bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-19. METHYLATION PROFILING OF PLASMA CELL-FREE DNA IN PEDIATRIC BRAIN TUMOR PATIENTS
Authors: An Shejuan , McCortney Kathleen , Walshon Jordain , Leonard Kaethe , DeCuypere Michael , Horbinski Craig 
Published: November 2024

Abstract

BACKGROUND
Circulating tumor DNA (ctDNA) assays are being evaluated to inform clinical decisions in cancer care in adult patients, but the study in pediatric brain tumor patients is rare partly due to very low levels of ctDNA in blood. Currently, treatment decisions require invasive diagnostic surgical biopsies that carry risks and morbidity. The aim of this study is to utilize methylomes from plasma ctDNA for non-invasive diagnosis in pediatric brain tumor patients.

METHODS
Using cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq), which with low input DNA requirement, we measured methylation profiles of plasma samples from 77 pediatric brain tumor patients and 16 patients with non-neoplastic diseases like epilepsy. Binomial GLMnet classifiers of tumor or tumor subtype were built, in 2000 iterations of 60% training sets. Performance was evaluated in 40% test sets. RESULTS. These 77 pediatric brain tumor patients were a mixture of the most common pediatric brain tumors, include circumscribed astrocytic gliomas (N=23), glioneuronal tumors (N=16), embryonal tumor (N=9), ependymal tumor (N=7), pediatric type diffuse high grade glioma (N= 5), glioma NOS (N=4), mesenchymal tumor (N=4) and other pediatric brain tumors (N=9). The methylation profile differentiated brain tumors from non-neoplastic diseases with 82.9% accuracy (precision = 92.6%, sensitivity = 86.2%, specificity = 66.7 %). For subtype analysis, the methylation profile detected circumscribed astrocytic glioma from non-neoplastic diseases with 85.7% accuracy (precision = 87.5%, sensitivity = 87.5 %, specificity = 83.3 %), and glioneuronal tumors from non- neoplastic diseases with 83.3% accuracy (all precision, sensitivity, and specificity = 83.3 %).

CONCLUSIONS
The results suggest that methylation profiling of plasma cell-free DNA has the potential to discriminate between pediatric brain tumor patients and patients with non- neoplastic diseases. Larger population cohorts to train even more accurate classifiers will be needed.
BIOM-20. EVALUATING THE POTENTIAL OF PSMA TARGETING IN CNS TUMORS: INSIGHTS FROM LARGE-SCALE TRANSCRIPTOME PROFILING
Authors: Kraya Adam , Rathi Komal , Jin Run , Kesherwani Varun , Resnick Adam , Nabavizadeh Ali 
Published: November 2024

Abstract

PURPOSE
Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 to assess whether transcriptome profiling can inform tumor theranostics.

EXPERIMENTAL DESIGN
We assessed FOLH1 expression from the Open Pediatric Cancer Project (OpenPedCan, n = 2132 specimens), The Cancer Genome Atlas (TCGA, n = 10411 specimens), and the Genotype Tissue Expression Project (GTEx, n = 17382 specimens) in relation to published reports of PSMA radionuclide uptake.

RESULTS
When comparing FOLH1 expression across tumor versus normal tissues, we found that non-CNS tumors exhibiting elevated expression of at least two-fold (FDR &lt; 0.05) were reported to have successful PSMA radionuclide uptake in contrast to tumors with less than a two-fold elevation or with lower expression of FOLH1 relative to normal. Notably, CNS tumors universally exhibited lower expression of FOLH1 relative to normal brain tissue, but we observed considerable variation in the expression of blood-tumor barrier (BTB) components associated with reports of BTB integrity and uptake of PSMA radiotracers.

CONCLUSIONS
Large-scale transcriptomics data may help guide the application of PSMA-based radionuclide therapies in non-CNS tumors, but care should be taken to account for BTB effects in CNS tumors when assessing the potential for radionuclide success. Our analysis demonstrated that FOLH1 showed a lack of tumor-specific expression for both adult and pediatric CNS tumors when compared to normal brain tissue, suggesting that PSMA is not a desirable target in this disease type. This study highlights the utility of utilizing large-scale molecular data to guide the selection of theranostic targets.
BIOM-25. MOLECULAR PROFILING PREDICTS EARLY AND LATE PROGRESSION IN GLIOBLASTOMA
Authors: Nikolopoulos Marina , Wu Megan , Bahcheli Alexander , Kellett Sorcha , Myrehaug Sten , Sahgal Arjun , Spears Melanie , Pai Shraddha , Bayani Jane , Das Sunit 
Published: November 2024

Abstract
Patients with glioblastoma experience a wide variation in response to standard treatment, with nearly 30% experiencing tumour progression during treatment, and nearly 6% surviving more than 5 years. To date, there are few non-invasive clinical biomarkers to predict response to first – line treatment. Chemical exchange saturation transfer (CEST) MRI may have the potential to fill this gap. CEST MRI is sensitive to treatment-induced changes and changes in tumor metabolism. Our team has obtained CEST data for patients before, during and after the end of standard chemoradiation treatment, and found that CEST provides markers of early response and can identify early, standard and late progressors before treatment initiation. In this study, we aimed to establish molecular profiles of early, standard and late progressors with IDH wild-type glioblastoma. Patients (n=180) with primary, IDH wild-type glioblastoma were imaged with CEST-MRI at multiple time points throughout standard chemoradiation treatment. DNA and RNA were co-extracted from matched normal and tumour pairs and processed for whole genome sequencing, enzymatic methyl-seq and gene expression analysis using Nanostring. Clinical variables such as age, extent of resection, sex, ECOG status and MGMT promoter methylated were also collected. A survival analysis was conducted using the Kaplan-Meier method with log-rank tests. Univariate and multi-variate hazard ratios for clinical variables were calculated by fitting Cox Proportional Hazards Models. Early progressors reported a median progression-free survival (PFS) of 142 days compared to 832 days in late progressors (p&lt;0.0001). Early progressors also harbored distinct and statistically significant differences in gene expression and genomic alterations, namely in DNA damage repair, glucose transport and arginine metabolism pathways. A gene signature was prognostic of PFS and overall survival. Collectively, this data has the potential to serve as a radiogenomic biomarker to assess treatment response before or within early phases of treatment and allow for individual tailoring of the treatment plan.
BIOM-27. VOXEL-WISE SURVIVAL ANALYSIS IN GLIOBLASTOMA: TUMOR PROBABILITY MAPS REVEAL CRITICAL REGIONS NEAR WHITE MATTER TRACTS
Authors: Nath Biprojit , Winiarz Aleksandra , Bobholz Samuel A , Lowman Allison K , Duenweg Savannah R , Kyereme Fitzgerald , Aaronson Daniel , Connelly Jennifer Connelly , Mrachek E Kelly , Krucoff Max , Banerjee Anjishnu , LaViolette Peter S 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma is the most aggressive primary brain tumor, characterized by rapid growth and poor prognosis. Understanding spatial determinants of survival in GBM is crucial for improving prognostic accuracy and treatment strategies. Our study employs voxel-wise survival analysis (VSA) of tumor probability maps (TPMs) derived from MRI to identify high-risk brain regions. TPMs are generated through radio-pathomic mapping and can predict non-enhancing tumor regions not captured by traditional imaging. We aim to determine if high tumor probability regions are near previously identified critical white matter (WM) tracts and assess their impact on survival outcomes.

METHODS
We analyzed data from 374 GBM patients from the UCSF-PDGM-v2 dataset. Using a pretrained radio-pathomic model, TPMs were predicted based on T1, T1C, ADC, and FLAIR MRI sequences. All TPMs were rigidly registered to MNI space using ANTs. A Cox proportional hazards model was applied voxel-wise to assess the association between tumor probability and overall survival (OS). A p-value map was generated, thresholded, and cluster corrected (p &lt; 0.05) for further analysis.

RESULTS
The VSA revealed that high tumor probability regions were significantly associated with poorer OS in GBM. Gray matter (GM) regions near WM tracts with high tumor probability showed markedly reduced survival. GM regions adjacent to the left IFOF (p &lt; 0.05, HR = 1.19, 845 vs. 961 days for high/low TPM), Corpus Callosum Forceps Minor (p = 0.0001, HR = 1, 740 vs. 902 days), Body of the Corpus Callosum (p = 0.005, HR = 0.97, 748 vs. 798 days for high/low TPM) and other WM tracts, such as the left thalamic radiation superior and left reticulospinal tracts had similar trends.

CONCLUSIONS
Our study demonstrates that regions with high tumor probability, particularly those in the GM near critical WM tracts, are strongly associated with worse overall survival in GBM patients.
BIOM-36. DETECTION OF CIRCULATING TUMOR DNA (CTDNA) IN CEREBROSPINAL FLUID (CSF) IN PATIENTS WITH GLIOBLASTOMA TREATED IN PHASE I CLINICAL TRIAL
Authors: Porte Marie , Beshiri Kristi , Ouali Kaissa , Postel-Vinay Sophie , Massard Christophe , Loriot Yohann , Champiat Stéphane , Hollebecque Antoine , Smolenschi Cristina , Sakkal Madona , Gazzah Anas , Bahleda Rastilav , Michot Jean-Marie , Hueso Thomas , Jeanson Aurore , Rouleau Etienne , Lacroix Ludovic , Baldini Capucine 
Published: November 2024

Abstract

BACKGROUND
As circulating tumor DNA (ctDNA) has been shown to be a source of tumor-specific biomarkers, liquid biopsy has emerged as a novel noninvasive tool in diagnosis, disease monitoring and treatment selection in several solid tumors. However, its use in brain tumors remains challenging because ctDNA is commonly not detected in blood. Thus, CSF (cerebrospinal fluid) has emerged as a potential source of ctDNA in the context of brain tumors.

PATIENTS AND METHODS
We prospectively evaluated the detection of ctDNA in CSF (CSF-ctDNA) +/- blood of patients with pre-treated MTAP-deleted glioblastoma, currently treated in a phase I clinical trial evaluating PRMT5 inhibitors. We did CSF samples at C2D15 and at progression, after patient’s oral and written consent. CSF was collected by lumbar puncture and analyzed with a panel of 35 genes including IDH1-2, TERT promoter and EGFR. Blood was collected, synchronously with CSF, by peripheral veinous punction and analyzed with the Foundation One Liquid CDx panel.

RESULTS
Between January and April 2024, five patients were included. All of them undergone initial surgical resection and received at least one previous systemic treatment associated with radiotherapy. At least one somatic mutation was identified in each patient, including EGFR amplification in 2/5 patients (40%). CSF was not available at baseline. One patient provided CSF only at progression. Four patients provided CSF at C2D15 on treatment, and among them, one patient was also collected at progression. At data cut-off, one patient was still on treatment. We identified a detectable level of CSF-ctDNA in only one patient with occipital tumor localization, with detection of EGFR amplification known at diagnosis. Synchronous blood analysis showed only clonal hematopoiesis variants.

CONCLUSION
We showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.
BIOM-38. OPPOSING EFFECTS OF LINKED CX3CR1 GERMLINE VARIANTS ON INCIDENCE, SURVIVAL, AND IMMUNE ACTIVATION IN GLIOMA
Authors: Basit Khan A , McDonald Malcolm , Curry Rachel , Lee Sungho , Yang Yuhui , Latha Khatri , Deneen Benjamin , Harmanci Akdes , Rao Ganesh 
Published: November 2024

Abstract
Linkage-disequilibrium connects CX3CR1 V249I and T280M single-nucleotide polymorphisms; V249I occurs as a single-variant (SV) and T280M exclusively as a double-variant (DV) concurrent with V249I. The effect of these combined haplotypes remains unexplored in glioma. We identified CX3CR1 haplotypes in internal LGG and TCGA GBM cohorts and analyzed median overall survival (mOS). The proportion of each haplotype in glioma and normal patients was assessed via meta-analysis. Bulk RNAseq analysis was conducted in TCGA and internal GBM cohorts and scRNAseq in internal IDH mutant gliomas. In LGG, SV improved mOS (n=14, 21.03yrs) by twofold compared to WT (n=45, 9.41yrs) and DV (n=31, 10.49yrs; p=0.037). In TCGA GBM, SV (n=69, 15.65mo) improved mOS over DV (n=106, mOS 11.74mo; p=0.044). In combined meta-analysis, SV patients had increased risk for glioma development (OR 1.11, 1.03-1.19 p = 0.006) and the WT genotype was protective (OR 0.95, p=0.048). Collagen genes associated with increased immunosuppression (COL6A3: log2FC=2.33, p-adj=0.004; COL6A2: log2FC=1.55, p-adj=.059) were reduced in SV. MME, an endopeptidase associated with radiation resistance, was downregulated in SV (log2FC=3.29, p-adj=2.53e-6). MN1, associated with improved glioma survival, was upregulated in SV (log2FC=-1.76, p-adj=0.001). CCL18, an immunosuppressive chemokine associated with M2 macrophage polarization was reduced in SV (log2FC=2.36, p-adj=0.014). Thus, concomitant with its improved survival, SV is biologically distinct from DV and WT. Using scRNAseq, myeloid-derived cells (microglia/macrophages; 7758 cells) were re-clustered, identifying fourteen clusters. Cells clustered by CX3CR1 status, with 58.2% of SV cells in cluster five and 84.9% of DV cells in clusters six or seven. Cluster five over-expressed IL1B (average-log2FC 3.16), a tumor-suppressive M1 macrophage marker. Clusters six and seven were characterized by IFIT genes (IFIT3 average-log2FC 2.72 and 2.16 respectively), which corresponds to glioma associated microglia from recent scRNAseq microglial atlases. We demonstrate that CX3CR1 SV has improved survival and reduced immunosuppression over wildtype and this is lost with in the linked CX3CR1 DV genotype.
BIOM-39. GENOMIC AND CLINICAL ASSOCIATIONS WITH RADIATION NECROSIS IN PATIENTS WITH DIFFUSE INFILTRATING GLIOMAS
Authors: Kienhöfer Michael , Lin Heather , Campbell Erick , Wathoo Chetna , Bhat Surya , Perni Subha , Puduvalli Vinay , Majd Nazanin K 
Published: November 2024

Abstract

BACKGROUND
Radiation necrosis (RN) is a complication of radiotherapy (RT) that can significantly affect quality of life and outcomes in patients with gliomas. Clinical and molecular factors predisposing patients to RN are not clearly established. We hypothesize that clinicogenomic data can be leveraged to identify patients at high risk for RN.

METHODS
We identified patients from 2014-2024 with diffuse gliomas and RN diagnosed based on Advanced-Brain-Tumor-Imaging which includes conventional MRI, 3 perfusion parameters, spectroscopy and/or pathology at MD Anderson. Inclusion criteria included diagnosis of RN 12-weeks after RT and concordance of 4 ABTI parameters. For each case, we identified 2 controls who were gender-,diagnosis-, and age-matched using a nearest neighborhood algorithm. We evaluated the correlation between 15 most mutated genes in baseline tissue and occurance of RN. A logistic regression model was employed to assess the multivariable relationship between patient characteristics, gene mutations, and RN.

RESULTS
We identified 62 patients with RN; 50 glioblastoma (80.6%), 8 diffuse astrocytoma (12.9%) and 4 oligodendroglioma (6.5%). Time from RT to RN diagnosis was 254 days (IQR 154-483). 18(29%) of RN cases and 29(24.4%) of controls had received more than one course of RT. Patients treated with bevacizumab before RT had significantly lower odds of developing RN compared to those who did not receive bevacizumab (OR 0.103 [0.011 – 0.960], p=0.0459). BRAF mutations were more frequent in the RN cohort (8.1% vs. 2.4%) and patients with BRAF mutation were more likely to have RN than those without BRAF mutation (OR 6.842 [1.2, 39.01], p=0.0304). Age, gender, diagnosis, IDH, MGMT or 1p19q status were not associated with RN.

CONCLUSION
We found that bevacizumab administration was associated with a significant reduction in RN development. We also found a novel association between presence of BRAF mutations and increased risk of RN in glioma patients, which warrants further investigation.
BIOM-40. BLOOD AND NASAL BIOMARKERS OF BRAIN MICROENVIRONMENT BLOOD–BRAIN BARRIER PERMEABILITY: CLINICAL AND APPLIED CONCEPTS
Authors: Garo Virginia , Turco Erica Lo , Quaranta Chiara , Galati Rosario , Gallucci Gianmarco , Ferrazzo Teresa , Bonapace Giuseppe , Donato Giuseppe , Ferrazzo Francesca , Policicchio Domenico , Mauro Giuseppe , Malara Natalia , Lavano Angelo , La torre Domenico 
Published: November 2024

Abstract

The limiting step to treating glioblastoma (GBM) patients is the close blood-brain barrier (BBB) which protects the brain making it an inaccessible compartment. Although multiple studies have highlighted the presence of circulating tumour cells (CTCs) in glioblastoma multiforme (GBM) patients their relationship with brain microenvironment and BBB permeability was not explored in depth. We studied the development of GBM by transferring tumour cells into the mouse brain and also in a subcutaneous location to verify how the different microenvironment affected the release of circulating tumour and endothelial cells. Glioblastoma U3T3MG IDHwt secondary cell line was transfected to track circulating tumour cells released. Moreover, both U3T3 cells and short-time-expanded CTCs1 from GBM patients were used for intracranial xenografts and patient-derived xenografts (PDX). The in vivo models demonstrated the correspondence between BBB permeability with the release of CTCs and the increment of endothelial progenitor cells in GBM HIFpos &gt;20% compared to subcutaneous xenografts releasing CTCs in GBM HIFpos&lt; 20%. These data were confirmed in HIFpos tissue biopsy of GBM-IDHwt patients with CTCs &gt;30 cells/ml. Both in PDXs and in the GBM patient demonstrated that the release of CTCs was intermittent, related to BBB opening induced by HIF-dependent cytokines release (IL8, TNFa)2. In parallel, the analysis of structural Glial fibrillary acidic protein (GFAP)3, on nasal secretion and interstitial fluid, collected in surgical treated GBM patients, demonstrated that the recognition of the two GFAP isoforms (p150 and p50 kDa) were the result of inflammatory microenvironment enriched for proteases induced by IL8, TNFa. Overall data indicate at least two different ways of monitoring the BBB and the brain microenvironment, one distal (blood) and one proximal (nasal secretion) useful to perform precision treatments in patients with GBM.

REFERENCES
1) Malara, N. et al. Mol Cancer 23, 32 (2024). doi.org/10.1186/s12943-024-01951-x2) Coluccio ML. et al Cancers (2020) doi: 10.3390/cancers12061362.3) Malara, N. et al Front. Oncol.(2021) doi.org/10.3389/fonc.2021.737730
BIOM-46. REAL-WORLD EXPERIENCE WITH CIRCULATING TUMOR DNA IN CEREBROSPINAL FLUID IN PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Hickman Richard , Miller Alexandra M , Holle Bridget M , Jee Justin , Liu Si-Yang , Ross Dara , Yu Helena , Riely Gregory J , Ombres Christina , Gerwitz Alexandra , Reiner Anne S , Nandakumar Subhiksha , Price Adam , Kaley Thomas J , Graham Maya S , Vanderbilt Chad , Rana Satshil , Hill Katherine , Chabot Kiana , Campos Carl , Nafa Khedoudja , Shukla Neerav , Karajannis Matthias , Li Bob , Berger Michael , Ladanyi Marc , Pentsova Elena , Boire Adrienne , Brannon A Rose , Bale Tejus , Mellinghoff Ingo K , Arcila Maria E 
Published: November 2024

Abstract
Next generation sequencing (NGS) of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) offers a minimally invasive approach to identify somatic alterations for individuals with central nervous system (CNS) cancers. Here, we review our ‘real world’ experience using a clinically validated, FDA-authorized platform, MSK-IMPACTTM, to comprehensively profile ctDNA from CSF samples with and without clinically documented CNS involvement by cancer (1007 samples, 711 patients). The patient cohort included patients with over 90 distinct tumor types of primary CNS and metastatic origin, with lung cancer (n = 188), breast cancer (n = 150), and glioma (n = 148) representing the most common broad categories. We identified genetic alterations (ctDNA-positive) in 489/922 (53.0%) CSF samples from patients with clinically documented CNS cancer. Over half of these ctDNA-positive samples (248, 50.7%) possessed a biomarker that was predictive of response to an FDA-approved drug (OncoKB level 1). Furthermore, the distribution of clinically actionable somatic alterations was consistent with tumor-type specific alterations across the AACR GENIE cohort. Of patients without clinical documentation of CNS cancer, none of these 85 CSF samples were ctDNA-positive (specificity = 100%). Successive CSF sequencing over time identified clonal evolution and the emergence of resistance mechanisms to therapies. ctDNA positivity corresponded with shortened overall survival after CSF collection (HR: 3.23, 95% CI: 2.58-4.05, P &lt; 0.001). NGS of CSF cfDNA can detect clinically actionable somatic alterations in a large subset of CNS cancer patients and allows tracking of tumor evolution. Detection of somatic alterations in CSF may be a useful prognostic biomarker for survival in cancer patients.