tbuckley/cabot-search huggingface dataset:
DNAR-15. GROUP 3 MEDULLOBLASTOMAS EXPLOIT A TRANSIENT MECHANISM OF TELOMERE REPAIR MEDIATED BY ZSCAN4 WHICH IS TARGETABLE FOR THERAPEUTIC BENEFIT WITH BRAIN-PENETRANT DRUGS
Authors: Jangham Jung, Bohyeon Yu, Aaron Diaz
Journal: Neuro-Oncology (2024)

Abstract All cancers need some mechanism of telomere repair. However, it is unknown how Group 3 (G3) medulloblastomas (MB) repair their telomeres, even though MB is the most common malignant brain tumor in kids and G3 is its most aggressive subtype. With rare exceptions, G3 MBs lack telomerase gain-of-function alterations or evidence of constitutive alternative-lengthening-of-telomeres pathway activation. We profiled tumors from N=38 MB patients from UCSF via single-nucleus RNA sequencing; 13 cases were also subjected to single-cell assay for transposase-accessible chromatin by sequencing, and 4 were subjected to single-cell cleavage under targets and tagmentation for H3K27ac. These data identified a network of gene enhancers that were specifically active in rhombic-lip progenitor-like MB cells, the putative G3 MB cell of origin. This program was driven by zinc finger and SCAN domain containing 4 (ZSCAN4), a gene reported to drive transient telomere repair during zygotic genome activation in early embryos. CRISPR inhibition of ZSCAN4 led to significant telomere shortening, telomeric DNA damage, telomere fusions, decreased proliferation, and increased survival of orthotopic xenografts. Conversely, ZSCAN4 over-expression induced significant telomere elongation, increased proliferation, and decreased survival in vivo. Analysis of endogenous-reporter cells indicated that ZSCAN4 is transiently expressed in response to telomere shortening and increases global histone acetylation by inducing chromatin-remodeling factors. Rebastinib targeted ZSCAN4, histone acetylation, and telomere repair, was brain penetrant, and significantly enhanced orthotopic-xenograft survival with no toxicity. Acetyltransferase inhibitor CPI-1612 was brain penetrant and extended xenograft survival with no toxicity. Our data support the hypothesis that G3 MBs exploit a transient mechanism of telomere repair mediated by ZSCAN4. Targeting ZSCAN4 or downstream histone acetylation is therapeutically viable. Pan-cancer whole-genome sequencing data showed that MBs have lower telomeric content than most other cancers. Thus, MBs may be particularly vulnerable to therapeutic strategies that inhibit telomere repair.
INNV-01. METASTATIC GLIOBLASTOMA TO THE LUNG TREATED WITH LENVATINIB
Authors: Carlen Yuen, Melike Pekmezci, Silin Bao, Xiao-Tang Kong
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is the most common malignant brain tumor. Despite its invasive nature, extra-cranial glioblastoma metastases are rare. We present a case of a 63 year-old woman with metastatic glioblastoma to the lung. Sarcomatous histology, a reported risk factor for disseminated disease, was found. Genomic alterations of TP53 mutation, TERT mutation, PTEN mutation, and +7/-10 were also uncovered. Early evidence suggests these molecular aberrations are common in metastatic glioblastoma. Treatment with third-line lenvatinib resulted in a mixed response. This case contributes to the growing body of evidence for the role of genomic alterations for predictive risk in metastatic glioblastoma. There remains an unmet need for treatment of metastatic glioblastoma.
RBIO-01. CHARACTERIZING THE TEMPORAL EVOLUTION OF BRAIN ARCHITECTURE DURING RADIOTHERAPY FOR GLIOBLASTOMA USING NONLINEAR IMAGE REGISTRATION
Authors: Nicholas DeWalt, Yuanguang Xu, Tony Wang, Jack Grinband
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Previous serial MRI studies following glioblastoma (GBM) resection reveal dynamic changes in the tumor cavity and surrounding tissue. However, the time course of these dynamics is unclear, especially in the immediate postoperative period. METHODS GBM patients (n=8) received three MRIs: within 72 hours post-resection, immediately preceding RT (RTstart), and at the RT midpoint (RTmid). The radiation field (RF) was based on the resection cavity (RC) and surrounding T2-FLAIR hyperintensities at the 72 hour MRI. Nonlinear image registration was performed across the two time intervals, allowing comparison between the intended radiation targets and the actual irradiated tissue. Dice coefficients (DRF and DRC), the relative volume of the RC (RCvol), and the volume of unintended iatrogenic radiation (IRvol) were measured at each timepoint, and IRvol was fitted to an exponential decay. RESULTS DRF showed modest reduction, with mean±SD of 0.97±0.02 at both RTstart and RTmid. In contrast, the RC showed more change, with mean DRC 0.63±0.13 and 0.60±0.12, and mean RCvol of 0.74±0.27 and 0.72±0.25 at RTstart and RTmid, respectively. DRF, DRC, and RCvol showed greater change during the first interval than the second (p=3.5x10-4, 4.1x10-4, and 0.1, respectively). The mean IRvol was 16.7±12.6 at RTstart and 21.7±12.8 at RTmid, with a time constant of -0.031 (95% CI=[-0.017, -0.060]), indicating that 80% of all voxels that receive unintended iatrogenic radiation moved into the radiation field by postoperative day 57, and 95% will have moved in by day 125. CONCLUSIONS Nonlinear registration demonstrated significant postoperative architectural changes, with most occurring in the first two months after surgery near the RC. This potentially suggests a role for adaptive planning during RT, particularly for protocols that focus on the RC rather than T2-FLAIR hyperintensities. Future prospective studies are needed to assess the role of adaptive radiotherapy for GBM.
SURG-12. CLINICAL OUTCOMES OF AWAKE SURGERY WITH INTRAOPERATIVE MRI FOR INSULAR GLIOMA
Authors: Shigeki Takada, Yasuhide Makino, Etsuko Yamamoto, Noritaka Sano, Masahiro Sawada, Masahiro Tanji, Yohei Mineharu, Takayuki Kikuchi, Yoshiki Arakawa
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Surgical resection of insular glioma remains challenging due to the complex functional involvement and the intricate vascularization of the insular lobe. We reviewed clinical outcomes of awake surgery with intraoperative MRI for insular glioma at our hospital. METHODS We retrospectively reviewed the records of 27 consecutive patients with insular gliomas who underwent surgical treatment between 2014 and 2024. The extent of resection (EOR), ischemic complication and Karnofsky Performance Status (KPS) at postoperative discharge were analyzed in the awake surgery (AS) group compared to the non-awake surgery (NAS) group. RESULTS There were basal ganglionic involvement (12 cases), Berger-Sanai zone III&amp;IV (10 cases), and I, II, III&amp;IV (6 cases). Surgical resection was performed in 24 cases (biopsy in 3 cases). Elective awake surgery: 18 cases (of which 5 were abandoned due to poor arousal); intraoperative MRI: 24 cases. Additional resection after intraoperative MRI review was performed in 10 cases. The followings were studied in 24 cases where surgical resection was performed. In characteristics, basal ganglionic involvement was significantly different (3 patients in AS group and 7 patients in NAS group, p=0.04). The mean EOR was 81.4% in AS group vs. 53.4% in NAS group (p=0.008). Ischemic complication rate on postoperative MRI was 15.4% (2 cases) in AS group and 9.1% (1 case) in NAS group; all of them had no permanent neurological symptoms. The deterioration of KPS at discharge was not found in both groups. CONCLUSION The clinical outcomes of insular glioma in awake surgery with intraoperative MRI in this study was comparable to those of the previous reports. It was indicated that awake surgery with intraoperative MRI contributes greatly to maximum safe resection for insular glioma.
DDEL-03. INTRANASAL DELIVERY OF PDGFRA-TARGETED NANOTHERAPEUTICS FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMA
Authors: Kentaro Mineji, Jun Watanabe, Eita Uchida, Savneet Kaur, Peng Zhang, Rintaro Hashizume
Journal: Neuro-Oncology (2024)

Abstract Pediatric high-grade glioma (pHGG) is the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Its anatomical location in the brainstem, infiltrative nature, and blood-brain barrier (BBB) limit surgical resection and the distribution of systemically administered drugs. Intranasal delivery (IND) is a noninvasive method that bypasses the BBB, by leveraging the unique anatomic connections of the olfactory and trigeminal nerve pathways with the nasal cavity. We previously demonstrated the efficacy of IND of nanoliposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor, irinotecan, LS-SN-38, in orthotopic human brainstem xenograft models. The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells leading to targeted drug delivery and reduced toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) plays a role in DMG oncogenesis and is expressed in as much as 70% of DMG by immunohistochemistry. In this study, we evaluated the effect of anti-PDGFRA monoclonal antibody-conjugated immunoliposome encapsulated SN-38 (PDGFRA-iLS-SN-38) in pHGG cell lines. PDGFRA signals were assessed in pHGG cells using western blotting. Cells were treated with rhodamine (Rho)-labeled PDGFRA-iLS and cellular uptake was confirmed with a fluorescent microscope. PDGFRA-iLS-SN38 had the additive effect on the LS-SN-38 in DIPG007 cells (PDGFRA positive), but not in SF8628 cells (PDGFRA negative) in vitro. We treated mice bearing human DMG xenografts with IND of PDGFRA-iLS-SN38. Tumor growth and response to therapy are quantitatively measured by bioluminescence imaging, and efficacy is assessed by survival analysis. Results of survival analysis will be reported at the meeting. PDGFRA-targeted nanotherapeutics represented a specific effect on glioma cells expressing PDGFRA, providing a promising therapeutic approach for targeting pHGG.
RTID-04. A MULTICENTER, RANDOMIZED, CONTROLLED PHASE 2B TRIAL OF SURVIVIN VACCINE SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY-DIAGNOSED GLIOBLASTOMA (SURVIVE)
Authors: Manmeet Ahluwalia, Michael Ciesielski, Ajay Abad, David Reardon, Ahmad Ozair, Atulya Khosla, Robert Aiken, Marissa Barbaro, Kaylyn Sinicrope, David Peereboom, Yazmin Odia, Andrew Brenner, Vyshak Venur, Ahmed Belal, Jingxin Qiu, Cathy Schilero, Danielle Casucci, Laszlo Mechtler, Robert Fenstermaker
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma cells express high levels of survivin protein, whose presentation by MHC class I gets recognized by antibodies and cytotoxic T-lymphocytes (CTLs). A phase 2a trial (NCT02455557) demonstrated a median overall survival (OS) of 25.9 months in newly-diagnosed glioblastoma (nGBM) patients with 15-amino-acid-peptide-conjugate survivin vaccine (SurVaxM), which also stimulated production of survivin-directed antibodies and anti-tumor CTL. This phase 2b trial aims to further investigate efficacy and safety of SurVaxM plus adjuvant temozolomide (TMZ) for nGBM. METHODS SURVIVE is an ongoing, multicenter, randomized, placebo-controlled, investigator- and patient-blinded, phase 2b trial that randomizes nGBM patients receiving standard-of-care therapies to either SurVaxM (SurVaxM arm) or saline (control arm) in 3:2 ratio at 15 sites. Included patients have age ≥18 years, normal organ function, KPS≥70, and receive surgical resection with ≤1cm3 residual MRI contrast enhancement within 72 hours post-resection plus TMZ. Patients with recurrent, multicentric, brainstem- or cerebellar-origin GBM are excluded as well as patients on TTFields or other immunotherapies. All patients undergo 3 phases: (1) vaccine priming (VP) phase, starting ≤4 weeks after completing chemoradiation – 4 doses of SurVaxM or placebo administered q2weeks; (2) TMZ phase, started after ≥1 VP dose; and (3) vaccine maintenance phase, started 8 weeks after VP, with SurVaxM or placebo given q8weeks. TMZ phase overlaps with VP and VM phases. Primary endpoint is median OS. Assuming 1-year-OS of 75% in SurVaxM arm, based on prior trials, and 60% for control, the required sample size is N=228; 137 in SurVaxM and 91 in control arm. Accounting for dropouts, we aimed to enroll 239 patients. A log-rank test stratified by KPS (70-80 vs 90-100), MGMT methylation status, and IDH mutation status will be used for analysis. Secondary endpoints are OS and PFS at 15, 18, and 24 months, median PFS, and toxicity. A single sequential OS-driven interim analysis is planned when 50% of deaths occur. Trial is fully enrolled (NCT05163080).
Correction to “Effectiveness of an unguided modular online intervention for highly anxious parents in preventing anxiety in their children: a parallel group randomised controlled trial” [The Lancet Regional Health – Europe, Volume 45, October 2024, 101038]
Authors: Abby Dunn, James Alvarez, Amy Arbon, Stephen Bremner, Chloe Elsby-Pearson, Richard Emsley, Christopher Jones, Peter Lawrence, Kathryn J Lester, Natalie Morson, Julia Simner, Abigail Thomson, Sam Cartwright-Hatton
Journal: The Lancet Regional Health - Europe (2024)
INNV-06. ADULT GLIOBLASTOMA WITH MISMATCH REPAIR DEFICIENCY FORMS A DISTINCT HIGH-RISK MOLECULAR SUBGROUP FOR WHICH TREATMENT WITH IPILIMUMAB-NIVOLUMAB SHOWS SURVIVAL ADVANTAGE
Authors: Maria-Magdalena Georgescu
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is the most frequent and malignant primary brain tumor. Although the survival is generally dismal for glioblastoma patients, risk stratification and the identification of high-risk subgroups is important for prompt and aggressive management. The G1-G7 molecular subgroup classification based on the MAPK pathway activation has offered for the first time a non-redundant, all-inclusive classification of adult glioblastoma. Five patients from the large, 220-patient prospective cohort showed germline mutations in mismatch repair (MMR) genes and significantly worse median survival (3.25 months post-surgery) than those from other subgroups or from the rest of the cohort adjusted for age. These tumors were assigned to a new subgroup, G3/MMR, a spin-off from the major G3/NF1 subgroup, as they generally show genomic alterations leading to RAS activation. An integrated clinical, histological, immunohistochemical and molecular analysis of the G3/MMR tumors showed distinct characteristics as compared to other glioblastomas, including those with iatrogenic high tumor mutation burden (TMB), warranting a separate subgroup. Among these, prior history of cancer, midline location or multifocality, presence of multinucleated giant cells, positive p53 and MMR immunohistochemistry, and specific molecular characteristics, including high TMB, alert to this high-risk G3/MMR subgroup. High TMB constitutes the criterium for treatment with immune checkpoint inhibitors in solid cancers. The FDA-approved first-line therapy for advanced non-small cell lung cancer and high-TMB colorectal cancer is with the dual ipilimumab-nivolumab regimen. One of the five G3/MMR subgroup patients received the dual ipilimumab-nivolumab regimen and survived much longer than the rest of the G3/MMR patients, setting a proof-of-principle example for the treatment of these very aggressive G3/MMR glioblastomas.
BIOM-01. <i>CDKN2A</i> HOMOZYGOUS DELETION HAS STRONGER PROGNOSTIC POWER THAN<i>IDH</i> MUTATION IN CNS WHO GRADE 4 GLIOMAS
Authors: Young Zoon Kim, Hyun Da Park
Journal: Neuro-Oncology (2024)

Abstract We conducted retrospective analysis of glioma cohorts in our institute. Medical records were reviewed for 142 glioblastoma patients for 15 years, and pathological slides were examined again for the updated diagnosis according to 2021 WHO classification of CNS tumors. The IDH mutation and CDKN2A deletion were examined by NGS analysis using ONCOaccuPanel®. Traditional prognostic factors were also examined. Mean follow-up duration was 27.5 months (ranged from 4.1 to 43.5 months) and mean overall survival (OS) was 19.4 months (95% CI 16.3 – 20.9 months). After the exclusion of 4 patients with poor status of pathologic samples, total 109 glioblastoma which were diagnosed by previous WHO criteria were changed into 26 (23.9%) astrocytoma, IDH-mutant, CNS WHO grade 4 and 83 (76.1%) glioblastoma, IDH-wildtype, CNS WHO grade 4. Among them, 61 patients (56.0%) had CDKN2A deletion. Group A was classified for 59 patients with IDH-wildtype and present CDKN2A deletion, group B was classified for 16 patients with IDH-mutant and present CDKN2A deletion, group C was classified for 48 patients with IDH-wildtype and absent CDKN2A deletion, and group D was classified for 13 patients with IDH-mutant and absent CDKN2A deletion. Group A had a mean OS of 15.70 months (95% CI 13.86 – 17.54 months), group B had a mean OS of 19.37 months (95% CI 13.43 – 25.30 months), group C had a mean OS of 22.63 months (95% CI 20.10 – 25.17 months), and group D had a mean OS of 33.38 months (95% CI 29.35 – 37.40 months). Multivariate analysis showed IDH mutation (mutant vs. wildtype; HR 6.358), and CDKN2A deletion (absence vs. presence; HR 13.452). The presenting study suggest that CDKN2A deletion should play a powerful prognostic role in CNS WHO grade 4 gliomas as well as low grade glioma. Even if CNS WHO grade 4 gliomas had mutant IDH, they can have poor clinical outcome due to CDKN2A deletion.
QOL-29. PREVALENCE, MANAGEMENT, AND OUTCOMES OF PROCARBAZINE-ASSOCIATED HYPERSENSITIVITY REACTIONS IN PATIENTS RECEIVING PCV FOR LOW-GRADE GLIOMA
Authors: Jack Knott, Simon Liebling, Lauren Reed-Guy, Desiree Croteau, Richard Phillips, Arati Desai, Stephen Bagley
Journal: Neuro-Oncology (2024)

Abstract Procarbazine is an alkylating agent commonly used to treat low-grade gliomas as part of the PCV regimen. The use of procarbazine is frequently limited by the development of hypersensitivity reactions (HSRs), which often require dose reduction or cessation of procarbazine therapy prior to the completion of a planned treatment course. The prevalence, clinical characteristics, and potential predictors of these reactions are not well defined. We conducted a retrospective cohort study of patients with low-grade glioma who received PCV between January 2016 and January 2024 at a tertiary academic hospital. Data on patient demographics, tumor type, clinical characteristics, treatment course, and hypersensitivity reactions were collected and analyzed. 61 total patients were included. The overall prevalence of HSRs was 60.7% (95% CI: 48.4% - 72.9%). The median cycle during which HSRs occurred was cycle 3 (IQR: 2-4, Range: 1-5). All HSRs involved the development of rash, with 86.5% being pruritic and 21.6% involving the face. Treatments for HSRs included antihistamines (62.2%), topical corticosteroids (35.1%), and systemic corticosteroids (27.0%). Three patients with HSRs presented to the emergency department with concern for anaphylaxis, and one required treatment with epinephrine. Out of six patients rechallenged with procarbazine after experiencing HSRs, one patient redeveloped a diffuse, pruritic rash that resolved with systemic corticosteroids. A multiple logistic regression analysis was performed to assess the association between HSRs and gender, age at PCV C1D1, elevated liver enzymes, and concomitant anticonvulsant use, but no significant correlation was observed. In summary, our study provides a contemporary and comprehensive analysis of the prevalence and severity of HSRs to procarbazine in patients with low-grade glioma. The high rate of HSRs in this population, including a relatively high rate of suspected anaphylaxis, should be considered carefully by clinicians in choosing chemotherapy for low-grade glioma and warrants routine counseling and close monitoring.
IMMU-67. INTRACRANIAL IL12 SECRETING CAR-T CELLS OBVIATE THE NEED FOR LYMPHODEPLETION AND COMBAT HETEROGENEITY VIA MICROGLIAL INTERACTIONS
Authors: Aditya Mohan, Steven Shen, Eliese Moelker, Emily Blandford, Andrew Hardigan, Daniel Wilkinson, Peter Fecci, John Sampson, Anoop Patel
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific antigen distinctively expressed in glioblastoma multiforme (GBM). However, its heterogeneous expression in GBM complicates its application as a target for Chimeric Antigen Receptor (CAR) T cells. Additionally, Interleukin-12 (IL12) has recently been identified as a potent cytokine in the treatment of solid tumors. In this study, we investigate the potential synergy between CAR-T cells and IL12 in targeting heterogeneous tumor antigens. METHODS To model tumor heterogeneity, mice were injected with a 50/50 mix of CT2A and CT2A EGFRvIII+ cells. EGFRvIII-specific third-generation CAR T cells, engineered with or without single-chain IL12, were cloned using an MSGV retrovirus backbone and transduced into murine T cells. The antitumor efficacy of CAR-T cells was evaluated through survival analysis. Additionally, the capability of CAR-T cells with or without IL12 to prolong survival and alter the tumor microenvironment was analyzed using single-cell sequencing. RESULTS EGFRvIII CARs alone were insufficient to cure mice with heterogeneous tumors, whereas EGFRvIII CARs co-expressing IL12 achieved a 60% cure rate. Interestingly, EGFRvIII CARs secreting IL12 demonstrated longer persistence in vivo compared to EGFRvIII CARs alone and did not require lymphodepletion before administration. We found that EGFRvIII CARs expressing IL12 promoted the elimination of EGFRvIII-negative tumor cells by recruiting endogenous CD8 T cells. Furthermore, among all Antigen Presenting Cell (APC) populations in the tumor microenvironment, we found that IL12 primarily acted on microglia to enhance antigen presentation pathways and support epitope spreading. CONCLUSION EGFRvIII CARs engineered to secrete IL12 effectively treat antigen-heterogeneous tumors by modulating local APCs and recruiting endogenous T cells. IL12-secreting CARs demonstrate longer persistence without the need for lymphodepletion compared to traditional EGFRvIII CARs. Employing CAR-T cells that secrete IL12 is a promising strategy to address tumor heterogeneity, offering therapeutic potential against GBM in clinical settings.