bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-39. GENETIC VARIANTS ASSOCIATED WITH DISTANT RECURRENCE IN GLIOBLASTOMA PATIENTS TREATED WITH STANDARD THERAPY
Authors: Fougner Vincent , Chiranth Shivani , Yde Christina , Nørøxe Dorte , Christensen Ib , Hasselbalch Benedikte , Lassen Ulrik , Poulsen Hans , Urup Thomas 
Published: November 2023

Abstract
Infiltrative growth is a hallmark of glioblastoma and is a major factor in therapeutic failure. Genetic variants predictive of distant recurrence may serve as novel treatment targets. The aim is to identify genetic variants associated with distance recurrence in glioblastoma patients. METHODS: From a prospective cohort of consecutive, non-selected glioblastoma patients administered standard therapy between 2016-2021 at Rigshospitalet, all patients with a genomic tumor profile were included. Distant recurrence was defined as a new contrast-enhancing tumor &gt; 2 cm from the initial lesion. Tumor tissue was analyzed by RNA- and DNA-sequencing (WES or WGS). Genetic variants were defined as pathogenic and likely-pathogenic variants based on genomic reports. Predefined candidate biomarkers included: i) the most common genetic variants in the cohort (mutational frequency &gt; 2%), ii) the number of reported variants per sample, and iii) groups of genetic variants according to the common signaling pathways. Candidates were screened for association with time to distant recurrence using univariate Cox regression analysis. Biomarkers with p &lt; 0.20 were considered for multivariate analysis adjusted for known prognostic factors with death as the competing risk. RESULTS: A total of 236 patients were included, and 208 patients (88%) were evaluable for recurrence pattern. Distant recurrence was observed in 40 patients (19%). Patients with distant and local recurrence showed no difference in progression-free survival (p = 0.58), while distant recurrence tended to have a poor overall survival (OS, p = 0.09). The OS from time of first recurrence was significantly poorer for patients with distant recurrence compared to local recurrence (p = 0.01) with a median OS of 7.2 months (95%CI: 5.9-8.5) and 10.9 months (95%CI: 9.8-12). The median frequency of called gene variants was 4 (range 0-11) per sample. CONCLUSION: Patients with distant recurrence have a poor prognosis. Final analyses will be presented.
BIOM-41. CITRULLINATED HISTONE H3 ELISA REVEALS NETOSIS AS A SOURCE OF PROGNOSTIC CIRCULATING CELL-FREE DNA IN GLIOBLASTOMA
Authors: Till Jacob , Ballinger Dominique , Wang Zhuoyang , Yazdani Zachariya , Macia Camilla , Yin Melinda , Abdalla Aseel , Nabavizadeh Ali , Desai Arati , Binder Zev , Gollomp Kandace , Zhou Wanding , Carpenter Erica , Bagley Stephen J 
Published: November 2023

Abstract

BACKGROUND
We have previously shown that higher concentrations of plasma cell free DNA (cfDNA), both at baseline and following chemoradiotherapy, are associated with worse survival in GBM. Because only scant amounts of GBM-derived cfDNA shed into the peripheral circulation, we sought to determine the predominant source of prognostic plasma cfDNA in these patients and hypothesized that this may help unravel the mechanism underlying the association of high cfDNA and survival.

METHODS
Plasma was obtained for 126 patients prior to resection of newly diagnosed GBM. A subset of 46 plasma samples had ccfDNA extracted, enzymatically converted, whole genome amplified, and analyzed on the Illumina Epic array for deconvolution of cfDNA methylation patterns. Based on these results demonstrating neutrophils as the predominant cfDNA source, we performed ELISA for citrullinated-histone 3 (citH3) in plasma from 113 of the patients as a specific marker of NETosis, a pro-tumor process of programmed neutrophil cell death during which DNA is released in web-like structures called neutrophil extracellular traps (NETs).

RESULTS
Deconvolution of cfDNA methylation patterns revealed that neutrophils were the dominant source of cfDNA (median percentage of cfDNA derived from neutrophils = 46% , range 17-67%) and correlated with baseline plasma cfDNA concentration (n = 46, r = 0.35, p = 0.017). Additionally, cfDNA concentration was significantly correlated with the concentration of citH3 (n = 113, r = 0.60, p &lt; 0.0001), which was higher in GBM patients compared to 26 healthy controls (p &lt; 0.0001).

CONCLUSION
Our findings suggest that NETosis may be the dominant source of plasma cfDNA, which we have previously shown to be highly prognostic in patients with GBM. Additional studies interrogating the tumor microenvironment for NETosis in GBM tumors are ongoing. These results lay the foundation for further exploration of NETosis as a therapeutic target and underscore the emerging importance of neutrophil biology in GBM.
BIOM-44. IMPROVED OVERALL SURVIVAL OF RECURRENT GLIOBLASTOMA (GBM) PATIENTS WITH EGFR AMPLIFICATION AND EGFR VIII MUTATIONS TREATED WITH OSIMERTINIB: A RETROSPECTIVE REVIEW
Authors: Nahm Joshua , Schumann Eva Highberg , Vu Mia , Sinha Mousumi , Ware Cornelius , Hsu Sigmund , Zhu Jay-Jiguang 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an overall survival (OS) of 14.6-23 months in clinical trial patients and 11 months for the real world population. There is no uniform standard of care for recurrent GBM (rGBM) patients. EGFR amplification and EGFRvIII mutations are common in GBM and are potential targets with EGFR tyrosine kinase inhibitors (EGFR-TKI). Osimertinib, a third-generation EGFR-TKI, effectively penetrates the blood brain barrier and is FDA-approved for non-small cell lung cancer. We conducted a retrospective review of rGBM patients with EGFR amplification and EGFRvIII mutations who received osimertinib in addition to other therapies such as bevacizumab, irinotecan, tumor-treating fields, and salvage radiation at recurrence. The primary outcome was OS. Secondary outcomes included recurrence free survival (RFS), overall survival after initiation of osimertinib (rOS), and adverse events (AE). Statistical analysis utilized the Kaplan-Meier estimate. AE were defined by the Common Terminology Criteria for Adverse Events Version 5.0. Twenty-seven patients (17 males) with a median age of 59 years (range: 29-75) were identified. All except one patient were IDH1-wild type (92.9%). MGMT promoter statuses included ten methylated (35.71%) and 11 unmethylated patients (39.29%). The median time on osimertinib was 5.1 months. The median OS was 28 months (95% CI 24, NA). Following osimertinib initiation, the median RFS was 6.4 months (95% CI 5.1, NA), and the median rOS was 12 months (95% CI 8.4, NA). AEs included grade I/II rash (44.4%), grade I/II diarrhea (40.7%), grade III leukopenia (18.5%), and grade III thrombocytopenia (11.1%). The data suggests that osimertinib improves the OS of rGBM patients with manageable and reversible AEs. Despite the limitations of a retrospective study and small sample size, osimertinib is a promising targeted therapy for rGBM. Further research is warranted in a clinical trial to evaluate this treatment prospectively.
BIOM-48. A NOVEL LIQUID BIOPSY-BASED APPROACH TO ISOLATE AND CHARACTERIZE GLIOBLASTOMA-DERIVED SMALL EXTRACELLULAR VESICLES FROM BLOOD
Authors: He Yangen , Almousa Sameh , Kumar Ashish , Su Yixin , Sharma Mitu , Singh Sangeeta , Kim Susy , Lesser Glenn , Deep Gagan 
Published: November 2023

Abstract
Glioblastoma multiforme (GBM) is a highly aggressive brain cancer characterized by a poor prognosis and limited treatment options. The absence of early diagnostic measures, prognostic biomarkers, and reliable methods for monitoring disease progression contribute to the high mortality rate among GBM patients. In recent years, liquid biopsy has emerged as a non-invasive tool for assessing cancer onset and therapeutic responses. Among the various liquid biopsy approaches, extracellular vesicles (EVs) have gained attention; as lipid bilayer membrane-delimited 30-150nm sized small extracellular vesicles (sEV) are released by all cell types. These vesicles carry molecular cargo reflecting the cell of origin and its pathophysiological state, making them a promising alternative to other liquid biopsy methods, such as circulating tumor cells and circulating nucleotides. However, the application of sEV-based liquid biopsy is hindered by the lack of methods to enrich GBM tumor-specific sEV in the blood. Our team has developed unique tools and expertise in isolating cell/tissue-specific sEV from biofluids. We have previously reported the isolation of sEV derived from specific brain cells in the blood, characterizing them for diagnosing neurodegeneration and predicting treatment response. In this study, we first isolated total sEV (TE) from the plasma of GBM patients (n = 11). Subsequently, we enriched GBM-specific sEV (sEVGBM) from TE using the astrocyte-specific surface marker glutamate aspartate transporter (GLAST). To achieve this, we utilized biotin-tagged GLAST antibody and streptavidin-coated magnetic beads for sEVGBM isolation. We then extensively characterized the size and concentration (number/ml) of sEVGBM by nanoparticle tracking analyses, while evaluating their purity through nanoflow cytometry for GLAST expression. Furthermore, we confirmed the expression of GBM-specific markers EGFRvIII, EPHB2 and IL-13Rα2 on the surface of sEVGBM (n = 3). Importantly, the expression of these markers was significantly enriched on sEVGBM compared to TE, underscoring the significance of our strategy as a potential liquid biopsy for GBM.
BIOM-51. IDENTIFICATION OF A LOW-FLIP ANGLE BASED CBV THRESHOLD FOR FRACTIONAL TUMOR BURDEN (FTB) MAPPING IN RECURRENT GLIOBLASTOMA
Authors: Anil Aliya , Stokes Ashley , Alhilali Lea , Karis John , Bell Laura , Eschbacher Jennifer , Hu Leland , Boxerman Jerrold , Schmainda Kathleen , Quarles C 
Published: November 2023

Abstract

INTRODUCTION
Differentiation of glioblastoma recurrence from post treatment radiation effects (PTRE) would improve patient management. Dynamic susceptibility contrast (DSC) MRI can be used to generate fractional tumor burden (FTB) maps, via application of regional cerebral blood volume (RCBV) thresholds, to spatially differentiate recurrence from PTRE. FTB maps derived from a DSC-MRI protocol that includes a contrast agent preload in addition to the bolus injection and a moderate-flip angle (MFA) been histologically validated. Recently, a single-dose, low-flip angle (LFA) protocol was shown to provide RCBV measurements consistent with the MFA protocol and has been recommended as a consensus protocol. This study aims to identify the RCBV thresholds for the single-dose, LFA protocol that generates FTB maps, concordant with those obtained from the reference double-dose, MFA protocol.

METHODS
Two sets of DSC-MRI data were collected sequentially from 52 patients using a single-dose, low-flip angle (30o) protocol and a double-dose, moderate flip angle (60o) protocol using TR = 1.5s and TE = 30ms. Standardized RCBV maps (sRCBV) were obtained and co-registered with the post-contrast T1-weighted images using the FDA-approved clinical software, IB Neuro™ and IB Delta Suite™, respectively. The ground truth MFA-based FTB maps were computed using multiple sRCBV thresholds (1.0 and 1.75). An ROC analysis was conducted to identify the optimal, voxel-wise LFA sRCBV thresholds to produce FTB maps that best match the reference maps. RESULTS/

CONCLUSIONS
The ROC analysis identified a lower LFA threshold of 1.0 to accurately distinguish PTRE from tumor recurrence and an upper threshold of 1.55 to differentiate aggressive tumor regions. The single-dose, LFA protocol eliminates variations in the contrast agent incubation time between the preload and bolus injection. This study provides motivation for the use of the single-dose LFA protocol in the management of patients with glioblastoma and is a reliable method for distinguishing tumor from PTRE.
BIOM-55. TARGETED GENE EXPRESSION PROFILING PREDICTS MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES
Authors: Chen William , Choudhury Abrar , Youngblood Mark W , Polly Mei-Yin , Lucas Calixto-Hope , Mirchia Kanish , Maas Sybren , Suwala Abigail , Won Minhee , Bayley James , Harmanci Akdes , Harmanci Arif , Klisch Tiemo , Nguyen Minh , Vasudevan Harish , McCortney Katy , Lam Tai-Chung , Pu Jenny Kan-Suen , Li Lai-Fung , Leung Gilberto Ka-Kit , Chan Jason , Perlow Haley , Palmer Joshua , Berghoff Anna , Preusser Matthias , Nicolaides Theodore , Mawrin Christian , Young Jacob , Boreta Lauren , Braunstein Steve , Schulte Jessica , Butowski Nicholas , Santagata Sandro , Bush Nancy Ann Oberheim , Villanueva-Meyer Javier , Chandler James P , Solomon David , Rogers Leland , Pugh Stephanie , Mehta Minesh , Sneed Penny , Berger Mitchel , Horbinski Craig , McDermott Michael , Perry Arie , Bi Wenya Linda , Patel Akash , Sahm Felix , Magill Stephen , Raleigh David 
Published: November 2023

Abstract

INTRODUCTION
Improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Here we report multicenter clinical and analytical validation of a gene expression biomarker using clinical and genomic data from 1856 meningiomas from 12 institutions across 3 continents.

METHODS
A previously-developed 34-gene expression biomarker was applied to 3 validation cohorts: (1) a multicenter retrospective clinical validation cohort (N = 6 centers, N = 866 meningiomas, median follow-up 5.2 years), (2) a prospective investigator-blinded clinical validation cohort from RTOG 0539 (N = 103 meningiomas, median follow-up 8.4 years), and (3) an analytical validation cohort for test/re-test and FFPE/frozen analyses, and comparison across platforms for gene expression quantification (N = 8 centers, N = 1219 meningiomas). Biomarker performance was compared to 9 other meningioma classification systems. Favorable versus unfavorable cases were defined as (1) gene expression low risk with any resection, or gene expression intermediate risk with GTR (favorable), versus (2) gene expression intermediate risk with STR, or gene expression high risk with any resection (unfavorable).

RESULTS
The biomarker improved on WHO 2021 grade (5-year local freedom from recurrence [LFFR] delta-AUC 0.11, 95% CI 0.07-0.17, p&lt; 0.001) and all other classification systems for LFFR and OS on multivariate analysis, achieving a negative predictive value for recurrence at 5-years of 91.9%. The biomarker predicted LFFR after postoperative radiotherapy, with a hazard ratio of 0.33 for unfavorable primary WHO grade 2 meningiomas (95% CI 0.14-0.76, P = 0.009), and 0.54 for unfavorable propensity-matched meningiomas across all WHO grades (95% CI 0.37-0.78, p = 0.0001). The biomarker reclassified 39.8% of meningiomas from RTOG 0539, including downstaging 30.5% of patients who received postoperative radiotherapy, and was independently prognostic for overall survival on multivariate analysis.

CONCLUSIONS
A 34-gene expression biomarker improves prognostication of meningioma outcomes and predicts postoperative radiotherapy responses.
BIOM-59. FEASIBILITY AND UTILITY OF THE NOVEL CANCER COMPREHENSIVE GENOMIC PROFILING RNA-SEQ FOR THE IDENTIFICATION OF THERAPEUTIC TARGETS AND DIAGNOSTIC BIOMARKERS IN GLIOMA
Authors: Takahashi Masamichi , Kohsaka Shinji , Ichimura Koichi , Mano Hiroyuki , Narita Yoshitaka 
Published: November 2023

Abstract

BACKGROUND
The detection of novel therapeutic targets is increasingly important in oncology. The Todai OncoPanel (TOP) RNA panel is a custom target RNA-seq using the junction capture method to maximize the sensitivity in detecting of known 456 fusion gene transcripts, which is approved in Japan in 2022 and covered by insurance in later 2023. Above, TOP RNA panel interrogates aberrantly spliced transcripts and analyzes the expression profiles of 1,390 genes. Primary brain tumors require various molecular profiles to be classified based on WHO2021 classification and also necessitates new therapeutic targets. In this study, we aimed to classify gliomas and identify the molecular targets by TOP RNA panel.

METHODS
Among 131 frozen samples of malignant gliomas, 124 samples passed quality control and were subjected to TOP RNA panel. Fusion detection and RNA expression analysis were conducted with the original pipeline. Cluster analysis and Gene Set Enrichment Analysis (GSEA) were performed to identify gene sets specific for individual subtypes. Copy numbers of tyrosine kinase genes, MDM2 and CDK4 were evaluated by digital droplet PCR (ddPCR).

RESULTS
Among 55 cases of glioblastoma, gene fusions were detected in 11 cases (20.0%) including novel MET fusions, and overexpression of seven tyrosine kinase genes were observed in 15 cases (27.3%). Of the 34 overexpressed genes, gene amplification was observed in 17 genes (50%) by ddPCR. In contrast to IDH-wildtype glioblastoma, IDH-mutant tumors hardly harbored fusion genes or gene overexpression. GSEA identified that the gene sets related to 1p36 and 19q were relatively enriched in astrocytoma, suggesting that regional genomic DNA copy number alterations can be evaluated by gene expression analysis.

CONCLUSION
TOP RNA panel detects more fusions than DNA panel and is utilized not only for the detection of molecular targets but also for the molecular classification of glioma, providing treatments optimized for the individual patients.
BIOM-62. DETECTION OF EXCLUSIVE MUTATIONS AND GENE-GENE FUSIONS IN GLIOBLASTOMA THROUGH ANALYSIS OF CIRCULATING CELL-FREE DNA (CFDNA) AS AN EMERGING DIAGNOSTIC TOOL
Authors: Frenkel-Morgenstern Milana , Giwa Olawumi , Baum Eliezer Gideon , Kaner Andrew , Laviv Yossef , Nof Sagi Har , Levy-Barda Adva , Siegal Tali 
Published: November 2023

Abstract
Tumor heterogeneity is a significant obstacle for developing tailored therapies for glioblastoma (GBM). We collected blood and tumors from 20 GBM patients at 4-time points and 20 blood samples from healthy controls. cfDNA was extracted from the plasma of GBM patients and healthy controls. Tumor DNA was extracted from fresh tumor samples. Extracted DNA was sequenced using a whole-genome sequencing procedure. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng·mL-1), as compared to healthy controls (1.4 ± 0.4 ng·mL-1). We identified unique mutations in cfDNA of GBM patients, including some of the most frequently mutated genes in GBM (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%) and built a unique clinical panel for further patients monitoring. Using our gene fusion database, ChiTaRS 5.0, we identified gene fusions in both tumor DNA and cfDNA, such as KDR-PDGFRA and NCDN-PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors. We identified ROS1 fusions (CEP85L-ROS1 and GOPC-ROS1) in 8% of samples, and those might be targeted by crizotinib analogs. Moreover, we analyzed TCGA/ICGC data of 180 GBM samples and observed FGFR3-TACC3, EGFR-SEPT14 fusions in silico. Next, we measured cfDNA levels in vitro in response to Temozolomide treatment and discovered a positive correlation between unique 2000bp cfDNA fragments (R = 0.8961, P-value = 0.015632) and treatment responses in vitro. We extracted exosomes from the in-vitro experiments and validated the concentrations of both the encapsulated cfDNA as well as the free cfDNA. We found that half of cfDNA was exosome encapsulated and it varied according to the tumor stage. CONCLUSION: cfDNA may be used for the detection of exclusive patient mutations and gene fusions and is an emerging diagnostic tool in GBM.
BIOM-66. ESTABLISHMENT OF A PROGNOSTIC MODEL FOR GLIOBLASTOMA MULTIFORME MAGNETIC RESONANCE IMAGING BASED ON IMBALANCED CLASSES, CLASSIFICATION, AND KAPLAN-MEIER SURVIVAL CURVE LEARNING ALGORITHMS
Authors: Cheng Wen-Yu , Yang Chih-Chan , Kao JuHsuan , Shen Chiung-Chyi , Yang Yi-Chin , Yang Meng-Yin 
Published: November 2023

Abstract
Glioblastoma multiforme (GBM) is a rapidly invasive brain tumor with a high mortality rate. It is accompa-nied by peripheral edema. Physicians use magnetic resonance imaging (MRI) to diagnose each patient’s con-dition in clinical practice. The current use of machine learning to classify brain tumors has an accuracy of about 90% in most studies. Therefore, this study aimed to improve its prediction accuracy using machine learning models to predict GBM patient survival or non-survival. The study used MRI T1-related and T2-related sequences to obtain GBM tumor and edema area attributes. It then divided them into four da-tasets: maximum tumor area, maximum edema area, total tumor volume, and total edema volume. These four datasets were used as inputs for classification models based on support vector machines, decision tree algo-rithms, random forest algorithms, and multilayer perceptron (MLP) to predict patient survival. A confusion matrix was used to evaluate each model and determine the most suitable models for each dataset based on their accuracy. MLP was the most appropriate for predicting the overall edema volume dataset, with the highest accuracy in predicting GBM patient survival or non-survival at 96.97%. Hopefully, this study can assist physicians in assessing and diagnosing GBM patients’ survival status in the future. Keywords: Classification Models; Glioblastoma Multiforme; KaplanMeier Curve; Magnetic Resonance Imaging; Peritumoral Edema
BIOS-01. EFFICACY AMONG THERAPEUTICALLY EFFECTIVE ABSORBED DOSE PATIENTS IN RESPECT-GBM PHASE I OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOBLASTOMA (RGBM) COMPARED TO AN EXTERNAL CONTROL ARM (ECA)
Authors: Ensign Lisa , LaFrance Norman , Diao Lihong , Tummagunta Kala , Boisvert Denis , Michalek Joel , Brenner Andrew , Moore Melissa , Hedrick Marc , Davi Ruthanna 
Published: November 2023

Abstract

BACKGROUND
ReSPECT-GBM is a Phase 1/2 study of 186RNL administered by convection enhanced delivery (CED) in patients with rGBM. In Phase I, 15 of 24 patients have achieved a therapeutic absorbed dose defined as &gt; 100 Gy. Based on prior work establishing the comparability of a bevacizumab (Bev) comparator to inform early-phase CED study results, OS of the 15 TAD patients were compared to a Bev ECA.

METHODS
Recent Bev-treated rGBM clinical trial patients meeting the same eligibility criteria as patients in the ReSPECT-GBM study were identified from the Medidata Enterprise Data Store of aggregated and deidentified patient-level historical clinical trial data. Propensity score (PS) methods were used to select the ECA and align the baseline characteristics of the Bev patients to the ReSPECT TAD cohort. OS estimates were generated using the weighted Kaplan-Meier method and compared with a weighted 2-sample 2-sided log-rank test at α = 0.05 based on a data cut-off of December 2022.

RESULTS
Baseline characteristics of the ReSPECT TAD and ECA patients were well-aligned after PS modeling. Although not achieving statistical significance due to small sample sizes (median OS 12.2 vs 10.1 months, hazard ratio 0.63, 95% CI: 0.26, 1.52), comparison of OS between the ReSPECT TAD and ECA patients demonstrate consistently longer OS at each 6-month interval: 6 months: 85.1% vs 73.3%, 12 mos: 51.1% vs 30.3%, 18 months: 30.6% vs 25.4%, 24 months: 30.6% vs 3.5%.

CONCLUSIONS
Single-arm studies can be challenging to interpret. By comparing the ReSPECT-GBM outcomes to an ECA of similar patients with balanced baseline characteristics, we can better appreciate the treatment effect of 186RNL administered via CED. The current results are encouraging, and updated results reflecting current follow-up will be presented at the meeting.