tbuckley/cabot-search huggingface dataset:
NIMG-75. SIMILARITY DISTANCES-BASED DELTA RADIOMICS (SDDR) ENABLES LONGITUDINAL MRI COMPARISONS FOR SURVIVAL PREDICTION IN GLIOMAS: A MULTI-INSTITUTIONAL VALIDATION
Authors: Gustavo Pineda, Michael Veronesi, Timothy J Stuhlmiller, Hope Lee, Sarah Ginn, Alaa Awawda, Zachariah Cole, Ankush Bhatia, Santosh Kesari, Manmeet Ahluwalia, Eduardo Romero, Marwa Ismail, Pallavi Tiwari
Journal: Neuro-Oncology (2024)

Abstract Radiomics (computerized feature analysis) on treatment-naive MRI scans has demonstrated great value in outcome prediction for Glioblastoma (GBM). However, delta radiomics (analysis of radiomic feature variation between different events, e.g., before and after treatment) has not been explored on account of challenges with precise spatial correspondences between pre- and post-operative scans. This work presents a survival prediction model for GBM, Similarity Distances-based delta radiomics (SDDR), based on the hypothesis that similarity distance-measures between radiomic features on pre-, and post-treatment images can accurately capture temporal changes within-and-around the tumor, and provide improved prediction of overall survival, compared to models based on a single timepoint. 150 patients from 2 publicly-available Glioma repositories (University of California San Francisco “UCSF” (n=48), LUMIERE (n=67)) and 2 two proprietary datasets (from xCures (n=13), and Cleveland Clinic (CCF) (n=74)) were obtained. UCSF and LUMIERE cohorts were used as separate hold-out sets, in each of which the remaining collections were used as discovery set. Following pre-processing, tumor segmentation into Edema (ED) and Enhancing tumor (ET) were performed. SDDR was then computed, which is the distance between probability densities functions from 156 gray co-occurrence (GLCM) and 52 gradient-based co-occurrences statistics (COLLAGE) features extracted from pre and-post-treatment MRI. Six statistical distances (e.g., Earth mover distance) normalized by the scanning interval (in weeks) yielded n=2496 SDDR measurements per tumor region (1248/region, 936 delta-GLCM, and 312 delta-COLLAGE). The same set of features were computed from pretreatment MRI (Pre-R) for comparison. Features were fed to LASSO-Cox regression for survival analysis. SDDR for GLCM features extracted from ET outperformed Pre-R, and demonstrated significant differences between high and low risk groups for both hold out tests: UCSF (p=0.0069, HR =2.8, C-index=0.69) and LUMIERE (p=0.0061, HR = 1.9, C-index 0.65). SDDR-based multi-institutional survival analysis demonstrated promise in reliable longitudinal risk-stratification in GBM.
BIOM-40. BLOOD AND NASAL BIOMARKERS OF BRAIN MICROENVIRONMENT BLOOD–BRAIN BARRIER PERMEABILITY: CLINICAL AND APPLIED CONCEPTS
Authors: Virginia Garo, Erica Lo Turco, Chiara Quaranta, Rosario Galati, Gianmarco Gallucci, Teresa Ferrazzo, Giuseppe Bonapace, Giuseppe Donato, Francesca Ferrazzo, Domenico Policicchio, Giuseppe Mauro, Natalia Malara, Angelo Lavano, Domenico La torre
Journal: Neuro-Oncology (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 &amp;gt;20% compared to subcutaneous xenografts releasing CTCs in GBM HIFpos&amp;lt; 20%. These data were confirmed in HIFpos tissue biopsy of GBM-IDHwt patients with CTCs &amp;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
PATH-23. SARCOMATOUS TRANSFORMATION OF GLIOBLASTOMA IS ASSOCIATED WITH A DISTINCT MOLECULAR SIGNATURE
Authors: Calixto-Hope Lucas, Nadeem Al-Adli, Jacob Young, Rohit Gupta, Ramin Morshed, Jasper Wu, Ajay Ravindranathan, Anny Shai, Nancy Ann Oberheim Bush, Jennie Taylor, John de Groot, Javier Villanueva-Meyer, Melike Pekmezci, Arie Perry, Andrew Bollen, Philip Theodosopoulos, Manish Aghi, Edward Chang, Shawn Hervey-Jumper, David Raleigh, Aaron Diaz, Joseph Costello, Jennifer Clarke, Nicholas Butowski, Joanna Phillips, Mitchel Berger, Susan Chang, David Solomon
Journal: Neuro-Oncology (2024)

Abstract A subset of IDH-wildtype glioblastoma (GBM) undergo sarcomatous transformation to gliosarcoma at recurrence which is associated with a propensity for dural and calvarial invasion. However, the underlying biology of sarcomatous transformation and predictive biomarkers for these aggressive tumors are unknown. We performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent GBM from 106 patients. Eighteen patients (17%) developed sarcomatous transformation at recurrence as defined by fascicular growth, intercellular reticulin deposition, and immunohistochemical evidence of glial to mesenchymal transdifferentiation. Compared to conventional GBM, patients who developed gliosarcoma had shorter interval between initial surgery and first recurrence (8.3 vs. 11.2 months, p=0.002) and reduced overall survival (18.2 vs. 21.9 months, p=0.164). While there were no differences in sex, age, tumor location, or adjuvant therapy, we found differences in the molecular signatures of GBM that transformed to gliosarcoma at recurrence, including a significant enrichment in NF1, TP53, and RB1 alterations and an absence of EGFR amplification. GBM which underwent sarcomatous transformation were enriched for the Mesenchymal epigenetic class at initial surgery (69% vs. 25%) and became enriched for the novel Mesenchymal subclass B at recurrence (43% vs. 2%). Among approximately 850,000 interrogated CpG sites, we identified 1,503 and 2,090 CpG sites within gene regulatory regions that were significantly more hypermethylated or hypomethylated in those initial GBM that transformed to gliosarcoma at recurrence compared to those that did not. Gene Ontology biologic processes enriched in these differentially methylated genes include immune cell signaling, cell-cell adhesion, and TGF-beta signaling. Together, these findings reveal GBM which undergo transformation to gliosarcoma represent a biologically distinct subtype with aggressive clinical course. Enrichment for NF1 and RB1 alterations and differentially methylated immune cell and TGF-beta signaling suggests potential unique therapeutic vulnerabilities for affected patients.
EPID-21. PRIMARY INTRAMEDULLARY LYMPHOMA OF SPINAL CORD (PILSC): A SYSTEMATIC REVIEW OF CASE REPORTS AND CASE SERIES FROM 2000 TO 2023
Authors: Haseeb Mehmood Qadri, Asif Bashir
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND AND OBJECTIVE Primary CNS lymphoma accounts for three percent of all newly diagnosed CNS tumours and 1-3% of all non-Hodgkin’s lymphomas. The oncologic origin of primary intramedullary lymphoma of the spinal cord (PILSC) is an enigma. We aim to determine the clinical manifestations, disease course and management of PILSC. MATERIALS AND METHODS A comprehensive literature search using PubMed Central and Google Scholar, was done, retrieving 17 case reports and two case series of 21 patients with PILSC and included using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, published between 2000 and 2023. RESULTS About 90.48% patients inflicted with PILSC were adult, with male predominance, 61.90%. The most common complaint at presentation was neurological deficit of motor type in 32.14% patients. MRI proved to be helpful in 76.19% cases, with spinal cord enlargement and high signal intensity in 19.04% cases. Adjuvant chemotherapy and radiotherapy was acquired by 52.38% and 38.09% patients. Non-Hodgkin type was reported in 90.47% cases and Hodgkin lymphoma was seen in 9.52% patients. Diffuse large B cell lymphoma was culprit in 41.10% cases. Five out of 21 cases had variable post-operative complications. The average follow-up was 16.16 months. CONCLUSION PILSC is a multifaceted neoplasm in all its clinico-pathological aspects of presentation. Although rare, PILSC can involve adult and paediatric populations with a clear male preponderance. The MRI findings are not reliable to make a preliminary diagnosis. Like other lymphomas, the role of chemoradiotherapy is clearly more significant than surgical intervention in improving patient prognosis. Histopathologically, it can be Non-Hodgkin or Hodgkin, B-cell type or T-cell type and has a wide array of immunohistochemistry positivity.
EPCO-05. GENOMIC AND CLINICAL INSIGHTS FROM A LARGE-SCALE STUDY OF 172 RETINOBLASTOMAS
Authors: Malak Abedalthagafi, Azza Maktabi, Saleh Mesfer, Giorgio Zauli, Deepak Edward, Yang Liu, Robert Hoehndorf
Journal: Neuro-Oncology (2024)

Abstract Retinoblastoma, a pediatric ocular cancer, is the only central nervous system tumor visible without specialized tools, readily detectable with the naked eye. This rare childhood cancer is mainly driven by mutations in RB1 or MYCN amplification, posing significant challenges in pediatric oncology. We conducted whole exome sequencing on 172 retinoblastoma tumors along with matched blood DNA from 171 patients, which included 119 unilateral, 49 bilateral, and three trilateral cases. Our analysis identified pathogenic variants in RB1 in 76 patients and MYCN duplication in 79 cases, highlighting their crucial roles in the disease. Additionally, we found mutations in RPTOR and TSC2, components of the mTOR signaling pathway, in two patients. Notably, our copy number alteration analysis revealed recurrent arm-level changes, including gains on 1q (23.3%), 2p (20.9%), and especially 6p (41.3%), along with other changes such as 5p gain (8.1%), 17q gain (8.1%), and 16q loss (5.8%). Our findings link these genetic alterations to specific clinical features; for instance, 6p gains were associated with Rubeosis, subretinal seeds, and tumor LC beyond, while 17q gains were linked to Rubeosis. Furthermore, gene collapsing techniques identified MATR3 and CYP4F2 as additional novel retinoblastoma-related genes, and module identification analysis pinpointed retinoblastoma-associated modules including HLA-DRB1-CBL, LPAR2, RB1, and TRIM28. Our study, the largest cohort of its kind, underscores the importance of next-generation sequencing from understudied populations in uncovering the complex genetic landscape of retinoblastoma, emphasizing the potential of precision medicine to enhance therapeutic strategies and improve outcomes for retinoblastoma patients.
EPID-23. HISTORY OF TYPE III IMMUNE HYPERSENSITIVITY IMPROVES SURVIVAL IN GLIOBLASTOMA
Authors: Corey Neff, Christine Ballard, Mackenzie Price, Zhen Liu, Gino Cioffi, Jill Barnholtz-Sloan, Kyle Walsh, Peter Fecci, Quinn Ostrom
Journal: Neuro-Oncology (2024)

Abstract Preexisting atopy, particularly allergic rhinitis, is consistently associated with decreased risk of glioma, and there is evidence that preexisting autoimmune conditions may also decrease risk. Glioblastoma is both locally and systemically immunosuppressive and, unlike many other forms of cancer, its initiation is not strongly linked with chronic inflammation. Therefore, history of immune hypersensitivity could be associated with improved anti-glioma immunosurveillance. We leveraged Surveillance, Epidemiology and End Results (SEER) data combined with Medicare claims to investigate the effect of preexisting immune hypersensitivities on overall survival of glioblastoma patients receiving resection, radiation, and temozolomide (standard of care, or SOC) from 2008-2019. Patients &amp;lt;66 years of age, enrolled in Medicare Advantage, not continuously enrolled in Medicare Part A/B, missing follow-up, reported by autopsy/death certificate only, or who did not receive surgery were excluded. Prior history of immune hypersensitivity (≥6 months prior to primary cancer diagnosis) was identified by ICD-9/ICD-10 codes. Treatment pattern was determined using ICD-9/ICD-10 and HCPCS/CPT codes. Conditions were classified into broad immune hypersensitivity types: type I (IgE-mediated, including atopy), type II (IgG- or IgM-mediated), type III (immune complex-mediated, including lupus and rheumatoid arthritis), and type IV (cell-mediated). Survival comparisons were made using Cox proportional hazard models adjusted for demographics, extent of resection, and Charlson comorbidity score (excluding immune conditions) to estimate hazard ratios, 95% confidence intervals, and p-values. Overall, 44% of 3,426 glioblastoma patients who received SOC had an immune hypersensitivity (type I: 33%, type II: 4%, type III: 8%, and type IV: 15%). These conditions were significantly more common in females (47% vs 41%, p&amp;lt;0.001). After adjustment, only type III immune sensitivity was associated with improved OS (HR=0.81, 95% CI:0.71-0.92, p=0.002). These results suggest that underlying immune-complex mediated hypersensitivity may improve treatment response and prognosis in glioblastoma, and that these pathways could potentially be exploited for therapy.
EPCO-17. CARM1 METHYLATES GLIOBLASTOMA TUMOR SUPPRESSOR QUAKING TO REGULATE ITS TRANSCRIPTIONAL COACTIVATOR FUNCTION
Authors: Kaylene Lu, Tanner Wright, Seula Shin, Mark Bedford, Jian Hu
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) represents the most prevalent and deadly primary brain tumor in adults, and it remains highly refractory to current therapeutic interventions. Significant intratumor heterogeneity drives rapid invasion, immune escape, and therapeutic resistance. Therapeutic paradigms based on deconvoluting key molecular mechanisms driving gliomagenesis are urgently needed. Quaking (Qki, encoded by Qk) is frequently altered in GBM patients; Qk mutations or deletions occur in 35% percent of cases, and the Qki protein is absent in 50-60% of cases. Our lab has characterized Qki as important tumor suppressor in GBM, where deletion of Qk enables pre-malignant neural stem cells to expand outside their niche and develop into tumors that recapitulate human GBM. We discovered that Qki functions as a transcriptional coactivator of lipid metabolism genes, whereby Qki loss disrupts lipid homeostasis and compromises the integrity of various membrane structures. Several downstream processes governed by Qki have been delineated; however, upstream regulators of Qki have yet to be identified. Recurrent cancer mutations to specific Qki arginine sites implicate the dysregulation of arginine methylation, a common post-translational modification catalyzed by protein arginine methyltransferases (PRMTs). Leveraging in vitro methylation assays, we demonstrate that Qki is selectively methylated by the PRMT coactivator-associated arginine methyltransferase 1 (CARM1), specifically in the Quaking regulatory domain where cancer mutations are reported. We observe that Qki interacts with known CARM1 substrates, functioning in the transcriptional complex assembled by CARM1. Through mutagenesis studies, we identified arginine 242 (R242) and arginine 256 (R256) as specific CARM1-mediated methylation sites on Qki. Importantly, mutations to these sites compromise Qki’s activity as a transcriptional coactivator. Moreover, brain-specific deletion of CARM1 in vivo results in neurological phenotypes reminiscent of Qki deletion. Altogether, we provide evidence that CARM1 represents a novel tumor suppressor in GBM that functions through the arginine methylation of Qki.
EPCO-03. METABOLIC INSIGHT INTO GLIOMA HETEROGENEITY: MAPPING WHOLE EXOME SEQUENCING TO<i>IN VIVO</i> IMAGING WITH STEREOTACTIC LOCALIZATION AND DEEP LEARNING
Authors: Mahsa Servati, Aaron A Cohen-Gadol, Jason G Parker
Journal: Neuro-Oncology (2024)

Abstract Intra-tumoral heterogeneity (ITH) complicates the diagnosis and treatment of glioma, partly due to the diverse metabolic profiles driven by genomic alterations. While multiparametric imaging captures spatial and functional variations enabling ITH characterization, it falls short in assessing the metabolic activities underpinning phenotypic differences. This gap stems from the challenge of integrating easily accessible, co-located pathology and genomic data with metabolic insights. This study presents a multi-faceted approach combining stereotactic biopsy with clinical open-craniotomy for sample collection, voxel-wise analysis of MR images, regression-based GAM, and whole-exome sequencing. The aim is to demonstrate the potential of machine learning algorithms to predict variations in cellular and molecular tumor characteristics. This retrospective study enrolled ten treatment-naïve patients with radiologically confirmed glioma who underwent multiparametric MR scans (T1W, T1W-CE, T2W, T2W-FLAIR, DWI) prior to surgery. During craniotomy, at least one stereotactic biopsy was collected from each patient, with the screenshots of sample locations saved for spatial registration to pre-surgical MR data. Whole-exome sequencing was performed on flash-frozen tumor samples, prioritizing five glioma-related genes: IDH1, TP53, EGFR, PIK3CA, and NF1. Regression was implemented with a GAM using a univariate shape function for each predictor. Standard ROC analyses were used to evaluate detection, with AUC calculated for each gene target and MR contrast combination. Mean AUC for five gene targets and 31 MR contrast combinations was 0.75±0.11, with individual AUCs as high as 0.96 for IDH1 and TP53 with T2W-FLAIR and ADC, and 0.99 for EGFR with T2W and ADC. An average AUC of 0.85 across the five mutations was achieved using the combination of T1W, T2W-FLAIR, and ADC. These results suggest the possibility of predicting exome-wide mutation events from non-invasive, in vivo imaging by combining stereotactic localization of glioma samples with a semi-parametric deep learning method. This approach holds potential for refining targeted therapy by better addressing the genomic heterogeneity of glioma tumors.
PATH-31. COMPLETE TUMOR DISAPPEARANCE ON BRAIN MRI AFTER STANDARD CHEMORADIATION THERAPY FOR A MOLECULAR GLIOBLASTOMA
Authors: Jeffrey Ahn, Hansen Bow, Ann Eapen, Xiao-Tang Kong
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Glioblastoma (GBM) is the most aggressive brain tumor. The WHO CNS5 classification has newly incorporated three molecular criteria in diagnosing molecular GBM, including a concurrent gain of chromosome 7 and loss of chromosome 10 (+7/-10), TERT promoter mutation, or EGFR amplification. Despite new classification, the Stupp protocol remains the standard of care for all GBMs. However, it is unclear if the treatment response of the molecular GBM with low grade features is the same as the limited response of the traditional histopathological GBM. CASE REPORT A 74-year-old male presented in August of 2023 with new onset left-sided facial numbness. The numbness resolved spontaneously that day. Brain MRI was notable for a diffuse left frontal T2/Flair hyperintense lesion extending across the corpus callosum into the right frontal lobe without definite enhancement. Brain biopsy from 8 sites of the tumor demonstrated a subset of areas with mild hyper-cellularity, suggesting a low-density infiltrating glioma. However, TERT promoter mutation (-124C&amp;gt;T), was detected along with wild-type IDH1, supporting molecular GBM. Studies also found unmethylated MGMT gene promotor. Brain MRIs after 3 and 6 months showed no tumor progression. The patient has remained asymptomatic apart from baseline mild forgetfulness. He was started on the 6-week standard concomitant temozolomide and radiation therapy. Follow-up brain MRI after the above treatment showed complete imaging resolution of the tumor. DISCUSSION It is very rare for complete imaging resolution of GBM on brain MRI after standard 6-week chemoradiation therapy. Our case suggests that molecular GBM with low-grade features on imagine and pathology might have a better response to the standard treatment than traditional histopathological GBM even though the molecular GBM patient has unfavorable prognostic factors such as unmethylated MGMT and older age (&amp;gt;70 years old). Our experience emphasizes the heterogenous response of molecular GBM to the current standard treatment.
PATH-24. NOVEL MOLECULAR SUBTYPES IDENTIFIED IN INTRACRANIAL GERM CELL TUMORS SHOWED UNIQUE WHOLE-GENOME METHYLATION PROFILE
Authors: Bo Li, Xiaoguang Qiu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND By integrating whole-genome sequencing (WGS) and RNA-seq data, we found that intracranial germ cell tumors (IGCTs) can be divided into three distinct molecular subtypes: immune-hot, MYC/E2F, and SHH, each characterized by a unique profile of genomic abnormalities. To further define these subtypes, we subsequently performed whole-genome bisulfate sequencing (WGBS) on IGCT tumors METHODS Within our prior discovery cohort (n=110), DNA from 84 samples was available for profiling methylation levels using Whole Genome Bisulfite Sequencing (WGBS). Fastq data was aligned to the human reference genome (hg19), with duplicates removed, and DNA methylation was extracted using bismark pipeline (ver0.24.0). After quality control, weight methylation level was calculated for each CpG island as the sum of methylated reads divided by coverage. To identify IGCTs molecular groups, we applied hierarchical consensus k-means clustering to the most variant methylated CpG island (n=1000) across 84 IGCTs tumor tissues. The methylation level of RNA-seq subtypes was visualized to further clarify the molecular subtypes of IGCTs RESULTS Unsupervised clustering revealed that IGCTs can be divided into three groups based on the CpG island methylation levels: hypomethylation group (n=32), moderate methylation group (n=27), and hyper methylation group (n=25). The hypomethylation and moderate methylation group are predominantly observed in germinoma (&amp;gt;90%). In contrast, hypermethylation group comprises the majority of non-germinomatous germ cell tumors. Furthermore, these subgroups derived from methylation analysis are highly consistent with the molecular subtypes previously defined through gene transcription profile analysis. We observed that the majority of MYC/E2F subtype (24/33) belonged to the hypomethylation group, whereas the majority of immune-hot subtype (14/23) fell into the moderate methylation group. The SHH subtype was the most common within the hypermethylation group (18/26) CONCLUSIONS The three molecular IGCT subtypes showed unique methylation profile. These results indicate different mechanisms of tumorigenesis among the subtypes and pave the way for the clinical application of methylation-based subtyping.