tbuckley/cabot-search huggingface dataset:
TMOD-29. BETA INTEGRINS REGULATE MITOCHONDRIALLY-MEDIATED CELL MIGRATION IN H3K27M-DIFFUSE MIDLINE GLIOMA
Authors: Rodrigo Cartaxo, Edwin Nieblas-Bedolla, Michael Niculcea, Siva Natarajan, Tiffany Adam, Madison Clausen, Madeline Miclea, Ruby Siada, Kallen Schwark, Sunjong Ji, Ananya Gera, Robert Doherty, Stefanie Galban, Nicholas Nuechterlein, Mariella Filbin, Sriram Venneti, Toshiro Hara, Carl Koschmann
Journal: Neuro-Oncology (2024)

Abstract Infiltration into the brain tissue is one of the main features of diffuse midline gliomas (DMG), also characterized by the histone mutation H3K27M and overall survival of 12-15 months from diagnosis. To study which genes are critical for H3K27M-DMG tumor cell migration in the brain, we established a novel two-step pooled whole genome CRISPR-Migration screen of metastatic H3K27M-DMG (n=3) and glioblastoma (GBM, n=2) stem cells by using serum-free conditions and laminin-dependent cell attachment, mimicking cell migration on brain vasculature scaffolds. Genes involved in focal adhesion (ITGB1, CRKL, PARVA, PTK2, FERMT2) were identified as significantly restricting migration in all H3K27M-DMG lines. From those, only knockout of ITGB1 (ITGB1-KO) fully ablated in vitro migration in all models. In human tumor RNAseq, expression of ITGB1 correlated with higher glioma grade and worse survival specifically in H3K27M-DMG across pediatric brain tumors. In H3K27M-DMG scRNAseq, increased ITGB1 expression was found in cells with OPC-like/Mesenchymal cell signature associated with leading edge and microvasculature. Unexpectedly, ITGB1-KO led to the decreased expression of multiple mitochondrial NADH dehydrogenase genes, and reduced levels of glycolysis and oxidative phosphorylation (OXPHOS) activity. Preliminary mechanistic data linked this phenotype to increased mitochondrial fusion. Genetic (ITGB1-KO) and pharmacologic (anti-ITGB1 antibody AIIB2, CNS delivered) targeting of ITGB1 in a novel orthotopic model of metastatic H3K27M-DMG (UMPED83) led to reduced proliferation and significant extension of survival (p=0.0003 ITGB1-KO, and p=0.0006 AIIB2). Interestingly, ITGB1-KO in another orthotopic H3K27M-DMG model (SVZ) led to upregulation of other integrins (ITGB3 and ITGB5) without change in survival, resulting in susceptibility to treatment with the ITGB3/5 inhibitor Cilengitide (p=0.006). Treatment with AIIB2 and Cilengitide alone or in combination was ineffective in an H3WT adult GBM orthotopic model suggesting unique H3K27M-DMG targetability. In summary, targeting of integrin pathways offers untapped therapeutic opportunities in H3K27M-DMG by impairing tumor cell survival through altered mitochondrial dynamics.
SURG-03. GENE EXPRESSION CHANGES ASSOCIATED WITH RECURRENCE AFTER GROSS TOTAL RESECTION OF NEWLY DIAGNOSED WHO GRADE 1 MENINGIOMA
Authors: Ramin Morshed, Minh Nguyen, Mark Youngblood, Haley Perlow, Calixto-Hope Lucas, Akash Patel, Joshua Palmer, James Chandler, Philip Theodosopoulos, Stephen Magill, William Chen, David Raleigh
Journal: Neuro-Oncology (2024)

Abstract Patients who undergo gross total resection (GTR) of Central Nervous System World Health Organization (WHO) grade 1 meningioma constitute a “low risk” group, but some low risk meningiomas can recur despite reassuring clinical and histological features. In this study, gene expression in newly diagnosed WHO grade 1 meningiomas that had undergone GTR were evaluated for their association with recurrence. This was a retrospective, international, multi-center cohort study that included WHO grade 1 meningiomas that underwent GTR as first treatment. Normalized gene expression values from a previously validated 34-gene panel were evaluated for their association with recurrence. Kaplan-Meier, multivariable Cox proportional hazard analyses, and K-means clustering were performed to assess the association of genes of interest with recurrence and identify molecular subgroups among clinically and histologically low risk meningiomas. 442 patients with WHO grade 1 meningiomas that underwent GTR and had available gene expression profiling data were included in the study. Median follow-up was 5.0 years (interquartile range 2.6-7.7 years), local recurrence occurred in 36 patients (8.1%), 5-year local freedom from recurrence (LFFR) was 90.5%, and median time to recurrence of 2.9 years (range 0.5-10.7 years). Eleven genes were associated with local recurrence, including lower expression of ARID1B, ESR1, LINC02593, PGR, and TMEM30B and higher expression of CDK6, CDKN2C, CKS2, KIF20A, PGK1, and TAGLN. K-means clustering based on these 11 genes distinguished 2 molecular groups of clinically and histologically low risk meningiomas with significant differences in LFFR (HR 2.5, 95% CI 1.2-5.1, p=0.016). In conclusion, gene expression profiling may help to identify newly diagnosed WHO grade 1 meningiomas that have an elevated risk of recurrence despite GTR.
TMIC-87. ICAM-1 REGULATE EXTRACELLULAR VESICLE-MEDIATED IMMUNOSUPPRESSIVE MONOCYTE IN HUMAN GLIOBLASTOMA CELL
Authors: Mi-Yeon Jung, Masahiro Oishi, Erin N Walker, David Barnes, Sabrina Nusraty, Yesh Banasavadi Siddegowda, Ian F Parney, Desmond A Brown
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is the most common malignant primary brain tumor and is universally fatal. Treatment involves maximal safe resection with adjuvant chemoradiation. Poor prognosis in glioblastoma is multifactorial, and local and systemic immunosuppression is an important factor. Extracellular vesicles (EVs) are small, membrane-bound particles released by cells into the external environment. They play a key role in intercellular communication. In glioblastomas, EVs regulate immunosuppression through induction of myeloid-derived suppressor cells (MDSCs) in a process dependent on the PD-1/PD-L1 and IL-6 axes. Primary cilia are microtubule-based organelles that play crucial roles in various cellular processes and signal transduction cascades. We recently showed that primary cilia modulate IL-6 expression and consequently, MDSC induction. Comparative proteomic analysis of EVs derived from human glioblastoma cells devoid of cilia showed loss of ICAM-1 expression compared to control glioblastoma cells. ICAM-1 (Intercellular Adhesion Molecule-1) is a cell surface glycoprotein that mediates cell-cell adhesion and immune responses. In this study, we showed that depletion of primary cilia in human glioblastoma cells result in increased PD-L1 but loss of IL-6 and ICAM-1. RNAi-meidated loss of ICAM-1 was synergistic with primary cilia depletion in preventing MDSC inductionn normal human monocytes exposed to glioblastoma-derived EVs. Exogenous IFN-g was sufficient to restore IL-6 levels and MDSC induction despite loss of primary cilia and ICAM-1 suggesting that primary cilia act upstream of IFN-g, IL-6 and ICAM-1 in glioblastoma-mediated MDSC induction. This study is the first to connect primary cilia signal transduction to IL-6 and ICAM-1 expression and to MDSC induction. The evidence suggests a potential parallel primary cilia regulatory cascade independent of the PD-L1 axis that controls tumor-mediated immunosuppression. These results may inform novel therapeutic strategies aimed at increasing efficacy of immunotherapy in the glioblastoma and other neoplastic processes.
CSIG-11. TUMOR-CELL INTRINSIC CALCIUM OSCILLATIONS DRIVE BRAIN METASTASIS
Authors: Nils R Hebach, Niels Olshausen, Joana S Schlag, Severin Bang, Theresa Kraft, Chanté Mayer, Zoe Linke, Dana Westphal, Michael Seifert, Jens Timmer, Wolfgang Wick, Frank Winkler, Matthia A Karreman
Journal: Neuro-Oncology (2024)

Abstract Calcium is a ubiquitous secondary messenger which regulates many cellular processes. Recently, we have shown that a subpopulation of glioblastoma cells can intrinsically generate calcium oscillations which drive proliferative signalling. Here, we set out to investigate whether such cancer cell autonomous oscillations are also present in secondary brain tumours. Employing longitudinal intravital two-photon microscopy in awake mice, we demonstrate that brain metastases of melanoma and lung cancer exhibit spontaneous calcium oscillations in vivo along the metastatic cascade. These oscillations are already observed during intravascular arrest and in in vitro monocultures, suggesting a tumour-cell intrinsic origin. We developed a fully automatic image analysis pipeline to accurately quantify calcium oscillations both in vivo and in vitro. Mathematical modelling of cytosolic and ER calcium stores can predict stable calcium oscillations with similar frequency and peak characteristics as those experimentally observed. We discovered that these oscillations are tightly regulated by an interplay of calcium-induced calcium release and store-operated calcium entry (SOCE). Similarly, SOCE-related ion channels are enriched in tissue from human melanoma brain metastases compared to healthy brain controls and calcium activity can also be observed ex vivo in patient-derived brain metastasis resections. Finally, by correlating calcium activity and EdU incorporation we discovered that the presence of calcium oscillations predicts their proliferative potential in vitro. Importantly, by intravital two-photon microscopy we show that calcium activity correlates with metastasis size in preclinical models, suggesting a potential new therapeutic angle from which to target brain metastases.
NIMG-64. SURVIVAL IMPLICATIONS OF POSTOPERATIVE RESTRICTED DIFFUSION IN HIGH-GRADE GLIOMA AND LIMITATIONS OF INTRAOPERATIVE MRI DETECTION
Authors: Daniel Aaronson, Brandon Laing, Ishan Singhal, Timothy Boerger, Ryan Beck, Kathleen Schmainda, Wade Meuller, Max Krucoff
Journal: Neuro-Oncology (2024)

Abstract AIMS In glioma surgery, surgically induced cerebral ischemia may poorly affect overall survival. While intraoperative MRI (iMRI) is an established tool used to maximize extent of resection, its ability to detect cerebral ischemia during surgery has not been studied. Here we evaluate both the association of post-surgical cerebral ischemia on survival independent of new functional deficits and the sensitivity of iMRI in detecting cerebral ischemia. METHODS We retrospectively reviewed 361 cranial surgeries that used a 3 Tesla iMRI. 165 patients met all inclusion criteria and were included in the final analysis. Diffusion weighted imaging (DWI) obtained during iMRI was compared to postoperative DWI obtained within 7 days of the operation in cases where no further resection occurred after the iMRI. RESULTS 42 of 165 patients (25%) showed evidence of restricted diffusion on postoperative (poMRI); 37 of these 42 (88%) lacked evidence of restricted diffusion on iMRI (false-negative rate of 88%, sensitivity of 12%). In high-grade gliomas, poMRI restricted diffusion volume was predictive of overall survival independent of new functional deficit (p = 0.011). CONCLUSION Here we present the largest case series to date analyzing the sensitivity of iMRI in detecting ischemia. In high-grade gliomas, increased volume of ischemia correlated with worsening median overall survival (OS) irrespective of postoperative neurologic deficits. Future work will focus on improving intraoperative detection of ischemia during the hyperacute phase when interventions such as blood pressure modulation or direct application of vasodilator agents may be effective.
SURG-46. ENDOLYMPHATIC SAC TUMORS: A CASE REPORT AND REVIEW OF THE LITERATURE
Authors: Scott Turner, Jose Carillo, Lars Anker, Adam Stelling
Journal: Neuro-Oncology (2024)

Abstract Endolymphatic sac tumors are rare, histologically benign tumors that pose a danger of local bony destruction. Definitive treatment is complete surgical resection but the use of subsequent radiotherapy remains controversial and is typically used for residual or recurrent disease. Additionally, these tumors are associated with von-Hippel-Lindau (VHL) syndrome and are present in 10-30% of patients with this autosomal dominant disorder. We present the case of a 69 year-old woman who presented with cranial nerve 7 and 8 palsies that had started in the 1990s and was found to have a left CPA mass. She underwent pre-operative embolization followed by 2 stage craniotomy and post-operative radiotherapy. Testing for the VHL mutation was negative.
RADT-25. IMPACT OF SAME-DAY MASK CREATION ON GAMMA KNIFE TREATMENT
Authors: Mark Mizrachi, Benjamin Hartley, Eric Hintz, Anuj Goenka, Michael Schulder
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Technological advances have allowed stereotactic radiosurgery (SRS) to be administered using fixation with a noninvasive mask, rather than with a stereotactic frame. While the use of such masks offers advantages including the ability to hypofractionate SRS and improved patient comfort, there has been criticism that it eliminates the possibility of same-day, “wheels in to wheels out” SRS. Our study examines the feasibility of conducting mask fitting and SRS treatment on the same day versus the conventional different-day approach. METHODS Eligible participants had either underwent single-fraction-SRS (SF-SRS) or were in their initial session of hypofractionated-SRS (HF-SRS). 100 patients who underwent SRS from September 2020 to June 2021 were assessed. 52 patients underwent same-day fabrication and treatment, and 48 patients received treatment at least one day following mask fabrication. The Leksell Gamma Knife (LGK) console data was processed, and operator reports from each patient were extracted and analyzed. RESULTS The average number of pauses, pause time, and number of gates was greater for same-day patients. There was no significant difference in the number of positioning alarms between the groups. There were no significant differences in percent overestimation of treatment time or number of treatment alarms. Treatment gates occurred on average 19 minutes earlier for same-day patients then different-day patients, which likely corresponds to “mask fatigue,” due to spending 20 minutes longer on the treatment table, while the masks are being fabricated. CONCLUSION Mask-based SRS can be done safely and efficiently in a single day, mirroring the approach of frame-based treatments.
BIOM-08. LEVERAGING CSF PROTEOMICS TO OPTIMIZE CNS LYMPHOMA MANAGEMENT
Authors: Alireza Mansouri, Hannah Wilding, Aastha Aastha, Nicholas Mikolajewicz, Leonardo Macedo de Filho, Michael Glantz, Thomas Kislinger
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Despite exquisite responses to initial therapy for CNS lymphoma (CNSL), relapse is common and overall responses are disappointing compared to other non-CNS diffuse large B-cell lymphomas. Incorporation of multi-agent intraventricular chemotherapy (MAIVC) alongside systemic therapy is novel. Identification of minimally-invasive biomarkers of response to MAIVC are necessary but lacking. The objectives of this study were to 1) identify baseline cerebrospinal fluid (CSF)-based proteomic predictive biomarkers of MAIVC treatment response and 2) identify tumor burden markers for longitudinal monitoring of MAIVC treatment response in CNSL. METHODS A cohort of patients with primary or secondary CNSL that were treated with MAIVC at Penn State Health (2015-2021) was included. Each MAIVC cycle was administered via Ommaya reservoir and included a 2-drug combination comprised of methotrexate, rituximab, cytarabine, etoposide, topotecan, gemcitabine, or thiotepa. Patient-matched CSF was sampled at pre- and post-therapeutic endpoints and profiled using shotgun proteomics. Patients were grouped by treatment response status. Early responders were defined as patients that achieved malignant cell-free CSF within 6 MAIVC cycles, whereas never responders were those patients that i) did not achieve malignant cell-free CSF by endpoint or ii) required salvage surgery or radiation during MAIVC. RESULTS 59 patients were included (21 primary; 38 secondary CNSL) with a median age of 66 years (range 25-90) and median number of MAIVC cycles of 8 (range 2-23). A proteomic-based classifier, comprised of SGCE, LCP1 and AGRN, discriminated between early and never responders with an AUROC of 0.95. Comparison of CSF at baseline (&amp;lt;3 cycles MAIVC) vs. post-treatment (&amp;gt;12 cycles MAIVC) identified H3F3A, YWHAE, LCP1, CA1 and GAPDH as tumor burden biomarkers. CONCLUSION Here we developed a proteomic signature capable of predicting CNSL patient response to MAIVC, with potential to improve clinical decision making. Furthermore, the biomarkers associated with tumor burden represent important indicators of treatment response. Ongoing efforts are underway to evaluate these candidates as actionable therapeutic targets.
EPID-37. PROGNOSIS OF BRAIN METASTASES PATIENTS WITH WHOLE BRAIN RADIATION THERAPY (WBRT) VS NON-WBRT AT THE NATIONAL CANCER CENTER OF INDONESIA, DHARMAIS HOSPITAL
Authors: Rini Andriani, Alfred Susilodinata, Siswanto Agus Wilopo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Limited treatment options for brain metastases (BM) remain a challenge for many cancer centers in Indonesia. To improve overall survival, Whole Brain Radiation Therapy (WBRT) is still widely used in many Indonesian cancer centers This study aims to evaluate the effectiveness of WBRT vs non-WBRT for overall survival of brain metastases patients. METHOD This retrospective study observed 148 brain metastasis patients admitted to our hospital from January 1st, 2021 to December 31st, 2022 and we followed their overall survival up to July 1st, 2023. The brain metastasis is confirmed by brain MRI. In addition to overall survival, we collected information on age, sex, primary tumor types, sides of metastasis, and treatment received (WBRT, non-WBRT, and surgery). To examine the overall survival among treatment received and tumor characteristics, we present median survival time, Kaplan-Meier curves, and its log-rank statistics using Stata program version 17. Additionally, we use Cox regression for further analysis. RESULTS The overall median survival of these patients was 4.3 months. Patients receiving WBRT exhibit higher survival rates than non-WBRT as presented in their median survival rates (1.5 months vs 6.9 months). The primary tumors (breast, lung, and others) have no difference in the median survival rates. The survival rate trends using Kaplan-Meier showed a significant difference between patients with WBRT vs non-WBRT (log-rank p=0.0). A Cox regression shows hazard rates(HR) for patients receiving WBRT =0.40 and it shows only a small change when adjusted for surgery and other variables. CONCLUSIONS Brain metastasis patients who received WBRT have better survival than non-WBRT patients who could reduce HR to 0.4. This means that WBRT patients are protected 60% of the risk for overall survival.
CNSC-21. THE EFFICACY OF TUMOR TREATING FIELDS IN TREATING IDH-MUTANT ASTROCYTOMA, WHO GRADE 4: AN EARLY RESULT FROM SHANGHAI HUASHAN HOSPITAL
Authors: Xianxin Qiu, Lingzhao Chen, Liping Liang, Zhirui Zhou, Jiabing Liu, Wenjia Zhu, Tianqi Wu, Mingyuan Pan, Zhiyong Qin, Yang Wang
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVES There is ongoing debate regarding the efficacy of Tumor Treating Fields (TTFields) for treating IDH-mutant grade 4 astrocytoma (IDHmA4). In fact, the evidence supporting TTFields in treating IDHmA4 is largely extrapolated from EF-14, of which the results stem form heterogeneous entities of glioblastoma lack of IDH status. This study was conducted by reviewing the database in our center following the release of WHO CNS 5, aiming to preliminarily explore the efficacy of TTFields and prognosticators of newly-diagnosed IDHmA4. METHODS This retrospective analysis included 53 consecutive patients with newly-diagnosed IDHmA4, who underwent radiotherapy at Huashan Hospital, Fudan University between September 2021 and December 2023. All patients were administered with concurrent and adjuvant temozolomide. Eleven patients received adjuvant TTFields after surgery. Information regarding patient baseline characteristics, treatment approaches and molecular markers were collected with the purpose of analyzing prognostic factors. RESULTS The median follow-up was 15.7 months. At the time of data cutoff of this analysis, 20 patients had tumor relapse; 3 patients died, all of them were without TTFields therapy. The most common tumor failure pattern was local recurrence (80%, 16/20). The median PFS for the entire cohort was 19.3 months, the median OS was not reached. Univariate analysis indicated that patients who received TTFields therapy tended to have longer median PFS than that of patients without TTFields therapy (24.4 months vs. 18.5 months, P=0.097). Additionally, patients younger than 40 years (24.4 vs. 18.5 months, P=0.107) or without homozygous deletion of CDKN2A/B (23.7 vs. 18.0 months, P=0.108) tended to have better median PFS. No significant independent prognostic factor was found in the multivariate analysis. CONCLUSIONS The overall prognosis of IDHmA4 is poor. TTFields may help to improve the outcome of patients with newly-diagnosed IDHmA4. Longer follow-up, larger sample size and prospective clinical trials are warranted for deeper comprehension.
NCOG-19. FUNCTIONAL OUTCOME AFTER RE-RESECTION OF TUMOR PROGRESSION, MIXED LESION OR TREATMENT-ASSOCIATED EFFECTS IN IRRADIATED DIFFUSE GLIOMAS (GRADE 2-4): IDENTIFYING CLINICAL AND RADIOLOGICAL DETERMINANTS
Authors: Maud Kortman, Maarten Kreek, Anouk de Jong, Christina Flies, Aline Becker, Jan-Willem Dankbaar, Pierre Robe, Joost Verhoeff, Tom Snijders
Journal: Neuro-Oncology (2024)

Abstract In cases of radiological progression in patients with irradiated diffuse gliomas, recurrence-resection is frequently performed. In our previous histological evaluation 19% of these re-resection cases were found to be due to treatment-associated effects (TAE). Limited literature substantiating which patients will benefit from surgery and which patients will deteriorate postoperatively is available. We aim to (a) describe the functional outcomes after re-resection of an irradiated diffuse glioma in adult patients; (b) compare early functional outcomes between patients with TAE versus progressive disease; (c) identify predictors of early functional outcome. In this single-center, retrospective, cohort study, we included consecutive adult patients with diffuse glioma who underwent first-line radiotherapy and, upon radiological progression, a re-resection. Re-resection tissue was classified histologically (based on mitosis presence/absence) and by the multidisciplinary tumor board as tumor progression, TAE or mixed lesion. The primary endpoint was the functional outcome 30 days postoperatively, expressed as the Karnofsky Performance Scale (KPS). Univariable and multivariable logistic regression were used to identify clinicoradiological predictors of KPS deterioration of any severity. Of 159 included patients, 41 (25.8%) experienced mild KPS deterioration (10 points) and 25 (15.9%) a clinically relevant KPS deterioration (20 or more). KPS improvement (10 points or more) occurred in 31 patients (19.4%). Histological diagnosis groups did not differ significantly in KPS outcome. Pre-operative steroid usage (any dose) was an independent predictor of KPS deterioration (OR 2.46, 95%CI 1.12-5.39, p=0.025). Analysis of pre-operative radiological determinants is in progress. In conclusion, in this large single-center cohort of diffuse gliomas undergoing re-resection with systematic clinical evaluation, clinically relevant deterioration after re-resection occurred in 15.9% of all patients. Risk of deterioration is comparable in all histological diagnosis groups. Pre-operative steroid usage was identified as predictor for deterioration (of any severity). These results may provide clinical guidance in identifying which patients will benefit from re-resection.