tbuckley/cabot-search huggingface dataset:
TMET-34. PYROPTOSIS IS AN ACQUIRED VULNERABILITY OF BRAIN METASTASES
Authors: Daniel Mobilio, Agata Kieliszek, Erik Peterson, Kanwaldeep Singh, Kui Zhai, Petar Miletic, William Gwynne, Patrick Ang, Chitra Venugopal, Shawn Chafe, Tobias Berg, Daniel Wahl, Sheila Singh
Journal: Neuro-Oncology (2024)

Abstract Metastasis, the spread of cancer cells from one part of the body to another, is a leading cause of death among cancer patients. Three particularly dangerous forms of metastases are the spread of lung, skin, and breast cancers to the brain. On average survival time of all brain metastasis (BM) patients is around 4 months, which is accompanied by a failing and undefined standard of care. We have strived to bridge the gap between novel safe therapeutics and brain metastasis patients by discovering and targeting metabolic vulnerabilities in brain metastases. Here, we conducted comparative metabolomic screening in patient-derived BM lines versus normal brain cells to identify dihydroorotate dehydrogenase (DHODH) as a cancer-selective targetable vulnerability. DHODH is an essential enzyme that is located within the inner membrane of the mitochondria which has a primary role in producing pyrimidine metabolites through the de novo uridine synthesis pathway and also contributes to the proper functioning of the electron transport chain. Through this, DHODH has been implicated in the essential functioning of energy metabolism, DNA and RNA synthesis, and most recently in the modulation of the immune system. In our studies we have elucidated the significant effect DHODH inhibitors and the induction of DHODH CRISPR knock-out has against the cell viability, sphere formation, and proliferation of patient derived BM samples in vitro and in vivo. Furthermore, through metabolomics we have discovered that following DHODH perturbation, there is a significant increase in a signaling lipid (D-ethryo-Dihydrosphingosine) that specifically inhibits Protein Kinase C (PKC) and initiates Gasdermin E (GSDME) mediated pyroptosis. By uncovering this mechanism we have discovered GSDME mediated pyroptosis is an aquired vulnerability of brain metastases. Overall, this study highlights the translational potential of DHODH inhibitors in BM and elucidates novel mechanistic underpinnings of nucleotide deprivation within the context of cell death.
TMET-40. UPREGULATION OF URIDINE SALVAGE IN MESENCHYMAL GLIOBLASTOMA STEM-LIKE CELLS
Authors: Tuvshintugs Baljinnyam, Mark Sowers, Bruce Chang-gu, Hui Tang, Jason Herring, Kangling Zhang, Lawrence Sowers
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is a heterogenous tumor comprised of multiple molecular subtypes of cancer cells and cancer stem-like cells. Of particular importance are the cancer stem-like cell niche population as they are believed to be more resistant to existing therapies and re-seed the tumor following initial response to standard-of-care treatment. To better understand glioblastoma stem-like cells we completed an untargeted proteomic analysisof 35 patient derived glioblastoma stem cell lines. This system driven analysis revealed an increase in several important proteins, in the mesenchymal subtype, involved in the uridine salvage pathway. A subset of these proteins, including ecto-5’-nucleotidase (NT5E/CD73), uridine phosphorylase (UPP1), phosphoglucomutase-2-like-1 (PGM2L1), nicotinamide phosphoribosyltransferase (NAMPT), and nicotinamide N-methyltransferase (NNMT), suggest an augmented pathway for utilization of UMP and uridine as a fuel source and to replenish NAD+. Uridine and UMP are present in human serum and are enriched in the tumor microenvironment providing a sustainable resource to resupply the tumor. The upregulation of this pathway was validated in established cell lines and orthogonal patient-derived xenograft cell lines not included in the proteomics study. Further work is underway to selectively inhibit or exploit this pathway with small molecule inhibitors.
SURG-48. LASER INTERSTITIAL THERMAL THERAPY REMODELS THE TUMOR IMMUNE LANDSCAPE IN A MOUSE GLIOMA MODEL
Authors: David Giles, Timothy Woodiwiss, Rowland Han, Colin McCornack, Loren Beck, Yiwei Fu, Will Leidig, Markus Anzaldua-Campos, David Mok, Ryan Cleary, Albert Kim
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Laser interstitial thermal therapy (LITT), a minimally invasive surgical technique for tumor ablation, is increasingly being used to treat primary and recurrent glioma. While the primary goal of using LITT has been to destroy tumor tissue, little is known about the impact of LITT on the overall immune response. To investigate changes in the tumor immune landscape, we utilized a mouse model of LITT and applied it to a poorly immunogenic mouse model of glioma. METHODS SB28 glioma cells were implanted in the right frontal lobe of C57BL/6 mice, and on day 7, an optical fiber is inserted into the tumor, paired with a thermocouple for real-time temperature monitoring. A 30W laser was activated in pulses to maintain a peri-lesional temperature of 44C for 150-180 seconds. The tumor and LITT-associated immune response was analyzed by multiparameter flow cytometry, single cell RNA-seq, and multiplex immunofluorescence. RESULTS LITT (versus sham control) triggered an increase in neutrophils in the tumor during the acute phase at day 3 following treatment. Total immune cell numbers increased over time in both sham- and LITT-treated mice, but there was a significant increase at post-LITT day 7 in select adaptive immune cell populations including type 1 conventional dendritic cells, NK cells, and gamma delta T cells. Monocytes/macrophages comprised the majority of the immune infiltrate, and multiplex immunofluorescence revealed these populations localized to the perimeter of the LITT lesion. scRNA-seq also revealed enrichment of a Fabp5- and Gpnmb-expressing macrophage subset following LITT. CONCLUSIONS LITT modifies the tumor immune infiltrate with increases in neutrophils as well as select adaptive cell and macrophage subsets. Future studies will explore adjunct therapies to further augment the immune response in the setting of LITT.
RADT-33. GAMMA KNIFE RADIOSURGERY FOR ORBITAL CAVERNOUS HEMANGIOMA: A SYSTEMATIC REVIEW AND SINGLE-ARM META-ANALYSIS
Authors: Hsien-Chung Chen, Brodus Franklin, Anurraag Punukollu, Felipe Pineda, Lucca Palavani
Journal: Neuro-Oncology (2024)

Abstract Gamma knife radiosurgery (GKRS) for orbital cavernous hemangioma (OCH) has emerged as a promising method due to its significant clinical improvement and low incidence of complications. This study aimed to evaluate the safety and efficacy of GKRS for the treatment of OCH. Following the PRISMA framework, we searched PubMed, Cochrane Central, and Embase for studies reporting outcomes of GKRS for OCH, including complications, visual improvement, proptosis, tumor reduction rate, and tumor progression rate. From 1856 search results, six studies with 100 patients were included. Only five minor complications related to GKRS were reported, including three with orbital pain and two with periorbital chemosis, resulting in a complication rate of 13% (95% CI: 7% - 25%). Visual acuity and visual field improvement rates after GKRS were 80% (95% CI: 63% - 96%) and 71% (95% CI: 47% - 95%), respectively. Proptosis improved in 94% of cases (95% CI: 83% - 100%). The tumor reduction rate was 77% after GKRS (95% CI: 69% - 85%). In conclusion, GKRS for OCH appears to be a safe technique, as evidenced by the rate of clinical improvement and radiological improvement. However, studies are limited by the absence of a control group, and additional studies are needed to evaluate the relative efficacy of GKRS compared with alternative surgical modalities for OCH.
PATH-01. SELLAR SOLITARY FIBROUS TUMORS WHO GRADE II AND III: MIMICS OF NON-FUNCTIONING PITUITARY ADENOMAS
Authors: Michele Persico, Brent Weinberg, Hui-Kuo Shu, Jim Zhong
Journal: Neuro-Oncology (2024)

Abstract Solitary fibrous tumors WHO grade II and III (SFTs II/III) are rare mesenchymal neoplasia accounting for 0.4% of primary central nervous system tumors. SFTs II/III located in the sella turcica region are even rarer and, since the first case described in 1983, only 21 case reports of sellar/suprasellar SFTs II/III (ssSFTs II/III) have been described to this day. We aim to analyze ssSFTs II/III and to demonstrate that can be differentiated from non-functioning pituitary adenomas through pathological examination alone. We analyzed 20 case reports of ssSFTs II/III identified through PubMed and Google searches and a new unpublished case presented at Emory University. ssSFTs II/III are equally represented in both sexes, with 11 cases over 21 occurring in females and the mean age of onset at 46 years old. Clinically, ssSFTs II/III present with compression symptoms related to the tumor location. Headache, visual field defects, and anterior hypopituitarism-related symptoms are frequent chief complaints. As such, almost all cases of ssSFTs II/III had a pre-biopsy working diagnosis of non-functioning pituitary adenomas. The differentiation between SFTs II/III and pituitary adenomas based on imaging findings remains challenging, and surgical biopsies are necessary for a definitive diagnosis. ssSFTs II/III surgical reports describe a unifying trait of a highly vascular tumor adherent to the dura that bleeds profusely after resection. These characteristics are less consistent with a pituitary adenoma. The genetic hallmark of SFTs at all anatomical sites is paracentric inversions at 12q13, fusing the NAB2 and STAT6 genes, with consequent overexpression of STAT6. Pituitary adenomas lack this genetic signature. ssSFTs II/III have an overlapping presentation and similar imaging findings of pituitary adenomas, but different management and prognosis. Hence, it is crucial to include ssSFTs II/III among the pre-biopsy differential of sellar/suprasellar masses identified on imaging. Pathology confirmation is required to guide therapy.
NCOG-11. FACTORS PREDICTING SPEECH AND GAIT RECOVERY IN CHILDREN WITH POST-OPERATIVE POSTERIOR FOSSA SYNDROME (PFS)
Authors: Emily Hanzlik, Stuart McAfee, Matt Scoggins, Tong Lin, Darcy Raches, Heather Conklin, Kristin Szymanek, Giles Robinson, Amar Gajjar, Arzu Onar-Thomas, Asim Bag, Raja Khan
Journal: Neuro-Oncology (2024)

Abstract Posterior fossa syndrome/cerebellar mutism syndrome is a surgical complication of posterior fossa tumor resection, especially midline tumors. Initially thought to involve complete mutism, PFS is now recognized as a complex syndrome involving loss of language (complete [PFS1] and incomplete [PFS2]). Additional symptoms include apraxia, movement disorder, motor and coordination deficits, and emotional lability. The aim of this study was to identify factors that influence delayed speech and independent gait recovery in children with PFS. We prospectively studied 73 children ≥3 years of age with medulloblastoma who developed PFS (SJMB12, NCT01878617). Enrolled children received standardized neurologic examinations and serial imaging before, during and up to five years after completion of therapy. Neurological examinations included scale for assessment and rating of ataxia (SARA), CTCAE grading of neurologic deficits, and severity of injury to the superior cerebellar peduncles (SCP) on post-operative MRI. Median time to speech recovery was 1.4 months (range 0.3-14.3); 81% had return of speech at 3 months and 97% at 12 months. On multivariable Cox regression analysis, complete mutism (HR 0.17, p&amp;lt;0.0001) and inability to sit (HR 0.40, p=0.001) were associated with delayed speech return. Independent ambulation was regained by 80.8% at a median of 2.3 (range 0.3-71.3) months. 70% had a return of ambulation at 12 months and 77% at 24 months. On multivariable Cox regression analysis, complete mutism (HR 0.32, p=0.016), inability to sit (HR 0.30, p=0.002), SARA score (HR 0.94, p=0.002), and right SCP injury (HR 0.47, p=0.014) were significantly associated with delayed return of ambulation. Presence of mutism, inability to sit unassisted, higher SARA score, and right SCP injury at the time of PFS diagnosis are associated with time to recovery of speech/language and ambulation. Our findings have prognostic implications for families and to help identify children in need of more intensive interventions.
SURG-52. LEPTOMENINGEAL DISSEMINATION AFTER GAMMATILE AND LITT IN HIGH GRADE ASTROCYTOMA PATIENTS
Authors: Rosalina Magalhaes Pereira, Tabarak Mian, Toral Patel, Tu Dan, Michael Youssef
Journal: Neuro-Oncology (2024)

Abstract PURPOSE To present a case series of leptomeningeal dissemination after localized treatment with GammaTile or laser interstitial thermal therapy (LITT) in patients with high grade astrocytoma. BACKGROUND Leptomeningeal dissemination occurs primarily in glioblastoma patients with prolonged survival and those who undergo aggressive treatment courses. Targeted therapies such as GammaTile (which contains cesium-131 radiation-emitting seeds) or LITT may provide localized disease control following recurrence and serve as an immediate treatment modality for patients with recurrent disease in the weeks leading up to radiotherapy or systemic treatment. METHODS We retrospectively reviewed all consecutive patients with high grade astrocytoma treated with GammaTile or LITT who were found to have leptomeningeal dissemination of disease. Histological diagnosis, NGS and immunohistochemistry of tumor tissue were performed at both original diagnosis and at time of GammaTile placement or LITT procedure. Leptomeningeal dissemination was diagnosed through MRI findings on brain and spine. Cases were analyzed for time to development of leptomeningeal dissemination, median overall survival, survival from time of leptomeningeal dissemination diagnosis, time of dissemination to second radiation therapy. Tumor location, MGMT status and other molecular markers were also reviewed. RESULTS Out of 90 high grade astrocytoma patients treated with gamma tile radiation, 4 progressed to exhibit disseminated disease. There were 2 female patients, mean age was 50 years. Location of tumor was in the left temporal lobe in 3 patients and right temporal in 1. They were all IDH wild type. Two were MGMT methylated, two were non methylated. The median time from initial glioma diagnosis to LMD was 221 months (range 11-152) and overall survival after disseminated disease diagnosis was 7.5 weeks (range 3–13). CONCLUSION Leptomeningeal dissemination is a devastating complication of aggressive gliomas. Currently, there is no standard treatment for disseminated disease in high grade astrocytoma patients. Systemic therapy is needed following localized therapies to control disease. Further research into new therapies is needed to allow for better outcomes.
PATH-02. MESENCHYMAL-TYPE GENETIC MUTATIONS ARE LIKELY PRE-REQUISITE FOR GLIOBLASTOMA TO METASTASIZE OUTSIDE THE CENTRAL NERVOUS SYSTEM: AN ORIGINAL CASE SERIES AND SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Bryce Laurin, Randall Treffy, Jennifer Connelly, Michael Straza, Wade Mueller, Max Krucoff
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma multiforme (GBM) is locally aggressive, yet it metastasizes outside the central nervous system (CNS) in only 0.4% of cases. Little is known about what enables this subset of GBMs to survive outside the CNS, so we conducted a PRISMA-compliant systematic review of metastatic GBM wherein we reviewed 3579 search results and 1080 abstracts, ultimately analyzing data from 139 studies and 211 unique patients. Additionally, we analyzed four modern-day cases treated at our institution. In our patients, primary GBM lesions revealed consistent mutations in NF1, TERT, TP53, CDK4, and RB1/PTEN genes. Unique to the metastatic lesions were amplifications in integral cell-cycle regulating genes such as p53 and PDGFRA/KIT, as well as increased vimentin and Ki-67 expression. These data support the hypothesis that glial cells likely underwent mesenchymal-like mutations prior to extra-CNS involvement. How these cells reach the extra-axial environment is still under debate. In our systematic review, we found that metastases were discovered near previous surgical sites in at least 36.9% of cases, suggesting tumor seeding into the scalp during surgery may facilitate mesenchymal-type mutation in some cases. However, this is unlikely to be sole mechanism of spread as there are several reports of spread without surgery, and other hypothesized mechanisms include spontaneously circulating cells and glymphatics. Other sites of GBM metastasis included bone (47.9%), lung (25.6%), lymph nodes (25.1%), and liver (14.2%). On average, metastases were diagnosed 12.1 months after the most recent resection, and the mean survival from discovery was 5.7 months. In sum, there is strong evidence that GBMs acquire novel mutations to survive outside the CNS, are spread spontaneously or iatrogenically, and portend a poor prognosis once disseminated. Routine genetic and molecular characterization of both primary and metastatic GBMs and widespread reporting will help further characterize mechanisms of spread for this rare but deadly pathology.
CNSC-63. THE COMPLEX RELATIONSHIP BETWEEN GENETIC ETIOLOGIES OF GLIOBLASTOMA AND PATIENT SURVIVAL: A RETROSPECTIVE ANALYSIS
Authors: Zarrar Nashman, Tasfiq Ullah, Pauline Hoffman
Journal: Neuro-Oncology (2024)

Abstract Data Analysis was done using the NIH GDC Data Portal with glioblastomas being the only selected primary diagnosis (n=1381). Kaplan Meier plots were generated for various genes and mutations and the survival data was compared between carriers and non-carriers. Median survival was 14 months post diagnosis when all patients are clustered together. Survival Plot of patients with IDH1 R132H mutation (n=35) vs without IDH1 R132H mutation (n=538) reveals that carriers have longer survival compared to non-carriers. The next seven cases with the highest number of specific mutations were a variation between TP53 and EGFR, both genes implicated in various cancers due to their roles in cancer suppression and proliferation respectively. The ten most frequent specific mutations observed were all missense mutations. Furthermore, patients without PTEN mutations (n=98) had better survival compared to patients who had PTEN mutations (n=623), particularly observed after one year. For specific mutations, IDH1 R132H was detected in 35 patients. All other specific mutation groups had less than 30 patients, therefore, a larger cohort would be beneficial in understanding the survival outcomes of various specific mutations. In terms of total number of mutations per gene, PTEN had the highest followed by TP53 and EGFR. In understanding the survival data, the best target for therapies can be narrowed, regardless of the increasingly evident polygenic pathology of glioblastoma.
SURG-47. SUPRAMAXIMAL RESECTION IMPROVES OVERALL SURVIVAL IN PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Eduardo Erasmo Mendoza Mireles, Hanne Blakstad, Awais Ahmad Mughal, Andres Server, Petter Brandal, Henning Leske, Mads Aarhus, Eirik Helseth, Pål Andre Rønning, Einar O Vik-Mo
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Glioblastoma is highly resistant to radio- and chemotherapy and its heterogeneity is a therapeutic challenge. O6-methylguanine–DNA methyltransferase (MGMT) promotor methylation is an established biomarker for favorable effect of chemotherapy. Supramaximal resection has proven predict the best overall survival (OS), but whether this benefit applies equally to patients with different MGMT-promotor methylation status is still to be debated. MATERIAL AND METHODS Population based retrospective study that examined all adult patients in South-Eastern Norway that underwent resection for IDH wildtype glioblastoma between January 2019 and December 2021. Extent of resection (EOR) was classified according to RANO resect classification and MGMT-promotor methylation status by pyrosequencing-qPCR. RESULTS The study included 281 patients. MGMT-promotor methylated patients (MGMT+) had a median OS of 18.4 months compared to 13.1 months in MGMT-unmethylated (MGMT-) patients (p&amp;lt;0.0001). Patients with supramaximal resection had a median OS of 20.4 months compared to 14.9 months (p&amp;lt;0.01) with maximal resection. For patients with supramaximal resection we found no significant difference in median OS (25.5 vs. 18.3 months (p=0.24)) dependent on MGMT-status. Separated analysis between MGMT-status and EOR showed a median survival of 18.3, 13.4 (p&amp;lt;0.001), and 8.5 (p&amp;lt;0.001) months for MGMT-, and 25.5, 18.4 (p=.99), and 9.0 (p&amp;lt;0.001) months for MGMT+ in patients where supramaximal-, maximal-, and submaximal resection was achieved, respectively. CONCLUSIONS Patients with supramaximal resection and MGMT+ have a 50% 2-years survival probability. In patients where supramaximal resection was achieved, survival benefit was not dependent on MGMT-status. There was a significant improved survival in MGMT- patients between supramaximal and maximal resection, that was not present for MGMT+ patients. Intraoperative molecular diagnosis has the potential to guide the surgical strategy dependent on MGMT-promotor methylation status, especially in tumors where supramaximal resection has a higher risk of new neurological deficits.
QOL-11. GBM PATIENTS CONTINUE TO FACE BARRIERS TO PERSONALIZED AND COMPREHENSIVE CARE THAT MAY IMPACT LONGEVITY AND QUALITY-OF-LIFE
Authors: Quinn T Ostrum, Fabio M Iwamoto, Lakshmi Nayak, Kelli Duprey, Ed Pilkington, Jacob Ellen, David Robles
Journal: Neuro-Oncology (2024)

Abstract We assessed the quality and accessibility of healthcare services provided to Glioblastoma (GBM) patients across the United States through an online survey distributed among the OurBrainBank community and partners and promoted on social media. A total of 297 patients or caregivers completed the survey (85% caregivers; 15% GBM patients). Median age at diagnosis was 57, lower than the national average of 64. 78% of our respondents described having some college education, and 69% had commercial insurance. Preliminary results revealed that 69% were informed about tumor testing. Among those informed, 64% did not have any molecular testing beyond initial diagnostic tests. For all respondents, 65% were not informed about storing tissue for future testing, and 79% reported not having their tissue stored for possible treatments or clinical trial qualification. Additionally, 52% reported no discussion of seeking a second opinion, and 64% reported not being offered enrollment in any clinical trial. Overall, people living with GBM face significant barriers to achieving comprehensive and personalized care. Lack of tumor testing and storage present missed opportunities for future access to emerging therapies that could improve individual outcomes. Over half of patients had no discussion about seeking a second opinion and were not offered enrollment in clinical trials, highlighting significant barriers to accessing life-extending or quality-of-life (QOL) improving treatments. Compared to the general population affected by GBM, survey respondents represented a disproportionately young and urban population, suggesting potential bias in who is able to respond to the survey. This may underestimate the challenges faced by patients with additional barriers. We are implementing strategies to reach a more geographically diverse participant group, particularly in rural areas. Ongoing targeted recruitment will further elucidate barriers to patient-centered care in GBM, with the potential for significant improvements in survival and QOL.