tbuckley/cabot-search huggingface dataset:
EPID-16. GENOMIC ANCESTRY-RELATED RISK RATIOS FOR GLIOBLASTOMA INCIDENCE AMONG GLOBAL POPULATIONS AND RACIAL/ETHNIC GROUPS WITHIN THE UNITED STATES
Authors: Christine Ballard, Minh Huy Giang, Quinn Ostrom, Kyle Walsh
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) incidence varies globally, elevated rates in Europe and lower rates in Asia, Latin America, and Africa. While partially attributable to national differences in cancer diagnosis and reporting practices, analogous patterns exist within diverse Western nations. Ancestry-associated differences in GBM risk allele frequencies (RAFs) could contribute, a hypothesis supported by our prior multiethnic genome-wide association studies (GWAS). Leveraging variant effect estimates from large GBM GWAS datasets and ancestry-stratified allele frequency data from diverse reference populations (ALFA, GNOMAD, 1000 Genomes Project), we estimate the extent of GBM incidence differences across populations that can be attributed to underlying variation in RAF at the seventeen known GBM risk loci. Aggregate differences in RAF between global populations (Europe, West-Africa, East Asia) were associated with a &amp;gt;20% reduction in the normalized GBM risk-ratio (RR) in Africans compared to Europeans (RR=0.78) and a &amp;gt;50% reduction in East Asians compared to Europeans (RR=0.47). The frequency of GBM risk alleles was generally highest in Europeans, but four alleles found most commonly in Africans are at loci regulating telomere maintenance (TERC, TERT, OBFC1/STN1, RTEL1). We repeated analyses using RAF data from U.S. populations (African-Americans, Latinos, and non-Hispanic Whites). Compared to non-Hispanic Whites, aggregate differences in RAF were associated with a 15% reduction in GBM risk among African-Americans (RR=0.85) and a 28% reduction among Latinos (RR=0.72). We conclude that a sizable proportion of the reduced GBM incidence in Latinos and Asians, relative to non-Hispanic Whites, can be accounted for by population-level differences in RAF at known loci. However, registry-based analyses consistently report a two-fold lower incidence of GBM in African Americans relative to non-Hispanic Whites which is poorly explained by RAF differences at known loci. Further work is needed to identify structural, environmental, and biological factors contributing to unresolved differences in GBM incidence.
BIOM-04. SINGLE-CELL RNA SEQUENCING PROTOCOL OF THE HUMAN METASTATIC PROSTATE SPINE TUMOR MICROENVIRONMENT
Authors: Annee Nguyen, Corinne Haines, Meghan Price, Cesar Baeta, Harrison Hockenberry, Eli Johnson, C Rory Goodwin
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION 90% of spine tumor patients can develop metastases with debilitating complications, such as sensorimotor dysfunction, paralysis, and spinal instability. As spine tumor patients have limited eligibility to participate in clinical trials and have heterogenous tumor pathology, there is a distinct lack of therapeutic targets and prognostication markers of disease. Thus, there is a distinct need for molecular profiling of spine tumors. OBJECTIVE We describe an OR-to-bench-top processing of spine tumors for single-cell omic studies, with samples from a metastatic prostate cancer patient to demonstrate the ability to compare molecular markers and microenvironments of difficult-to-process spine tumors and adjacent normal tissue. METHODS Under IRB protocol #Pro00101198, patients undergoing spine surgery with the Department of Neurosurgery at Duke University were consented for tissue collection. Vertebral osseous metastases and adjacent normal tissue were confirmed histologically (H&amp;E, immunohistochemistry) and radiologically (MRI, PET, CT, and x-ray). Tissues were manually and enzymatically homogenized in serum-free media with collagenase A and DNAse I to obtain a single cell suspension. Cells were then filter sterilized, erythrolyzed, counted to determine live-death ratio, resuspended to 10-20 million cells per mL, then cryopreserved for downstream standard library preparation for single-cell sequencing using the 10X genomics platform. Downstream analysis was performed using Seurat pipeline, InferCNV analysis, and SingleR. RESULTS P404S and PSA expression confirmed tumor was prostate in origin. Radiological imaging and H&amp;E staining confirmed the presence of T7 osseous metastasis. Uniform manifold approximation and project (UMAP) plots identified 12 unique clusters of immune cell subpopulations between normal and tumorous vertebrae, with their own subsets of differentially expressed genes. CONCLUSION We have developed a protocol to generate granular single cell molecular profiling for spine tumors and metastases. Applications of this protocol can aid in identifying therapeutic targets, molecular predictors of disease, and potentiate increased eligibility of patients for clinical trials.
NIMG-84. BELZUTIFAN REDUCTION OF CEREBRAL BLOOD FLOW IN VHL-ASSOCIATED HEMANGIOBLASTOMA PREDICTS RESPONSE TO TREATMENT
Authors: Amit Persad, Ayse Banu Yagmurlu, David Park, Aroosa Zamarud, Yuhao Huang, Yusuke Hori, Steven Chang, Michael Iv
Journal: Neuro-Oncology (2024)

Abstract Hemangioblastoma (HMB) is a vascular-origin tumor occurring primarily in the cerebellum. Treatment typically involves surgical resection of the solid part of the tumor or stereotactic radiosurgery. An emerging treatment for hemangioblastoma is belzutifan (BZF), a hypoxia-inducible factor 2a (HIF2a) inhibitor. A recent trial found BZF to control hemangioblastoma in patients with von Hippel Lindau (vHL) syndrome. Perfusion MRI techniques including arterial spin labelling (ASL) and can be used to determine relative cerebral blood flow (rCBF). No prior studies have investigated rCBF in hemangioblastoma with relation to belzutifan, and the mechanism of action of belzutifan on hemangioblastoma is not well understood. Here, we aim to measure the response in rCBF in patients with vHL-associated hemangioblastoma treated with belzutifan. This retrospective cohort study constituted a group of seven patients with vHL-associated hemangioblastoma treated with Belzutifan at a daily oral dose of 120mg. Perfusion MRI with ASL sequences were acquired as part of the tumor imaging protocol. We quantified rCBF of the tumors prior to treatment, following intiation of BZF, and at most recent follow-up. Statistics were performed using R studio. The long axis diameter, volume of the solid tumor, rCBF mean, rCBF max, N mean, N max of lesions all decreased after Belzutifan treatment (p&amp;lt;0.001). While the long axis diameter of the cyst in cystic lesions did not show statistically significant change, the volume of cysts decreased significantly on Belzutifan (p=0.016). Spearman’s rank correlation analysis demonstrated association between change in rCBF mean, rCBF max, N mean and N max to % reduction in tumor volume. In addition, change in rCBF mean, change in rCBF max and change in N max all showed statistically significant association on multiple linear regression. Finally, early change in CBF and N predicted further volumetric response to treatment with belzutifan. We demonstrate that vHL-associated hemangioblastoma demonstrates decrease in rCBF in conjunction with and predictive of decreased volume following treatment with belzutifan.
RTID-05. STUDY PROTOCOL: A MULTICENTER, INTERNATIONAL RANDOMIZED CONFIRMATORY TRIAL: LOW-ENERGY X-RAY INTRAOPERATIVE RADIATION THERAPY (LEX-IORT) VS. ADJUVANT FRACTIONATED STEREOTACTIC RADIOTHERAPY (FSRT) IN THE MANAGEMENT OF BRAIN METASTASES (LEXIMATE)
Authors: Christian D Diehl, Güliz Acker, Stefanie Brehmer, Oliver Ganslandt, Frank A Giordano, Motaz Hamed, Henning Kahl, Marc Münter, Julian P Layer, Gustavo R Sarria, Matthias Schneider, Ehab Shiban, Arthur Wagner, Bernhard Meyer, Stephanie E Combs
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Fractionated stereotactic radiotherapy to the resection cavity boosts local control of resected brain metastases significantly. However, start of systemic tumor-directed treatment may be protracted and in-hospital times prolonged. Lately, lex-ioRT of BM has been described as a safe and effective one stop-shop treatment modality with a 1-year local control rate of up to 98% while potentially improving patient convenience. Study Design: The LEXIMATE-trial is a multicenter, international, randomized open-label confirmatory trial comparing lex-IORT with FSRT of resected BM. In the experimental arm, INTRABEAM (Carl Zeiss Meditec AG) is used to deliver IORT by application of 50-kV photons at a standard dose of 30 Gy prescribed to the applicator surface. Standard linear accelerator or Gamma Knife based FSRT (3-7 fractions) to the surgical bed is used in the control arm. The primary endpoint is the cumulative incidence of local recurrences (as per RANO-BM) considering death without prior local recurrence as competing event. Inclusion criteria include histologically confirmed BM with indication for resection according to EANO-ESMO/ASCO-SNO-ASTRO guidelines, ≤5 other brain lesions compatible with BM and amenable to radiosurgery and history of solid cancer or CT scan suggestive for localized or metastasized solid cancer (except germ cell tumors, lymphoma, small-cell lung cancer). The resection cavity must be &amp;lt;5cm in size, IORT doses to brainstem or optical tract may not exceed 8 Gy. Study design: Randomized, open-label, non-inferiority. Sample size: 70 patients per group to show a non-inferiority of the experimental therapy compared to the control therapy with a power of approximately 80%. DISCUSSION The best radio-oncologic procedure for resected BM remains under debate. The LEXIMATE-trial offers an opportunity to provide more solid prospective data on effectiveness, safety and patient comfort both for established and new RT techniques.
RADT-34. RE-IRRADIATION REGIMENS FOR RECURRENT GLIOMA: SURVIVAL AND TOXICITY
Authors: Anouk de Jong, Fia Cialdella, Arthur van der Boog, Cathalijne Post, Jan-Willem Dankbaar, Jeroen Hendrikse, Karin Kleynen, Marielle Philippens, Ernst Smid, Filip de Vos, Pierre Robe, Szabolcs David, Tom Snijders, Joost Verhoeff
Journal: Neuro-Oncology (2024)

Abstract Re-irradiation is a common treatment option for recurrent high-grade glioma (HGG), though the optimal dose-fractionation regimen remains unclear. This report presents single-center data from an ongoing multicenter, retrospective study in the Netherlands. We included adult HGG patients treated with re-irradiation. Dose-fractionation regimens were categorized in 3 groups: conventionally fractionated radiotherapy (CFRT, &amp;lt;3Gy/fraction), hypofractionated radiotherapy (HFRT, 3-5 Gy/fraction) and stereotactic radiotherapy (SRT, ≥5Gy/fraction). We compared baseline characteristics, overall survival, and toxicity including incidence of radionecrosis between groups to identify the optimal dose-fractionation regimen. Of 112 patients, 33 underwent CFRT, 60 HFRT and 19 SRT. 21 patients had a good prognostic Niyazi score, 70 intermediate and 6 poor, with more poor scores in the SRT group. SRT patients had smaller median GTVs compared to HFRT and CFRT (1.9, 20.5, 32.8 respectively, p=0.003). Radiation groups also differed in primary histology (less grade 4 in CFRT, p=0.009), but not in age and KPS. Overall survival (OS) was worse for HFRT (median OS 9 months (95%-CI 6.5-11.5)) compared to CFRT (12 months (8.9-15.2, p=0.039)) and SRT (12 months (9.2-14.8, p = 0.012)), but did not differ between CFRT and SRT (p=0.437). In Cox regression, Karnofsky performance score &amp;lt;80 (hazard ratio (HR): 1.874, p=0.006) and large GTV (HR: 1.011, p=0.003) were independently associated with poor survival, while the fractionation schedule was not. Multivariable logistic regression on toxicity analysis indicated an increased risk of radionecrosis in the CFRT and HFRT groups compared to the SRT group (OR 5.861, p=0.011), even after adjusting for GTV and age. In conclusion, re-irradiation schemes in HGG are univariably, but not independently, associated with overall survival; this relationship seems to be confounded by differences in GTV and possibly by KPS. Radionecrosis was more common in HFRT and CFRT than in SRT. Extension and/or validation of findings will be performed in a multicenter cohort.
EPCO-23. LONGITUDINAL TRACKING AND LONG-READ CHROMATIN FIBER SEQUENCING OF HUMAN ASTROCYTES WITH TELOMERE DYSFUNCTION REVEALED ALTERED CHROMATIN ACCESSIBILITY AND INCREASED STRUCTURAL VARIATION
Authors: Yue Hao, T Rhyker Ranallo-Benavidez, Noelle Fukushima, Maria Kyriakidou, Michael E Berens, Floris P Barthel
Journal: Neuro-Oncology (2024)

Abstract Glioma is an aggressive cancer of the central nervous system that is genetically characterized by aneuploidy and frequent structural variation (SV). We sought to investigate the role of telomere dysfunction (TD) in shaping the SV landscape in glioma. Normal human astrocytes (NHA) were engineered to express viral E6E7 oncoproteins which are known to spontaneously trigger TD by suppressing p53/pRb. We hypothesized that NHA-E6E7 cells gradually accumulate SVs and aneuploidy over time because of progressive TD. We therefore longitudinally tracked bulk and single-cell clones of NHA-E6E7 cells for a period of over 6 months since viral infection. Overall, NHA-E6E7 cells demonstrate a growth benefit over primary NHA cells. We obtained Illumina short-read sequencing for NHA-E6E7 cells at multiple time points. Three time points were additionally selected for both Oxford Nanopore and PacBio HiFi long-read sequencing using the single-molecule chromatin fiber sequencing (fiber-seq) protocol. Copy number variation (CNV) analysis of short-read data showed deletion events in chromosome 13 as early as population doubling level (PDL) 48. K-mer based CNV analysis using the long-read data confirmed this finding and also detected deletion events in chromosome 7 at PDL 50. From the long-read data, we found an elevated number of SVs in NHA-E6E7 cells compared to the primary NHA cells. In particular, we detected telomere junctions and found that telomere-associated SVs were more prevalent in NHA-E6E7 cells compared to primary cells. Next, chromatin accessibility and regulatory elements were predicted from fiber-seq data with exogenous N6-methyladenosine (m6A) stencils. We observed large-scale chromatin actuation changes in various regulatory elements across the genome that intensified in later passages of NHA-E6E7 cells. For example, we found a decrease in the accessibility in FBXO7 which is a gene that maintains chromosome stability. Our preliminary results indicated that TD is an important mediator of structural variation in glioma.
CTNI-54. RESPONSE BY RANO2.0 CRITERIA IN ONC201 (DORDAVIPRONE)-TREATED PATIENTS WITH RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Timothy Cloughesy, Joshua E Allen, Isabel Arrillaga-Romany, Marissa Barbaro, Tracey T Batchelor, Nicholas Butowski, Andrew Cluster, John de Groot, Jerome Graber, Aya M Haggiagi, Lindsay B Kilburn, Sylvia C Kurz, Allen S Melemed, Samuel C Ramage, Michael E Salacz, Nicole Shonka, Ashley Sumrall, Rohinton Tarapore, Lynne Taylor, Patrick Wen
Journal: Neuro-Oncology (2024)

Abstract PURPOSE Response assessment in neuro-oncology (RANO) 2.0 is a recently established response assessment for glial tumors that is agnostic to WHO grade. This updated response assessment includes quantitative evaluation of enhancing and non-enhancing disease and recommendations to account for pseudoprogression. This analysis evaluated response to ONC201 by RANO2.0 in recurrent, H3K27M-mutant diffuse midline glioma (DMG), which was previously assessed by RANO-HGG/RANO-LGG (Arrillaga-Romany, JCO, 2024). METHODS Fifty patients with recurrent H3 K27M-mutant DMG were selected based on criteria designed with input from regulators to evaluate objective response to ONC201 monotherapy. Patients had contrast-enhancing, measurable, progressive disease, and were ≥90 days from radiation, with adequate washout from other anti-cancer therapies. Diffuse intrinsic pontine glioma, primary spinal tumors, leptomeningeal spread, or CSF-disseminating tumors were ineligible. Response was assessed using RANO2.0 criteria by two-party blinded independent central review. RESULTS Best response by RANO2.0 included one complete response (CR, 2.0%), nine partial responses (PR, 18.0%), and four minor responses (MR, 8.0%). Overall response rate (CR+PR+MR) by RANO2.0 criteria was 28.0% (n=14; 95%CI, 16-42). Disease control rate (CR+PR+MR+SD) was 40.0% (n=20; 26-55). Median duration of response was 10.4 months (95%CI, 7.4-15.4). Median time to response was 4.6 months (range, 1.6-15.9). 6- and 12-month progression free survival rates were 32.0% (95%CI, 19-47) and 27.0% (15-41), respectively. RANO2.0 response as a time-varying covariate was significantly associated with overall survival in a multivariate analysis considering baseline performance score, multiple enhancing target lesions, enhancing tumor size, and number of prior recurrences (HR [95%CI], 0.22 [0.08–0.58]; p=0.0023). Patients with an objective response by RANO2.0 were more likely to be alive at 12 (100%) and 24 (86%) months, have reduced corticosteroid usage, and have improved performance status. Responses occurred at a higher rate among patients with a higher performance score and fewer target lesions. CONCLUSIONS RANO2.0 assessment of ONC201-treated patients suggests durable and clinically meaningful efficacy in recurrent H3K27M-mutant DMG.
CTNI-53. A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH ADULT-TYPE DIFFUSE GLIOMA WITH AN IDH1/2 MUTATION (INDIGO): UPDATED EFFICACY RESULTS
Authors: Ingo K Mellinghoff, Martin J van den Bent, Mehdi Touat, Deborah T Blumenthal, Katherine B Peters, Benjamin M Ellingson, Jennifer L Clarke, Joe Mendez, Shlomit Yust-Katz, Warren P Mason, Francois Ducray, Yoshie Umemura, Burt Nabors, Andreas F Hottinger, Yoshiki Arakawa, Juan M Sepulveda, Wolfgang Wick, Riccardo Soffietti, James R Perry, Pierre Giglio, Macarena de la Fuente, Elizabeth A Maher, Adriana E Tron, Dan Zhao, Shuchi S Pandya, Lori Steelman, Islam Hassan, Patrick Y Wen, Timothy F Cloughesy
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION The Phase 3 INDIGO study (NCT04164901) evaluated vorasidenib, an oral, brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), in patients with mIDH1/2 diffuse glioma. The primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint of time to next intervention (TTNI), were met in the positive, preplanned second interim analysis (IA2). The study was unblinded in March 2023 following independent data monitoring committee recommendation. Here, we present results after an additional 6 months of follow-up between the database lock for IA2 (September 6, 2022) and study unblinding (March 7, 2023). METHODS Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (≥12 years; Karnofsky Performance Status ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy). Patients were randomized 1:1 to vorasidenib 40 mg or placebo daily in 28-day cycles. RESULTS Overall, 331 patients were randomized (median age: 40.0 years; oligodendroglioma: 172; astrocytoma: 159). As of March 7, 2023, 123/168 (73%) patients remained on vorasidenib and 72/163 (44%) remained on placebo. PFS per BIRC remained in favor of vorasidenib (HR, 0.35; 95% CI, 0.25–0.49), and was consistent with PFS per investigator assessment (HR, 0.34; 95% CI, 0.23–0.50). Median PFS per BIRC: vorasidenib, not estimable (NE; 95% CI, 22.1–NE); placebo, 11.4 months (95% CI, 11.1–13.9). TTNI also remained in favor of vorasidenib (HR, 0.25; 95% CI, 0.16–0.40). Median TTNI: vorasidenib, NE (95% CI, NE–NE); placebo, 20.1 months (95% CI, 17.5–27.1). No new safety signals emerged. CONCLUSIONS Vorasidenib is a targeted therapy for patients with predominantly non-enhancing mIDH1/2 diffuse glioma following surgical intervention, as shown in the INDIGO population. These additional 6 months of follow-up confirm the previously reported statistically significant and clinically meaningful improvements in PFS and TTNI with vorasidenib.
TMIC-38. INTEGRIN BLOCKING PEPTIDE REPROGRAMS THE IMMUNOSUPPRESSIVE MICROENVIRONMENT OF EXPERIMENTAL GLIOMAS IMPROVING ANTI-PD-1 THERAPY OUTCOME
Authors: Bozena Kaminska, Aleksandra Ellert-Miklaszewska, Paulina Pilanc-Kudlek, Anna Lenkiewicz, Katarzyna Poleszak, Salwador Cyranowski, Adria-Jaume Roura, Maria Pasierbinska, Szymon Baluszek, Juliana Hovorova, Karol Jacek, Kamil Wojnicki, Mitrajit Ghosh, Bartlomiej Gielniewski, Paulina Szadkowska
Journal: Neuro-Oncology (2024)

Abstract Clinical trials with immune checkpoint inhibitors (ICI) have benefited many cancer patients but failed in a number of tumors, including glioblastoma (GBM), the most common and aggressive primary brain tumor in adults. The main obstacle for ICI efficacy in GBM is the continuously evolving tumor microenvironment (TME), in which antitumor immunity is inhibited or eluded by tumor-secreted factors. Accumulation and reprogramming of myeloid cells (GAMs) creates a “cold” immunosuppressive TME with a poor infiltration and exhaustion of effector T cells. We employ Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) with 40 protein markers along with spatial transcriptomics and immunophenotyping to dissect identities and functionalities of immune cells (CD45+) in experimental GL261 gliomas. The results revealed identities of immune cells instrumental for creating the immunosuppressive milieu and cell-cell communication networks. We have developed a designer RGD peptide that blocks the reprogramming of GAMs by targeting tumor-GAMs interactions. We demonstrate that RGD efficiently blocks microglia-dependent invasion of murine and human glioma cells in vitro. We explored if the intratumorally delivered RGD can revert tumor-induced changes in the TME of experimental gliomas and improve anti-PD-1 immunotherapy. While RGD alone did not reduce tumor growth in vivo, it prevented reprogramming of myeloid cells into protumoral GAMs and led to the normalization of peritumoral blood vessels. Combining RGD with anti-PD-1 antibody resulted in reduced tumor growth, increase in percentages of proliferating, interferon-ɣ producing CD8+T cells and depletion of regulatory T cells. Transcriptomic profiles of GAMs were altered by the combined treatment, consistently with the restored “hot” inflammatory TME which resulted in boosting immunotherapy responses. Intratumorally delivered RGD modified in the same way functionalities of GAMs in the TME of human U87MG gliomas in nude mice. Our results demonstrate that the integrin blockade combined with immune checkpoint inhibitors reinvigorates both innate and adaptive antitumor immunity. The results pave the way to improve responses to immunotherapy in GBM and other cancers.