tbuckley/cabot-search huggingface dataset:
BIOM-68. OUTCOMES IN PATIENTS WITH HIGH-GRADE MENINGIOMA (HGM): A MULTI-INSTITUTIONAL STUDY
Authors: Nasser Mohammed, Chirag Patel, Ashish Balar, Samuel Van Buskirk, Susan McGovern, Shaan Raza, Franco DeMonte, Leomar Ballester, Michael Youssef, Carlos Kamiya-Matsuoka
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade meningiomas (HGMs) are associated with increased risk of recurrence after primary treatment. This study aimed to evaluate factors affecting survival. METHODS We performed a multi-institutional retrospective chart review study of patients with HGM (defined as grade 2 or 3 meningioma) whose tumor had undergone next-generation sequencing. Statistical testing was performed in Stata/MP version 16.1 (StataCorp, College Station, TX) on the patients’ demographic, anatomic, clinical, and survival data (using Kaplan-Meier survivor function and long-rank test). Data are presented as mean±SD, median [interquartile range], or percent. Age/time reported in years. RESULTS There were 46 patients (45.7% female) with an age of 57.9±14.0 at initial HGM diagnosis. The most frequent HGM sites were middle cranial fossa (37.0%), frontal (28.3%), parietal (15.2%), posterior fossa (13.0%), parasagittal (10.9%), and petrous (10.9%). The most common presenting symptoms were headache (37.0%), seizure (23.9%), weakness (21.7%), vision changes (19.6%), memory issues (10.9%), and diplopia (10.9%). The most frequent gene mutations were in NF2 (58.7%), CDKN2A (13.0%), and TERT (8.7%). Median follow-up was 2.85 [1.4-7], during which time 65.2% of patients experienced recurrence. mPFS was 2.7 [0.83-6]. Kaplan-Meier analysis showed a mPFS of 5 [1.2-9] and 2.3 [0.8-3] in females and males, respectively (p=0.26). Age and Ki67 proliferative index at diagnosis did not significantly predict PFS. mOS was not reached (NR) [7-NR]. NF2 mutation status and presence of extracranial invasion did not significantly separate the PFS Kaplan-Meier curves on log-rank testing. However, the presence of NF2 mutation [mOS NR (5.2-NR) vs. NR (7-NR), p&amp;lt;0.0001], extracranial invasion [mOS 10 (2.4-NR) vs. NR (NR-NR), p&amp;lt;0.0001], and HGM recurrence [mOS NR (2.7-NR) vs. NR (7-NR), p&amp;lt;0.0001], were associated with shorter mOS. CONCLUSIONS These HGM patients experienced a high recurrence rate during the follow-up period. The presence of NF2 mutation, extracranial invasion, and recurrent HGM were associated with shorter OS.
STEM-14. INTEGRATED ANALYSIS OF GLIOBLASTOMA PROGENITOR SUBTYPES REVEALS A TUMOR-DERIVED STEM CELL POPULATION WITH NEURAL AND VASCULAR POTENTIAL
Authors: Elisa Fazzari, Daria Azizad, Matthew Li, Kwanha Yu, Weihong Ge, Patricia Nano, Ryan Kan, Jose Soto, Elizabeth Crouch, David Raleigh, Dimitri Cadet, Christopher Tse, Andrew Tum, Nicholas Bayley, Benjamin Deneen, Kunal Patel, David Nathanson, Aparna Bhaduri
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) exhibits a vast heterogeneity in cell types and states. Recent research highlights the reactivation of neurodevelopmental programs in GBM, contributing to this heterogeneity and, ultimately, therapy resistance. To characterize the landscape of progenitor cell types in human primary GBM, we compiled a meta-atlas of single-cell transcriptomes from seven published studies. Using a novel bioinformatic method for gene program analysis, we derived GBM gene expression meta-modules represented across multiple tumors. Our analyses validated previously described GBM gene programs and revealed novel tumor progenitor subtypes. Among these subtypes, we identified a tumor-derived stem cell population exhibiting a mixed vascular identity and transcriptional programs reminiscent of neural stem cells, which we identified as a putative neurovascular progenitor (NVP). To our knowledge, this population has not been previously described in GBM. We validated the existence of NVPs in situ using immunofluorescence from primary patient GBM samples. We then performed an enrichment for NVPs using fluorescence-activated cell sorting direct from patient tumors, followed by single-cell RNA sequencing. Examination of data from traditional model systems, including gliomaspheres and mouse GBM models, confirmed the preservation of NVP identity across systems. In vivo analysis of NVPs in multiple mouse models of GBM elucidate the influence of NVPs on GBM cell type composition, highlighting their role as multipotent progenitors. Finally, we utilized single-cell lineage barcoding to trace the progeny of patient-derived NVP cells in a novel organoid transplantation model, revealing NVP differentiation into vascular-like and neural-like cells. These data indicate that NVP cells play crucial roles in tumor plasticity and may represent a valuable therapeutic target for future exploration.
PATH-15. DIGITAL PCR ANALYSIS FOR DETECTING<i>TERT</i> PROMOTOR MUTATION IN MENINGIOMAS
Authors: Yuzaburo Shimizu, Takuma Kodama, Ryo Miyahara, Mario Suzuki, Osamu Akiyama, Ikuko Ogino, Akihide Kondo
Journal: Neuro-Oncology (2024)

Abstract The WHO Classification of Brain Tumors 5th edition requires the evaluation of TERT promoter mutations and CDKN2A/B homozygous deletions for the diagnosis of malignant meningiomas. Digital PCR (dPCR) is an emerging method for highly sensitive quantitative analysis. In this study, we performed TERT promoter mutation analysis using Pyrosequencing and dPCR in specimens with atypical and anaplastic meningiomas to investigate its utility and clinical significance. Adult patients diagnosed with atypical or anaplastic meningiomas after tumor resection between January 2009 and June 2023 were included. Genomic DNA was extracted from the excised specimens. TERT promoter mutations was analyzed by using the Pyrosequence and dPCR methods and compared with the clinical course. A total of 37 meningioma cases (13 males and 24 females) with 64 specimens were included. Atypical meningioma, grade II (WHO 2016) at diagnosis was 53 specimens (83%) and anaplastic meningioma, grade III (WHO 2016) was 11 specimens (17%). Of these, 7 (10%) were diagnosed with TERT promoter mutations by pyrosequencing, and one case with a low frequency (15%) of mutations by dPCR that tested negative by pyrosequencing had repeated recurrences in a short period of time. The dPCR method is highly sensitive in detecting low frequency TERT promoter mutations in tumor cell subpopulations and may contribute to the determination of treatment by predicting the malignant course of the disease. The results suggest that dPCR could contribute to therapeutic decision-making by detecting low-frequency TERT promoter mutations in tumor cell subpopulations.
CTIM-15. LOCOREGIONAL ADMINISTRATION OF B7-H3-CAR T CELLS EXPRESSING 41BB LIGAND FOR PEDIATRIC PATIENTS WITH PRIMARY CNS TUMORS: PRELIMINARY RESULTS FROM A PHASE I STUDY
Authors: Kelsey C Bertrand, Anna Kostecka, Kyle Smith, Katie Han, Jason Chiang, Soniya Pinto, Dana Tlais, Subodh Selukar, Brent Orr, Emily Hanzlik, Deanna Langfitt, Jean-Yves Metais, Timothy Lockey, Catherine Willis, Frank Fazio, Raghu Shanmugam, Liqing Tian, Tara Walhart, Yu Wang, Patricia Allmon, Scott Perry, Sarah Schell, Polly Adams, Meghan B Ward, Michaela Meehl, Salem Akel, Leigh Poston, Asim Bag, Stephen C Mack, Markos Leggas, Paul Klimo, Amar Gajjar, Paul Thomas, Giles W Robinson, Julie R Park, Jeremy Chase Crawford, Stephen Gottschalk, Paul A Northcott, Giedre Krenciute, Christopher DeRenzo
Journal: Neuro-Oncology (2024)

Abstract Outcomes for pediatric patients with diffuse midline glioma (DMG) and relapsed/refractory CNS malignancies remain poor. Loc3CAR is an ongoing, first-in-human, phase I clinical trial (NCT05835687) evaluating intracranial delivery of B7-H3-CAR T cells expressing 41BB ligand (B7-H3-CAR-T) for patients ≤21 years old with i) relapsed/refractory B7-H3+ CNS tumors (Cohort A), or ii) DMG post-radiation (Cohort B). Treatment included 6 intracerebroventricular B7-H3-CAR-T infusions administered over 7 weeks. Primary and secondary outcomes were safety and disease response, respectively. To date, 84% (21/25) of tumors screened were B7-H3+ (median H-score 200; range 0-300). CAR-T products were successfully manufactured for all patients enrolled on the collection/manufacture phase of the trial (n=11). Eight patients (7 cohort A; 1 cohort B) were treated with a total of 42 infusions on dose level 1 (1x107/3x107 CAR+ T cells/dose). Post-infusion, multiple participants exhibited neurologic findings suggestive of on-tumor CAR-T activation, including seizure, dysphasia, and localized pain. One patient, with a large tumor burden and high B7-H3 expression (H-score = 300), experienced a dose limiting toxicity with unresponsiveness and decorticate posturing approximately 16 hours post-infusion #1. Their clinical status rapidly improved following CSF removal and intravenous dexamethasone. Common adverse events attributable to B7-H3-CAR-T included headache (8/8), fever (7/8), and nausea/vomiting (5/8). Two of 7 (29%) evaluable patients achieved clinical benefit with stable disease at week 8. B7-H3-CAR-T and inflammatory cytokines were detected in the CSF from all patients evaluated. Circulating tumor DNA (ctDNA) was measured using a novel DNA methylation-based sequencing pipeline and detected in the CSF from 6/8 patients. For 2 patients, ctDNA abundance increased post-infusion, followed by clearance, suggesting subclinical antitumor activity. Single cell RNAseq of immune cells in the CSF from 1 patient analyzed to date, demonstrated abundant Tregs post-infusion #4, suggesting B7-H3-CAR-T may induce local anti-inflammatory responses. Overall, intracranially administered B7-H3-CAR-T have an acceptable safety profile and warrant continued exploration for pediatric patients with CNS tumors.
CNSC-24. REAL-TIME HIGH-DENSITY ECOG MAPPING OF SENSORIMOTOR REGIONS AND CONSCIOUSNESS DIFFERENTIATION IN PERI-ROLANDIC GLIOMA SURGERY
Authors: Priscella Asman, Sujit Prabhu, Mathew Hall, Israt Tasnim, Guiseppe Pellizzer, Shyreyas Bhavsar, Sudhakar Tummala, Nuri Ince
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Accurately mapping sensorimotor regions is crucial for preserving motor and sensory functions in the treatment of gliomas located in the peri-Rolandic areas of the brain. OBJECTIVE We examined the use of high-density electrocorticography (ECoG) for passive mapping of sensorimotor regions in treating peri-Rolandic gliomas by analyzing the spatial-temporal and spectral features of real-time somatosensory evoked potentials (SSEPs), and their spectral patterns in differentiating states of consciousness. METHODS During surgery, SSEPs were recorded using high-density ECoG on fourteen patients (n=14), both in anesthetized and awake states. Neural data from 0.6Hz median nerve stimulation were captured at 2.4kHz and processed in real-time using MATLAB Simulink. The system displayed SSEPs’ peak activations as a 2D heat map on a screen, particularly around the 20ms time point (N20), and generated the spectral power in the gamma range using the Stockwell transform. Accuracy in delineating the central sulcus (CS) was assessed using the ROC curve, and paired t-tests compared gamma oscillations between states of consciousness. RESULTS Patients consistently showed clear discrimination between anterior and posterior channels at the 20ms time point, with 93.6±14.9% accuracy. Color contrast delineated the CS, correlating with the sulcus in the 3D reconstructed magnetic resonance imaging of each patient. Late gamma (60–250 Hz) modulation occurred 50 ms after stimulation onset, extending up to 250 ms in the primary somatosensory area. It was suppressed in the anesthetized state and significantly increased in the awake state (delineation accuracy: 81±10.3% and 91±13.4%, respectively). CONCLUSIONS These results demonstrate that SSEPs and gamma modulations can delineate sensorimotor areas and assess consciousness, significantly impacting neurosurgical planning.
TMIC-08. PATTERNS OF PSTAT3 EXPRESSION IN REACTIVE ASTROCYTES OF BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER AND CORRELATIONS WITH OUTCOME
Authors: Alessia Pellerino, David Wasilewski, Luca Bertero, Alessia Andrea Ricci, Luca Mangherini, Andrea Bianconi, Diego Garbossa, Paola Cassoni, Neibla Priego, Manuel Valiente, Riccardo Soffietti, Roberta Rudà
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND pSTAT3 expression in peritumoral reactive astrocytes (RA) of brain metastases (BM) from breast cancer may favor a pro-metastatic environment and negatively affect the intracranial progression-free survival (i-PFS) (Pellerino, 2023). We aim to evaluate whether pSTAT3 plays the same role also in BM from NSCLC. MATERIAL AND METHODS Seventy-two BM specimens from NSCLC were identified from the biobank of Pathology Unit of University of Turin and Berlin. STAT3 expression was scored in RA of peritumoral tissue according to Priego et al. (Nat Med 2018). Clinical and molecular data, and i-PFS were retrospectively retrieved. RESULTS Median age was 64 years (IC95% 59-67). Immunohistochemistry for GFAP and pSTAT3 was feasible in 66/72 (91,6%). 42/66 (63,6%) had BM with druggable mutations, while 24/66 (36,4%) did not show any actionable mutations. Druggable mutations were as follows: 8/42 (19,1%) KRAS G12C, 6/42 (14,3%) EGFR, 5/42 (11,9%) ALK, 1/42 (2,4%) BRAFv600E, 31/42 (73,8%) PDL1 expression. Overall, 53/66 (80,3%) showed positive staining of pSTAT3: 22/66 (33,3%) with score 3, 21/66 (31,8%) with 2, 10/66 (15,1%) with 1, and 12/66 (19.8%) with 0 (negative). High pSTAT3 expression (score 2-3) was observed in 32/42 (76,2%) BM with actionable mutations and in 12/24 (50%) without actionable mutations (p 0,031). PDL1 expression was significantly correlated with high pSTAT3 expression (29/31, 93,5%), while most of BM without PDL1 (20/35 – 57,1%) had low or absent pSTAT3 (score 0-1) (p&amp;lt;0,0001). Median i-PFS was 12 months (IC95% 8-23): low pSTAT3 BM had a median i-PFS of 18 months (IC95% 14-28) versus 9 months (IC95% 8-12) for high pSTAT3 BM (HR 5,3;p 0,0001). CONCLUSION pSTAT3 overexpression in RA is associated with PDL1 expression and may negatively impact the i-PFS in BM from NSCLC. These data support the investigation of STAT3 inhibitor silibinin in preventing intracranial recurrence in a clinical trial (NCT05689619).
SURG-32. OPTIMIZING TUMOR TREATING FIELDS THERAPY FOR FIRST RECURRENT GLIOBLASTOMA WITH SKULL REMODELING SURGERY. FINAL RESULTS FROM OPTIMALTTF-2, A MULTI-CENTER, RANDOMIZED, CLINICAL TRIAL
Authors: Nikola Mikic, Jane Skjøth-Rasmussen, Frantz Rom Poulsen, Rene Johannes Laursen, Slavka Lukacova, Søren Møller, Charlotte Aaquist Haslund, Rikke Hedegaard Dahlrot, Ole Skeidsvoll Solheim, Tora Skeidsvoll Solheim, Jens Christian Hedemann Sørensen, Eric T Wong, Anders Rosendal Korshøj
Journal: Neuro-Oncology (2024)

Abstract Studies indicate that increasing the electric field intensity of Tumor Treating Fields therapy (TTFields) may prolong survival for glioblastoma (GBM) patients. Skull remodeling surgery (SR-surgery) aims to increase electric field intensity by 30-100% by removing the poorly conductive skull, and OptimalTTF-1 (pilot trial) concluded that SR-surgery was safe with a median overall survival (mOS) of 15.5 months for first recurrence GBM (rGBM). OptimalTTF-2 is a 1:1 randomized, comparative, multi-center, investigator-initiated, interventional clinical phase 2 trial investigating the efficacy and safety of TTFields and standard of care with or without SR-surgery for 84 rGBM subjects, with a planned interim analysis after enrollment of the first 52. Randomization is solely for SR-surgery and involves five burr holes of 15mm each in diameter, located in the skull between the tumor and the transducer arrays. The trial was nationwide in Denmark and active from 2020-2024. Major eligibility criteria include age ≥18 years, histopathological confirmed first recurrence of supratentorial GBM, and KPS ≥70. The primary endpoint is OS after 12 months (OS12), while secondary endpoints include PFS, QoL, ORR, QoL, KPS, steroid dose, and toxicity. The trial recruited 58 subjects and 52 had follow-up of 12-months or longer. Randomization was balanced and both arms had a median age of 59 years and no statistical difference in prognostic markers. Intent-to-treat analysis revealed the following for the intervention and control respectively, OS12 55% [95%CI 37-74%] vs. 45% [95%CI 27-64%](p=0.4), mOS 12.2 [7.9-19.1,95%CI] vs. 11 [6.5-17.1, 95%CI] months, and PFS 4.5 [3.4-9.5,95%CI] vs. 3.5 [3-6.4,95%CI] months. All the secondary outcomes were statistically insignificant. The trial was terminated early after interim analysis indicated no survival benefit from SR-surgery and a conditional power calculation that showed a low expected survival benefit for the planned cohort of 84 subjects. Post hoc analysis examining potential negative outcome modifiers is needed.
IMMU-25. B-CELL BASED THERAPY (BVAX) PRODUCES ANTIBODIES TO SUPPRESS GLIOBLASTOMA TUMOR MIGRATION AND INVASION
Authors: Joshua Katz, Brandyn Castro, Si Wang, Victor Arrieta, Hinda Najem, Gustavo Ignacio Vazquez-Cervantes, Ian Olson, David Hou, Mark Dapash, Hanxiao Wan, Aida Rashidi, Tarlan Arjmandi, Zainab Shaikh, Grace Jones, Leonidas Platanias, Kathleen McCortney, Craig Horbinski, Roger Stupp, Peng Zhang, Atique Ahmed, Adam Sonabend, Amy Heimberger, Maciej Lesniak, Cécile Riviere-Cazaux, Terry Burns, Jason Miska, Mariafausta Fischietti, Catalina Lee-Chang
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) presents as a highly aggressive and malignant brain tumor with limited treatment options. Despite the availability of existing therapies, the invasive characteristics of GBM frequently result in tumor recurrence and poor prognosis. We previously developed a B-cell-based therapy (BVax) that has shown promising results in its ability to induce therapeutic responses in preclinical models of GBM. Our research revealed potency of BVax can be attributed to its robust antigen-presenting capability, cognate antigen specificity with T cells, and ability to generate tumor-reactive antibodies. The present study aims to characterize the unique antigenic reactivity of BVax-derived antibodies by evaluating their immunological effects and therapeutic potential in both murine models and GBM patient-specific samples. Leveraging CD45.1 and CD45.2 congenic mouse models, we first revealed that BVax preferentially migrated to glioma-bearing brains upon intravenous injection, resulting in a CD38+CD20-CD19+ plasmablast phenotype. To further characterize the reactivity of BVax-derived immunoglobulins (Ig), we utilized proteomic analysis and identified preferential targets of Gelsolin, Fibronectin, Versican, Fibrinogen, and collagen type IV alpha, commonly associated with cell motility and the extracellular matrix. Microdialysis data confirmed the increased presence of many of these BVax-derived Igs-recognized antigens in tumor regions compared to normal brain regions in GBM patients. Utilizing purified BVax-derived antibodies from patient specimen, in vitro cell motility assays demonstrated a significant prevention of the invasion and migration of cell lines from patient derived xenograft (PDX). In this study, we concluded that BVax elicits antitumor activity through targeted migration to tumor-bearing regions, differentiation into plasmablasts, and robust secretion of specific Igs that retain the ability to inhibit functionalities associated with cell invasion and migration. Here, we present the first in-depth study that characterizes GBM patients’ antibody reactivity, specifically a subset of inflammatory B cells (BVax) with therapeutic effects that offer an indication for a new direction of immunotherapies.
EXTH-72. INTEGRATED MULTIOMIC ANALYSIS OF ISOGENIC EGFRVIII MODELS OF GBM REVEALS EXPLOITABLE THERAPEUTIC VULNERABILITIES
Authors: Benjamin Lin, Abigail Shelton, Kasey Skinner, Erin Smithberger, Julia Ziebro, Ryan Bash, Steven Angus, Michael East, Gary Johnson, Frank Furnari, C Ryan Miller
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor with an abysmal 15-month median survival. Therefore, novel therapeutic interventions are urgently needed. EGFR is a receptor tyrosine kinase that is mutated in over 50% of GBM and is a logical target for precision oncology approaches. While aberrant EGFR signaling has been successfully targeted in other cancers, early attempts to target EGFR in GBM clinical trials have not been successful. Since these early trials, several studies have revealed that GBM EGFR biology is unique and cannot be generalized from other EGFR-driven neoplasms. To better understand EGFR biology in a GBM-specific context, we have characterized the GBM transcriptome with RNAseq, the epigenome with CUT&amp;RUN, and the kinase proteome with Multiplexed inhibitor beads with Mass Spectrometry (MIB-MS), collectively referred to as ‘multiomics’, after modeling EGFR resistance. An isogenic mouse astrocyte (mAc) model of GBM was genetically engineered to overexpress EGFRvIII (CEv3), the most common EGFR mutation in GBM. Expression of EGFRvIII induces a unique multiomic profile that mediates many hallmark cancer phenotypes including proliferation and stemness. Chronic EGFR resistance was modeled both in vitro and in vivo through continuous exposure to erlotinib or gefitinib, EGFR tyrosine kinase inhibitors (TKI). Additionally, acute EGFR resistance was modeled using a single exposure to EGFR TKI afatinib or neratinib in vitro over a 48-hour time course. Preliminary multiomic characterization of these data has revealed several targets that can be further investigated for therapeutic exploitation. Further investigation into these targets using orthotopic allografts with CEv3 cells shows that combinatorial therapy with neratinib and abemacilib, a CDK inhibitor, significantly (p &amp;lt; 0.001, n= 20 mice per group) extends survival (56 days) compared to neratinib alone (31.5 days). Future integrated multiomic analysis aims to elucidate the synergistic relationship between neratinib and abemacilib.