detected in plasma from patients with IDH-mutant or wild-type grade 4 astrocytomas and correlated with changes in disease burden. Further work is currently ongoing to evaluate these promising results in a larger cohort of patients with serial plasma samples.
CNSC-10. WHEN GOOD THINGS GO OFF TRK: THE INTERSECTION OF NEUROSCIENCE & ONCOLOGY
Authors: Pattwell Siobhan 
Published: November 2024

Abstract
How and why do processes and molecular players that were once an integral part of normal neurodevelopment go awry in pathological conditions, such as cancer? Embryogenesis, and neurodevelopment in particular, comprise an elegant and well-orchestrated series of tightly regulated events, culminating in an organized and highly functioning organism. Cancer, on the other hand, can often be viewed as an uncontrolled, unrestrained, genetically chaotic disease, lacking the precise spatial and temporal rigidity associated with normal development. While appearing to be on opposite sides of the organizational spectrum, the similarities between early neurodevelopment and oncogenesis are numerous. The link between developmental signaling and cancer initiation, maintenance, and metastasis has long been known for several members of the Wnt, Hedgehog, and Notch pathways and years of gene-level analyses have provided a wealth of knowledge and mechanistic insight. As advances in next generation sequencing allow for deeper characterization of genetic programs, it is increasingly possible to explore various isoforms of cancer associated genes. It is widely known that neurotrophins and their receptors (TrkA, TrkB, TrkC) are instrumental for neurodevelopment and that they remain critical for proper neuronal functioning throughout life. Our work highlights a previously unidentified role for an alternatively spliced neurotrophin receptor in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in humans and mice. This specific isoform, TrkB.T1, is the predominant NTRK2 isoform across embryonic organogenesis, and forced overexpression of this embryonic pattern causes multiple solid and nonsolid tumors in mice. TrkB.T1 also emerges as the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring various NTRK fusions. This work hopes to address the fundamental question of how neurodevelopmental processes can go awry in cancer, while seeking to better characterize the role of TRKs, in normal developmental processes and oncogenesis.
CNSC-15. DURATION AND TIMING ANALYSIS OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR NEWLY DIAGNOSED HIGH-GRADE GLIOMA PATIENTS: A REAL-WORLD RETROSPECTIVE STUDY IN TWO CENTERS
Authors: Wang Chun , Chen Lingchao , Ji Jianxiong , Zhang Junyan , Song Kun , Pan Yanhong , Ma Nainai , Zheng Huijuan , Xiao Yang , Chen Gao , Liu Fuyi , Qin Zhiyong 
Published: November 2024

Abstract

BACKGROUND
In the EF-14 phase 3 trial, tumor treating fields (TTFields) plus temozolomide improved progression-free and overall survival versus temozolomide alone in newly diagnosed glioblastoma. However, the optimal duration and timing of TTFields treatment have not been reported yet. In this study, we aimed to analyze the relationship between the timing of TTFields use, the total duration of therapy, and daily compliance with overall survival in high-grade glioma (HGG) and, therefore, provided detailed suggestions for clinical use of TTFields.

METHODS
A total of 343 patients were screened retrospectively after resection or biopsy at two centers and received TTFields treatment from April 2019 to April 2023. All the patients were re-evaluated based on the 2021 WHO CNS5 Classification. We collected clinical data, including basic clinical information, pathology, surgery, radiotherapy, and TTFields. Follow-up for survival was performed for all patients in December 2023, and another follow-up is planned for June 2024.

RESULTS
After excluding non-HGG or lacking critical diagnostic information, 308 patients were included. Of these, 264 were Glioblastoma, IDH-wildtype, 27 were Astrocytoma, IDH-mutant, 3 were Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, and 14 were Diffuse midline glioma, H3 K27-altered, or Diffuse hemispheric glioma, H3 G34-mutant. Baseline characteristics were listed below: median age was 53 years; 56.82% male; median baseline KPS was 90; 75.97% underwent gross total resection; 51.30% received chemoradiation with concurrent TTFields. Only 26.30% of patients were still using TTFields by December 31, 2023. The median time difference between TTFields and surgery was 55.5 days. The overall TTFields median duration was 334 days, with a median compliance rate of 85%. By December 31, 2023, 59.09% of the patients were still alive.

CONCLUSION
The study group will continue to follow up on patients’ survival. Further analysis of the correlation between treatment duration, compliance or timing and survival will be performed.
CNSC-31. INVESTIGATING THE THERAPEUTIC POTENTIAL OF STK17A INHIBITION IN GLIOBLASTOMA
Authors: Castro Jesus , Seetharam Deepa , Chaudhry Sana , Chander Jay , Taylor Justin , Shah Ashish 
Published: November 2024

Abstract
For decades, the survival rate for glioblastoma (GBM) has remained nearly stagnant, with a 5-year survival rate of only 5%. There is an unmet medical need for therapeutic development, because while GBM is the most common primary brain tumor, only four FDA approved drugs have been developed for GBM over the last century. By taking advantage of RNA sequencing, a potential target for GBM has been identified: the kinase STK17A (Serine/Threonine Kinase17A). We confirmed that STK17A is overexpressed in gliomas by analyzing public databases and single-cell RNA sequencing from our own GBM patients, and further associated it with poor patient outcome. Little is known about STK17A, but it has been found to be involved in cell proliferation and tumorigenesis. The role of STK17A in GBM pathophysiology and its therapeutic potential as a drug target remains a critical knowledge gap. To better understand STK17A’s role in GBM pathophysiology, we first knocked down STK17A in GBM cell lines and determined that STK17A had functional roles in proliferation and morphology. Similar conclusions were drawn after removing STK17A in GBM xenograft mouse models. These findings support STK17A as a viable therapeutic target. We then designed and optimized novel STK17A inhibitors for evaluations through kinase enzymatic and biological assays, in vitro proliferation and toxicity assays, and in vivo Drug Metabolism and Pharmacokinetics (DMPK) assays. We then used these potent, selective, and highly brain penetrant STK17A inhibitors to investigate the anti-tumor effects of STK17A inhibition in GBM and demonstrate the efficacy of our novel STK17A inhibitors in vivo. In conclusion, this work seeks to contribute to the field of targeted therapies for GBM by optimizing and examining a novel brain penetrant STK17A inhibitor, initiating studies for the treatment of GBM in vitro and in vivo, and providing proof of efficacy for further studies in GBM patients.