bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-16. A TARGETED GENE EXPRESSION BIOMARKER PREDICTS LOW GRADE MENINGIOMA RECURRENCE AND OVERALL SURVIVAL
Authors: Nguyen Minh , Morshed Ramin , Youngblood Mark , Perlow Haley , Lucas Calixto-Hope , Patel Akash , Palmer Joshua , McCortney Kathleen , Horbinski Craig , Magill Stephen , Chen William , Raleigh David 
Published: November 2024

Abstract
Targeted gene expression profiling improves risk stratification for meningiomas, but the utility of this approach for low grade meningiomas is incompletely understood. To address this, 466 meningiomas that were initially used to validate a 34-gene expression biomarker were combined with 270 previously unpublished samples for an analysis of biomarker performance in newly diagnosed (n=691) or recurrent (n=45) WHO grade 1 meningiomas treated with gross total (GTR) or subtotal resection (STR), and newly diagnosed WHO grade 2 meningiomas treated with GTR. Prediction of local freedom from recurrence (LFFR) or overall survival (OS) was measured using Cox proportional hazards models and the Kaplan-Meier method. The cohort included 736 patients, 69.4% female, with a median age at diagnosis of 58 years. There were 635 WHO grade 1 meningiomas, 498 with GTR and 133 with STR, and 101 WHO grade 2 meningiomas with GTR. The median follow-up was 4.6 years, the local recurrence rate was 12.0% and the rate of death was 8.4%. The biomarker classified 51.5% of meningiomas as intermediate risk and 9.6% as high risk. Combining the biomarker with extent of resection identified 19.7% as unfavorable (intermediate molecular risk with STR or high molecular risk), including 7.4% of newly diagnosed WHO grade 1 meningiomas with GTR. The risk score was prognostic for LFFR overall (hazard ratio per 0.1 increase in risk score 1.89, 95% confidence interval 1.58-2.25) and across WHO grades, extents of resection, and newly diagnosed or recurrent settings. Gene expression risk groups were prognostic for LFFR, with improved outcomes among low molecular risk compared to intermediate molecular risk (Log-rank, p=0.0002) and high molecular risk meningiomas (Log-rank, p&lt;0.0001). These data suggest that a targeted gene expression biomarker can identify low grade meningiomas that are more likely to recur after surgery, possibly changing management for approximately one-fifth of cases.
BIOM-22. SPATIAL, SINGLE-CELL, AND BULK RNA SEQUENCING IDENTIFY MOLECULAR PROGRAMS UNDERLYING MENINGIOMA BRAIN INVASION
Authors: Aggarwal Ayush , Youngblood Mark W , Mirchia Kanish , Najem Hinda J , Magill Stephen T , Heimberger Amy B , Raleigh David R 
Published: November 2024

Abstract
Brain invasion is a negative prognostic factor for meningiomas, but the molecular programs underlying meningioma brain invasion are poorly understood. To address this, we performed transcriptomic analyses of 3 independent datasets: Bulk RNA sequencing from 199 meningiomas (n=33 with brain invasion), single-cell RNA sequencing of 2 regionally distinct samples from the brain tumor interface (BTI) versus tumor core (TC) (n=22,118 single-cell transcriptomes), and spatial RNA sequencing from 6 samples with (n=4) versus without (n=2) brain invasion (n=18,471 spatial transcriptomes). Single-cell and spatial datasets were integrated with Harmony, cell interactions were defined using CellChat, and cross-platform comparisons were performed with the Seurat data integration pipeline. Bulk RNA sequencing revealed enrichment of 1835 genes in meningiomas with brain invasion compared to those without brain invasion, including glial markers (GFAP, NCAN) and markers of extracellular matrix remodeling (PDGFRA, COL9A1). Single-cell RNA sequencing comparison of BTI versus TC meningioma cells identified 2793 genes that were enriched in BTI cells, 268 of which were conserved across bulk and single-cell transcriptomes from brain-invasive meningiomas. Gene ontology enrichment analysis showed molecular programs underlying cell migration and regulation of neurogenesis at the BTI, while glycolysis and antigen presentation programs were enriched in the TC. Cholesterol, CSPG4, and LIF signaling were active in the TC, while SLIT signaling was enriched at the BTI. Spatial RNA sequencing showed enrichment of 439 genes at the BTI, and a conserved set of 12 genes were enriched in BTI meningioma cells across bulk, single-cell, and spatial datasets (TGM2, APOC1, IGFBP6, PLEKHO1, GFPT2, ZYX, IQGAP3, LUM, S100A11, ARPC1B, CDK1, CYCS). Comparison of tumor microenvironment monocytes at the BTI versus TC demonstrated enrichment of 1571 genes that were associated with macrophage migration and activation. These data elucidate molecular programs underlying meningioma brain invasion and provide insights into meningioma intratumor heterogeneity.
BIOM-24. GLIOBLASTOMA DNA ALTERATIONS AND RAPID EARLY PROGRESSION AFTER SURGERY
Authors: Samimi Kayla , Saini Aren , Cullison Kaylie , Herr Janette , Mellon Eric A 
Published: November 2024

Abstract
Glioblastoma is the most common primary brain cancer with overall poor prognosis. In the weeks following initial resection, approximately 50% of glioblastoma patients will demonstrate rapid early progression (REP) on MRI prior to the start of radiation therapy (RT). REP is associated with worse overall survival (OS), however associations between REP and biomarkers in glioblastoma have yet to be evaluated. A single institution sample of 100 patients (age 61.2 years median, 57 males) with a primary diagnosis of glioblastoma were included in this study. Patients underwent gross or subtotal resection followed by RT within 60 days of their surgery. Patients who received biopsy only were excluded. For this analysis, REP was defined as increased nodular enhancement at the border of the resection cavity between the post-operative MRI and RT planning MRI. DNA mutations were collected from commercial next generation sequencing (NGS) results. Biomarkers with a mutational incidence of &gt;10% were used in the analysis, which included TERT promoter (N=80), EGFR (N=38), PTEN (N=40), TP53 (N=36), CDKN2A/2B (N=41), NF1 (N=16), MTAP (N=24), PIK3CA (N=14), and MGMT methylation status (N=32). Statistical analysis was performed using SPSS Statistics 28.0. Of the patients sampled, 45 met the classification of REP. The presence of EGFR alterations (p=0.001) and MGMT methylation (p=0.016) strongly correlated with REP. After multivariate linear regression, only EGFR alterations significantly correlated with REP (p=0.006). There was no significant correlation between REP or overall survival and mutations in TERT promoter, PTEN, TP53, CDKN2A/2B, NF1, MTAP, and PIK3CA. This is the first study to analyze molecular contributors to REP. We identified that EGFR alterations are most strongly correlated with REP. This suggests that patients with EGFR alterations identified on pathology should move rapidly to adjuvant therapies given their propensity to quickly re-grow after resection.
BIOM-26. ROLE OF EXTRA-DOMAIN B FIBRONECTIN IN MODULATING GLIOBLASTOMA CELL INVASIVE PROPERTIES
Authors: Kang Bo Ram , Yun Minji , Bae Eunkyung , Chong Kyuha 
Published: November 2024

Abstract
Glioblastoma (GBM) is a highly malignant tumor characterized by its resistance to current treatment modalities and high recurrence rates. Extra-domain B Fibronectin (EDB-FN), a glycoprotein not found in normal tissues but selectively expressed in the tumor microenvironment, was previously identified by our team as a promising molecular marker for brain tumors, offering potential for both prognostic prediction and therapeutic targeting. However, the specific role and mechanism of action of EDB-FN in GBM cells remain unclear. In this study, we sought to elucidate the potential role of EDB-FN and the underlying mechanisms contributing to GBM malignancy through in vitro investigations. Our findings reveal that silencing EDB-FN in GBM cells leads to a decrease in cell migration, invasiveness, extracellular matrix adhesion ability, and stem cell-like properties. Furthermore, we discovered that FAK and ERK signaling pathways play a crucial role in GBM cell progression in response to EDB-FN. This study underscores the potential of EDB-FN as a specific biomarker for GBM treatment, paving the way for future research in this area.
BIOM-31. MOLECULAR ANALYSIS OF RESECTED BREAST CANCER BRAIN METASTASES REVEALS CEREBELLAR LOCATION AND TRIPLE NEGATIVE SUBTYPE ARE NEGATIVE PROGNOSTIC FACTORS
Authors: Huppert Laura , Salans Mia , Kuwahara Kelsey , Zhou Maggie , Boreta Lauren , Braunstein Steve , Melisko Michelle , Aghi Manish , Morshed Ramin , Vasudevan Harish 
Published: November 2024

Abstract

BACKGROUND
Brain metastases (BMs) are a significant cause of morbidity and mortality in metastatic breast cancer (MBC), yet prognostic and predictive biomarkers remain poorly understood.

STUDY DESIGN
90 consecutive patients with breast cancer BMs who underwent surgical resection from 2006-2022 were retrospectively identified. Review of the electronic medical record and institutional cancer registry were completed to identify baseline clinical parameters and outcomes. BM mutation analysis was performed using a CLIA-certified targeted DNA mutation sequencing assay as part of routine clinical care.

RESULTS
All patients were female, median age at first BM resection was 57.9 years (range 27.0-81.3 years), and receptor subtypes included HR+/HER2- (n=27, 30.0%), HER2+ (n=33, 36.7%), and triple negative BC (TNBC; n=30, 33.3%). At time of first BM resection, most patients had a solitary BM (n=55, 61.1%), with anatomic locations including cerebellar (n=29, 32.2%), frontal (n=26, 28.9%), and parietal (n=17, 18.9%) sites. BM DNA mutation analysis (n= 20) revealed pathogenic alterations in TP53 (n=17, 85.0%), ERBB2 amplification (n=7, 35.0%), PIK3CA (n=4, 20.0%), BRCA1 (n=3, 15.0%), and BRCA2 (n=2, 10.0%). Most patients received postoperative radiation (n=82, 90.8%) and/or systemic therapy (n=67, 82.7%). Cerebellar location was significantly associated with the risk of developing leptomeningeal disease compared to other BM resection sites (HR = 2.75, p=0.02). Among all patients, median overall survival (OS) from first BM resection was 27.8 months (range 0.1-196.6 months). HR+/HER2- (median 37 months) or HER2+ (median 36 months) MBC was associated with significantly increased OS compared to TNBC (14.4 months) (p&lt;0.01, log-rank test).

CONCLUSIONS
Patients with breast cancer BMs exhibited a median OS of &gt;2 years following BM resection, and patients with TNBC had a significantly worse prognosis. Targetable mutations were observed in 40% of resected BM specimens, supporting the utility of molecular analysis of resected BMs to help guide clinical management.
BIOM-32. GENOMIC DETERMINANTS OF DIFFUSELY INFILTRATIVE GLIOMATOSIS CEREBRI PATTERN
Authors: Dasgupta Pushan , Dagher Samir , Chi Xiaohan , Soomro Zaid , Wathoo Chetna , Lin Ruitao , Wintermark Max , Chen Melissa , Puduvalli Vinay K , Majd Nazanin K 
Published: November 2024

Abstract
Gliomatosis cerebri (GC), though no longer a distinct pathological entity in WHO 2021, is a unique and aggressive phenotype of diffuse gliomas with extensive and widespread infiltration. GC can present as primary de novo or secondary after treatment. We aimed to study the genomic determinants of GC. We identified 72 GC cases from 2013-2023 at MD Anderson Cancer Center. Cases were confirmed by detailed radiographic review. This included 57 glioblastoma (79%), 13 IDH mutant astrocytoma (18%), 1 IDH mutant oligodendroglioma (1.4%), and 1 high-grade astrocytoma with piloid features (1.4%). 53/72 (73.6%) were primary and 19/72 (26.4%) were secondary GC. We used 40 patients without the GC pattern as controls. Among glioblastoma GC cases and in comparison with controls, mutations in PTEN and EGFR were significantly associated with the GC pattern: 18/57 (32%) vs 3/38 (7.9%), p-value=0.01 and 23/57 (40%) vs 6/38 (16%), p-value=0.013, respectively. This held true in primary but not secondary GC. Out of 20 most commonly mutated genes in GC, mutations in EGFR, TERT, and MDM4 were associated with worse PFS: p-value=0.004, p-value=0.007, p-value=0.013, respectively and mutations in TERT and MDM4, but not EGFR, were associated with worse OS: p-value=0.003, p-value=0.015, respectively. Secondary GC was associated with IDH mutation compared to control non-GC cases: 8/19 (42%) vs 2/40 (5%), p-value=0.001. As expected, IDH mutation was associated with improved PFS, p-value&lt;0.001 and OS, p-value=0.003 in GC. No genes were significantly associated with laterality of GC. We found novel associations between PTEN and EGFR mutations and the GC phenotype and IDH mutation with the occurrence of secondary GC after treatment. While MDM4 is not associated with outcomes in gliomas, we show that MDM4 mutation is associated with poor survival in GC. These findings shed light into molecular basis of GC and need to be further validated in larger studies.
BIOM-33. INVESTIGATING MIR-21 AS A NON-INVASIVE PROGNOSTIC BIOMARKER IN GLIOMA PATIENTS IN RESOURCE CONSTRAINT SETTINGS
Authors: Laghari Altaf Ali , Naeem Sana , Sufiyan Sufiyan , Amin Wajiha , Ilyas Sahar , Bajwa Mohammad Hamza , Qazi Siraj Uddin , Mughal Nouman , Enam Syed Ather 
Published: November 2024

Abstract

BACKGROUND
Glioma treatment remains challenging due to high recurrence rates and resistance to treatment. Diagnosis and follow-up in resource-constrained regions often leads to significant patient attrition. Serum microRNA (miRNA) expression profiles are shown to be expressed in tumor tissue and peripheral samples, offering a pathway for non-invasive, repetitive liquid biopsies. miR-21 shows promise in many populations; however, there is a dearth of data from our region.

METHODOLOGY
we collected 89 intraoperative tumor tissue samples, 42 pre- and post-operative serum samples from glioma patients, and included 10 control tissue samples along with 8 normal serum samples and analyzed for miR-21 expression through qPCR. Serum samples were collected before tumor resection and post-surgery (pre- and post-operative). Correlational analysis with molecular markers IDH, Ki-67, ATRX, p53, and survival curves through the Kaplan-Meier method were calculated in high and low miR-21 expression groups, The hazard ratio was quantitatively determined using Cox regression analysis, considering both univariate associations and multivariate correlations with clinical parameters.

RESULTS
miR-21 expression in tissue increased with higher grades of glioma (p=0.00064), of patients above 50 years (p=0.0027), and shows a positive correlation with tumor volume (r= 0.22, p=0.081). IDH-wildtype (p=2.06e-03) and high Ki-67 (p=2.50e-03) expression in tumors showed significant upregulation of miR-21 compared to IDH-mutant and low Ki-67. Patients with low miR-21 expression had significantly longer overall survival (OS) than patients with high miR-21 expression (p =0.006). Quantitative hazard analysis indicates that patients in the high expression group have a 2.77 times higher risk of mortality (95% CI: upper - 0.19, lower - 0.92), in comparison to patients in the low expression group (p= 0.008).

CONCLUSION
Our findings validate the future utility of miR-21 as a serum assay to help diagnose and assess treatment response in different grades of glioma, within our population. Keywords: Glioma, Biomarker, Molecular markers, Liquid biopsy
BIOM-35. COMPREHENSIVE IDENTIFICATION OF MRNA ISOFORMS AND THEIR DIAGNOSTIC POTENTIAL IN GLIOMAS
Authors: Goel Pallavi , Sadasivam Subhashini , Ghanekar Yashoda , Roy Vijaylaxmi , Sreegiriraju Vijay , Kumari Neha , Madiraju Surya , Ray Amit 
Published: November 2024

Abstract
Most genes generate multiple mRNA isoforms which may differ in their protein-coding capacity. Also, cancer and its prognosis are associated with the altered expression of specific isoforms of a variety of genes as cancer cells can manipulate regulatory mechanisms to express isoforms that provide a survival advantage and/or resistance to therapy. However, the underlying mechanisms behind their pathology are poorly understood. Fifty seven glioma samples that could be categorized unambiguously into Astrocytoma (n=17), Oligodendroglioma (n=16) and Glioblastoma (n=24) based on pathology reports and according to WHO standards were selected for this analysis. Total RNA-Sequencing (RNA-Seq) was performed on RNA isolated from these 57 samples. RNA-Seq data analysis was performed using the DRAGEN RNA application in Illumina BaseSpace and transcript counts were generated after alignment. From these counts, isoforms that were significantly differentially expressed in Astrocytoma (Astro) vs Oligodendroglioma (Oligo), and Astrocytoma vs Glioblastoma (GBM) were identified using the R package, IsoformSwitchAnalyzeR. Approximately 93,000 transcripts were screened in both comparisons of which 4388 and 44 transcript switches were identified as significant at FDR&lt;0.05 in the Astro vs GBM and Astro vs Oligo comparisons, respectively. Applying an additional cut-off based on the difference in isoform fraction or dIF of a transcript between the two groups being compared (dIF&gt;1.0 and dIF&lt;-0.1), the most significant top switches were identified.. Similarly, in the Astro vs GBM comparison, the isoform switch in genes such as MDF1 and RER1 whose overexpression is known to be involved in tumorigenesis and metastasis were among the 155 top switches. Among the six top switches in the Astro vs. Oligo comparison were transcripts of the RENBP and GCNT2 genes which play an important role in the progression of melanoma, gastric and lung cancers. These results indicate that there may be isoform-specific dysregulation within gliomas, and further suggest that their biological significance and diagnostic potential can be explored.
BIOM-42. RESPONSE TO DABRAFENIB/TRAMETINIB IN A PATIENT WITH WHO-CNS GRADE 3 BRAF V600E-MUTATED PLEOMORPHIC XANTHOASTROCYTOMA
Authors: Alalami Huda , Bannykh Serguei , Vail Eric , Patil Chirag , Rudnick Jeremy , Hu Jethro 
Published: November 2024

Abstract

BACKGROUND
Pleomorphic xanthoastrocytoma (PXA) is a rare central nervous system tumor. Mutations in BRAF V600E are present in 60-80% of cases. While traditionally managed with surgical resection and adjuvant radiation, emerging evidence suggests targeted therapies may be effective, particularly in cases harboring the BRAF V600E mutation.

CASE SUMMARY
A 35-year-old male with no significant medical history presented in November 2023 with diplopia and headache leading to the discovery of a large left temporal/parietal tumor. A partial resection was performed. Initial histopathological diagnosis was glioblastoma (GBM); thus, the patient was treated with concurrent radiation and temozolomide for 6 weeks. Molecular pathological analysis demonstrated the presence of BRAF V600E mutation and CDKN2A/B copy number loss. Methylation-based tumor profiling was performed at the National Cancer Institute, with composite methylation profile indicating a consensus match to pleomorphic xanthoastrocytoma. Following chemoradiation, a repeat brain MRI in March 2024 showed tumor progression, prompting the initiation of dabrafenib and trametinib therapy. After 1 month of targeted treatment, a repeat brain MRI demonstrated a partial response with a decrease in tumor size and enhancement. In April 2024, he underwent a planned repeat resection. Symptomatically, the patient experienced intermittent headaches and nausea that were responsive to oral steroids with no serious adverse effects to targeted therapy.

DISCUSSION
This case highlights the therapeutic potential of double BRAF/MEK blockade with dabrafenib and trametinib in BRAF V600E-mutant anaplastic PXA. The observed partial response on imaging suggests the efficacy of targeted therapy in this molecular subtype. These findings underscore the importance of molecular profiling in guiding treatment decisions.
BIOM-44.18F-DOPA-PET THRESHOLDS FOR BOTH NEWLY DIAGNOSED AND RECURRENT ASTROCYTOMA USING PATHOLOGICAL GROUPING OF SPATIALLY CORRELATED BIOPSIES
Authors: Pafundi Deanna , Parney Ian , Burns Terry , Giannini Caterina , Raghunathan Aditya , Hunt Christopher , Dooley Katharine , Kabat Brian , Lowe Val , Kaufmann Timothy , Morris Jonathan , Zakhary Mark , Grams Michael , Seaburg Maasa , Breen William , Sarkaria Jann , Johnson Derek , Laack Nadia , Brinkmann Debra 
Published: November 2024

Abstract

BACKGROUND
Glioma radiotherapy planning requires accurate tumor delineation. While T1- contrast-enhanced-MRI (T1-CE-MRI) is the standard, due to blood-brain-barrier breakdown dependencies, T1-CE-MRI fails to reflect the extent of glioma. Studies using amino acid PET tracers report glioma uptake up to 3cm-4cm beyond T1-CE. In this study, amino acid tracer 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) uptake was correlated with histopathological features to determine tumor thresholds.

METHODS
Using registered 18F-DOPA-PET and T1-CE-MRI images in the Stealth Neuronavigation system targeting concordant and discordant regions, 181 stereotactic biopsy samples (newly-diagnosed=74; recurrent=107) were obtained from 59 enrolled astrocytoma patients across two prospective phase II clinical trials between 2010-2019. An experienced neuropathologist reviewed each sample with hematoxylin and eosin stain and assigned an alphanumeric score: mitotic activity (0=no tumor; 1=no mitosis; 2=few/scattered mitosis; 3=frequent mitosis) and cellular density (A=&lt;25%; B=25%-50%; C=50%-75%; D=&gt;75%). Samples assigned 1C-1D, 2B-2D, or 3A-3D were categorized as histopathological high-score (aggressive disease), remaining samples as low-score. Relative mean (rFDOPA_mean) tumor-to-background uptake ratios were computed for 5mm uniformly expanded volumes from each Stealth biopsy coordinate using the crescent and wedge normalization methods. Relative uptake was compared overall and separately within newly-diagnosed/recurrent disease subgroups. An optimal rFDOPA_mean threshold to delineate high- from low-score was determined using the maximal Youden index of ROC curves.

RESULTS
Overall, high-score samples (n=116) had higher median (IQR) rFDOPA_mean uptake than low-score samples (n=65): high-score rFDOPA:mean=1.70(1.16-2.26), low-score rFDOPA:mean=1.16(0.83-1.49), Kruskal-Wallis p&lt;0.001. The uptake difference between high- vs. low-score samples was observed within newly-diagnosed and recurrent subgroups, but was only significant for newly-diagnosed (p&lt;0.001). For newly-diagnosed, an rFDOPA:mean=1.49 cutoff between high- and low-score groups shows 69% accuracy, 63% sensitivity, 80% specificity (AUC=0.782). Using the wedge normalization method, rFDOPA_mean values were 0.2 higher than crescent method values.

CONCLUSIONS
This work presents histologically verified 18F-DOPA-PET thresholds for aggressive disease in newly-diagnosed astrocytoma patients. Separate thresholds will need to be determined for recurrent glioma patients.