tbuckley/cabot-search huggingface dataset:
PATH-05. CLINICAL, PATHOLOGICAL AND MOLECULAR DISEASE CHARACTERISTICS OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Emilie Le Rhun, Andrea Bink, Joerg Felsberg, Dorothee Gramatzki, Sebastian Brandner, Jamal K Benhamida, Antje Wick, Joerg C Tonn, Malte Mohme, Ghazaleh Tabatabai, David Capper, Matija Snuderl, Evangelia Razis, Michael Ronellenfitsch, Nicolas Neidert, Ho-Keung Ng, Ute Pohl, Tejus Bale, Stefanie Quach, David Rieger, Ulrich Schüller, Julia Onken, Katharina Drueschler, Claude Alain Maurage, Luca Regli, Estelle Healy, Maya Graham, Tibor Hortobagyi, Simon Paine, Olaf Ansorge, Leslie Bridges, Tereza Lausova, Valentina Medici, Philipp Sievers, Daniel Schrimpf, Wolfgang Wick, Felix Sahm, Guido Reifenberger, Andreas von Deimling, Michael Weller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse hemispheric glioma, histone 3 (H3) G34-mutant, is a pediatric-type diffuse high-grade glioma newly defined in the World Health Organization (WHO) classification of central nervous system tumors 2021. Here we sought to define the prognostic roles of clinical, neuroimaging, pathological, and molecular features of these tumors. METHODS We retrospectively assembled a cohort of 114 patients with diffuse hemispheric glioma, H3 G34-mutant and profiled the imaging presentation and the molecular landscape of their tumors. RESULTS Compared with glioblastoma, H3 G34-mutant tumors exhibited less avid contrast enhancement, less necrosis and less edema on MRI. Comprehensive analyses of mutational and DNA copy number profiles revealed recurrent mutations in TP53 and ATRX, homozygous deletions of CDKN2A/B, and amplifications of PDGFRA, EGFR, CCND2, and MYCN. MGMT promoter methylation was detected in 79 tumors (75%); 11 tumors (13%) showed DNA copy number profiles suggestive of circumscribed deletions on 10q26.3 involving the MGMT locus. Median survival was 21.5 months (95% CI 15.3-27.7) and eight patients (7.0%) survived for ≥ five years. Female sex, gross total resection, and MGMT promoter methylation were positive prognostic factors on univariate analysis. Among radiological, pathological and molecular features, absence of pial invasion, and presence of microvascular proliferation and CDK6 amplification were positive prognostic factors on univariate analyses. CONCLUSION This study refines the clinical and molecular landscape of H3 G34-mutant diffuse hemispheric gliomas. Dedicated trials for this novel tumor type are urgently needed.
PATH-47. AGE-, SEX-, AND GRADE-ASSOCIATED MOLECULAR DIFFERENCES IN A MULTI-INSTITUTIONAL COHORT OF CHOROID PLEXUS TUMORS
Authors: Erik Williams, Richard Hickman, Sakir Gultekin, Tareq Juratli
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Choroid plexus tumors (CPT) are central nervous system tumors where prognosis has been correlated to histologic grade, with aggressive clinical behavior and reduced survival rate in higher grade cases. Here, we present a genomic survey of a large multi-institutional cohort of CPTs across all grades. MATERIAL AND METHODS Fifty-eight CPT samples were analyzed by comprehensive genomic profiling (CGP) by a hybrid capture-based DNA sequencing platform (FoundationOne®CDx). Pathology reports, histopathology reviews, and patient clinical data were assessed. RESULTS Our cohort included 11 choroid plexus papillomas (CPP; grade 1), 16 atypical CPP (grade 2), and 31 choroid plexus carcinomas (CPC; grade 3). Males were slightly more affected than females (31 vs. 27 cases). Median patient age at tissue sampling was 11 years (range: 1–72 years). Median age of patients with CPC was younger at 3 years compared CPP at 34 years (p &amp;lt; 0.01). Genomic analyses identified three frequent, mutually exclusive mutations in TP53, TERTp, and DAXX. TP53 mutations (n = 15, 26%) were significantly more prevalent in CPC (n=14 CPC, p=0.0003), and were identified predominantly in children (n=12 CPC at &amp;lt;20 years). By contrast, TERT promoter mutations (TERTp; n = 5, 8.6%) were identified exclusively in CPP (p=0.019), predominantly grade 2 (4 of 5 cases), and exclusively in adult patients, with a median age of 48 years. DAXX mutations (n=4, 6.9%) were more common in CPC (n=3). Other alterations included PTEN (n=4, all adults) and MYCN amplification (n=3, all children &amp;lt;6 years), both exclusively in CPC. In 21 cases, including 9 out of the 11 Grade 1 CPP, no known cancer mutation was detected. CONCLUSION This study provides comprehensive genomic profiling of CPTs, highlighting distinct genetic alterations associated with different histological grades and patient demographics. These findings may inform future research and therapeutic strategies targeting specific molecular pathways in CPTs.
DISP-20. SEX DIFFERENCES IN MENINGIOMA AGGRESSIVE BEHAVIOR IN RURAL POPULATIONS: A GEO-ECOLOGICAL RISK ASSESSMENT OF MENINGIOMAS IN A SINGLE RURAL HEALTH CARE SYSTEM
Authors: Haadi Ali, Na Tosha Gatson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cause for health outcome disparities in rural populations is multifactorial. These populations are potentially more vulnerable due to rural area environmental policies and practices. Environmental justice populations (EJP) are designated by the Environmental Protection Agency as at risk for generational exposer to environmental contaminants. We assessed these population for an association between EJP density and aggressiveness of indolent brain tumors. Meningiomas are the most common benign intracranial tumor and have a female predominance. We evaluated meningioma patients in a large rural health system for oncogenic risk associated geo-ecological factors. METHODS A retrospective review of 415 pathology confirmed CNS WHO grades 1-3 meningiomas cases between 2007 – 2017 within the Geisinger Health system in Pennsylvania. Cases were mapped by county for meningioma incidence, tumor grade, and tumor recurrence. Counties were rated for EJP density. We mapped geographic areas with a higher meningioma incidence, grade, and rates of recurrence, and evaluated sex-predilections. RESULTS Seventy-three percent of tumors were WHO grade 1 (n=303), 23.4% (n=97) were grade 2, and 3.6% (n=15) were grade 3. The highest incidence of meningiomas were localized to higher density EJP counties that bordered riverbeds, Lackawanna and Luzerne. Females had a 3.5:1 predominance as compared to males. The grade 1 10-year progression free survival rate was 54.7% in Luzerne, Columbia, and Montour counties (moderate to high density EJP). Males in high EJP counties had a 12% increased risk for developing high grade meningiomas. Males aged 51-60 were more likely to develop a grade 2 or 3 meningioma as compared to males aged 61-70 in these counties. Females aged 50-60 more likely had grade 1 meningiomas but demonstrated consistently increasing risk for recurrence every decile. CONCLUSIONS Pennsylvania high density EJP counties (especially along the Lackawanna River supply) have a disproportionate risk for aggressive meningiomas and lower progression free survival as compared to national averages. A sex-discrepancy exists for males in these areas to have the most aggressive tumors.
RADT-43. RADIOSURGERY FOR BRAIN METASTASES FROM GYNECOLOGICAL PRIMARIES: AN INSTITUTIONAL PERSPECTIVE OF 58 METASTATIC LESIONS
Authors: Sanjeev Sreenivasan, Jessica Jung, Emel Calugaru, Michael Schulder, Anuj Goenka
Journal: Neuro-Oncology (2024)

Abstract Stereotactic radiosurgery (SRS) is being increasingly employed in the treatment of brain metastases. The evidence of radiological response of metastatic lesions from gynecological primary is lacking in literature. To assess the response rate of metastatic lesions to gamma knife SRS over a longitudinal follow-up period, a single centre prospectively maintained database was analysed retrospectively from 2014 to 2024. Lesion volumes were contoured at each follow up scan using Leksell Gammaplan software. Response assessment in neuro-oncology (RANO) criteria was used to assess radiological tumor response rates. Fifteen patients with 58 lesions were included. Average duration of radiological follow-up available was 16.7 months. The primary gynecological source of brain metastases in patients were cervical(n=4), ovarian(n=7), endometrial(n=3) and vulvar (n=1). Single fraction SRS was used for 49 lesions (range 16-20 Gy) and hypofractionated SRS for 9 lesions (8Gy x 3 to 9Gy x3). Average time to complete response was 9.01 months (range 1-25.7). The average follow-up for lesions with partial response was 12.2 months (range 1 -32) As per RANO criteria, complete response was seen in 33(56.9%) lesions and partial response in 25(43.1%). At 6month follow up, complete response was seen in 58.49% (n=31) of the lesions available(n=53) for assessment and partial response in 41.51%(n=22). At 18-months, complete response was seen in 66.67%(n=22) and partial response in 33.33%(n=11). Within pathological subgroups, endometrial (60%,n=3) primary showed higher rate of complete response at 6months than ovarian (52.7%,n=19), vulvar (50%, n=1) and cervical (40%,n=6) subgroups. Brain metastases from ovarian primary source were most encountered and endometrial metastases showed highest response rates to SRS. Six month and 18-month response rates were better than previously reported literature.
INNV-02. BRAINMETS: A CLINICIAN-FRIENDLY SOFTWARE TO MANUALLY SEGMENT BRAIN METASTASES AND DETECT PRIMARY TUMOR ORIGIN USING DEEP LEARNING
Authors: Suhrud Panchawagh
Journal: Neuro-Oncology (2024)

Abstract Estimates suggest that around 20%-40% of cancer patients are affected by brain metastases. A subset of these patients first present with central nervous system manifestations with an unknown primary. The issue then arises regarding which region of the body should be imaged, if not the entire body, exposing the patient to more radiation. To address this issue, streamline workflows, and save precious time, we developed a software clinicians can use to identify primary tumor locus. “BrainMets” is a user-friendly software that handles a DICOM input, allows the user to segment the region(s) of interest manually, and uses a deep learning model to predict the most likely tumor origin. The model is a mixed-effects neural network pre-trained on radiomic features from open-source data by Ocaña-Tienda et al. (2023) using 637 high-resolution imaging studies from 10 different medical centers with an accuracy of 90.5%, precision of 92.7%, recall of 87.8%, and F1 score of 90.2%. The software leverages the open-source software 3D-Slicer to help segment regions of interest, extract radiomic features, and make predictions. It is built using Flask, a Python package for backend development. The frontend user interface is created using HTML/CSS and Bootstrap. The “BrainMets” software thus strives to enhance diagnostic workflow significantly, reduce appointment times for scans, and improve patient experience. Future enhancements include integrating more AI models, improving healthcare IT system compatibility, and updating datasets to boost predictive accuracy and generalizability. This tool sets a new standard in personalized medicine, optimizing treatment strategies for cancer patients with brain metastases. As adoption increases, it could substantially improve patient outcomes and reduce healthcare costs associated with misdiagnosis and overtreatment. Further research and development will focus on expanding its applicability across various types of cancers.
BIOM-76. EXPLORING CSF MICRORNA SIGNATURES AS DIAGNOSTIC BIOMARKERS IN IDH-WILDTYPE DIFFUSE GLIOMAS
Authors: Maryam Pirhoushiaran, Kamilah Walker-Charles, Satwik Putluri, Nehal Patel, Daniel H Wang, Srividya Arjuna, Antonio Dono, Sophia Nguyen, Jason T Huse, Brittany C Parker Kerrigan, Yoshua Esquenazi, Chirag B Patel, Frederick F Lang, Leomar Y Ballester
Journal: Neuro-Oncology (2024)

Abstract The most prevalent malignant tumors of the central nervous system are adult-type diffuse gliomas. Isocitrate dehydrogenase (IDH) mutations are identified in a subset of diffuse gliomas, leading to two distinct subtypes of gliomas: IDH-wildtype and IDH-mutant. In comparison to IDH-mutant gliomas, IDH-wildtype gliomas tend to be associated with a more rapid progression and lower overall survival rates. The analysis of differentially expressed microRNAs (DE-miRNAs) in cerebrospinal fluid (CSF) of IDH-wildtype diffuse gliomas could provide an effective and non-invasive approach to assist in the early diagnosis, classification, and management of the disease. Extracellular vesicle (EV)-derived miRNAs obtained from the CSF of 11 patients with IDH-wildtype diffuse gliomas and 8 controls were analyzed by microRNA sequencing (miRNA-seq). DE-miRNAs were defined using p-value≤0.05 and absolute log2 fold change (log2FC) ≥1. Candidate DE-miRNAs were validated by qRT-PCR in 24 samples (15 IDH-wildtype vs. 9 control) using the 2-ΔΔCT method, followed by receiver operating characteristic (ROC) curve analysis. Hsa-miR-24-3p was used as the internal control. miRNA-seq analysis identified hsa-miR-484, hsa-miR-223-3p, hsa-miR-1246, hsa-miR-323a-3p, hsa-miR-106b-3p, hsa-miR-21-5p, hsa-miR-15a-5p, has-miR-15b-5p, and hsa-miR-92a-3p among the top 20 upregulated miRNAs in the CSF of patients with IDH-wildtype diffuse gliomas. Further analysis by qPCR showed that patients with IDH-wildtype diffuse gliomas had significantly higher levels of has-miR-21-5p (2.28 ± 2.33) compared to control subjects (-2.22e-007 ± 1.08, p=0.012). The ROC curve analysis revealed an area under the curve (AUC) of 0.84 (95% CI, 0.68-1.0) for has-miR-21-5p CSF levels in distinguishing IDH-wildtype diffuse gliomas from control subjects. EV-derived miRNAs in CSF, including has-miR-21-5p, have the potential to distinguish IDH-wildtype diffuse gliomas from control individuals in a minimally-invasive manner and serve as diagnostic biomarkers.
BIOM-46. REAL-WORLD EXPERIENCE WITH CIRCULATING TUMOR DNA IN CEREBROSPINAL FLUID IN PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Richard Hickman, Alexandra M Miller, Bridget M Holle, Justin Jee, Si-Yang Liu, Dara Ross, Helena Yu, Gregory J Riely, Christina Ombres, Alexandra Gerwitz, Anne S Reiner, Subhiksha Nandakumar, Adam Price, Thomas J Kaley, Maya S Graham, Chad Vanderbilt, Satshil Rana, Katherine Hill, Kiana Chabot, Carl Campos, Khedoudja Nafa, Neerav Shukla, Matthias Karajannis, Bob Li, Michael Berger, Marc Ladanyi, Elena Pentsova, Adrienne Boire, A Rose Brannon, Tejus Bale, Ingo K Mellinghoff, Maria E Arcila
Journal: Neuro-Oncology (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 &amp;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.
DDEL-13. ENHANCING THE EFFICACY OF THE BBB-PENETRANT PEPTIDE-DRUG CONJUGATE PT(IV)-M13 WITH THE KINASE INHIBITOR BIA TO IMPROVE INTRA-TUMORAL DELIVERY AND INHIBIT DNA REPAIR
Authors: Philippa Vaughn-Beaucaire, Jorge Luis Jimenez Macias, Edward Miller, Bradley Pentelute, Sean Lawler
Journal: Neuro-Oncology (2024)

Abstract The blood-brain and blood-tumor barriers (BBB and BTB) constitute major obstacles to effective GBM therapy. These barriers impede the penetration of the great majority of pharmacological agents into brain tumors. This study introduces a dual-modality approach aimed at enhancing drug delivery to GBM through manipulating BTB permeability and facilitating targeted drug delivery through a novel BBB penetrant drug conjugate. First, we investigated the effects of the broad specificity kinase inhibitor 6-bromo-indirubin-3’-acetoxime (BIA), a derivative of the natural medicinal indirubin, on BTB integrity. These studies revealed that BIA diminishes trans-endothelial electrical resistance and reduces the expression of VE-cadherin in human cerebral microvascular endothelial cells (hCMEC/D3), indicating a loosening of tight junctions. This effect was also observed in mouse GBM models, suggesting a BIA-induced increase in BTB permeability, enhancing the intra-tumoral accumulation and efficacy of non-brain-penetrant therapeutic agents in murine GBM models. Secondly, we have developed Pt(IV)-M13, a perfluoroaryl stapled variant of the cell-penetrating peptide TP10 conjugated to Pt(IV), a prodrug form of cisplatin. This conjugate demonstrates an ability to penetrate the BBB, enhancing drug delivery while limiting exposure to healthy brain tissue, Pt(IV)-M13 exhibits a promising cytotoxic effect on GBM cells, sparing non-tumorous cells, and increases the survival of GBM tumor-bearing mice significantly compared to controls. Our data includes quantitative analysis of platinum accumulation in tumor tissues versus non-targeted regions, highlighting the specificity and potential of this approach. Furthermore, we have found that BIA synergizes with Pt(IV)-M13 in vitro, via inhibition of DNA repair, and are currently investigating the safety and efficacy of administering BIA in conjunction with Pt(IV)-M13 in vivo. This novel strategy holds potential to significantly impact the clinical management of GBM, emphasizing the importance of targeting the BTB in future therapeutic strategies.
CTNI-69. A FIRST-IN-HUMAN FEASIBILITY STUDY TO EVALUATE THE SAFETY OF SELECTIVE YTTRIUM-90 ENDOVASCULAR RADIOTHERAPY IN PATIENTS WITH RECURRENT GBM: INTERIM RESULTS FROM THE FRONTIER TRIAL
Authors: Samdeep Mouli, Sameer Ansari, Erik Middlebrooks, John Boockvar, Jonathan Weinstein, Yafell Serulle, Nicholas Butowski, Kazim Narsinh, Paul Kennedy, Amanda Eldridge, Franco Basarabescu, Kianna Elahi-Gedwillo, Riad Salem, Roger Stupp
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Yttrium-90 (Y90) microsphere treatment is an FDA-approved endovascular radiotherapy for Hepatocellular Carcinoma; however, extra-hepatic experience is limited. The FRONTIER trial (NCT05303467) is a first-in-human study conducted under an IDE from the FDA evaluating the safety and feasibility of intra-arterial Y90 endovascular radiotherapy in patients with recurrent glioblastoma (rGBM). METHODS The primary endpoint is the incidence of treatment-related limiting toxicities through 30 days, in 12 patients with rGBM. Eight subjects (50% male) with non-dominant hemisphere rGBM have been enrolled to date, with 6 patients reported herein. The treatment region, encompassing the recurrent lesion, excluding eloquent regions, and defined using cerebral angiography-MRI fusion, was selectively targeted with 40±4Gy. Immediate post-treatment imaging included MRI to evaluate acute treatment-related effects and Y90-PET to evaluate the absorbed dose distribution. Neurological assessments were performed pre- and post-treatment. Analysis of post-contrast T1w enhancing tissue volume (T1wvol) inside and outside the treated region was performed longitudinally. RESULTS All patients tolerated the procedure well and were discharged the following day. No decrease in neurological function and no limiting toxicities were reported through 30 days. Post-treatment MRI revealed no device-related acute ischemia or hemorrhage. Mean absorbed dose to the treatment region was 42.1±2.4Gy, within 3% of the targeted value, suggesting technical feasibility. Mean tumor absorbed dose within the treatment region was 65.1±22.6Gy most likely due to increased tumor perfusion in the treatment region. A reduction in T1wvol at 2m was observed in 4/6 patients, with the remaining 2 patients showing increased T1wvol. Disease progression by T1wvol occurred more rapidly outside the treatment region than within. All patients received subsequent therapy, with 2 patients receiving surgery 82 and 120 days post Y90 treatment. CONCLUSION Interim results in this first-in-human feasibility study demonstrated technical feasibility and no limiting toxicities through 30 days. Enrollment is ongoing. These data warrant additional investigation.
NCMP-21. COMPARATIVE ANALYSIS OF VENTRICULOPERITONEAL SHUNT PLACEMENT FOR POST-TREATMENT HYDROCEPHALUS FOLLOWING VESTIBULAR SCHWANNOMA MANAGEMENT: SURGICAL INTERVENTION VERSUS STEREOTACTIC RADIOSURGERY
Authors: Amirhossein Akhavan-Sigari, Amit R L Persad, Ahed H Kattaa, Yusuke S Hori, Sara C Emrich, Louisa Ustrzynski, Armine Tayag, David J Park, Steven D Chang
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Hydrocephalus may present in patients with vestibular schwannoma (VS) at initial diagnosis, primarily due to the obstructive effects of tumor mass on cerebrospinal fluid (CSF) dynamics. Notably, occurrences of hydrocephalus following either radiosurgery or surgical interventions have also been documented in clinical literature. OBJECTIVE To compare the clinical features of patients who have undergone surgical resection or radiosurgery for VS and subsequently developed hydrocephalus necessitating shunt placement. METHODS We conducted a retrospective analysis of patients diagnosed with VS who underwent management via surgery or radiosurgery at Stanford Medical Center between 1998 and 2024, focusing on those who subsequently required shunt placement. RESULTS A total of 30 patients with VS underwent shunt placement due to hydrocephalus after tumor treatment; 5 patients (16.7%) were managed with radiosurgery and 25 patients (83.3%) with surgery. The median age at treatment was 64 years versus 57 years for the radiosurgery and surgery groups, respectively. There were no significant differences in age, sex, tumor volume, largest diameter at treatment, and tumor Koos grades, between the two groups. Nonetheless, the median time from tumor treatment to shunt placement was significantly longer in the radiosurgery group compared to the surgery group (21.53 versus 1.17 months, p-value=0.002). Regarding CSF parameters, mean white blood cell (WBC) and red blood cell (RBC) counts prior to shunt placement was significantly higher in the surgery versus the radiosurgery group (WBC=83.6 versus 2.0/mm3, p-value=0.001, RBC=3453.4 versus 313.33/mm3, p-value=0.02). CSF protein and glucose were not significantly different between the groups. CONCLUSION The median time from VS treatment to shunt placement due to hydrocephalus was longer in the radiosurgery group compared to the surgery group. Furthermore, pre-shunt CSF WBC and RBC counts were higher in the surgery group. Future studies are needed to better understand treatment outcomes and optimize management strategies for these patients.