tbuckley/cabot-search huggingface dataset:
IMMU-71. CRANIOENCEPHALIC FUNCTIONAL LYMPHOID UNITS IN GLIOBLASTOMA
Authors: Celia Dobersalske, Laurèl Rauschenbach, Yichao Hua, Christoph Berliner, Ken Hermann, Florian Rambow, Igor Cima, Ulrich Sure, Björn Scheffler
Journal: Neuro-Oncology (2024)

Abstract The general accessibility of the brain to immune cells has been a subject of intense debate and reinterpretation within the last decade. While glioblastoma’s brain tumor ecosystem is typically considered immunosuppressed, we report the presence of a tumor-reactive immune cell niche within the cranial bone marrow (CB) situated adjacent to treatment-naive tumors. At time of initial diagnosis, glioblastoma patients underwent clinical and anatomical imaging, which revealed an unexpected co-morbid association between the CB and the tumor. Following this observation, we conducted an extensive experimental study including multiplex immunofluorescence, immunoprofiling, functional assays, and single-cell analysis, which identified an active lymphoid niche within the patient’s CB. CD8+ T cell effector cells residing in this niche exhibited acute and durable antitumor responses, and, compared to cells from the distal bone marrow, showed increased expression of the lymphoid egress marker S1PR1. Single-cell T cell receptor sequencing revealed a rich reservoir of non-exhausted tumor-shared CD8+ T cell clonotypes within the CB lymphoid niche, suggesting re-circulation between the proximal bone and the tumor tissue. These clonotypes were characterized by a high predicted tumor-reactivity, significantly surpassing levels found in blood and distal bone marrow. We discovered the entire developmental spectrum of CD8+ T cells in the CB, indicating that anatomical proximity may play a critical role in the process of early anti-tumor response. Correspondingly, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker, indicating focal association with improved progression-free survival. Our findings support the preservation and further exploitation of these cranioencephalic units to improve clinical care in glioblastoma patients.
RBIO-08. INVESTIGATING THE EFFICACY AND MECHANISMS OF TUMOR TREATING FIELDS IN RADIATION-RESISTANT GLIOBLASTOMA MODELS
Authors: Taylor Schanel, Rhea Pandit, Joshua Anderson, Hasan Alrefai, Amber Jones, Patricia Hicks, Anita Hjelmeland, Christopher Willey
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is an aggressive malignant brain tumor with poor prognosis despite current treatment regimens involving surgical resection, radiation, temozolomide, and the newly approved use of Tumor Treating Fields (TTFields; a noninvasive, transdermal, administration of alternating low-intensity, intermediate-frequency electrical fields). Acquired radiation resistance, thought to be partially driven by brain tumor-initiating cells (BTICs), underscores therapeutic challenges in GBM. While clinical evidence supports the therapeutic benefit of TTFields, its precise mechanisms of action are poorly understood, and TTFields impact on radiation-resistant GBM is unknown. To better understand the effect and mechanism of TTFields in radiation-resistant GBM, we utilized patient-derived xenolines (PDX) and their acquired radio-resistant pairs to assess changes in viability and molecular signaling. PDX were previously developed by subcutaneous implantation of patient GBM cells into immunodeficient (nu/nu) mice. Acquired radiation-resistant PDX were generated through serial in vivo radiation. TTFields were administered with the Novocure inovitroTM device in a cooling incubator to maintain 37oC sample temperature in the ceramic well plates of the device. PDX were cultured on geltrex-coated coverslips under serum-free conditions. Cytotoxicity was quantified 72h post TTFields with crystal violet. Molecular signaling was captured with PamChip peptide-based kinase activity arrays and RayBiotech proteomic arrays. We found that TTFields inhibit cell growth in both parental and acquired radiation-resistant PDX. Differences in molecular signatures between the PDX lines suggest molecular mechanisms of TTFields sensitivity signatures and interactions with acquired radio-resistant PDX. We are currently trying to generate TTFields-resistant PDX lines through serial treatment with plans to examine BTIC populations relative to TTFields efficacy. We also plan to explore targetable TTFields-induced alterations in the future.
NIMG-72. VOXEL-WISE, MULTIVARIABLE, COX PROPORTIONAL HAZARD STATISTICAL PARAMETER MAPPING TO INVESTIGATE THE INTERPLAY BETWEEN TUMOR LOCATION, PROGNOSTIC VARIABLES, AND EXPERIMENTAL TREATMENT IN A PHASE 3 TRIAL OF NEWLY-DIAGNOSED GLIOBLASTOMA TREATED WITH CHEMORADIATION WITH OR WITHOUT BEVACIZUMAB
Authors: Francesco Sanvito, Catalina Raymond, Lauren Abrey, Josep Garcia, Brian Simmons, Olivier Chinot, Frank Saran, Ryo Nishikawa, Roger Henriksson, Warren Mason, Wolfgang Wick, Timothy Cloughesy, Benjamin Ellingson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor location is known to impact overall survival (OS) in glioblastoma. However, there is a lack of quantitative tools for studying the interplay between tumor location, prognostic variables, and treatments. In the current study we develop a voxel-wise statistical parameter mapping technique using a multivariable Cox regression model to describe the influence of tumor location on treatment effects in newly diagnosed glioblastoma. METHODS 598 newly diagnosed glioblastoma patients from the phase 3 AVAglio trial were studied. Areas of T2/FLAIR hyperintensity and resection cavities on post-surgical MRI scans were segmented and aligned to MNI atlas space. Voxel-wise Cox proportional hazards models for OS were run for each image voxel and included tumor presence in a specific voxel, age, MGMT promoter methylation, baseline tumor volume, and treatment (chemoradiation with or without bevacizumab). Results. After adjusting for other variables, tumor location was an independent predictor of favorable OS for tumors with involvement in the right prefrontal cortex (p&amp;lt;0.05, HR ranging ~0.48–0.65) and a predictor of shorter OS for tumors in the left mesial/basal temporo-occipital areas (p&amp;lt;0.05, HR ~3–6.2) and in the left hemisplenium of the corpus callosum (p&amp;lt;0.05, HR ~2.5–3). Baseline tumor volume (HR ~4–6 x10-6), MGMT status (HR ~0.38–0.41), and age (HR ~1.020–1.025) were significative predictors regardless of location (p&amp;lt;0.05 in all locations). Interestingly, chemoradiation plus bevacizumab treatment showed a favorable OS compared with chemoradiation alone for tumors with involvement in the right corticospinal tract, right motor and sensory cortices, and left hemisplenium of the corpus callosum (p&amp;lt;0.05, HR ~0.82). CONCLUSIONS Tumor involvement in the prefrontal cortex is associated with favorable prognosis, while tumors in mesial/basal temporo-occipital areas or splenium of the corpus callosum are associated with shorter OS. Chemoradiation plus bevacizumab may improve OS for tumors involving eloquent motor areas and the corticospinal tract.
NIMG-61. TRANSVENTRICULAR MIGRATION OF CESIUM-131 BRACHYTHERAPY SEEDS TO THE SACRAL THECAL SAC IN A PATIENT TREATED FOR RECURRENT GLIOBLASTOMA
Authors: Mahnoor Islam, Abhay Varma, Charlotte Rivers, William Godwin, Istvan Takacs, Alicia Zukas
Journal: Neuro-Oncology (2024)

Abstract Cesium-131 brachytherapy (GammaTileTM) is a relatively new form of surgically targeted radiation therapy for recurrent glioblastoma. While seed migration is a well-documented complication of solid tumor brachytherapy, it has not been reported in the treatment of glioblastoma. Here, we describe a rare occurrence of seed migration in a 71-year-old patient treated for recurrent left temporal lobe glioblastoma. The GammaTile is comprised of a resorbable collagen matrix containing four titanium-encapsulated radioactive Cs-131 seeds. Each seed emits a localized dose of radiation with a 9.7-day half-life. To prevent displacement from the resection cavity, oxidized regenerated cellulose (SurgicelTM) was applied to the cavity surface under the tiles and fibrin sealant (TisseelTM) was applied over the tiles. Margins of the lateral ventricles were not breached during the surgery and surface was non-ulcerated. The tiles remained in place on follow-up imaging for at least 7 weeks. At least 97% of the prescribed dose was delivered before seed migration. Bevacizumab systemic treatment was initiated. Abdominal CT obtained after 3 months incidentally noted migration of 2 seeds to the sacral spinal canal. Additional seeds had migrated to the suprasellar region, left lateral ventricle, and lateral cerebellomedullary cistern. Despite seed migration, the patient maintained progression-free survival for at least 10 months, with at least 30 months of overall survival from the time of diagnosis. Although the patient did not experience any symptoms related to seed migration, this has the potential to cause radiation-related toxicity to healthy tissue, particularly if it occurs early after surgery. The use of bevacizumab may have contributed to penetration of the lateral ventricle. Despite meticulous surgical technique, the potential for seed migration should be considered during treatment planning when using anti-angiogenic therapies. Further research is needed to better understand the factors contributing to seed migration and to develop strategies for minimizing this risk.
BIOM-27. VOXEL-WISE SURVIVAL ANALYSIS IN GLIOBLASTOMA: TUMOR PROBABILITY MAPS REVEAL CRITICAL REGIONS NEAR WHITE MATTER TRACTS
Authors: Biprojit Nath, Aleksandra Winiarz, Samuel A Bobholz, Allison K Lowman, Savannah R Duenweg, Fitzgerald Kyereme, Daniel Aaronson, Jennifer Connelly Connelly, E Kelly Mrachek, Max Krucoff, Anjishnu Banerjee, Peter S LaViolette
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma is the most aggressive primary brain tumor, characterized by rapid growth and poor prognosis. Understanding spatial determinants of survival in GBM is crucial for improving prognostic accuracy and treatment strategies. Our study employs voxel-wise survival analysis (VSA) of tumor probability maps (TPMs) derived from MRI to identify high-risk brain regions. TPMs are generated through radio-pathomic mapping and can predict non-enhancing tumor regions not captured by traditional imaging. We aim to determine if high tumor probability regions are near previously identified critical white matter (WM) tracts and assess their impact on survival outcomes. METHODS We analyzed data from 374 GBM patients from the UCSF-PDGM-v2 dataset. Using a pretrained radio-pathomic model, TPMs were predicted based on T1, T1C, ADC, and FLAIR MRI sequences. All TPMs were rigidly registered to MNI space using ANTs. A Cox proportional hazards model was applied voxel-wise to assess the association between tumor probability and overall survival (OS). A p-value map was generated, thresholded, and cluster corrected (p &amp;lt; 0.05) for further analysis. RESULTS The VSA revealed that high tumor probability regions were significantly associated with poorer OS in GBM. Gray matter (GM) regions near WM tracts with high tumor probability showed markedly reduced survival. GM regions adjacent to the left IFOF (p &amp;lt; 0.05, HR = 1.19, 845 vs. 961 days for high/low TPM), Corpus Callosum Forceps Minor (p = 0.0001, HR = 1, 740 vs. 902 days), Body of the Corpus Callosum (p = 0.005, HR = 0.97, 748 vs. 798 days for high/low TPM) and other WM tracts, such as the left thalamic radiation superior and left reticulospinal tracts had similar trends. CONCLUSIONS Our study demonstrates that regions with high tumor probability, particularly those in the GM near critical WM tracts, are strongly associated with worse overall survival in GBM patients.
EPCO-61. THE LANDSCAPE OF ALTERNATIVE SPLICING IN PEDIATRIC GLIOMA
Authors: Baobao Geng, Lin Wang
Journal: Neuro-Oncology (2024)

Abstract Recent studies have identified alternative splicing (AS) as a novel source of neoantigens for immunotherapy. Surprisingly little is known about the AS milieu in Pediatric glioma, including diffuse intrinsic pontine glioma (DIPG), pediatric high grade glioma (pHGG) and medulloblastoma. We analyzed 20 primary DIPG, 22 pHGG and 20 medulloblastoma human specimens via RNA sequencing and re-analyzed RNA-sequencing data from non-malignant human brain tissues. From these data, we reconstructed the landscape of AS in Pediatric glioma and contrasted that to observed isoforms in non-malignant brain. We identified novel splicing events in cell-surface proteins that are suitable targets for engineered T-cell therapies in DIPG, pHGG and medulloblastoma. We also identified novel splicing events derived neoantigens in DIPG, pHGG and medulloblastoma respectively, which are potential immunotherapy targets. We found DIPG specific isoforms of Platelet-derived growth factor pathway genes which are expressed exclusively by DIPG tumor cells. Our studies shed light on the effect of immunotherapy on AS and identify novel targets for emerging immunotherapies in pediatric glioma.
BIOM-24. GLIOBLASTOMA DNA ALTERATIONS AND RAPID EARLY PROGRESSION AFTER SURGERY
Authors: Kayla Samimi, Aren Saini, Kaylie Cullison, Janette Herr, Eric A Mellon
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is the most common primary brain cancer with overall poor prognosis. In the weeks following initial resection, approximately 50% of glioblastoma patients will demonstrate rapid early progression (REP) on MRI prior to the start of radiation therapy (RT). REP is associated with worse overall survival (OS), however associations between REP and biomarkers in glioblastoma have yet to be evaluated. A single institution sample of 100 patients (age 61.2 years median, 57 males) with a primary diagnosis of glioblastoma were included in this study. Patients underwent gross or subtotal resection followed by RT within 60 days of their surgery. Patients who received biopsy only were excluded. For this analysis, REP was defined as increased nodular enhancement at the border of the resection cavity between the post-operative MRI and RT planning MRI. DNA mutations were collected from commercial next generation sequencing (NGS) results. Biomarkers with a mutational incidence of &amp;gt;10% were used in the analysis, which included TERT promoter (N=80), EGFR (N=38), PTEN (N=40), TP53 (N=36), CDKN2A/2B (N=41), NF1 (N=16), MTAP (N=24), PIK3CA (N=14), and MGMT methylation status (N=32). Statistical analysis was performed using SPSS Statistics 28.0. Of the patients sampled, 45 met the classification of REP. The presence of EGFR alterations (p=0.001) and MGMT methylation (p=0.016) strongly correlated with REP. After multivariate linear regression, only EGFR alterations significantly correlated with REP (p=0.006). There was no significant correlation between REP or overall survival and mutations in TERT promoter, PTEN, TP53, CDKN2A/2B, NF1, MTAP, and PIK3CA. This is the first study to analyze molecular contributors to REP. We identified that EGFR alterations are most strongly correlated with REP. This suggests that patients with EGFR alterations identified on pathology should move rapidly to adjuvant therapies given their propensity to quickly re-grow after resection.
QOL-19. IMPROVING SLEEP IN THOSE WITH PRIMARY BRAIN TUMORS (PBT): A GLIMPSE INTO THE CAREGIVER’S PERSPECTIVE FOLLOWING COGNITIVE BEHAVIORAL THERAPY FOR INSOMNIA (CBT-I)
Authors: Ashlee Loughan, Autumn Lanoye, Kelcie Willis, Amber Fox, Alicia Zukas
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Sleep disturbance is commonly endorsed by individuals diagnosed with primary brain tumor (PBT), yet few providers in neuro-oncology assess for sleep disturbance, and even less recommend the gold standard treatment for insomnia: Cognitive Behavioral Therapy for Insomnia (CBT-I). In our pilot of a group-based, six-session, telehealth-delivered CBT-I program, PBT patients (N=44) demonstrated clinically significant improvements in self-reported insomnia, fatigue, and sleep quality. The aim of this secondary analysis was to examine informal caregivers’ perspectives of the CBT-I intervention and its impact on patients sleep. METHODS Caregivers (N=15, Mage=47.2±14; 53% female; 80% spouses; 93% cohabitating) of patients with PBT and insomnia completed a semi-structured exit interview, following their loved ones’ participation in CBT-I. Descriptive analysis included: perceived improvement in patient and caregiver sleep (rating 1-10; 1=no improvement, 10=great improvement), perceived benefits and drawbacks of CBT-I (open-ended), and caregivers’ recommendation of CBT-I to others with PBT and insomnia (Y/N). RESULTS Most caregivers (73%) noticed a moderate-to-great improvement (≥5/10) in the patient’s sleep and 20% endorsed improvements in their own sleep, following CBT-I. Observed patient benefits included: increased sleep, energy, motivation for change, use of a sleep regimen, and support. Caregivers noted minimal drawbacks of CBT-I, though some found the inflexible sleep schedule disrupted family plans and others wished to be more actively involved in the intervention. Nearly all (87%) would recommend CBT-I to others with PBT and insomnia. CONCLUSIONS Findings suggest that caregivers observed benefit in the patients’ sleep following a brief behavioral intervention for insomnia, further supporting the acceptability of CBT-I for patients with PBT and insomnia. Future directions include a randomized, two-arm pilot of CBT-I and encouraging caregiver participation in the intervention, both to increase their understanding of CBT-I intervention components for maximum benefit in the patient and to possibly improve their own sleep.
EPCO-42. SINGLE-CELL MULTIOMIC ANALYSIS OF BRAIN METASTASES ACROSS MULTIPLE PRIMARY TUMOR TYPES
Authors: Emily Blandford, Jennifer Delegard, Andrew Hardigan, Aditya Mohan, Simon Gregory, Anoop Patel
Journal: Neuro-Oncology (2024)

Abstract Brain metastases are the most common form of intracranial tumor in adults, however the prognosis remains dismal due to lack of effective treatments and limited understanding of the underlying physiology allowing them to thrive in the foreign cell type environment of the brain. Here we characterized the transcriptomic and epigenomic landscape of 35 human brain metastases obtained from surgical resection using combined scRNA-seq and ATAC-seq spanning the most prevalent primary tumor types including lung adenocarcinoma (n=16), melanoma (n=14), breast (n=10), and renal cell carcinoma (n=6). Varying molecular subtypes across primary tumors were included allowing for a comprehensive analysis between and within primary tumor types. Approximately 200,000 cells total were profiled to a sequencing depth of 50,000 mean reads per cell with 2,500 median genes per cell. ATAC-seq libraries were sequenced to a depth of 25,000 reads per cell with 10-15,000 median fragments per cell. Unbiased clustering and integrated analysis identified various cell types within the tumor, immune microenvironment, and normal brain tissue. Tumor cell identities were confirmed throughout multiple clusters via inferred copy number alteration analyses. Integration with primary tumor atlases highlight differences between cell states of primary and metastatic tumors, revealing shifts of enhancer function in transcriptional regulation of metastatic cells. Overall, our findings describe the genetic and epigenetic states of metastatic cells contributing to the understanding of CNS metastatic colonization.
SURG-06. IMPACT OF LASER INTERSTITIAL THERMAL THERAPY VERSUS RESECTION FOR METASTASES ASSOCIATED WITH THE MOTOR CORTEX
Authors: Joshua Jackson, Aden Haskell-Mendoza, Ann Marie Flusche, Joshua Woo, Ellery Reason, Ariel Gonzalez, Ethan Srinivasan, Emily Lerner, Ryan Edwards, David Huie, Evan Calabrese, Peter Fecci
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND For brain metastases (BM), resection remains a mainstay for the upfront management of large, symptomatic lesions, while laser interstitial thermal therapy (LITT) has become a key treatment for radiographically progressive BM following stereotactic radiosurgery (SRS). Compared to LITT, resection-associated morbidity may delay systemic therapies. We evaluated functional outcomes for resection versus LITT to primary motor cortex (PMC)-associated metastases. METHODS Patients receiving resection or LITT for BM radiographically associated with the PMC from 2015-2023 were retrospectively reviewed. Demographic and survival data were collected, with patient Karnofsky Performance Status (KPS) or modified Rankin Scale (mRS) scores assessed out to 1-year by independent raters. RESULTS Forty-one patients underwent resection and 30 underwent LITT to a PMC-associated lesion. Median age was 67 (range 38 – 80) vs 65 (44 – 80) for resection vs LITT; median pre-operative KPS (70 vs 80, P = 0.1) or mRS (2 vs 2, P = 0.66) did not differ between groups. Lung was the most common primary (56.1% resections vs 56.7% LITTs). Resected lesions were of larger median diameter than LITT, 2.8 vs 1.9 cm, P = 0.0001. For resections, length of stay was longer, median 2 vs 1 day, P = 0.0002, and ICU use more frequent (75.6% versus 20.0%, P &amp;lt; 0.0001). At 1-month post-op, 66.7% of resection patients and 51.7% of LITT patients had stable or improved symptoms from pre-op, P = 0.21, with parity at 3-months (65.7% vs 62.9%) and therafter. Further, there was no significant decrement in KPS or mRS score out to a year for either intervention. CONCLUSIONS While there is a short-term increased risk of post-operative neurologic worsening due to LITT-associated edema, our data shows that, relative to resection, this is a transient and clinically limited phenomenon. With careful patient selection, LITT to lesions involving the PMC is feasible.
SURG-13. PATHOLOGICAL EXAMINATION OF MENINGIOMA RECURRENCE AFTER ABSORBABLE ARTIFICIAL DURA MATER RECONSTRUCTION
Authors: Nozomi Hirai, Norihiko Saito, Yuki Koyahara, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Satoshi Iwabuchi
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION In meningioma surgery, the removal of the tumor and tumor-attached dura mater is essential. Due to its high affinity, absorbable artificial dura mater is used for the reconstruction of dural defects. In this study, we report a pathological examination of dural-like tissue in a case of meningioma that recurred at the same site after the use of absorbable artificial dura mater during initial surgery. METHOD We investigated two cases in which absorbable artificial dura mater was used for dural reconstruction during meningioma resection, and subsequently, a recurrent lesion was identified at the site of the dural reconstruction. We examined MRI images and surgical and pathological findings at the time of recurrence in these cases. RESULT All patients underwent total resection, and the pathological diagnosis was atypical meningioma. MRI images at the time of recurrence revealed multiple meningiomas along the artificial dura site. Gross findings during recurrent surgery indicated that the absorbable dura had been replaced by dura-like tissue, with the tumor also attached to the same site. Pathological findings showed bundles of fibrous tissue within the dura-like tissue, albeit with a sparser density compared to autologous dura mater. Meningioma cell invasion and angiogenesis were also observed in the dural-like tissue. DISCUSSION In all cases, multiple meningiomas were found along the dural-like tissue. This suggests that meningioma cells invading the dural-like tissue may have used it as a scaffold for meningioma recurrence. Future studies are necessary to determine the appropriateness of absorbable artificial dura mater for dural defect sites during malignant meningioma surgery.