tbuckley/cabot-search huggingface dataset:
EPID-22. MUTATIONAL SIGNATURE ASSOCIATED WITH HALOALKANE EXPOSURE ENRICHED IN FIREFIGHTERS IN THE ADULT GLIOMA STUDY
Authors: Vincent Cannataro, Paige Bracci, Jennie Taylor, Lucie McCoy, Terri Rice, Helen Hansen, Annie Heffernan, Joe Wiemels, John Wiencke, Margaret Wrensch, Elizabeth Claus
Journal: Neuro-Oncology (2024)

Abstract Using data from The Cancer Genome Atlas (TCGA) and Glioma Longitudinal Analysis (GLASS), we identified specific environmentally related mutational signatures in glioma including a signature associated with haloalkane exposure (SBS42) from the Catalogue of Somatic Mutational Signatures (COSMIC). Haloalkanes are widely used commercially including in flame retardants and fire extinguishants and are an intriguing finding given an observed increased glioma risk in firefighters. To validate our findings, we use new study participants with data on occupation (not available in either TCGA/GLASS) from the University of California, San Francisco Adult Glioma Study (AGS) to compare mutational signatures in tumors from 17 persons with glioma and documented occupational exposure to firefighting with those of 18 matched glioma patients without history of firefighting. Using whole exome sequencing, we identified environmental exposure signatures in tumor tissue from firefighters as well as in non-firefighters who had other relevant occupational exposure (e.g. auto/truck mechanic work). In these data, glioma is largely associated with aging and mutational signatures relating to endogenous mutational processes that correlate with age, such as spontaneous or enzymatic deamination of 5-methylcytosine. However, some gliomas have detectable signatures associated with exogenous mutational processes, such as SBS42 haloalkanes. Thus, we confirm detection of haloalkane signatures in persons likely highly exposed, i.e. long-term firefighters. Identifying exogenous mutational processes in cancers are important as they may inform public health intervention strategy to reduce mutagenesis and prevent cancer inception. Identifying occupational correlates with SBS42, associated with occupational exposure to haloalkanes, will pinpoint occupational hazards that may be avoidable. This is especially important for glioma and other cancers where exogenous mutagenesis is not well established.
PATH-29. LONGITUDINAL EPIGENOMIC EVOLUTION OF IDH-WILDTYPE GLIOBLASTOMA
Authors: Nadeem N Al-Adli, Jacob S Young, Calixto-Hope G Lucas, Rohit Gupta, Ramin A Morshed, Jasper Wu, Ajay Ravindranathan, Anny Shai, Nancy Ann Oberheim Bush, Jennie W Taylor, John de Groot, Javier Villanueva-Meyer, Melike Pekmezci, Arie Perry, Andrew W Bollen, Philip V Theodosopoulos, Manish K Aghi, Edward F Chang, Shawn L Hervey-Jumper, David R Raleigh, Aaron A Diaz, Joseph F Costello, Jennifer L Clarke, Nicholas Butowski, Joanna J Phillips, Susan M Chang, Mitchel S Berger, David A Solomon
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma, IDH-wildtype remains a molecularly heterogeneous disease that is refractory to current therapies. To investigate how longitudinal epigenomic evolution of glioblastoma drives tumor progression and treatment resistance, we performed comprehensive histopathologic assessment, targeted genomic sequencing, and genome-wide DNA methylation profiling of paired initial and recurrent IDH-wildtype glioblastoma samples from 98 patients, as well as a separate longitudinal cohort of IDH-mutant astrocytomas for comparison. Primary treatment-naïve IDH-wildtype glioblastomas had more globally hypomethylated genomes compared to primary IDH-mutant astrocytomas. At time of recurrence, IDH-mutant astrocytomas uniformly became more hypomethylated similar to the global methylation levels in IDH-wildtype glioblastomas. In contrast, recurrent IDH-wildtype glioblastomas were heterogeneous with subsets becoming more globally hypermethylated (27%), hypomethylated (22%), or remaining stable (51%). Accordingly, a substantial proportion (52%) of recurrent glioblastomas underwent methylation class switching compared to their matched primary tumor, with a predominance of the RTK2 epigenetic subtype at initial surgery and the Mesenchymal epigenetic subtype at recurrence. Among approximately 850,000 interrogated CpG sites, we identified only 110 and 153 sites that consistently became more hypermethylated or hypomethylated between initial and recurrent IDH-wildtype glioblastomas, which regulate genes involved in neuronal morphogenesis, oligodendrocyte differentiation, and myelination. In contrast, we identified 260 and 18,527 CpG sites that consistently became more hypermethylated or hypomethylated between initial and recurrent IDH-mutant astrocytomas, which regulate genes involved in neuronal stem-like differentiation, cell cycle control, and other biologic processes. Finally, we developed a DNA methylation evolution signature incorporating change in mean beta-methylation values from initial to recurrent tumor specimens across 347 critical CpG sites that significantly correlated with clinical outcomes for patients with IDH-wildtype glioblastoma. In summary, IDH-wildtype glioblastomas demonstrate heterogeneous epigenomic evolution patterns distinct from IDH-mutant astrocytomas. These changes in epigenetic patterns may identify unique subgroups of glioblastoma with differential treatment response and inform future therapeutic studies targeting differentially methylated gene programs.
PATH-38. INTRACRANIAL SARCOMA WITH DICER1 MUTATION IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1
Authors: Allison Weisnicht, Nicholas Pytel
Journal: Neuro-Oncology (2024)

Abstract A 16-year-old male with neurofibromatosis type 1 (NF1) and a history of low-grade gliomas presented for resection of a progressively enlarging, known low-grade glioma. On follow-up imaging for surgical planning of the low-grade glioma, a new area of concern was detected of a leptomeningeal-based lesion over the left frontal lobe. A biopsy of the frontal lobe lesion subsequently showed a primary intracranial sarcoma with DICER1 mutations, DICER1 p.Q1552 and p.D1709G. An important histology finding was that of prominent eosinophilic cytoplasmic globules, which are associated with intracranial sarcomas with DICER1 mutations. Additional molecular findings of this tumor included NF1 p.K1986fs and TP53 p.G279E mutations in the setting of this patient’s known history of NF1. A DICER mutation was not detected in the concurrent low-grade glioma at the time of his intracranial sarcoma diagnosis, thus thought not to be a germline-derived mutation. He went on to have a surgical resection with subsequent photon radiation therapy followed by consolidation chemotherapy. A Ewing sarcoma based regimen as per COG protocol AEWS1031 was selected for his therapy consisting of vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide (VDC-IE). This was chosen based on prior cases showing response to anthracycline-based regimens. This patient has overall shown improvement without signs of progression now 7 months out from his initial diagnosis. This case highlights the importance of recognizing the association of patients with NF1 being at an increased risk for the development of intracranial sarcomas with DICER1 mutations and correlation with histologic findings of eosinophilic cytoplasmic globules. It also points to the need for reporting these rare cases for optimization of therapy selection to provide a more standardized and evidence-based approach in the care for these patients.
CNSC-34. SURGICAL INTERVENTION ASSOCIATION WITH THE DEVELOPMENT OF SUBSEQUENT DISSEMINATION IN CHILDHOOD DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Authors: Shoaib Bashir, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive pediatric central nervous system tumors, and currently, there are no curative treatment options available. With the increasing application of molecular diagnostics, more and more DIPG patients are recommended to undergo surgery; however, its correlation with dissemination needs to be better understood. Hence, we conducted this cohort to analyze the predictors of subsequent metastasis in pediatric DIPGs. METHODS The final analysis included 142 pediatric (age ≤ 12) DIPG patients treated at Sanjiu Brain Hospital between January 2017 and September 2023. The data were retrospectively collected following the initial diagnosis. Patients were followed up for 6 months. The primary endpoint was the occurrence of subsequent metastasis. Univariable and multivariable logistic regression analyses were utilized to identify statistically significant predictors of subsequent dissemination. All statistical assessments were two-tailed, and only P &amp;lt; 0.05 was deemed to be statistically significant. RESULTS Among 142 patients, 14(9.9%) developed metastasis within the follow-up time. There were 77(54.2%) males and 65(45.8%) females. The median age was 7 years (ranging 1 - 12 years). The overall cohort demonstrated that surgery was the only predictor of dissemination both in univariable (OR 4.567, 95%CI 1.351 – 20.901, P = 0.024) and multivariable (OR 5.501, 95%CI 1.560 – 26.105, P = 0.014) analyses. However, subgroup analysis involving patients who received surgical intervention showed that biopsy was not superior nor inferior to resection in terms of relative risk for subsequent dissemination (16.7% vs. 15.8%). CONCLUSION Surgical intervention increases the relative risk of dissemination occurrence to four times more than those who did not receive surgery. Surgical intervention is crucial given the potential of molecular analysis leading to improved therapeutic options. Nonetheless, patients should be informed about the risks associated with surgery, including subsequent metastasis.
NIMG-35. IMPACT OF RESECTION AT TIME OF FIRST RECURRENCE IN WHO GRADE 2 IDH-MUTANT GLIOMAS
Authors: Juan Pablo Ospina, Maya Viera, Ethan Wetzel, Daniel Cahill, Elizabeth R Gerstner, Julie J Miller
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Maximal safe resection standard of care treatment of IDH-mutant gliomas and is associated with improved overall survival (OS). However, the impact of extent of resection (EOR) at first recurrence is not well established and there are no data on its impact on prognosis. METHODS We retrospectively collected clinical data on patients with IDH-mutant WHO grade 2 astrocytoma and oligodendroglioma treated at our institution from 1997 to 2023. To assess the impact of EOR at first recurrence, we excluded patients who exclusively underwent diagnostic biopsy. Dates of progression were determined by the treating neuro-oncologist or tumor board consensus. Volumetric measurements of contrast-enhancing (CE) tumor and total T2/FLAIR pre- and post second surgery were obtained with BrainLab SmartBrush tool. RESULTS One-hundred patients with recurrent astrocytoma and 35 patients with recurrent oligodendroglioma were identified, of whom 57 and 25, respectively, underwent a second resection and had imaging available for volumetric analysis. In patients with astrocytoma, 13/57 had CE at diagnosis, and 28/57 at first recurrence. EOR of T2/FLAIR and CE volume correlated with improved OS. In multivariate regression analyses, T2/FLAIR EOR at first recurrence correlated with improved OS adjusted for gender, preoperative T2/FLAIR volume, prior radiotherapy or chemotherapy, and initial CE (HR 0.977, p&amp;lt; 0.001). In patients with CE, contrast-EOR correlated with OS adjusted for gender, initial CE, preoperative contrast volume, and prior radiotherapy or chemotherapy (HR 0.929, p&amp;lt; 0.001). Conversely, in patients with WHO grade 2 oligodendroglioma, T2/FLAIR EOR did not significantly impact OS (EOR&amp;gt; 90% p= 0.92, EOR&amp;gt; 20% p= 0.13). Only 5/25 patients had CE at first recurrence precluding further analysis. CONCLUSIONS The EOR of CE and total FLAIR hyperintensity at first recurrence appears to positively impact prognosis in patients with WHO grade 2 astrocytoma but not in oligodendroglioma. These findings should be evaluated in prospective trials.
EPID-01. PEDIATRIC BRAIN TUMORS IN SUB-SAHARAN AFRICA:A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Arsene Daniel Nyalundja, Ulrick Sidney Kanmounye, Claire Karekezi, Tsegazeab Laeke, Nqobile Thango, James A Balogun
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE brain tumors are a global problem, leading to higher cancer-related morbidity and mortality rates in children. Despite the progressive though slow advances in neuro-oncology care, research, and diagnostics in sub-Saharan Africa (SSA), the epidemiological landscape of pediatric brain tumors (PBTs) remains underestimated. This study aimed to systematically analyze the distribution of PBT types in SSA. METHODS major databases and grey literature were searched for literature on PBTs in SSA published before October 29, 2022. A proportional meta-analysis was performed. RESULTS forty-nine studies, involving 2360 children, met the inclusion criteria for review; only 20 (40.82%) were included in the quantitative analysis. South Africa and Nigeria were the countries with the most abundant data. Glioma not otherwise specified (NOS) was the common PBT in the 4 SSA regions combined. However, medulloblastoma was more commonly reported in Southern-SSA(p=0.01) than in other regions. The prevalence and the overall pooled proportion of the 3 common PBTs was estimated at 46.27% and 0.41 (95%CI 0.32–0.50, 95% prediction interval [PI] 0.11–0.79), 25.34% and 0.18 (95%CI 0.14–0.21, 95%PI 0.06–0.40), and 12.67% and 0.12 (95%CI 0.09–0.15, 95%PI 0.04–0.29) for glioma-NOS, medulloblastoma, and craniopharyngioma, respectively. Sample size moderated the estimated proportion of glioma-NOS (p = 0.02). The highest proportion of craniopharyngiomas was in Western-SSA, and medulloblastoma and glioma-NOS in Central-SSA. CONCLUSION these findings provide insight into the trends of PBT types and the proportion of the top 3 most common tumors across SSA. Although statistical conclusions are difficult due to the inconsistency in the data. We identify critical areas for policy development and collaborations that can facilitate improved outcomes in PBTs in SSA. More accurate epidemiological studies are needed to better understand the burden of the disease and the geographic variation in their distribution, and to raise awareness in their subsequent management.
NCOG-01. VOCATIONAL STATUS OF PATIENTS WITH GLIOMA AT 5 YEARS AFTER DIAGNOSIS
Authors: Karl Cristie Figuracion, Christine Mac Donald, David Hunt, Tresa McGranahan, Frances Lewis, Jason Rockhill, Myron Goldberg, Lia Halasz, Hilaire Thompson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioma (WHO grade 2-3) commonly affects adults, with a mean age at diagnosis of 41 years old. Given the demographic age of these brain tumor (BT) survivors, employment is the primary source of income, medical benefits, and financial stability. Unfortunately, job performance problems can occur at any time after diagnosis. This study aims to describe the vocational status and symptoms of these patients approximately five years following diagnosis. METHODS The study employed a cross-sectional cohort design among persons with glioma treated with radiation approximately 5 years from the original diagnosis. Vocational-Independence Scale was used to ascertain employment status. Patients were asked about their experience returning to work after treatment. Symptoms were measured using the MDASI-BT Module. RESULTS Thirty-nine participants completed the study. The median age was 44 years old (range 26-78). Nineteen were diagnosed with oligodendroglioma, 18 with astrocytoma. Thirty-seven (95%) were working full-time at the time of diagnosis. Approximately five years following diagnosis, only 49% of participants are employed, working at least 15 hours per week (n=19). The remainder are unemployed (n=15, 39%), in a volunteer position (n=2, 5.1%), or working &amp;lt;15 hours per week (n=3, 7.7%). Interview data suggest those who are unemployed (n=9, 23%), retired early (n=2, 5%), or had reduced roles (n=11, 28%), were unable to return to prior roles due to symptoms they were experiencing 1-2 years after treatment. The frequently reported symptoms were fatigue (n=29, 74%), sleep disturbance (n = 24, 62%), distress (n = 25, 64%), drowsiness (n = 26, 67%), sadness (n = 25, 64%), issues with speaking (n = 25, 64%), short-term memory issues (n=35, 90%), and difficulty with concentration (n=20, 74%). CONCLUSION In addition to financial stability, employment is a valuable contributor to the quality of life, maintenance of identity, and physical and emotional health. Future research should examine and evaluate interventions that promote the return to work or engagement in the community.
EXTH-42. GLIOMA-DERIVED CD200 PROMOTES TUMOR GROWTH AND SUPPRESSES NK CELL AND CD8 T CELL ANTI-GLIOMA ACTIVITY
Authors: Itay Raphael, Michael Graner, Christopher Moertel, Gary Kohanbash, Michael Olin
Journal: Neuro-Oncology (2024)

Abstract Immune-checkpoint inhibitors, such as anti-PD1 and anti-CTLA4, have emerged as promising therapeutic options for several malignancies yet show little efficacy against malignant brain cancers. CD200 is a newly recognized immune-checkpoint which is expressed by a marid of cell types, modulating immune homeostasis through multiple receptors. There is currently limited information regarding CD200 effects in brain tumors. Furthermore, while it is well accepted that CD200 binding to its inhibitory receptor induces a pro-tumorigenic environment through its ability to suppress immune responses, there are increasing evidence that CD200 could also have anti-tumor characteristics. Here we evaluated the role of tumor-derived CD200 on anti-glioma immunity. We demonstrate that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in serum of patients undergoing immunotherapy. Transcriptomic analysis of CD200 knockout (KO) glioma models reveals that glioma-derived CD200 significantly modifies the glioma tumor microenvironment (TME), not only through immune regulation but also through immune-independent pathways, such as tumor metabolism. Furthermore, we show that CD200 KO gliomas have reduced proliferation and are rejected by their hosts. Downstream analysis revealed that rejection of CD200 KO gliomas relied on a functional adoptive immune system, while decreased proliferation was linked to reduced CXCL10 production by the CD200 KO gliomas. Additionally, we demonstrate that glioma-mediated CD200 strongly suppresses anti-glioma NK cell function within the tumor microenvironment (TME), while secreted CD200 inhibits the priming of antigen-specific CD8 T cells in the lymphatic. Notably, NK cells were essential for the initial rejection of CD200 KO gliomas, while CD8 T cells played a critical role in establishing durable anti-tumor responses. Our work provides new mechanistic insights on glioma-derived CD200-mediated immunosuppression and an untapped potential for targeting CD200 by immunotherapies for malignant gliomas.
NIMG-74. A NOVEL APPROACH FOR PERSONALIZED RADIOTHERAPY TARGET VOLUME DEFINITION USING METABOLIC MRI AND DEEP LEARNING-DRIVEN PREDICTIONS OF GLIOBLASTOMA RECURRENCE
Authors: Nate Tran, Tracy Luks, Jacob Ellison, Yan Li, Angela Jakary, Tiffany Ngan, Bo Liu, Javier Villanueva-Meyer, Annette Molinaro, Jennifer Clarke, Nicholas Butowski, Susan Chang, Steve Braunstein, Hui Lin, Janine Lupo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Machine-learning models have demonstrated great promise in predicting tumor infiltration beyond anatomical margins in glioblastoma. Yet standard-of-care (SOC) radiation therapy (RT) planning only utilizes a uniform, isotropic 2cm-expansion of the T1-post-contrast-lesion or T2-lesion to generate a clinical target volume (CTV), without considering heterogeneity in tumor infiltration. We hypothesize that using a novel deep-learning approach to predict regions of tumor progression with metabolic and diffusion-weighted MRI will result in personalized CTVs that are more sensitive to detecting normal-appearing infiltrating tumor beyond the T2-lesion, sparing more healthy brain compared to SOC-CTVs. METHODS Anatomical, diffusion-weighted, and metabolic MRI from 101 patients with glioblastoma, acquired post-surgery but prior to chemoradiation, were retrospectively used to predict regions of new contrast-enhancement or T2-hyperintensity at confirmed progression. A segmentation-based predictive deep-learning approach with personalized loss-functions and evaluation metrics (“Progression-Coverage-Coefficient”, PCC) that weight Dice coefficient terms by tumor size was employed with a 66/17/18 train/validation/test split of patients and the resulting DL-CTV compared to two SOC-CTVs: 1) the RTOG[T2-FLAIR+2cm]-CTV, 2) the EORTC[T1c+2cm]-CTV. RESULTS Our best deep-learning-CTV trained using anatomical, diffusion, and metabolic MRI achieved significantly improved median test specificity (0.87 vs. 0.77; p&amp;lt;0.005) and comparable sensitivity (0.92 vs. 0.95; p=0.1) and PCC (0.81 vs. 0.79; p=0.1) to the SOC RTOG[T2-FLAIR+2cm]-CTV, sparing more normal brain tissue. Compared to the more conservative EORTC[T1c+2cm]-CTV, our approach had significantly higher test sensitivity (0.92 vs. 0.85; p&amp;lt;0.00001) and PCC (0.81 vs. 0.77; p=0.003) in covering the progressed lesion, while maintaining similar specificity (0.87 vs. 0.89; p=0.3). Test performance dropped by 9.6% and 12.4% when removing metabolic and both metabolic and diffusion metrics, respectively (p&amp;lt;0.001). CONCLUSION This study demonstrates the benefit of using metabolic and diffusion MRI with deep learning for personalized RT planning by targeting regions of anatomically normal infiltrative disease that are highly likely to progress, while reducing treatment to normal brain.