tbuckley/cabot-search huggingface dataset:
CTIM-07. A PHASE II, OPEN LABEL, SINGLE ARM STUDY OF NIVOLUMAB FOR RECURRENT OR PROGRESSIVE IDH MUTANT GLIOMAS WITH PRIOR EXPOSURE TO ALKYLATING AGENTS
Authors: Eunji Yim, Laura Donovan, Alicia Bargo, Lakshmi Nayak, Yazmin Odia, Eric Wong, Krystelle Pring, Mervin Malig, Yacha Genfi, Nathaniel Wright, Lakshmi Kesari, Alyssa Russ, Rae Chang, Denisse Torres, Kriti Bagri Manjrekar, Sarah Sta Ana, Naomi Sender, Suzanne Mistretta, Fabio Iwamoto
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are an important prognostic factor in patients with gliomas. IDH-mutant gliomas are prone to develop hypermutation after exposure to alkylating agents; in other solid tumors, hypermutation may be a predictive biomarker for PD-1 inhibitor response. In this study, we hypothesize that this specific subgroup of patients would clinically benefit from nivolumab as measured by overall response rate (ORR), duration of response (DOR), median progression-free survival (PFS), and overall survival (OS). METHODS Patients aged 18 years and older with recurrent/progressive IDH-mutant (WHO Grades 2-4) gliomas and prior exposure to alkylating agents were included. Nivolumab was given 240 mg q2w for 8 cycles, then 480 mg q4w until progression, toxicity, study withdrawal, or completion at 2 years. Efficacy was evaluated by ORR of partial (PR) and complete responses (CR) per RANO criteria; low-grade glioma RANO criteria was used for patients with non-enhancing disease. Secondary endpoints included median PFS, median OS, DOR. Toxicity and survival were followed every 3 months until death/study completion. RESULTS Thirty-three patients (66.7% male) were evaluable at study completion. Histology consisted of oligodendroglioma (N=11; 55% Grade 3) and astrocytoma (N=22; 36% Grade 3, 32% Grade 4). Median number of prior lines of systemic therapy was 1 (range 1-6). Median dexamethasone dose at screening was 0 mg (range 0-4). ORR was 9% with two PR and one CR, median DOR 33 months. 11 (32%) patients had stable disease (7 stable for 6+ months) with median PFS 2.2 months and median OS 29.1 months. There were two treatment-related Grade 3 adverse events (lymphopenia and hypotension). One patient discontinued treatment for Grade 2 transaminitis. CONCLUSIONS Though the primary endpoint was not met, three patients have ongoing CR and PR at 54+, 33+ and 24+ months. Future combination therapies with PD-1 inhibitors may increase efficacy in recurrent IDH-mutant gliomas.
NCOG-34. CORRESPONDENCE BETWEEN INTRAOPERATIVE GAMMA BAND ELECTROCORTICOGRAMS AND DIRECT ELECTRICAL STIMULATION ACROSS DIVERSE NAMING TASKS IN PATIENTS WITH LANGUAGE-ELOQUENT BRAIN TUMORS
Authors: Kyle Noll, Israt Tasnim, Priscella Asman, Chandra Swamy, Katherine Connelly, Matthew Muir, Matthew Hall, Guiseppe Pellizzer, Nuri Ince, Sujit Prabhu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Few studies have examined concordance between intraoperative electrocorticography (ECoG) and direct electrical stimulation (DES) language mapping, especially across varied naming tasks. METHODS Twelve patients (Mdn age=59; 75% HGG) underwent awake craniotomy with ECoG and DES language mapping. Mapping utilized iPad stimulus presentation coupled to a 4x8 electrode array for both ECoG and DES. Time-frequency ECoG gamma band activity (Early and Late) was visualized for 3 naming paradigms (Object, Action, Auditory). Bipolar DES was also conducted for each task at each electrode pair. ECoG activations and DES hits were overlayed on preoperative MRI. DES hits represented ground truth for eloquence. ECoG accuracy was examined for each task with 3 different criteria: exact (identical electrodes for ECoG activation and DES hits), adjacent (ECoG &amp;lt;1cm of DES hits), and adjacent within a predefined peritumoral region of interest (&amp;lt;2 cm from boundaries). RESULTS 32 DES hits (40% Auditory, 32% Action, 28% Obj) were observed across patients. Exact ECoG-DES accuracy ranged from 78%-90% [Object: Sens=11%, Spec=91%, PPV=6%, NPV=95%; Action: Sens=40%, Spec=93%, PPV=24%, NPV=97%; Auditory: Sens=69%, Spec=78%, PPV=19%, NPV=78%]. Adjacent ECoG-DES accuracy ranged from 82%-91% [Object: Sens=33%, Spec=92%, PPV=18%, NPV=97%; Action: Sens=44%, Spec=93%, PPV=25%, NPV=97%; Auditory: Sens=91%, Spec=81%, PPV=37%, NPV=99%]. When restricted to the peritumoral region, adjacent ECoG-DES accuracy ranged from 94%-97% [Object: Sens=14%, Spec=99%, PPV=25%, NPV=97%; Action: Sens=25%, Spec=99%, PPV=25%, NPV=99%; Auditory: Sens=100%, Spec=94%, PPV=54%, NPV=100%]. For patients with DES hits (N=10), all had at least 1 task activation &amp;lt;1 cm of DES hits, with 7/10 having convergence of activations across at least 2 tasks. CONCLUSIONS Negative ECoG mapping is strongly predictive of non-eloquence confirmed by DES for all naming tasks. Additionally, gamma band activation elicited by auditory naming within the peritumoral region is strongly predictive of eloquence. Findings support task-based ECoG language mapping for prediction of eloquence and identification of targets for DES confirmation.
PATH-03. SPATIAL-RESOLVED METABOLOMICS ANALYSIS IN HISTOLOGICAL AND MOLECULAR GLIOBLASTOMAS USING A MOF/MXENE-ASSISTED LDI-MSI PLATFORM
Authors: Xiaopeng Guo, Weiqiang Liang, Chunxia Ma, Yuanli Zhao, Yu Wang, Wenbin Ma
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is a highly aggressive primary brain tumor encompassing both histological and molecular subtypes. Metabolites within the tumor microenvironment play critical roles in regulating tumor behavior and response to therapy. Understanding their spatial distribution provides valuable insights for diagnosis and treatment. We investigated metabolite patterns of histological GBMs (hist-GBMs) and molecular GBMs (mol-GBMs) by developing a novel MOF/MXene platform for enhanced surface-assisted laser desorption/ionization mass spectrometry. Utilizing this platform, we analyzed the metabolomes of three hist-GBMs and three mol-GBMs. Our platform exhibited exceptional sensitivity, repeatability, and stability in detecting metabolite molecules. Analysis of the metabolomes revealed distinct spatial distributions and concentrations of various metabolites, including carbohydrates, amino acids, organic acids, nucleotides, and their precursors. Notably, certain metabolites such as TG(15:0/20:3n6/20:5(5Z,8Z,11Z,14Z,17Z)), PG(20:3(6,8,11)-OH(5)/i-21:0), and SM(d20:1/20:3(6,8,11)-OH(5)) were significantly enriched in hist-GBMs compared to mol-GBMs, while others, including lithocholic acid glycine conjugate, PE(P-16:0/14:1(9Z)), and CE(11:1D5), exhibited higher peak intensity in mol-GBMs. Overall, our findings underscore the existence of unique metabolomic signatures distinguishing hist-GBMs from mol-GBMs. In conclusion, heterogeneous metabolite distributions among hist-GBMs and mol-GBMs were revealed by our novel MOF/MXene assisted LDI-MSI platform, and unique metabolic signatures were identified. Advanced metabolomics analysis holds promise for precise biomedical diagnostics and individualized therapeutic strategies in GBMs.
EPID-12. NEIGHBORHOOD SOCIOECONOMIC STATUS PREDICTS SURVIVAL IN GLIOBLASTOMA: A SINGLE CENTER COHORT STUDY
Authors: Yifei Sun, Dagoberto Estevez-Ordonez, Travis Atchley, James Markert, Burt Nabors
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most common primary brain malignancy. Despite recent progress in treatments, prognosis for patients remain poor. Recent literature has suggested the association of GBM outcomes and socioeconomic status. However, there is limited evidence regarding the association of neighborhood-level socioeconomic status on GBM outcomes. OBJECTIVE To investigate the impact of neighborhood-level socioeconomic status on GBM outcomes. METHODS We retrospectively reviewed all adult GBM patients at a single institution from 2008 to 2023. Patient addresses underwent geospatial analysis and Area Deprivation Index (ADI) was extracted. Univariable and multivariable survival analyses were performed. A Cox proportional hazards model was used to assess the effect of ADI and other socioeconomic variables while controlling for a priori selected clinical variables with known relevance to survival. RESULTS In total, 1492 patients met inclusion criteria. The average age at diagnosis was 62±14.2 years with a median overall survival of 12.1 [Interquartile Range (IQR) 5-22] months. The median ADI was 66 (IQR 46-84). Patients with high socioeconomic deprivation (ADI&amp;gt;75) were less likely to receive chemotherapy (92% vs 96%, p=.03), and had worse overall survival compared to patients with low socioeconomic deprivation (10 vs 13 months, p=.001). In the multivariable model, patients with high ADI had worse overall survival (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.16-1.73, p&amp;lt;.001). To account for changes in WHO guidelines, we implemented the model on patients diagnosed between 2017-2023 and findings were consistent (HR 1.34, 95%CI 1.07-1.68, p=.011). CONCLUSIONS We present the largest study reporting the effect of neighborhood-level socioeconomic status on overall survival of GBM patients. Neighborhood-level socioeconomic status provides the most accurate capture of the patient-level socioeconomic determinants of health. Patients with higher ADI have worse overall survival after controlling for other socioeconomic and clinical variables. These results suggest significant association between neighborhood-level socioeconomic status and overall survival in GBM patients.
TMIC-46. TRANSCRIPTIONAL HETEROGENEITY AND MECHANISTIC PATHWAYS OF RECURRENT GLIOBLASTOMA: INSIGHTS FROM A PRE-CLINICAL RECURRENT TUMOR MODEL
Authors: Mohammad Fayyad Zaman, Marc Daou, Lynette M Phillips, Sanjay Singh, Lihong Long, Joy Gumin, Daniel Ledbetter, Frederick F Lang
Journal: Neuro-Oncology (2024)

Abstract Despite aggressive therapy combining surgical resection, radiation and chemotherapy, glioblastoma (GBM) almost always recurs. Currently, there is no standard treatment for recurrent GBM, and patient inclusion in clinical trials is based on the genetic and molecular profile of the primary tumor even though the effects of chemoradiation on the transcriptional subtype in matched primary and recurrent GBM remain largely understudied. Paralleling the GLASS consortium, we sought to perform a longitudinal assessment of GBM recurrence after therapy based on molecular subtype with the hypothesis that recurrent tumors exhibit a distinct transcriptional landscape different from treatment-naive tumors. To address this, we utilized primary tumor-derived glioma stem cells (GSCs) representing classical and proneural subtypes. We then undertook in vivo intracranial implantation studies and performed standard concomitant treatment that mimics the Stupp protocol. Upon bulk RNAseq data analyses of untreated (n=21) and recurrent tumors (n=17) we identified that while the molecular subtype of recurrent tumors does not change post therapy, their transcriptional profile is more heterogenous compared to untreated tumors for both subtypes. Hierarchical cluster analyses revealed distinct sub-clusters of recurrent tumors. Common mechanisms of recurrence include upregulation of angiogenesis pathways and PI3k/Akt/mTOR signaling pathways. Interestingly, recurrent tumors exhibit upregulation of genes involved in cellular metabolism and membrane transport/ potential. The source of heterogeneity in recurrent tumors in both subtypes appears to be due to the diversity in expression of gene sets involved in hallmark of cancer pathways such as cell cycle, Notch and Wnt signaling pathways and heterogeneity in oncogenic signatures and cell states resembling fetal or neural cells. Further research into the recurrent tumor microenvironment by spatial multi-omics approaches using this pre-clinical recurrent GBM model will elucidate the linkage between cellular as well as molecular heterogeneity and enable identification of targets that can help drive therapeutic decisions for recurrent GBM patients.
EPID-13. PREDICTORS OF HISTOPATHOLOGIC RESULTS OF BRAIN BIOPSY IN PATIENTS SUSPECTED OF SECONDARY CNS LYMPHOMA
Authors: A Basit Khan, Dima Suki, Eric Goethe, Luis Fernandez, Rajan Patel, Jason Westin, T Linda Chi, Jeffrey Weinberg
Journal: Neuro-Oncology (2024)

Abstract Patients suspected of secondary CNS lymphoma (SCNSL) often undergo brain biopsies. Recent studies doubt biopsy utility due to high SCNSL diagnosis rates. We sought to enumerate histopathologic biopsy results in suspected SCNSL patients to evaluate utility of biopsy. We furthermore assess clinical and radiographic factors based on ability to distinguishing SCNSL from non-SCNSL. 109 patients with non-CNS lymphoma who subsequently presented with brain lesions that underwent biopsy at MD Anderson Cancer Center were included. Histopathologic diagnoses were obtained. Pre-operative imaging was assessed for contemporary radiologic diagnoses by obtaining the leading differential reported at the time of the study. Subsequently, a staff neuroradiologist, blinded to biopsy outcomes and clinical considerations, provided a retrospective diagnosis. 61 patients had SCNSL whereas 48 did not. Non-SCNSL biopsy results included infection (n=16, 33%), glioma (n=12, 25%), nonspecific (n=12, 25%), and other metastases (n=3, 6%). Patients with non-indolent lymphoma (DLBCL, mantle cell, Burkitt’s, and lymphoblastic lymphoma) were more likely to have SCNSL on biopsy (p&amp;lt;0.001, OR 12.55). Patients with SCNSL had shorter time interval since initial diagnosis (median 18.1mo vs. 63.2mo, p=0.008). Systemic progression of disease at biopsy was not associated with SCNSL (p=0.35). There was no difference in age, stage, LDH, Albumin, ECOG, IPI, anatomic location, or B-symptoms at times of diagnosis or neurosurgery. No patient had positive CSF cytology prior to biopsy. Neither retrospective nor contemporary radiographic diagnoses had sufficient accuracy to replace biopsy. A positive retrospective diagnosis trended towards association with SCNSL pathology (sensitivity=0.94, specificity=0.23, PPV=0.65, NPV=0.70, p=0.08). A positive contemporary diagnosis was associated with SCNSL pathology (sensitivity=0.67, specificity=0.73, PPV=0.76, NPV=0.64, p&amp;lt;0.001). Similar biopsy proportions yielded SCNSL and non-SCNSL. Although some factors are associated with SCNSL, none can reliably distinguish patients. Given the divergent treatments for the reported pathologies, our study reiterates the necessity of biopsy in suspected SCNSL.
CTIM-10. PHASE 1 TRIAL OF PERSONALIZED NEOANTIGEN VACCINES IN COMBINATION WITH STANDARD CARE TO TREAT GLIOBLASTOMA
Authors: Cansu Cimen Bozkus, Julia Kodysh, Szu Jung Cheng, Samantha Cheng, Alex Rubinsteyn, Tim O’Donnell, Mansi Saxena, Guray Akturk, Marcia Meseck, Raymund Yong, Bojan Losic, John Mandeli, Ryung S Kim, Sacha Gnjatic, Nina Bhardwaj, Adilia Hormigo
Journal: Neuro-Oncology (2024)

Abstract The tumor microenvironment (TME) of glioblastoma (GBM) is populated by cells that foster immunosuppression. Reversing immunosuppression and promoting tumor surveillance by T cells that recognize the antigens generated by tumor-specific mutations (neoantigens) is critical to eliminating the tumor cells. In a phase 1 clinical trial of newly diagnosed GBM (NCT03223103), patients were treated with personalized neoantigen vaccines (PNV) combined with standard of care (resection, radiotherapy, temozolomide chemotherapy, and TTFields). The neoantigens were identified using the OpenVax computational pipeline. Primary endpoints included safety and feasibility, and the secondary endpoints included PFS, OS, TME analysis, and immunogenicity assays. The study enrolled 12 patients, ages 32-84, between December 2017 - July 2020. With a feasibility endpoint of one successful PNV administration, all patients got at least 6. All developed PNV-related injection site reactions, and flu-like symptoms grade 1-2. Concomitant use with TTFields did not increase toxicity. None of the patients exhibited dose-limiting toxicity within 30 days of receiving the PNV. However, one developed grade 3 SAE, consisting of seizures, neck pain, and progressive neurological deficits, after vaccine 10, culminating in a grade 5 SAE and brain demyelination 10 months later. Assays performed on this subject showed induction of neoantigen-specific responses with PNV. PNV induced CD4+ and CD8+ T cells reactive against multiple vaccine peptide sequences with CD8+ T cell cross-reactivity against one wild-type epitope. Other patients had immunogenicity against the vaccinated peptides. Overall, the 6 months PFS was 100%, with 67% 2-year and 58% 3-year survival. Although the mutation burden is low in GBM, neoantigens were detected in all tumors, and PNV were manufactured for all patients. PNV with synthetic long peptides combined with standard care treatment may help improve outcomes in GBM. Cross-reactivity may potentially be responsible for post-vaccination T-cell demyelination. Further evidence is needed to substantiate a direct effect. Funding: CRI - V Foundation CLIP (#3680)
INNV-35. DATA-DRIVEN MODELING OF EMERGING TRENDS AND COLLABORATIVE NETWORKS ACROSS BRAIN METASTASES RESEARCH: THE PAST DECADE OF INNOVATION
Authors: Sulaman Durrani, Ian Cote, Sabrina Carpintieri, Joseph Martinez, Ashley Metzler, Joacir Graciolli, Ashish Shah, Eric Oermann, Ricardo Komotar, Michael Ivan, Carolina Benjamin, Jason Sheehan, Douglas Kondziolka, Najib El Tecle
Journal: Neuro-Oncology (2024)

Abstract With recent significant growth in brain metastases literature output, more comprehensive research is necessary to understand emerging trends and novel methods of diagnosis and treatment. We aimed to address this by providing a contemporary systematic global analysis of emerging brain metastases research in the last decade while visually depicting the international collaborative environment among its researchers. Data mining was performed on all brain metastases publications across the last decade indexed in Elsevier’s Scopus database. Our Scopus search revealed 6,362 publications from 1,184 sources from 2013-2022. Of those, 252 were identified as high-impact articles with an annual citation rate (CR) &amp;gt; 10. The compounded annual growth rate (CAGR) of brain metastases publications was 7.2% per year since 2013. There was an acceleration of scientific production, from 5.9% CAGR across 2013-2018 to 9.6% across 2019-2022. Authors per document increased from 7.2% to 8.5% while international co-authorships increased from 16.6% to 18.3% in the same periods, respectively. Recent trending topics were noted to be artificial intelligence, understanding the brain microenvironment, exosomes, novel mechanisms of diagnosis (such as circulating tumor cells), and targeted treatments. High-impact articles tended to revolve around specific therapies or biomarkers as opposed to general synopses. Clustering analysis revealed three separate pivotal collaborative communities centered around Brown PD/Sahgal A, Ahluwalia MS, and Wang Y, with Brown PD as most notable for high impact research. While the top institutional collaborative group centered around Mayo Clinic, the highest impact research centered around the Dana-Farber Cancer Institute. Sub-analyses revealed that studies involving multiple countries tended to have a higher impact. The median overall survival of brain metastases, by primary source, was illustrated across the last five decades. Overall, significant growth in scientific production is driven by the integration of novel technologies (such as artificial intelligence), interdisciplinary approaches, and collaboration across global communities.
EPID-07. MAJOR CONGENITAL ANOMALIES AND RISK OF CHILDHOOD BRAIN TUMORS IN 9 STATES
Authors: Thanh Hoang, Jeremy Schraw, Michael Taylor, Sharon Plon, Philip Lupo, Michael Scheurer
Journal: Neuro-Oncology (2024)

Abstract Children with congenital anomalies have a higher risk of developing a childhood brain tumor (CBT), but it remains unclear if associations vary by cancer histology, which could inform our understanding of these associations. Thus, we characterized co-occurrences of major congenital anomalies with six CBTs. We leveraged a population-based registry linkage study of live births, congenital anomalies, and cancer from nine states. Dates of birth and last follow-up varied by state, ranging between January 1, 1990 to December 31, 2018, for a total of 22,599,099 live births. CBT classification was based on the International Classification of Childhood Cancer for children diagnosed up to age 18 years. Major congenital anomalies were classified based on the National Birth Defects Prevention Network Surveillance Guidelines. Children with any genetic anomalies were excluded. We used Cox regression to evaluate associations between major congenital anomalies and astrocytoma, medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor (ATRT), primitive neuroectodermal tumors (PNET), and mixed and unspecified gliomas (“mixed gliomas”), adjusting for sex, state, maternal education, maternal race/ethnicity, and maternal age. Sensitivity analyses were conducted stratifying by number of major anomalies (0, 1, 2+) and age at cancer diagnosis (&amp;lt;1, 1-4, 5-9, 10+ years). There were 5,685 diagnosed with any CBT. Having any major congenital anomaly was significantly associated with astrocytoma, ATRT, medulloblastoma, mixed glioma, and PNET (aHR range: 1.79-5.78) but not ependymoma. When stratified by number of major anomalies, effect estimates were similar. Due to small numbers when stratified by age at cancer diagnosis, unadjusted analyses were conducted. Associations were strongest in children diagnosed with astrocytoma, ATRT, medulloblastoma, mixed glioma, or PNET before age 1 (HR range: 3.03-5.47) compared to other age groups (HR range: 1.25-3.07). Children with any major congenital anomaly have an increased risk of developing astrocytoma, ATRT, medulloblastoma, mixed glioma, or PNET, particularly by 1 year.