tbuckley/cabot-search huggingface dataset:
DISP-03. HEALTH DISPARITIES IN NEURO-ONCOLOGY
Authors: Joshua Budhu, Nara Michaelson, Amanda Watsula, Anu Bakare, Mali Mohamadpour, Ugonma Chukwueke
Journal: Neuro-Oncology (2024)

Abstract Significant disparities in diagnosis, research, and treatment exist in neuro-oncology. Patients who identify as racial or ethnic minorities, sexual or gender minorities, elderly, rural, or have low socioeconomic status are more likely to have adverse outcomes. Using PubMed and expert opinion, we summarized the existing literature on health disparities in neuro-oncology. We categorized disparities based on primary central nervous system tumors (CNS), secondary CNS tumors, pediatric neuro-oncology, clinical trial enrollment and diversity, and financial toxicity. For patients with primary CNS tumors, we found that marginalized groups faced delays in diagnosis, lower rates of resection, and lower rates of postoperative radiation. For secondary CNS tumors, marginalized groups had lower rates of indicated cancer screening, less access to genetic testing, less access to advanced imaging, and lower rates of stereotactic radiosurgery and targeted therapies. Pediatric neuro-oncology patients had differences in morbidity and mortality based on socioeconomic status and race and faced substantial delays in diagnosis. Financial toxicity, the side effects of the high financial cost of a cancer diagnosis, disproportionately affects marginalized populations. This may be further exacerbated by the use of long-term medications such as IDH inhibitors. There is also unequal representation of diverse populations in neuro-oncology clinical trials. Compared to other cancer subspecialties, there is less available data on disparities, however, the types of disparities such as delays in diagnosis and outcomes are similar. Notably, there are not many interventions focused on mitigating these disparities. There needs to be additional research on health disparities in neuro-oncology, including both descriptions of existing disparities, but also on methods and interventions to address these disparities.
DISP-07. CURRENT NEURO-ONCOLOGY CAPACITY IN SUB-SAHARAN AFRICAN COUNTRIES: A QUESTIONNAIRE-BASED SURVEY
Authors: Lateef Odukoya, Nathalie Ghomsi, Gloria Kabare, David Kamson, Jeanette Eckel-Passow, Robert Jenkins, Gaspar Kitange, Andrea Akinjo, Kabir Badmos, Olufemi Bankole, Olufemi Idowu, Claire Karekazi, Kwadwo Darko, Elias Edrick, Chukwuyem Ekhator, Victoria Katasi, Daniel Lachance, Desmond Brown, Jason Huse, Henry Llewellyn, Margreth Magambo, Michael Magoha, Advera Ngaiza, Arsene Nyalundja, Dominique Higgins, Minda Okenwa, Lawrence Osei-Tutu, Bernard Petershie, Elorm Yevudza, Charles Anunobi, Liadi Tiamiyu, Gbetoho Gankpe, Kashaigili Heronima, Kristin Shroeder, Ekokobe Fonkem, Totimeh Teddy, James Balogun, Beverly Cheserem, Francis Zerd
Journal: Neuro-Oncology (2024)

Abstract Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). There is no previous large-scale effort focusing on brain tumor genetics in SSA. This project aims to map out the current neuro-oncology capacity in terms of workforce and available services in SSA. This is an ongoing online survey among a cross section of neuro-oncology practitioners spread across SSA countries to capture information on the distribution, number of available neuro-oncology care practitioners, capacity for neuropathology and molecular diagnosis, management of brain tumors, cancer registration, and tumor biobanking. The survey was disseminated by the Society for Neuro-oncology in SSA (SNOSSA). There were 83 respondents representing 15 countries and 52 health institutions: 46 tertiary, 4 secondary, 1 private and 1 other. Here, we present data on the 52 institutions. The prevalence of specialties was 87% neurosurgery, 75% anatomic pathology, 69% medical oncology, 64% neurology, 60% radiation oncology, and 39% neuropathology. For radiologic evaluation, 81% of institutions were reported to have both CT and MRI, 17% CT only, and one institution neither. For molecular testing, 46% have access to IHC or NGS testing, whereas 52% were reported to have neither. A neuro-oncology tumor board was reported at 58% of institutions. A general cancer registry is available in 64% of institutions, 31% have a brain tumor specific registry and 10% have a brain tumor biorepository. This study shows that SSA has substantial potential in neuro-oncology care practice capacity and facilities. Most significant gaps remain in areas such as neuropathology and molecular testing, which makes widespread implementation of the WHO 2021 diagnosis challenging. Understanding the prevalence of CNS tumor subtypes is also difficult due to low number of brain tumor registries and biobanks in SSA. The present findings reveal strategic opportunities, especially in neuropathology, tumor registries, biobanks, and infrastructure for IHC and NGS in SSA.
EXTH-66. ONCOLYTIC ADENOVIRAL INFECTION SYNERGIZES WITH IMMUNE CHECKPOINT INHIBITION TO MEDIATE INTRACRANIAL TUMOR CONTROL IN DISPARATE MODELS OF MELANOMA BRAIN METASTASES
Authors: Yi Du, Sanjay Singh, Hussein Tawbi, Mike Davies, Fred Lang, Candelaria Gomez-Manzano, Juan Fueyo, Christopher Alvarez-Breckenridge
Journal: Neuro-Oncology (2024)

Abstract Amongst all solid cancers, melanoma brain metastases (MBM) have the highest likelihood of metastasizing to the brain. The emergence of immune checkpoint inhibitors (ICI) for metastatic melanoma have demonstrated increasingly promising results; however, intracranial progression remains a challenging obstacle. Oncolytic viral (OV) therapy leverages tumor cell replication machinery to selectively replicate and kill tumor cells and promote anti-tumor immunity. We propose this OV strategy can be applied to MBM through direct tumor infection that simultaneously sustains a distant antitumor immune response. To counteract immunosuppressive features of the tumor microenvironment (TME), a third-generation oncolytic adenovirus (Delta-24-RGDOX) has been developed which expresses the immune stimulatory OX40 ligand (OX40L). We quantified the cytotoxic capacity of Delta-24-RGDOX and its ability to achieve immunogenic cell death (ICD) in vitro along with cerebral organoid co-culture models. Additionally, we used a series of syngeneic murine melanoma models to explore local and systemic antitumor immunity following Delta-24-RGDOX infection. Delta-24-RGDOX inoculation achieved viral infection, OX40L cell surface expression, tumor cell cytotoxicity, and ICD in vitro. Viral oncolysis was recapitulated in a cerebral organoid melanoma co-culture model with concomitant alterations in microglia activation and detection of viral transcripts within microglia using single cell RNA sequencing, suggesting a viral-clearing role of microglia within the TME. Local tumor clearance was achieved in orthotopic intracranial models following direct intracranial viral inoculation alone, and in combination with ICI. Lastly, we demonstrated improvement in overall survival in a synchronous subcutaneous/intracranial B16F10 model where the subcutaneous tumor was treated with Delta-24-RGDOX in combination with ICI. In summary, Delta-24-RGDOX achieves viral infection, oncolysis, and ICD following infection of melanoma cell lines. These findings translated in multiple in vivo models including immune cell activation and systemic antitumor immunity against uninfected MBM. Future studies are needed to explore the role of immune cell trafficking, myeloid cell modulation, T cell priming, and clonal expansion withing locally infected and the distant melanoma TME.
NCOG-33. MTOR INHIBITORS AS ADJUVANT TARGETED THERAPY IN PEDIATRIC PATIENTS WITH PROGRESSIVE OR REFRACTORY LOW-GRADE GLIOMA: A SINGLE-CENTER RETROSPECTIVE STUDY
Authors: Aaron E Fan, Jonathan Cunningham, Susan McGovern, Mary McAleer, David I Sandberg, Gregory K Friedman, Wafik Zaky
Journal: Neuro-Oncology (2024)

Abstract Low grade gliomas (LGG) represent about one-third of all pediatric central nervous system tumors, with about half having disease progression despite upfront surgery and adjuvant therapies. Current treatments for LGG progression either produce toxic side effects (i.e., radiation therapy) or do not generate durable responses. Targeted agents are an effective way of attacking tumors with identified genetic mutations, but in some cases, a complete response can be subverted by the heterogeneity of tumors. Additionally, most tumors do not carry any targetable mutations. Temsirolimus and everolimus are mTOR inhibitors that have previously been shown to be well-tolerated in early clinical studies in pediatric solid tumors. We performed a retrospective study to look at the toxicity profile of mTOR inhibitors when given in combination therapy and treatment response in patients with progressive or refractory LGG. We examined 20 patients with a diagnosis of LGG including mixed glioma and glioneuronal tumors who received treatment at our institution from 2016-2024 with targeted therapy, of which 8 patients also received temsirolimus or everolimus. Of these 8 patients, 2 had partial response, 2 had minor response, 3 had stable disease, and 1 had progressive disease. The average number of cycles received was 13.6 (range 3-24). Most observed side effects were grade 2 or less, including nausea, transaminitis, myelosuppression, diarrhea, and hyperlipidemia while grade 3/4 toxicities that required dose modification included mucositis, hyperglycemia, and hyperlipidemia. Overall, the addition of temsirolimus to treatment regimens of pediatric patients with heavily pretreated refractory LGG prolonged progression free survival by an average of 478 days with only one patient progressing while on therapy. These results demonstrate feasibility and preliminary efficacy of adding mTOR inhibitors as adjuvant therapy in this patient population. There is dire need of large prospective collaborative studies in the future.
DISP-01. FACTORS AFFECTING POST-ABLATION OUTCOMES AND TRIAL ENROLLMENT IN DIVERSE PATIENTS UNDERGOING LASER INTERSTITIAL THERMAL THERAPY
Authors: Aden Haskell-Mendoza, Ariel Gonzalez, Ellery Reason, Joshua Jackson, Andreas Seas, Saif Zaidi, Aditya Mohan, Emily Lerner, Ethan Srinivasan, Claire Bradbury, James Herndon II, C Rory Goodwin, Peter Fecci
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Laser interstitial thermal therapy (LITT) is a surgical treatment for progressive brain metastases (BM) following stereotactic radiosurgery (SRS). Although LITT has been increasingly accepted, little is known regarding factors influencing presentation and outcomes of patients with diverse backgrounds. METHODS Retrospective review of all patients receiving their index LITT treatment for BM at a single center from 2015 – 2023. Patient demographics and geospatial data was used to compare differences in receipt of LITT by race or ethnicity, survival outcomes, and clinical trial enrollment. RESULTS From 2015-2023, 137 patients presented for LITT to 146 intracranial lesions. One hundred and six patients (77.3%) were non-Hispanic White (NHW), while among Hispanic or non-White (HNW) patients, 25 (18.2%) were Black or African American, 5 (3.6%) were Asian American, and 1 (0.7%) was Hispanic/Latino. Among HNW patients, women more frequently received LITT (p = 0.022), with skin cancers being a more frequent indication among NHW patients (P = 0.019). NHW patients traveled a median of 62.0 (6.2 – 1045.9) miles to receive LITT vs 25.9 (1.31 – 238.3) miles for HNW patients (p = 0.001). Length of stay, discharge location, or readmission rates did not differ between groups. In multivariate analyses, probability of clinical trial enrollment was less among those of female sex (P = 0.049), HNW race/ethnicity (P = 0.041), or external referral status (P = 0.035), while post-LITT overall survival was predicted by pre-LITT KPS (P = 0.0007) and recurrent tumor on biopsy (P = 0.0002). CONCLUSIONS Differences in presentation for LITT by race or ethnicity may be influenced by underlying patient factors, including sex, systemic disease histology, and distance from a treating center, which do not influence post-LITT procedural outcomes or survival. Accordingly, clinical trial enrollment should be prioritized for vulnerable patient populations to realize the full benefits of laser ablation.
NIMG-52. ARTIFICIAL INTELLIGENCE-BASED VOLUMETRIC KINETICS FOR EVALUATING TREATMENT RESPONSE IN IDH-MUTANT GLIOMA TREATED WITH IMMUNOTHERAPY
Authors: Zach Sergi, Mason Belue, Kelly Fernandez, Olga Kim, Qi Li, Peng Lu, Baris Turkbey, Stephanie Harmon, Jing Wu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Interpretating radiographic findings of glioma patients receiving immunotherapy is challenging. Repeated imaging is often required for clinical decisions, potentially delaying next line of treatment. Here we assess a glioma segmentation AI model to evaluate treatment response in IDH-mutant glioma patients receiving nivolumab. METHODS Clinical magnetic resonance imaging (MRI)s from twenty-nine patients enrolled in a clinical trial (NCT03718767) were retrospectively analyzed. All patients had at least two sequential MRIs, including baseline study. T2, T1 (pre/post-contrast), and T2 FLAIR MRI sequences were pre-processed using publicly available AI-based whole-brain segmentation models. Lesion contours were derived from a validated 4-class brain tumor segmentation AI model, distinguishing healthy brain parenchyma, peri-lesional edema, non-contrast enhancing volume (NEV), and contrast-enhancing volume (CEV). Total lesion burden volume (TLBV=NEV + CEV + Edema) was also calculated. Growth rates between responders (R) and non-responders (NR), defined as progression-free survival ≥ or &amp;lt; 6months, respectively, were compared using a Wilcoxon Rank Sum Test. RESULTS The R group displayed significantly lower median rates of change for CEV (R -35% vs. NR +142% p = 4.31e-04) and TLBV (R +6% vs NR +43% p = 1.55e-03), compared to NR from baseline to post-cycle 1-2. Additionally, similar trends persisted at post-cycle 3-4 for CEV (R -41% vs. NR +367% p = 3.03e-03) and TLBV (R +12% vs. NR +40% p = 7.74e-03). Although NR showed a higher average baseline TLBV, there was no discernible correlation detected between baseline TLBV and the rate of change during treatment. CONCLUSIONS AI-based volumetric analysis offers an objective response assessment, showing promise in tracking disease progression in IDH-mutant glioma patients on nivolumab, potentially enabling earlier identification of progressive disease and allowing for timely treatment adjustments. A larger prospective study is warranted to refine volumetric pattern analysis for early clinical decisions in immunotherapy.
DNAR-06. EPITRANSCRIPTOMIC TRNA MODIFICATIONS TARGETING ADENOSINE (A) AT POSITION 37 IN GBM
Authors: Takahiro Yamamoto, Jin Matsuura, Atsushi Fujimura, Takeshi Chujo, Fan-Yan Wei, Naoki Shinojima, Jun-ichiro Kuroda, Akitake Mukasa, Kazuhito Tomizawa
Journal: Neuro-Oncology (2024)

Abstract GBM stands as the most aggressive brain tumor in adults. The median overall survival is less than 2 years despite conventional treatments. Recent advancements in DNA analysis have delineated the molecular characteristics of gliomas, leading to revisions in the WHO classification based on DNA profiles. However, the role of RNA modifications, epitranscriptomics, remains poorly understood in glioma. In this study, we underscore the significance of tRNA modifications targeting adenosine at position 37 in GBM. Transfer RNA isopentenyl transferase 1 (TRIT1) is identified as an isopentenyl transferase catalyzing the conversion of A into i6A at position 37 of tRNA, a nucleotide adjacent to the anticodon region. Additionally, i6A is further modified to 2-methylthio i6A (ms2i6A) by cyclin-dependent kinase 5 regulatory subunit associated-protein 1 (CDK5RAP1) within mitochondrial tRNA. Analysis of TCGA data reveals elevated TRIT1 mRNA expression levels in GBM compared to non-tumor samples. Furthermore, a low expression group of TRIT1 in gliomas demonstrates improved survival outcomes according to data from the CGGA, implicating TRIT1 in glioma progression. Functional assays involving TRIT1 knockdown in human GBM cell lines result in decreased cell viability, indicating its functional significance. Moreover, our data suggest that this phenotype may be mediated through translational control of selenoprotein W (SEPW1) via tRNA^(Ser)Sec modification. GO analysis of TRIT1 and SEPW1 in TCGA data further supports this proposed mechanism. At position 37 of tRNA, we also found that CDK5RAP1 in mitochondrial tRNAs is indispensable for sustaining glioblastoma initiating cell (GIC)-related traits. CDK5RAP1 maintains the self-renewal capacity, undifferentiated state, and tumorigenic potential of GICs, independent of translational control of mitochondrial proteins. Notably, CDK5RAP1 abrogates the antitumor effect of i6A by converting i6A to ms2i6A and shields GICs from excessive autophagy triggered by i6A. This work underscores the critical role of tRNA modifications in glioma pathogenesis. We will report these findings alongside RNA modification profile data and clinical data from glioma patients.
EXTH-67. ONCOLYTIC ADENOVIRAL INFECTION OF CHORDOMA ACHIEVES TREATMENT EFFICACY THROUGH IMMUNOGENIC CELL DEATH AND TUMOR MICROENVIRONMENT ALTERATION
Authors: Xizi Wu, Daniel Ledbetter, Romulo Andrade de Almeida, Sanjay Singh, Anthony Conley, Wein-Lien Wang, Alex Lazar, Fred Lang, Candelaria Gomez-Manzano, Juan Fueyo, Christopher Alvarez-Breckenridge
Journal: Neuro-Oncology (2024)

Abstract Chordomas are locally aggressive neoplasms of the axial skeleton with recurrence rates approaching 40%. Moreover, recurrent chordomas are nearly impossible to eradicate—highlighting an unmet clinical need. Immunotherapeutic approaches, such as immune checkpoint inhibition (ICI), has been a successful tool to modulate the tumor microenvironment (TME) towards a pro-inflammatory, antitumor state. There is emerging interest in exploring immunomodulatory agents for chordomas. Oncolytic viral (OV) therapy uses genetically modified viruses which selectively replicate in tumor cells, mediate tumor cell lysis, and initiate a pro-inflammatory response within the infected TME. These findings suggest that OV therapy may be a clinically relevant, novel immunotherapeutic approach for chordoma. Using the replicating oncolytic adenovirus Delta-24-RGD, we investigate the efficacy of chordoma treatment using in vitro approaches, ex vivo bone scaffolds, and in vivo murine models. Additionally, we explore the underlying mechanism of OV cytotoxicity, immunogenic cell death, Brachyury modulation, and reshaping of the TME towards a pro-inflammatory state. Across a panel of human chordoma cell lines, Delta-24-RGD achieved viral infectivity, oncolysis and immunogenic cell death. This treatment response was similarly demonstrated in chordoma cultured in bone scaffold models. Delta-24-RGD infection was associated with concomitant Brachyury downregulation within both infected and uninfected chordoma cells in vitro, suggesting a pleiotropic effect following oncolytic viral infection. In vivo models of CH22 chordoma treated with Delta-24-RGD demonstrated shrinkage in tumor volume and enhanced overall survival. Utilizing a human chordoma tissue microarray, the immunosuppressive macrophage marker CD163 was associated with shortened recurrence free survival. Using macrophage/chordoma co-culture, Delta-24-RGD infection achieved a reduction in macrophage expression of CD163. Taken together, Delta-24-RGD demonstrated efficacy in multiple models of chordoma including mice bearing CH22 tumors. The chordoma TME is associated with clinical outcomes and Delta-24-RGD infection reverses a deleterious immunosuppressive immune profile. These studies provide a framework for future clinical trial implementation for patients with metastatic or recurrent chordoma.
TMIC-56. LONGITUDINAL SINGLE CELL RNA SEQUENCING UNVEILS PHENOTYPIC CO-OPTION AND LINEAGE TRAITS OF MESENCHYMAL GLIOBLASTOMA AND GLIOMA-ASSOCIATED FIBROBLASTS
Authors: Jiyong Liang, Longfei Huo, Jihong Xu, Madhuri Saidane, Xiaohua Chen, Katherine Zhang, Pratibha Sharma, Truc Kuo, Lisa Norberg, Gregory Buchold, Chetna Wathoo, Malcolm McDonald, Frederick Lang, Ganesh Rao, Vinay Puduvalli
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Adult gliomas exhibit a high level of heterogeneity presenting a substantial challenge hampering development of targeted therapies. Bulk RNAseq studies have identified a mesenchymal gene expression signature across the glioma continuum, based on which a mesenchymal subtype of glioblastoma (MES-GBM) has been described. However, the mesenchymal phenotype of gliomas remains inconsistently defined and the origin of the mesenchymal signature has been debated). Single cell transcriptomic profiling has allowed resolution of gene expression profiles of tumor and non-tumor cells, leading to recent identification of cancer-associated fibroblasts in gliomas and improved understanding of the mesenchymal gene expression signature. METHODS We performed longitudinal scRNAseq analysis of organotypic human glioma slices from 8 patients cultured ex vivo for up to 3 weeks. RESULTS We found 2 of the 6 IDHwt glioblastomas exhibit the mesenchymal phenotype based on Consensus Methylation Profiling (NIH) and scRNAseq analysis, annotated as Mes-1 and Mes-2. The gene expression profiles of mesenchymal glioblastomas show limited concordance with that of either the proneural or classical glioblastoma signatures or of cell types in physiological human brain, with Mes-2 deviating more extensively from non-mesenchymal gliomas. Instead, single cell transcriptomics suggests a hyper-secretory phenotype and overlaps broadly with that of cancer-associated fibroblasts (CAFs) and both express FGF2, other growth factors, and cytokines. Notably, Mes-2 cells express minimal to no levels of genes associated with brain cell lineages, such as PTPRZ1 and SCG3, which are abundantly expressed in other glioma subtypes. CONCLUSIONS Taken together, our data reveals extended depth of glioma heterogeneity that distinguishes MES-GBM from other glioma subtypes and suggests a phenotypic and lineage linkage between MES-GBM and glioma-associated fibroblasts. Thus, new diagnostic and treatment strategies leveraging auto- and paracrine mechanisms underpinning tumor and non-tumor interactions including disruption of the FGF2-FGFR1 circuitry may apply specifically to MES-GBM.