tbuckley/cabot-search huggingface dataset:
BIOM-59. INDIVIDUALIZED TUMOR-SPECIFIC AMPLIFIED DNA JUNCTIONS FOR PLASMA-BASED MONITORING IN PATIENTS WITH HIGH-GRADE GLIOMAS
Authors: Mohamed Ali, Cecile Riviere-Cazaux, Sarah Johnson, Rebecca Salvatori, Alan Penheiter, James Smadbeck, Stephen Murphy, Faye Harris, Alexa McCune, Michael Barrett, Farhad Kosari, Leila Jones, Cristiane Ida, Mitesh Borad, Bernard Bendok, Aleeshba Basil, Alfredo Quinones-Hinojosa, Alyx Porter, Maciej Mrugala, Kurt Jaeckle, Panos Anastasiadis, Sani Kizilbash, John Cheville, David Routman, Terry Burns, George Vasmatzis
Journal: Neuro-Oncology (2024)

Abstract Accurate response assessment in patients with high-grade gliomas (HGGs) is complicated by post-treatment radiographic changes that are equivocal for treatment effect versus progression. Plasma-based liquid biopsy assays for circulating tumor DNA (ctDNA) have had limited sensitivity to date, due in part to the presence of the blood-brain barrier that limits the diffusion of tumor-derived analytes out of the central nervous system. To address this challenge, we developed a ctDNA plasma-based assay to detect individualized tumor-derived amplified junctions in patients with HGGs. These junctions occur due to large-scale chromosomal rearrangements, such as those associated with epidermal growth factor receptor (EGFR) or cyclin-dependent kinase 4 (CDK4) amplification. To identify these amplified junctions, whole genome sequencing was performed on resected tissue. Primers were designed to flank junction breakpoints and were then utilized on each patient’s plasma samples to detect the amplified junction via qPCR. Tumor-specific amplified junctions were robustly detected in plasma from 14/14 (100%) patients with IDH-mutant or wild-type grade 4 astrocytomas whose tumor genomes demonstrated amplification-related junctions, located at chromosomes 7, 11, or 12. In comparison, ctDNA could not be detected in three control cases that did not have an amplification or did not have high copy number junctions. Importantly, serial plasma samples obtained prior to and at disease recurrence in 4 patients demonstrated an increasing abundance of amplified junctions that accurately correlated with disease progression in 4/4 patients (100%). In two of these patients, increasing abundance of amplified junctions preceded radiographic changes compatible with disease progression by approximately 2 or 4 months, respectively. In conclusion, tumor-specific amplified junctions could reliably be detected in plasma from patients with IDH-mutant or wild-type grade 4 astrocytomas and correlated with changes in disease burden. Further work is currently ongoing to evaluate these promising results in a larger cohort of patients with serial plasma samples.
CNSC-67. ANATOMICAL ORGANIZATION AND ELECTRICAL PROPERTIES OF GLIOMA-INNERVATING NEURONS
Authors: Annie Hsieh, Sanika Ganesh, Tomasz Kula, Madiha Irshad, Emily Ferenczi, Wengang Wang, Yi-Ching Chen, Song-Hua Hu, Zongyu Li, Shakchhi Joshi, Marcia Haigis, Bernardo Sabatini
Journal: Neuro-Oncology (2024)

Abstract Gliomas are the most common malignant primary brain tumors and are often associated with severe neurological deficits and mortality. Unlike many cancers, gliomas rarely metastasize outside the brain, indicating a possible dependency on the brain’s unique microenvironment. Recent discoveries have highlighted the existence of neuron-glioma synapses, suggesting that glioma cells depend on neuronal inputs and AMPA-receptor-mediated glutamate signaling for their proliferation. Yet, the specific locations and properties of the neurons that innervate gliomas remain elusive. In this study, we utilized transsynaptic tracing with a pseudotyped, glycoprotein-deleted rabies virus to specifically infect TVA and glycoprotein-expressing human glioblastoma cells in an orthotopic xenograft model. This approach allowed us to identify the presynaptic neuronal inputs to the glioma. Comprehensive whole-brain mapping and quantification revealed that these glioma-innervating neurons, predominantly glutamatergic, exhibit a consistent input pattern influenced by the tumor’s locations and engage selective neuromodulatory pathways. Notably, the electrophysiological properties of these neurons mirror those innervating the cortex in vivo. Our study introduces a novel method for investigating glioma-innervating neurons and reveals that these neurons are consistently integrated into the glioma network, displaying distinctive location-dependent neuromodulatory patterns. Our findings offer a promising scaffold for future interventions aimed at disrupting these critical neuronal inputs, potentially redefining therapeutic strategies against brain tumors.
BIOM-26. ROLE OF EXTRA-DOMAIN B FIBRONECTIN IN MODULATING GLIOBLASTOMA CELL INVASIVE PROPERTIES
Authors: Bo Ram Kang, Minji Yun, Eunkyung Bae, Kyuha Chong
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is a highly malignant tumor characterized by its resistance to current treatment modalities and high recurrence rates. Extra-domain B Fibronectin (EDB-FN), a glycoprotein not found in normal tissues but selectively expressed in the tumor microenvironment, was previously identified by our team as a promising molecular marker for brain tumors, offering potential for both prognostic prediction and therapeutic targeting. However, the specific role and mechanism of action of EDB-FN in GBM cells remain unclear. In this study, we sought to elucidate the potential role of EDB-FN and the underlying mechanisms contributing to GBM malignancy through in vitro investigations. Our findings reveal that silencing EDB-FN in GBM cells leads to a decrease in cell migration, invasiveness, extracellular matrix adhesion ability, and stem cell-like properties. Furthermore, we discovered that FAK and ERK signaling pathways play a crucial role in GBM cell progression in response to EDB-FN. This study underscores the potential of EDB-FN as a specific biomarker for GBM treatment, paving the way for future research in this area.
SURG-01. INTRAOPERATIVE FLUORESCENCE ACTIVITY OF 5-AMINOLEVULINIC ACID IN BRAIN METASTASIS OF LUNG CANCER IS ASSOCIATED WITH THE GENETIC ALTERATION OF CELL CYCLE REGULATION
Authors: Young Zoon Kim, Kyeong-O Go
Journal: Neuro-Oncology (2024)

Abstract With advancement of technology in brain tumor surgery, fluorescence image, such as 5-Aminolevulinic Acid (5-ALA), can help detect the residual tumor during surgery. Recently, genetic alteration of cancer is additionally considered as prognostic factor with being added into traditional prognostic system, such as Graded Prognostic Assessment (GPA) scoring system. The primary objective of this study was to investigate the association of certain genetic alterations and intraoperative fluorescent activity of 5-ALA in brain metastasis (BM) of lung adenocarcinoma. A retrospective cohort study was conducted among 72 patients who underwent surgical resection of BM of lung adenocarcinoma at our institute for five years. Cancer cell infiltration was estimated by the intraoperative fluorescent activity of 5-ALA, and genetic alterations were analyzed by next-generation sequencing (NGS). Total 72 patients were eligible for analysis. Strong fluorescence was obtained in 56 (77.8%) patient during surgery. The sensitivity and specificity for detecting cancer cell infiltration using 5-ALA were 87.5% and 96.4%, respectively. In the NGS data of BM, genetic alteration of cell cycle regulation, DNA repair, tumorigenesis, proliferation, epigenetic regulation, and cancer immunology were detected in 73.6%, 44.4%, 56.9%, 66.7%, 30.6%, and 2.8%, respectively. Genes associated with cell cycle regulation (p = 0.003) and cell proliferation (p = 0.044) were significantly associated with positive fluorescence activity of 5-ALA in the adjacent brain tissue. Genetic alterations in cell cycle regulation and cell proliferation were also associated with shorter recurrence-free survival (p = 0.013 and p = 0.042, respectively) and overall survival (p = 0.026 and p = 0.042, respectively) in the multivariate analysis. Additionally, age, KPS, status of NSCLC, RPA class, GPA score, modality of adjuvant treatment were associated with PFS and OS.The results suggest that genetic alterations in cell cycle regulation and cell proliferation are associated with positive fluorescence activity of 5-ALA in the adjacent infiltrative brain tissue and influence the clinical outcome of BM of lung adenocarcinoma.
QOL-03. CAREGIVER PROGRAM IN NEURO-ONCOLOGY: UCSF EXPERIENCE CARING FOR MORE THAN 4,000 CAREGIVERS OVER THE LAST 10 YEARS
Authors: Jennie Taylor, Margaretta Page, Eduardo Rodriguez Almaraz, Anh Huan Vo, Candice Velasco, Desiree Angelo, Cherrie Demayo, Susan Chang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Caregivers of patients with primary brain tumors are at high risk for distress as they navigate caring for their loved one with both a cancer diagnosis and neurologic disorder. The UCSF Gordon Murray Neuro-Oncology Program, the first of its kind, addresses caregiver needs and is fully integrated into clinical care, providing personalized care and programming to address common challenges and foster resilience. The Program includes a nurse, administrator, and social worker. Referrals occur at the initial clinic appointment; from clinical staff; and caregivers of patients with GBM receive proactive outreach. Dedicated programming provides educational materials around common concerns and building community through support groups, annual retreats and family camp. We report our practical experience of the Program serving over 4,000 caregivers. METHODS Total number of individual caregivers were included from 01/2014 – 12/2023. Detailed demographics were extrapolated during clinical interviews from a subset. Caregiver concerns and interventions were extracted from the medical records between 01/2017 – 12/2023. RESULTS The Program serves an average of 400 caregivers and 800 encounters annually. Demographics revealed 66% females; 77% between 41-64 years of age; 60% spouse; 89% working full time; and 30% with children at home. The most common concerns were informational (42%), followed by emotional (25%), and practical (23%). Examples of informational concerns included desire for resources, understanding treatment plan/side effects, and patient behavioral changes. Emotionally, they feel overwhelmed, uncertain, and sad. Practical concerns included physically caring for patients and issues around medical insurance, disability, and finances. Most common intervention was providing emotional support (40%). CONCLUSIONS Caregivers of patients with primary brain tumors are at high risk of distress and have unique needs. Our practical 10 year experience of a dedicated, fully integrated, caregiver program highlights real world concerns of caregivers and identifies opportunities to develop tailored interventions to address these needs.
EPCO-30. TRANSCRIPTOMIC ANALYSIS IDENTIFIES REGIONAL BIOLOGY AND OUTCOME HETEROGENEITY IN MEDULLOBLASTOMA AND EPENDYMOMA SUBTYPES
Authors: Sonali Arora, Nicholas Nuechterlein, Matt Jensen, Gregory Glatzer, Felix Sahm, Stephen Mack, Michael Taylor, Eric Holland
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma, the most common malignant pediatric brain tumor, includes four distinct subtypes: Wnt, Sonic Hedgehog (Shh), Group 3, and Group 4. In contrast, ependymomas, which account for 10% of pediatric brain tumors and 4% of adult brain tumors, are categorized into three types: supratentorial (ST), posterior fossa (PF), and spinal (SP). While molecular subgrouping has significantly advanced the classification of these diseases, the extent of heterogeneity within these subgroups remains unknown. To address this, we collected bulk RNA sequencing (RNASeq) data from 888 medulloblastoma and 370 ependymoma from various institutions in North America and Europe. Our goal was to establish a comprehensive reference landscape for both medulloblastoma and ependymoma. We also included 42 forebrain and 52 hindbrain fetal samples to contrast against the tumor samples. Our analysis revealed that each disease subtype forms distinct clusters. Previously, subtyping was primarily achieved using methylation data; however, we demonstrate that bulk RNASeq data can also accurately identify disease subtypes. By examining gene expression patterns, gene fusions, and copy number aberrations, we validated existing molecular features and discovered new ones for each subtype. Additionally, we developed an innovative pipeline to identify specific biological patterns for a given region within the landscape. This resource coupled with mapping of new patients’ bulk RNASeq data onto the reference landscape, facilitating accurate disease subtype identification for new patients. This extensive dataset, available through the online tool Oncoscape, will assist the scientific community in uncovering novel therapeutic targets and advancing research in pediatric brain tumors.
NCOG-10. LONGITUDINAL MULTIDISCIPLINARY MONITORING OF NEUROCOGNITIVE FUNCTION FOR COLLOID CYST RESECTION: THE IMPACT OF SURGERY
Authors: Umberto Tosi, Amanda Sacks-Zimmerman, Francis Villamater, Jessica Spat-Lemus, Kenneth Perrine, Mark Souweidane, H Allison Bender
Journal: Neuro-Oncology (2024)

Abstract Endoscopic resection of colloid cysts, a rare pathology of the third ventricle, is now accepted clinical practice. Owing to their location proximal to numerous deep gray nuclei and to the forniceal columns, colloid cysts have always been feared to cause cognitive decline, whether operated on or not. Detailed cognitive testing before and after endoscopic resection, however, has rarely been described. Thus, out objective was to determine the neurocognitive effects of endoscopic colloid cyst resection. We analyzed formal pre- and postoperative neuropsychological testing performed in 20 patients undergoing endoscopic colloid cyst resection. Performance was compared either for each individual patient on a test-by-test basis or according to aggregated neuropsychological factor scores grouped via expert census. A clinical change was defined significant if (i) reaching statistical significance, and (ii) it was greater than 1.5 times the standard deviation of the preoperative performance distribution. Overall, 20 adult patients with colloid cysts (diameter 13.3 ± 1.3 mm) underwent matched pre- and postoperative testing generating 679 data points. No patient had a significant change in cognitive performance. When neurocognitive metrics assessing cognitive functions typically subsumed by the temporal (p = 0.35), extratemporal (p = 0.20), occipitoparietal (p = 0.31), or frontal lobes (p = 0.11), no statistically significant difference was observed between pre- and postoperative cognitive performance. No significant differences emerged when factor scores were generated according to composite score of different neurocognitive domains: attention (p = 0.32), executive function (p = 0.14), language (p = 0.98), and visuospatial function (p = 0.42). In conclusion, neuropsychological testing allows for the careful longitudinal monitoring of cognitive status and the identification of patients who may benefit from pre- and postoperative cognitive rehabilitation, and should be used as a valuable surgical psychometric marker and adjuvant. No significant cognitive decline was observed, again confirming the safety of endoscopic colloid cyst resection.
NIMG-83. THE PROGNOSTIC VALUE OF PARAMETRIZED KI-67 MAPS DERIVED FROM CONVENTIONAL MRI AND MACHINE LEARNING IN A LARGE RETROSPECTIVE COHORT OF ADULT-TYPE DIFFUSE GLIOMAS
Authors: Samir-Anthony Dagher, Evan Gates, Max Wintermark, James Long, David Fuentes, Dawid Schellingerhout
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ki-67 is a well-established proliferation marker relied upon for glioma grade assessment. Advances in machine learning (ML) now allow researchers to non-invasively predict the voxelwise Ki-67 index with reasonable accuracy based on anatomical MRI.The purpose of this study is to evaluate the prognostic ability of these predictions in adult-type diffuse gliomas. METHODS We included adult patients with untreated gliomas of various histopathologic grades who underwent their first resection at a comprehensive cancer center from 1993 to 2018. Anatomic MR images were pre-processed, segmented, normalized, then run through a pre-trained ML algorithm to generate Ki-67 parametric maps. The maximum estimated Ki-67 (maxKi-67) for each patient was documented, and the optimal threshold stratifying the cohort into low- and high-risk patients was computed using 10-fold cross-validation. Kaplan-Meier survival curves were then generated for both risk groups and compared using the log-rank and Breslow tests. MaxKi-67 was correlated with OS using Cox proportional hazard regression analysis adjusted for age and preoperative KPS. RESULTS 1,179 patients (age 52±15; 701 males) were included in this study. 727 tumors were histologic grade IV, while 246 and 206 were histologic grade III and II. The mean maxKi-67 was 15.9± 5.2. A maxKi-67 threshold of 13 was computed from the 10-fold cross-validation to dichotomize the cohort by OS. The low-risk group (maxKi-67&amp;lt;13) had a median OS = 2,435 days, significantly different from the high-risk group (maxKi-67&amp;gt;13) which had median OS = 551 days (p&amp;lt;.001). A maxKi-67 index above this threshold significantly increased the hazard of death: unadjusted HR = 2.53 [95% CI 2.17-2.96] and adjusted HR = 1.55 [1.31-1.83]. Age &amp;gt; 55 and preoperative KPS &amp;lt; 90 were also negative prognosticators in the Cox model: adjusted HR for age = 2.79 [2.36-3.31] and for KPS = 2.08 [1.77-2.46]. CONCLUSION Image-based derivation of maxKi-67 index using ML accurately predicts survival in glioma patients with a cut-off of 13 segregating these patients into 2 risk groups.
BIOM-43. SOMATIC<i>TP53, PIK3R1, NF1</i> OR<i>TERT</i> MUTATIONS ARE ASSOCIATED WITH INFERIOR CLINICAL OUTCOME IN H3K27M-ALTERED DIFFUSE MIDLINE GLIOMA: AN INTERNATIONAL, MULTI-INSTITUTIONAL STUDY
Authors: Thien Nguyen, Benjamin Lerman, Schuyler Stoller, Timothy Müller, Lion Comfort, Steven Leal-Ekman, Samantha Lyons, Lynette Holman, Calixito Hope Lucas Junior, Anu Banerjee, Alyssa Reddy, Nalin Gupta, Nicholas Whipple, Nicolas Gerber, Ana Stuecklin, Esha Areza, Rizo Marion, Truman Knowles, David Solomon, Andrea Franson, Carl Koschmann, Sonia Partap, Michelle Monje, Laura Prolo, Samuel Cheshier, Reuben Antony, Aashim Bhatia, Jessica Foster, Michael LaRiviere, Laura Maule, Andrea Webster Carrion, Cassie Kline, Sarah Bruningk, Javad Nazarian, Sebastian Waszak, Sabine Mueller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND H3K27-altered diffuse midline gliomas (DMGs) have poor prognosis with no standard of care therapy beyond radiation (RT). While RT prolongs survival, not all patients respond. Molecular biomarkers can be a strategy to predict RT response and thus patient outcomes. METHODS We performed a retrospective analysis of patients with biopsy-proven H3K27M-altered DMG between 2013-2023 from six US medical centers and the DMG Center in Zurich. Patients with tumor genomic sequencing and completion of RT were eligible. Genomic alterations were evaluated for somatic mutations, fusions, and chromosomal instability. Cox proportional hazard models were used to evaluate associations between genomic alterations and survival. Multivariate analysis included all significant variables at P &amp;lt;0.1 in initial analysis, including age at diagnosis, tumor location, TP53 and PIK3R1 alterations. RESULTS 297 patients (135 female; median age 8.3 years; range 0.2-71.4 years) were included. Median progression-free survival (PFS) and overall survival (OS) was 7.6 months (95%CI: 6.9-8.6) and 14.0 months (95%CI: 12.9-15.7). In univariate analysis, TP53 or PIK3R1 status correlated with shorter OS (TP53-mutant 12.5 vs. TP53-wildtype 17.5 months; HR=1.5; 95%CI: (1.1-2.0), P= 0.005); (PIK3R1-mutant 12.6 vs. 14.5 months; HR=1.9, 95%CI: (1.1-3.4), P = 0.03). Multivariate analysis corroborated TP53-mutant status with poorer OS (HR=1.5; 95%CI: (1.2-2.0), P= 0.003). Subgroup univariate analysis of pontine DMG patients showed poorer OS with TP53, NF1, or TERT mutations (TP53-mutant 11.9 vs. 15.2 months; HR= 1.6; 95%CI: (1.1-2.3), P= 0.02); (NF1-mutant 8.4 vs. 13.6 months; HR= 2.3; 95%CI: (1.1-5.0), P=0.03); (TERT 8.5 vs. 13.6 months; HR= 2.5; 95%CI: (1.1-5.7), P= 0.03). Subsequent multivariate analysis corroborated the association of TERT mutations with poorer OS in pontine DMG (HR=2.5; 95%CI:1.05, 5.9, P= 0.03). CONCLUSIONS This is the largest cohort of H3K27M-altered DMG patients with volumetric imaging analysis ongoing. Taken together, our data suggests these genetic alterations can risk-stratify patients for RT and future investigations of radiosensitizers targeting these alterations may improve survival.
DDDR-17. A FACILE HIGH THROUGHPUT DRUG SCREENING PLATFORM ENABLES THE CONSTRUCTION OF A PHARMACO-PROTEOGENOMIC INTERACTION LANDSCAPE IN GLIOBLASTOMA
Authors: Ze-Yan Zhang, Yingwen Ding, Ravesanker Ezhilarasan, Melanie Graciani, Aram Modrek, Jerome Karp, Erik Sulman
Journal: Neuro-Oncology (2024)

Abstract Despite decades of intensive research, the number of treatment options for glioblastoma (GBM), a devastating disease, remains very limited. The vast tumor heterogeneity of GBM and the blood-brain barrier (BBB) represent major hurdles to developing effective therapeutics. Here, we present CARPOOL, a high-throughput therapeutic screening approach designed to facilitate accurate and parallel interrogation of numerous patient-derived GBM spheroid cultures (GSCs), capturing the disease’s heterogeneity. We validated CARPOOL in vitro and in vivo and then applied it for drug screening using a library of over 700 BBB-penetrating compounds across 23 omics-profiled GSCs. This screening identified numerous potential anti-GBM compounds, including previously non-oncology drugs. Clustering analysis provided insights into the mechanisms of action of some of the compounds. Coupling these results with omics data of the GSCs enabled the identification of genetic, subtype, and gene expression-based predictors of drug sensitivity. Our study presents a new approach for advancing drug screening and in vivo preclinical therapy evaluation for precision oncology. Furthermore, our construction of a pharmaco-proteogenomic interaction landscape offers a valuable resource for both basic and translational glioblastoma research.