tbuckley/cabot-search huggingface dataset:
CNSC-17. UPREGULATION OF CCL4 AFTER TREATMENT WITH A NOVEL MRNA VACCINE SHIFTS THE PHENOTYPE OF CCR5-EXPRESSING MICROGLIA WITHIN TUMOR MICROENVIRONMENT
Authors: Anjali Chauhan, Nagheme Thomas, Farhad Dastmalchi, Kyle McGrath, Gregory Pal Takacs, Jeffrey K Harrison, Vignesh Subramaniam, Thomas Angelini, Ghaidaa Ebrahim, Macaulay Y Tomdio, Matthew Frain, Hector Mendez-Gomez, Elias J Sayour, Christine von Roemeling, Duane A Mitchell A Mitchell, Maryam Rahman
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Intra-tumoral immunosuppression is a major cause of treatment failure for patients with glioblastoma (GBM). Our group has developed a proprietary vaccine that combines mRNA encapsulated in lipid nanoparticles with PEG hydrogel and a chemokine (CXCL9). This hydrogel-chemokine-mRNA (HCM) vaccine is delivered subcutaneously (SQ) and results in significant anti-tumor efficacy in syngeneic murine glioma models. The objective of this study was to evaluate the effects of the vaccine on the tumor microenvironment (TME). METHODS C57BL/6 mice underwent intracranial implantation of KR158-luc tumor cells and underwent SQ injection of the HCM vaccine using total tumor mRNA. Tumors were collected for analysis at different time points. Q-PCR and flow cytometry were done to evaluate the differential gene expression and CCR5 expression (receptor for CCL4) in the TME following HCM vaccination. RESULTS CCL4 was found to be upregulated in tumor-bearing animals treated with HCM vaccine using PCR. In a separate experiment, CCL4 blockade was given prior to HCM vaccination and this resulted in abrogation of the survival benefit of the vaccine. Next, flow cytometry results revealed that microglia in the TME had the highest expression of the CCR5 receptor. Further, QPCR on the isolated microglia from TME revealed significant up-regulation of inflammatory gene CCL5 (25 fold) and down-regulation of anti-inflammatory genes as compared to untreated control and empty hydrogel control. CONCLUSION The HCM vaccine results in significant anti-tumor efficacy in murine syngeneic murine glioma which is dependent on upregulation of CCL4 in the TME. The CCL4 exerts its effect through microglia expressing CCR5 in the TME. HCM vaccination shifted the microglia phenotype from immune-suppression to inflammatory state. Further analysis of the effect of CCR5 knock out on the HCM vaccine survival efficacy are under current investigation.
RADT-12. DERIVING IMAGING BIOMARKERS FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA USING DEEP LEARNING
Authors: Joshua Zhu, Tommy Hager, Saahil Chadha, Durga Sritharan, David Weiss, Sajid Hossain, Klara Osenberg, Nicholas Moore, Sanjay Aneja
Journal: Neuro-Oncology (2024)

Abstract PURPOSE Primary central nervous system lymphoma (PCNSL) is typically treated with chemotherapy, steroids, and/or whole brain radiotherapy (WBRT). Determining which patients benefit from WBRT after chemotherapy and which are adequately treated with chemotherapy alone remains a clinical challenge. Although WBRT is associated with improved outcomes, it also carries a risk of neurocognitive side effects. This study aims to refine PCNSL patient phenotyping by leveraging deep learning (DL) extracted imaging biomarkers to enable personalized therapy. METHODS Our study included 71 patients treated between 2009-2021. The primary outcome of interest was overall survival (OS) assessed at one- and two-year cutoffs. The DL model leveraged an 8-layer 2D convolutional neural network analyzing individual slices of post-contrast T1-weighted pre-treatment MRI scans. Survival predictions utilized a weighted voting system related to tumor size. Model performance was assessed with accuracy, sensitivity, specificity, and F1 scores. Time-dependent AUCs were calculated and C-statistics were computed to summarize the results. Kaplan-Meier (KM) survival analysis assessed differences between low and high-risk groups and were evaluated using the log-rank test. RESULTS The cohort’s average age was 65.6 years with average OS of 2.80 years. For one-year OS, the model achieved an AUC of 0.73 (0.60-0.85), accuracy of 0.73 (0.61-0.82), sensitivity of 0.72 (0.54–0.85), and specificity of 0.73 (0.58–0.84). For two-year OS, the model achieved an AUC of 0.70 (0.58-0.82), accuracy of 0.70 (0.58-0.79), sensitivity of 0.68 (0.55–0.81), and specificity of 0.71 (0.55–0.84). Model performance is presented with respective 95% confidence intervals. KM curves showed the one and two-year models effectively discriminated between low- and high-risk group, reporting c-statistics of 0.73 (p&amp;lt;.001) and 0.71 (p&amp;lt;.001) respectively. A sub-analysis confirmed consistent model performance across different tumor volumes and focality. CONCLUSION DL classifiers of PCNSL MRIs can stratify patient phenotypes beyond traditional risk paradigms. Given dissensus surrounding PCNSL treatment, DL can augment risk stratification and treatment personalization, especially with regards to WBRT decision making.
CTIM-28. NEOADJUVANT ANTI-PD1 IMMUNOTHERAPY FOR SURGICALLY ACCESSIBLE RECURRENT GLIOBLASTOMA: CLINICAL AND MOLECULAR OUTCOMES OF A STAGE 2 SINGLE-ARM EXPANSION COHORT
Authors: J Ricardo McFaline-Figueroa, Lu Sun, Gilbert Youssef, Raymond Huang, Gang Li, Jiyoon Kim, Eudocia Lee, Lakshmi Nayak, Ugonma Chukwueke, Rameen Beroukhim, Tracy Batchelor, E Antonio Chiocca, Richard Everson, Lisa Doherty, Jennifer Stefanik, Kathryn Partridge, Amanda Spearman, Alexa Myers, Catharina Westergaard, Alyssa Russ, Maria Lavallee, Anna Smokovich, Corey LaForest-Roys, Rachel Garcia Fox, Christine McCluskey, Wenya Linda Bi, Omar Arnaout, PierPaolo Peruzzi, G Rees Cosgrove, Keith Ligon, Isabel Arrillaga Romany, Jennifer Clarke, David Reardon, Timothy Cloughesy, Robert Prins, Patrick Wen
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we performed bulk-RNA seq on resected tumor tissue from an additional 25 patients with recurrent glioblastoma treated with neoadjuvant pembrolizumab. Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. PF6 for the stage 2 expansion cohort was 0%, while overall survival and progression-free survival were similar to historical controls at 6.8 months and 2.5 months, respectively. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not observe a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma in our expansion cohort. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.
NCOG-21. ADJUVANT RADIATION THERAPY IN ATYPICAL MENINGIOMA TREATMENT DOES NOT IMPROVE PROGRESSION FREE SURVIVAL OR OVERALL SURVIVAL: A RETROSPECTIVE COHORT STUDY
Authors: Dheeraj Kagithala, Anneliese Rademacher, Jacob Pawloski, Katie Latack, Hassan Fadel, Florence Dallo, James Snyder, Ian Lee, Adam Robin
Journal: Neuro-Oncology (2024)

Abstract Treatment of atypical meningiomas (AMs) presents a challenge due to their aggressive nature and tendency to recur. While there is clear evidence for the role of surgical resection of AMs, the use of adjuvant radiation therapy (ART) is a topic of ongoing debate. The aim of this study is to explore the impact of ART following surgical resection of AMs. The primary outcomes of interest are progression free survival (PFS) and overall survival (OS). Records were reviewed for all patients treated for Ams at our institution between January 1, 2014 and January 1, 2024. Patients were grouped into two cohorts, those who were initially treated with surgical resection only and those who also received adjuvant RT. PFS and OS were compared between the two groups using Kaplan Meier curves and Log Rank test. Additionally, multivariable cox proportional hazard models were used to adjust for age, MIB, and resection Simpson grading. There were 76 patients who were initially treated with surgery only and 23 patients who had surgery and ART. No significant difference in PFS or OS was observed between the groups (p=0.3522 and p=0.3636, respectively); including after adjusting for age, MIB, and Simpson grading (HR= 1.55 [0.64-3.76], p= 0.330; and HR = 0.95 [0.31-2.93] p= 0.934, respectively). On multivariate analysis, MIB &amp;gt;10 was associated with a significant difference in PFS (HR=2.76 [1.15-6.59], p=0.023). With ART, PFS was 91% at 12 and 60% at 36 months (versus 89% and 57%, respectively, with surgery only). OS was 95% at 12 and 88% at 36 months (versus 91% and 85%, respectively, with surgery only). In this series, ART was not observed to significantly improve PFS or OS compared to surgery alone. Larger series are needed to determine if there is a subset of patients who benefit from ART.
CNSC-53. SHH ACTIVATION IN DEDIFFERENTIATION DURING TUMOR PROGRESSION IN MPNST
Authors: Rebeca Yakubov, Severa Bunda, Gelareh Zadeh
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with little progress on outcomes and treatment strategies. Previously, unsupervised analyses of methylome and transcriptome profiles of 108 peripheral nerve sheath tumors uncovered two subgroups of MPNSTs that predict progression-free survival, MPNST-G1 (characterized by SHH-pathway activation) and MPNST-G2 (characterized by WNT/ß-catenin/CCND1-pathway activation). Further, single nuclear RNA sequencing revealed that MPNST-G1 and MPNST-G2 cells resemble neural crest-like and Schwann cell precursor-like cells, respectively. PURPOSE &amp; HYPOTHESIS To examine whether the activation of the SHH pathway in MPNST-G1 cell lines induces overexpression of factors known to play canonical roles in early neural crest cell specification (TWIST1, SNAI2, PAX3, PAX6, SOX9, OTX2) and to investigate the role of Src activation on SHH pathway-induced dedifferentiation. We hypothesize that MPNST-G1 cells will exhibit SHH pathway activation, synergizing with Src to induce the overexpression of early neural crest cell (ENCC) transcription factors. METHODS SHH pathway activation, expression of ENCC transcription factors, and effects of inhibitors were analyzed in MPNST-G1 cells using RT-PCR, western blotting, Alamar Blue assay, Trypan Blue assay, and Soft Agar Transformation assay. RESULTS Compared to MPNST-G2 cells, MPNST-G1 cells displayed SHH-pathway activation, SMO-dependent activation of Src, and elevated expression of the ENCC transcription factors. Sonidegib (SMO inhibitor) and Dasatinib (Src inhibitor) were able to revert dedifferentiation. CONCLUSIONS The SHH-pathway cooperates with Src to promote expression of important transcription factors in dedifferentiation. This finding provides insights into the transformation process of MPNST and novel therapeutic options.
RADT-07. HYPOFRACTIONATED RADIOTHERAPY IN BRAINSTEM GLIOMAS- EXPERIENCE FROM A TERTIARY CARE CENTRE IN INDIA
Authors: Abhilash Dagar, Adrija Ghosh, Aashita Aashita, Abiramasundari Vivekananda, Adhar Amritt, Jaswin Raj, Sangeeta Hazarika, Aman Sharma, D N Sharma, Supriya Mallick
Journal: Neuro-Oncology (2024)

Abstract Brainstem Gliomas have limited therapeutic options and poor outcomes. Radiation forms the cornerstone of management but data is lacking. We performed an audit of brainstem glioma patients treated with hypofractionated radiation between July 2021 to May 2024. Diagnostic MRI was co-registered with planning CT to delineate GTV with an isotropic 5 mm margin for CTV and 3mm for PTV. Baseline clinical and imaging details, radiation details, acute toxicities, steroid usage, progression, and overall survival data were recorded. PFS and OS were defined from the date of diagnosis to progression and death respectively. This study included 31 Brainstem glioma patients. The median age at presentation was 14 years (2–80 years). Majority of patients were male (67.7%). The baseline performance status assessed by ECOG/Lansky was 0-2 in 83.9%. The most common presenting complaint was motor weakness in 51.6% followed by cerebellar symptoms in 29%. Baseline neurological deficit was seen in 90.3%. The most common epicenter of the disease was pons (67.7%). Biopsy was available in only 9.7% (2 patients: Diffuse Midline Glioma H3k27 altered,1: High-Grade Glioma). VP shunting was done in 29%. All patients were planned via VMAT technique. Median GTV volume 34.3cc (4.9-109.5cc). Median PTV volume was 95.1 cc (7.9-363.1 cc). Most frequently used regimen was 40Gy/15#/3 weeks in 74.3% of patients. Median PTV coverage D95% was 98.7% (90.5-99%). Only one patient received concurrent Temozolamide. Median Radiation treatment time was 22.5 days (-46 days). Steroid usage during radiation was seen in 41.9% of the patients. Naso-gastric tube was required in 12.9% patients. During radiation, aspiration and raised ICT were seen in in 12.9% each. At a median follow-up of 6.42 months, the median PFS was 6.42 months (3-9.83 months) and OS was 7.18 months (3-11.37 months). Hypofractionation seems a feasible approach in brainstem gliomas. International collaborative efforts are required.
TMOD-26. GENERATION OF A CHROMOSOME 8 GAIN;NF1-/- HIPSC-DERIVED SCHWANN CELL PRECURSOR MODEL
Authors: Gorkem Oztosun, Simge Acar, Himanshi Bhatia, Amber Neilson, Xiaoxia Cui, Angela Hirbe
Journal: Neuro-Oncology (2024)

Abstract Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome caused by a germline mutation in the NF1 gene. The loss of the second copy of NF1 within Schwann cell precursors (SCPs) contributes to the formation of plexiform neurofibromas (PNs) found in 30-50% of NF1 patients. PNs can progress into malignant peripheral sheath tumors (MPNSTs), an aggressive form of cancer and a leading cause of mortality in NF1 patients. Our lab previously demonstrated frequent chromosome 8 (Chr8) gain in NF1-MPNST patient-derived xenografts (PDX) and patient tumors. To investigate Chr8 gain’s role, we created isogenic NF1-/- iPSC cell lines with and without Chr8 gain. Trisomy 8 fibroblasts were obtained and single-cell cloned to establish wildtype (WT) and Chr8 gain populations. Washington University’s Genome Engineering &amp; Stem Cell Center (GESC@MGI) reprogrammed these cells into human induced pluripotent stem cells (hiPSCs). Using synthetic gRNA and CRISPR/Cas9, NF1 knockout lines were generated. Four iPSC cell lines were differentiated into SCPs, and cell survival and proliferation were assessed using Incucyte cell survival and CellTiter-Glo® Assay. Fluorescence in situ hybridization (FISH) and karyotyping validated the human iPSCs. qPCR revealed high expression of iPSC markers OCT3/4 and SOX2 in all iPSC lines. After differentiation, SCP markers (GAP43 and ITGA4) were upregulated in WT, NF1-/-, and Chr8 gain;NF1-/- SCP lines, demonstrating successful differentiation. Furthermore, Chr8 gain; NF1-/- SCPs displayed enhanced proliferation and increased cell survival compared to WT and NF1-/- SCPs, suggesting improved characteristics in the presence of Chr8 gain. In summary, our research provides insights into Chr8 gain and NF1 loss effects on SCP differentiation, proliferation, and survival. Understanding these molecular mechanisms may contribute to developing targeted therapies for NF1.
CTNI-83. PROPOSAL FOR A PILOT PHASE 1B CLINICAL TRIAL WITH ADDITION OF NATURAL MARINE PRODUCT FUCOIDAN TO ANTI-NEOPLASTIC THERAPY FOR PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM) TO IMPROVE FATIGUE AND OTHER HEALTH-RELATED QUALITY OF LIFE (HRQOL) SYMPTOMS
Authors: Xiao-Tang Kong, Carlen A Yuen, Yoon Jae Choi, Yoshiyuki Miyazaki, Daniela A Bota, Geoffrey Winston Abbott
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recurrent Glioblastoma (rGBM) has poor outcome with limited treatment options. rGBM causes significant fatigue and other health-related quality of life (HRQOL) symptoms secondary to tumor progression and anti-neoplastic therapies. More than 80% of brain tumor patients were found to experience fatigue during anti-neoplastic therapy and the incidence of cancer related fatigue may reach 89-94% among patients with rGBM. Therefore, improvement of fatigue and HRQOL in rGBM patients are crucial. Marine natural product, fucoidan, available as health supplement in the US, was found to play important roles in oncological management as supportive therapy against cancer and chemoradiation-related adverse effects and as a potential anti-neoplastic therapy. Fucoidan is a seaweed-derived sulfated polysaccharide. Data resulted from randomized clinical trials for colon, head and neck, and lung cancer patients suggest that fucoidan can improve cancer and chemotherapy or chemoradiation therapy related negative symptoms. In addition, Tachikawa et al. reported &amp;gt;50% tumor regression and increased natural killer (NK) cell activity in sarcoma-transplanted mice treated with Fucoidan. In Vitro anticancer investigation found that Fucoidan fractions clearly suppressed the growth of GBM U-251MG cancer cells. Multiple studies have also shown that fucoidan is tolerable with a good safety profile. METHOD 18 rGBM patients will be enrolled. Fucoidan based product will be administered orally at established dose for cancer patients daily with anti-neoplastic therapy over 6 months. Patients will be evaluated monthly for AEs and HRQOL score; laboratory and brain MRI monitoring will be performed per SOC guidelines. NK cell activity will be measured. POTENTIAL OUTCOME Fucoidan is safe and has good tolerability in combination with anti-neoplastic therapy for rGBM and improves fatigue and other HRQOL symptoms by ameliorating tumor progression and treatment related negative impact. Fucoidan may also improve survival in rGBM patients by improving the tolerability of anti-tumor therapy, augmenting cytotoxic effects, and inhibiting angiogenesis.
NIMG-17. PREDICTIVE VALUE OF THE BRAIN TUMOR REPORTING AND DATA SYSTEM SCORE (BT-RADS) ON FUNCTIONAL OUTCOMES AND PROGRESSION-FREE SURVIVAL IN GLIOBLASTOMA PATIENTS
Authors: Michele Persico, Tsion Assaye, Michael Essien, Brent Weinberg
Journal: Neuro-Oncology (2024)

Abstract The Brain Tumor Reporting and Data System Score (BT-RADS) is a novel eight-point classification system that standardizes magnetic resonance imaging (MRI) reporting in glioblastoma (GB) patients. While previous studies have demonstrated BT-RADS predictive value in the prognosis and overall survival of high-grade glioma patients, its association with functional outcomes and progression-free survival (PFS) in GB patients is unclear. We aim to evaluate the BT-RADS predictive value on functional outcomes assessed through the Karnofsky Performance Scale (KPS) at one year post-diagnosis and on PFS. BT-RADS from MRI ~3 months post-diagnosis after chemo-radiation therapy (BT-RADS_1), and ~6 months post-diagnosis after the 6-month maintenance temozolomide (TMZ) cycle (BT-RADS_2) were analyzed. BT-RADS was classified as low (BT-RADS score 0-3a) and high (BT-RADS score 3b-4). In a univariate logistic regression analysis, BT-RADS_1 was a significant predictor (p=0.04) in discriminating an unfavorable KPS from a favorable one. In a multivariate logistic regression, in which the best model fit was the model containing BT-RADS_1 and MGMT tumor status (model p value=0.03), the ROC analyses indicate that BT-RADS_1 is not better than chance in differentiating an unfavorable KPS from a favorable one (model AUC=0.65; 95% CI=0.55, 0.76). The discriminatory ability of BT-RADS scores alone in predicting KPS outcomes was modest, as indicated by the AUC. This underscores the need for larger sample sizes. In a final model of BTRADS_1 and BT-RADS_2, accounting for MGMT tumor status, the risk of tumor progression was 50% lower (p value=0.003) with a low BT-RADS (0-3a) in the BT-RADS _1 group and 38% lower (p value=0.03) with a low BT-RADS (0-3a) in the BT-RADS_2 group. Considering the above-discussed findings, BT-RADS may represent a new tool in the clinical management of glioblastoma patients by informing on disease progression, prognosis, and quality of life.
QOL-22. VACILLATING EMOTIONS AND SHIFTING INFORMATION PREFERENCES: A QUALITATIVE ANALYSIS OF CAREGIVER DISTRESS IN FACING A MALIGNANT GLIOMA DIAGNOSIS
Authors: Pooja Patnaik, Daniel Chiu, Jessica Whitman, Sumita Strander, Anna Hauswirth, Kelcie Willis, Jennifer Temel, Lara Traeger, Deborah Forst
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Caregivers of patients with malignant gliomas (MG) experience considerable psychological distress as they contend with the implications of their loved one’s terminal illness. However, caregivers’ specific reactions to the patient’s diagnosis/prognosis and optimal ways to support caregivers in the months following diagnosis remain poorly understood. METHODS At a single academic medical center, we enrolled English-speaking adults identified by patients with newly diagnosed MG as their primary caregiver. Using a semi-structured interview guide, we conducted in-depth interviews with caregivers at the conclusion of concurrent chemoradiation exploring their experiences learning about the patient’s diagnosis and their prognostic information preferences. We used rapid qualitative analysis to analyze interview data. RESULTS We interviewed 7 caregivers (female: 5/7; spouse/partner: 6/7, sibling: 1/7) of MG patients (glioblastoma: 5/7). Caregivers described the time following diagnosis as tumultuous and difficult as they struggled to cope with their distress related to navigating the practical burdens of cancer treatment while also managing the emotional burden (e.g. fear, sadness) of living amidst uncertainty. Caregivers vacillated between feeling devastated by the patient’s poor prognosis and wanting to remain hopeful (e.g., by seeking out inspiring survivorship stories). Caregivers also reported varying and often evolving preferences regarding the manner, timing, and context in which they received information about the patient’s MG. Many caregivers desired more prognostic information (e.g., to facilitate planning for their future and for the patient’s eventual demise) while some chose to focus on the present (e.g., to avoid “dwelling” on potential negative outcomes), in light of inherent uncertainty about the patient’s trajectory. CONCLUSIONS Caregivers experience significant distress in the context of vacillating emotions and shifting information needs as they adapt to life in the aftermath of a MG diagnosis. These results highlight the need for tailored prognostic information and support for caregivers during this stressful, emotionally fraught time.