tbuckley/cabot-search huggingface dataset:
QOL-21. PSYCHOMETRIC VALIDATION OF THE FEAR OF CANCER RECURRENCE INVENTORY FOR PRIMARY BRAIN TUMOR PATIENTS
Authors: Emilie Cheng, Samantha Mladen, Sarah Cook, Autumn Lanoye, Ashlee Loughan, Sebastian Simard, Sarah Braun
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Fear of cancer recurrence and progression (FCR) is a significant concern among those living with primary brain tumor and may be distinct compared to FCR in other cancer populations due to poorer prognosis, neurologic symptoms, and often lifelong treatment. The gold-standard comprehensive assessment tool for FCR–the FCR Inventory (FCRI)–includes 42 items with seven subscales. Validation of the FCRI scale excluded those with primary brain tumors. The present study is the first examination of the psychometric properties of the full FCRI in a heterogeneous sample of patients with primary brain tumors. METHODS Adult patients with primary brain tumors (n=334) completed the FCRI, with six additional brain tumor-specific items, and psychological, medical, and demographic questionnaires. In accordance with best practices of measure development, exploratory factor analysis (EFA) was conducted on the FCRI at the subscale level. Correlations investigated construct validity. RESULTS EFA largely supported the overall psychometric properties of the original FCRI. Several subscales were unchanged: Psychological Distress, Functioning Impairments, Insight, and Reassurance. One brain tumor-specific item (researching treatments) exhibited good fit on the Coping Skills subscale. On the Severity subscale, one item (belief that the tumor will not return) did not fit with an otherwise strong one-factor model. Additionally, five new brain tumor-specific items demonstrated good fit with the Triggers subscale. The resultant FCRI-Brain includes 41 original FCRI items plus six new brain tumor-specific items. FCRI-Brain demonstrated good convergent validity with measures of depression (r=.72), anxiety (r=.75), and death anxiety (r=.80; ps&amp;lt;.05). CONCLUSIONS This is the first validation of the comprehensive FCRI in patients with primary brain tumors. Factor analysis identified a theoretically similar and brain-tumor specific seven-factor model for the FCRI-Brain. Item-level and subscale statistics will be presented, including factor iteration and construction. Future work will use the FCRI to investigate FCR intervention efficacy in neuro-oncology.
RBIO-02. DEVELOPMENT OF FLASH-CAR RADIOIMMUNOTHERAPY FOR PEDIATRIC BRAIN TUMORS
Authors: Haiwei Ni, Zachary Reitman, David Kirsch, Yanqing Gong, Yi Fan
Journal: Neuro-Oncology (2024)

Abstract Pediatric brain tumors including medulloblastoma and high-grade glioma are generally refractory to T cell-based immunotherapy, largely due to an immune-hostile microenvironment infiltrated extensively with immunosuppressive macrophages. Ultra-high dose rate (FLASH) radiotherapy holds promise for treating solid tumors, given the potential lower toxicity in normal tissues and possible favorable impact on tumor immunity. Using a genetically engineered mouse model of medulloblastoma and glioma, we show that FLASH radiation stimulates pro-inflammatory polarization in tumor macrophages. Single-cell transcriptome analysis shows that FLASH proton beam radiation skews macrophages towards proinflammatory phenotypes and increases T cell infiltration in the medulloblastoma model. Further bulk transcriptome analyses reveal that FLASH radiation reduces peroxisome proliferator-activated receptor (PPAR)-γ and arginase-1 expression and inhibits immunosuppressive macrophage polarization under stimulus-inducible conditions. Mechanistically, FLASH radiation abrogates lipid oxidase expression and oxidized low-density lipid (oxLDL) generation to reduce PPARγ activity, while standard radiation induces reactive oxygen species (ROS)-dependent PPARγ activation in macrophages. Notably, FLASH radiotherapy improves infiltration and activation of chimeric antigen receptor (CAR) T cells and sensitizes tumors to GD2 CAR T immunotherapy in the autochthonous medulloblastoma and syngeneic glioma models. These findings suggest that FLASH radiotherapy may reprogram macrophage lipid metabolism to reverse tumor immunosuppression and that combination FLASH-CAR radioimmunotherapy may offer exciting opportunities for treatment of pediatric brain tumor.
EXTH-10. TARGETING EPHA3 AND EPHRIN A5: ADVANCED PRECISION THERAPY FOR GBM
Authors: Rochelle Dsouza, Niclas Skarne, Onkar Mulay, Lachlan Harris, Emily Holton, Ashraf Zaman, Seckin Akgul, Carolin Offenhauser, Hamish Alexander, Zarnie Lwin, Rosalind Jeffree, Po-Ling Inglis, Joseph Powell, Quan Nguyen, Andrew Boyd, Bryan Day
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is an aggressive brain cancer and is associated with very poor prognosis. Standard treatment involves surgical resection, post-operative radiation and TMZ chemotherapy. Further research into new therapeutic approaches which target chemo-resistant tumor propagating cells, are urgently required. The EphA3 receptor is frequently elevated in GBM, particularly in the mesenchymal subtype and expressed on tumor-initiating cells (Day et al. Cancer Cell 2013). Our data in GBM tissue shows that tumor cells expressing the high-affinity EphA3 ligand, ephrin A5; are distinct from EphA3 expressing cells. The ephrin A5-positive cells express the glial differentiation marker GFAP, are less proliferative and less stem cell-like. EphA3 is expressed on the vimentin-positive, highly proliferative cell population. Single cell RNA-sequencing revealed that EphA3 and ephrin A5 are highly expressed in recurrent GBM, and are markers of MES-like and AC-like cell states respectively. Ephrin A5 over-expression in-vivo led to extension of survival in orthotopic xenograft animal models. GBM aggressiveness and downregulation of stem cell markers. Spatial transcriptomics of xenograft tumors revealed a reduction in proliferation markers including Ki67, MCM7 and PCNA. We detected an increase in expression of AC-like cell-state with a concomitant reduction of the MES-like and NPC-like cell-states. Consistently, over-expression of ephrin-A5 in primary GBM lines led to a reduction in neurosphere formation, Ki67 staining and growth rates. Thus we propose that dual targeting of EphA3 and ephrin-A5 might better capture GBM tumour heterogeneity and lead to an extension GBM patient survival. Whilst better understanding the biology of ephrinA5 expression, we also aim to validate antibody-based approaches to perform dual targeting of EphA3 and ephrin A5, leading to an extension GBM patient survival.
CNSC-06. NAVIGATING BRAIN CANCER: PATIENT STORIES AND MEDICAL BREAKTHROUGH
Authors: Kiran Deepthi Vanukuru
Journal: Neuro-Oncology (2024)

Abstract The complex interplay of genetic mutation, dys regulated signalling pathways, Epigenetic modifications and Interaction with tumor microenvironment are the major aggravating factors for Brain Tumors. Neurological complications involve Increased Intracranial pressure, Seizures, Motor and Sensory deficits, Aphasia, Hydrocephaly, Behavioral and personality changes, Cerebellar Symptoms. It is diagnosed in a sequential steps. Collecting good history from patient in primary then examining the patient all through and making some investigations to come to a final diagnosis. On asking history to a patient he complains of recurrent convulsions, Personality changes and some motor activity deficit and loss of few senses. On examination we can reveal defect in cranial nerve functions, Motor or sensory deficits, loss of reflexes and coordination. Then Investigations being the next step for diagnosis, We ask the patient to undergo for a test for Blood Biomarkers and CSF analysis in case of suspection of metastatic Brain tumors. Biopsy to obtain for Histopathological Examination. Histopathological examination is done for analysis of genetic mutations and molecular markers. The other imaging techniques like MRI, MRS, CT, PET, EEG are done. This gives a clear picture of what actually caused tumor and shows a way for treatment. Now the treatment involves both Medical and Surgical treatment. Medical treatment includes Chemotherapy along with radiation therapy where the drugs given are Temozolomide and targeted therapy included EGFR BRAF inhibitors for glioblastoma and low grade gliomas respectively. Tumor treating fields- Optune is given. Surgical treatment involves Craniotomy for removal of primary Brain tumors, Neuro Endoscopy if tumor is present in ventricles or base of Brain, Laser interstitial Thermal therapy for deap seated and recurrent brain tumors. This is all about the treatment and now the patient management is very important for further clinical help. Physical, occupational and speech therapy helps patients recover. Symptomatic approach for inoperable tumors Provide comprehensive support for patients nearing end of life, Emphasise confidence and Quality of life.
NCMP-02. UTILITY OF ICE PACK TEST FOR EARLY RECOGNITION OF IMMUNE CHECKPOINT INHIBITOR MEDIATED OCULAR WEAKNESS
Authors: Anza Zahid, Nithisha Thatikonda, Dalton Amador, Mujtaba Saeed, Sudhakar Tummala
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Immune checkpoint inhibitors (ICI) are associated with neurological immune-related adverse events (NiArE) such as myasthenia gravis (MG) and myositis. These conditions often present with overlapping symptoms, notably ptosis, dyspnea, and extremity weakness. Early recognition and treatment are warranted to prevent disease progression. OBJECTIVE To test the utility of simple bedside ice pack test (IPT) in early recognition and distinction of ICI-mediated MG and myositis ocular manifestations. METHODS We administered IPT in 14 patients who had received ICI in the past 6 months and presented with ptosis. Improvement in ptosis was considered positive IPT (non-fixed, fatigable ptosis) that is suggestive of Immune-mediated MG-predominant process. Work up included myasthenia antibodies, EMG, serum markers of muscle injury (creatine kinase, aldolase), myositis panel and muscle biopsy. Statistical analyses employed median for continuous and frequencies for categorical variables. RESULTS Positive IPT was found in 2 (14%) patients with positive myasthenia antibodies and neuromuscular junction dysfunction on EMG in one patient with repetitive nerve stimulation. These patients had mild elevation in creatine kinase (CK). Muscle biopsy did not reveal a myositic process. Twelve (86%) patients had negative IPT (fixed and non-fatigable ptosis) with significantly elevated CK (&amp;gt;4000), positive myositis panel and muscle biopsy consistent with myositic process. Six of these patients (42%) also had positive myasthenia antibodies. Concomitant myocarditis was observed in 5 (36%) patients. CONCLUSION Clinical overlap between myasthenia and myositis is observed in immune mediated toxicity that may be due to cross-reactivity of antibodies, however, IPT was able to distinguish MG vs myositis-predominant process, thus helping guide management.
EXTH-17. THERAPEUTIC EFFICACY OF B7-H3 CAR T CELLS IN PEDIATRIC HIGH-GRADE GLIOMAS WITH H3G34R/V MUTATION
Authors: Monika Yadav, Siddharth Subham, John Jeppson, Syed M Faisal, John Szarejko, Doug Myers, David Akhavan, Viveka Nand Yadav
Journal: Neuro-Oncology (2024)

Abstract Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors responsible for significant childhood mortality. These tumors often carry mutations in the H3F3A gene, which encodes histone H3.3 proteins. However, current treatment options are limited, underscoring the need for innovative approaches. Chimeric antigen receptor (CAR) therapy, which was successful in treating certain childhood cancers, holds promise for pHGGs with H3G34R/V mutation. In this study, we examined the expression of B7-H3 in patient tumor specimens and various pHGG cell lines with H3G34R/V mutation. Data revealed substantial B7-H3 expression, confirming its potential as a therapeutic target. Co-culturing B7-H3 CAR T cells with H3G34R/V mutated KNS42 and SJ-HGG-X42 cells led to significant increase in the expression of markers associated with T cell activation (IL2, IL6, IF-γ, TNF-α) and immune responses involving cytolytic cells (Granzyme A, B, Perforin) and elevated levels of exhaustion markers (2B4, PD1, Tim3, Lag3) in comparison to mock-treated cells. We evaluated the capability of B7-H3 CAR T cells for cytolytic activity against KNS-42 and SJ-HGG-X42 cells through in vitro testing. Our results after 72 hours of co-culture revealed a strong killing potential of B7-H3 CARs against B7-H3 positive KNS-42 and SJ-HGG-X42 cells, while minimal or no killing was observed on B7-H3KO KNS-42 and B7-H3 negative MDA MD 453 cells. In vivo efficacy of B7-H3 CAR T cells in an orthotopic mouse xenograft model implanted with KNS-42 cells. B7-H3 CAR T cell treated mice showed a marked reduction in tumor burden and a substantial improvement in survival in contrast of CD19-CAR T cell treated control group. Lastly, we have developed a novel In-Utero Electroporation (IUE) immune-competent mouse model of pHGGs with H3G34R/V mutation, that enables exploration of the impact of immune suppressive tumor microenvironment on CAR T cells efficacy. In conclusion, B7-H3 emerges as a promising therapeutic target, and CAR T cells display encouraging functionality within the context of pHGGs with H3G34R/V model.
CNSC-35. TEMOZOLOMIDE POTENTIALLY POSTPONES THE DEVELOPMENT OF SUBSEQUENT METASTASES IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PATIENTS
Authors: Shoaib Bashir, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Surgical intervention is thought to increase the likelihood of subsequent dissemination in diffuse intrinsic pontine glioma (DIPG) patients. However, there is no study evaluating the factors influencing the timing of metastasis development. Hence, the present analysis was conducted to shed light on factors associated with subsequent dissemination timing. METHODS This analysis included 28 pediatric (age≤12) DIPG cases with metastasis treated at Sanjiu Brain Hospital between June 1, 2017 and June 30, 2023. The clinical data were retrospectively collected following the initial diagnosis. The diagnosis was established by typical imaging features of DIPG. The same three radiologists analyzed the imaging data independently. Time to subsequent metastasis was estimated using Kaplan–Meier analysis, and a log-rank test evaluated the differences between groups. RESULTS Of 28 patients, 13 (46.4%) were males and 15 were females. 23 (82.1%) underwent surgical intervention, while 5 (17.9%) did not receive surgery. The patients’ median age was 7 years (2-12 yrs.). The Kaplan-Meier method showed that the median time to metastasis was 5.8 months (95%CI 4.2-9.1). The log-rank test demonstrated that adjuvant temozolomide was the only variable that could significantly delay metastasis in the pediatric DIPG population (P=0.03). The median time to metastasis from the day of initial diagnosis for those who received adjuvant temozolomide was 6.8 months (95%CI 5-10.7) vs. 3 months for those who did not receive adjuvant temozolomide (95%CI 2.3-NA). Sex, age, surgical intervention, and concurrent irradiation and temozolomide were not associated with metastasis timing. CONCLUSION Adjuvant temozolomide administration might benefit DIPG patients by delaying metastasis, especially in those who are at higher risk for subsequent metastasis, such as those who underwent surgical intervention. However, prospective studies are warranted to confirm these results.
NIMG-62. SEX-DISTINCT TRANSCRIPTOMIC SIGNATURES UNDERLY MRI-DEFINED EDEMA PATTERNS IN HUMAN GLIOMAS
Authors: Pamela Jackson, Lee Curtin, Kyle Singleton, Maciej Mrugala, Richard Zimmerman, Bernard Bendok, Peter Canoll, Kristin Swanson
Journal: Neuro-Oncology (2024)

Abstract Magnetic resonance imaging (MRI) is key to clinically managing brain tumor patients, however connecting the biology to imaging remains challenging. We previously developed a two-compartment model of MRI signal intensity to quantitatively estimate relative edema abundance from T2-weighted MRIs. Using this model, we previously identified the fatty acid metabolism (FAM) and oxidative phosphorylation (OxPhos) pathways as sex-distinct, with both pathways amplified for high edema in males and low edema in females. The purpose of this project was to further delineate sex-distinct biology associated with MRI-estimated brain tumor edema abundance. We analyzed 179 multiregional samples (Female: 75; Male: 104) from 55 high grade glioma patients (Female: 21; Male: 34) for bulk RNA-Seq. Patients’ pre-surgical multiparametric MRIs were preprocessed and segmented for abnormal regions and normal tissue. Utilizing the segmentations and preprocessed images we estimated the relative fractions of extracellular and intracellular space based on the edema mathematical model. Samples were characterized by their edema scores, which were analyzed using differential expression for high and low edema, gene set enrichment analysis (GSEA) using MSigDB hallmarks, and leading edge interpretation. Based on transcriptomic leading edge analyses of high and low edema samples from sex-separated cohorts, we identified common and sex-distinct enrichment of the FAM and OxPhos pathways underlying edema patterns. Of the OxPhos pathway leading edge genes, 45 were common, 36 were unique to females, and 66 were unique to males. Of the FAM pathway leading edge genes, 8 were common, 39 were unique to females, and 29 were unique to males. Notably, expression of both IDH1 and IDH2 were increased for males in regions of high edema in the OxPhos pathway. IDH3a was decreased for females in regions of low edema in the OxPhos pathway. These data suggest that there may be sex-distinct metabolism underlying MRI measurable edema formation.
RADT-10. CEREBELLAR RE-IRRADIATION AFTER WHOLE BRAIN RADIOTHERAPY SIGNIFICANT SYMPTOM RELIEF WITH MINIMAL TOXICITY IN METASTATIC BRAIN PATIENTS
Authors: Ory Haisraely, Yaccov Lawerence, Alicia Taliansky
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Whole-brain irradiation (WBRT) remains a standard treatment for patients with extensive brain metastases, providing symptom relief and prolonging survival. However, patients often experience recurrent metastases, necessitating re-irradiation. This study evaluates the efficacy and safety of cerebellar-only re-irradiation for improving symptoms and reducing toxicity in patients with recurrent cerebellar metastases following WBRT. METHODS A retrospective review was conducted on patients who underwent cerebellar re-irradiation between 2017 and 2023 after prior WBRT for symptomatic cerebellar metastases. Clinical, dosimetric, and outcome data were collected. Symptom improvement was assessed based on patient, caregiver, and physician reports three months post-treatment. RESULTS The study included 56 patients with a median age of 53 years. Symptom domains included gait dysfunction, nausea/vomiting, dysarthria, movement disorder, dizziness, and headache. Breast cancer was the most common histology. The median interval from WBRT to cerebellar re-irradiation was 15 months. Symptomatic improvement was observed in 75% of patients, with notable improvements in nausea/vomiting (84.6%) and headache (80%). Age, dose deliver and time from WBRT were significant for clinical improvement. Dexamethasone use decreased in 76.3% of patients post-treatment. Radiological responses correlated with clinical improvements in 90% of cases. Only one patient developed symptomatic radiation necrosis. Six-month overall survival and progression-free survival were 50% and 39.2%, respectively. CONCLUSION Cerebellar-only re-irradiation is an effective and safe option for managing recurrent cerebellar metastases, significantly improving symptoms with minimal toxicity. This approach also allows for subsequent systemic therapy or radiosurgery for supratentorial lesions, potentially reducing the need for additional WBRT. Further studies are required to validate these findings in larger cohorts.
SURG-37. ADVANCING GLIOBLASTOMA RESEARCH THROUGH RESECTION MODELS
Authors: Thenzing Judá Silva Hurtado, Raymund Yong, Nadejda Tsankova
Journal: Neuro-Oncology (2024)

Abstract Regardless of its cellular and molecular heterogeneity, glioblastoma (GBM) tumors share a common hallmark: an infiltrative growth pattern that poses challenges to surgical resection and leads to incomplete tumor removal. As part of the current standard-of care treatment, patients undergo surgery in addition to temozolomide and radiation therapy. In GBM research, mice are often used to replicate tumor development and test treatments, but this approach typically omits the crucial aspects of surgical intervention, and thus fails to recapitulate important aspects of human GBM disease progression at the surgical margin. Here we address this challenge by developing a technique for tumor resection in mice. First, we implant the infiltrative patient derived GBM cell line Akaluc G16302 in the frontal cortex, specifically at anteroposterior 2mm, mediolateral 0.5mm, dorsoventral 1mm starting from bregma. After 6 weeks, we anesthetize the mouse and do a craniotomy at the injection site, approximately 3-4mm in diameter. We perform a circumferential cut using a curved Fukushima scissor at the edges of the craniotomy area and scoop the tumor core, mimicking surgical resection. Mice survive the surgery and are alive up to 37 days post-resection. Histology confirms resection of tumor cells and a surgical tumor margin remaining in the xenograft animal. In our pilot study, mice undergoing resection displayed significantly increased overall survival compared to mice without surgery (log-rank p-value = 0.0448; n=6; survival range of 91-100 days for control and 97-107 days for resected mice), recapitulating survival benefit also seen in humans. This preliminary data demonstrates the feasibility of the technique and resection-associated survival benefit. Such advancements enable researchers to more accurately replicate the biology of GBM progression and treatment response observed in human patients, bringing us closer to modeling the clinical scenario in mice. Key words: Glioblastoma, resection, biopsy