tbuckley/cabot-search huggingface dataset:
NIMG-60. SUBTYPING GLIOBLASTOMA FROM JOINT CLUSTERING OF IMAGING AND GENOMIC DATA
Authors: Jun Guo, Anahita Fathi-Kazerooni, Erik Toorens, Hamed Akbari, Fanyang Yu, Yuji Matsumoto, Chiharu Sako, Elizabeth Mamourian, Russell Shinohara, Constantinos Koumenis, Ioannis Verginadis, Stephen Bagley, Jennifer Morrissette, Zev Binder, Steven Brem, Suyash Mohan, Robert Lustig, Donald O’Rourke, Tapan Ganguly, Spyridon Bakas, Mariam Aboian, MacLean Nasrallah, Christos Davatzikos
Journal: Neuro-Oncology (2024)

Abstract PURPOSE To comprehensively unravel the heterogeneity of glioblastoma, we developed a subtyping method using integrated imaging and genomic data. METHODS We assembled a retrospective cohort of 571 IDH-wildtype glioblastoma patients, obtaining pre-operative multi-parametric MRI (T1, T1-GD, T2, T2-FLAIR, DSC, DTI) scans (available for 462 patients) and targeted next-generation sequencing (NGS) data (available for 355 patients). We extracted 971 radiomic features from these MRI scans, selecting 12 significant dimensions through L21-norm minimization guided by 13 key driver genes from the five most frequently altered pathways in glioblastoma compared to healthy controls (RB1, P53, MAPK, PI3K, and RTK). Subtypes were identified using a joint clustering approach that integrated radiomics and genomics. RESULTS Our method identified three glioblastoma subtypes with distinct risk levels: high-risk (subtype 1), medium-risk (subtype 2), and low-risk (subtype 3), each characterized by their differential overall survival outcomes (Kaplan-Meier analysis, p &amp;lt; 0.05). The intensities of axial diffusivity in enhancing tumor regions and radial diffusivity in non-enhancing cores increased across three subtypes. All subtypes shared a common tendency for more frequent mutation co-occurrence pattern in [TP53,RB1] but exhibited unique molecular characteristics. For example, subtype 1 displayed a relatively high frequency of co-occurring mutations in [TP53,KDR] and [NOTCH2,MDM4]; subtype 2 had six co-occurring pairs [TP53,KDR], [PTPN11,NF1], [RB1,FUBP1], [PTEN,CIC], [PTEN,KRAS], and [NOTCH2,CDKN2A]; subtype 3 showed six co-occurring pairs [PTPN11,NF1], [PDGFRA,NF1], [NTRK1,NOTCH2], [MET,ATRX], [KRAS,KDR], and [FGFR2,DNMT3A] plus four significant patterns of mutual exclusivity in [TP53,PTPN11], [TP53,EGFR], [EGFR,RB1], and [EGFR,NF1]. CONCLUSION Our study discovered distinct glioblastoma subtypes, revealing complex patterns and structures across multiple data modalities without relying on prior clinical assumptions. This is promising to help enhance the precision of diagnosis and treatment of glioblastoma.
NCOG-25. STEREOTACTIC RADIOSURGERY VERSUS SURGICAL MICRODISSECTION FOR JUGULAR FORAMEN SCHWANNOMAS: A RETROSPECTIVE COMPARATIVE STUDY
Authors: Amirhossein Akhavan-Sigari, David J Park, Yusuke S Hori, Amit R L Persad, Sara C Emrich, Louisa Ustrzynski, Armine Tayag, Steven D Chang
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Jugular foramen schwannomas (JFS) are rare, benign tumors arising from lower cranial nerves. Given their delicate location, surgical microdissection carries a substantial risk of neurological morbidity. Stereotactic radiosurgery (SRS) presents an alternative, particularly for smaller or residual tumors. OBJECTIVE This study aims to compare the outcomes and symptomatic improvements between these two treatment modalities. METHODS We conducted a retrospective analysis of 32 patients with JFS who underwent SRS (13 cases [40.6%]) or surgical dissection (19 cases [59.4%]) as their primary management at Stanford Medical Center between 1998 and 2024. Outcomes included progression-free survival (PFS), post-management adverse events based on common terminology criteria for adverse events (CTCAE), symptom improvement, overall survival (OS), and the necessity for secondary interventions. RESULTS Significant differences were observed in baseline characteristics between the SRS and surgery groups, including mean age (62.52 vs. 46.87 years, p&amp;lt;0.001), mean largest diameter (34.38 vs. 53.66 mm, p=0.02), and median total tumor volume (6.50 vs. 19.70 mm3, p=0.009). There were no significant differences in sex or lesion shape (dumbbell vs. non-dumbbell shaped). After adjusting for baseline characteristics, no significant differences were noted in PFS (85.71 vs. 77.77%), OS (92.3 vs 100%), symptom improvement (61.53 vs. 52.63%) or mean CTCAE grade (1.31 vs. 1.58) between the SRS and surgery groups. SRS patients had significantly lower odds of requiring secondary treatment procedures after their primary intervention as compared to those in the surgery group (OR=0.01, 95% CI: 0.0001-0.59, p=0.02). CONCLUSION Both SRS and surgery provide exceptional outcomes for JFS with no significant differences in PFS, OS, CTCAE grades, or symptom improvement between the two groups. However, SRS patients had lower odds of requiring secondary interventions for JFS. This is among the first studies comparing surgical microdissection and SRS for JFS. Future controlled prospective studies are necessary to derive more definitive conclusions.
DDEL-05. IMPRESSIVE RESPONSE TO IDH-INHIBITOR THERAPY IN IDH-MUTANT, H3K27M INTACT BRAINSTEM GLIOMAS
Authors: Trusha Shah, Lynne Taylor, Vyshak Venur
Journal: Neuro-Oncology (2024)

Abstract IDH-mutated brainstem gliomas in adults are a rare entity, with only a handful of cases reported in the literature. Diagnosis and treatment of these gliomas remain challenging. There is significant morbidity associated with a surgical biopsy, thus biopsies are often deferred, and tumors of the brainstem are treated presumptively with radiation and temozolomide. However, in the presence of new targeted therapies, confirming pathology for these patients is becoming increasingly important. We present two cases of IDH-mutant grade 2 astrocytomas of the brainstem that revealed both clinical and radiographic responses to IDH-inhibitor therapy. Interestingly, both patients had the same non-canonical IDH mutation, IDH-R132C, towards which ivosedinib is known to have activity. One patient had tumor progression following radiation therapy and 8 cycles of temozolomide and had subsequently exhibited a dramatic radiographic improvement, including resolution of enhancing disease following initiation of ivosidenib therapy. Clinically, this patient improved from a KPS 50 to KPS 100 after 2.5 years of ivosedinib. The other patient also had an impressive clinical improvement after only 3 months of ivosedinib treatment, with radiographic stability, improvement in balance, and resolution of his previous refractory nausea. These case reports suggest that consideration should be given to brainstem biopsy in adults specifically to evaluate for the presence of a targetable IDH mutation.
NCOG-49. EFFICACY OF POSTOPERATIVE RADIOTHERAPY AFTER GROSS TOTAL RESECTION FOR INTRACRANIAL SOLITARY FIBROUS TUMORS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Sae Min Kwon, Min Kyun Na
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The efficacy of postoperative radiotherapy (PORT) after gross total resection (GTR) for intracranial solitary fibrous tumors (SFT) remains unclear as previous studies yielded inconsistent results. Therefore, this study aimed to clarify this uncertainty using a comprehensive meta-analysis. By evaluating and synthesizing data from relevant studies, we sought to investigate the role of PORT, as compared with surgery alone, in survival outcomes after GTR of intracranial SFT. METHODS We conducted a systematic literature search, adhering to PRISMA guidelines, using Medline, Embase, and the Cochrane Library to identify relevant literature. The outcomes of interest included progression-free survival (PFS), overall survival (OS), and metastasis-free survival (MFS) at 3, 5, and 10 years, respectively. Differences between the two cohorts (GTR+PORT vs. GTR only) were estimated by calculating the hazard ratios. Results. Twelve studies, including data from 419 patients (PORT, n = 225 vs. surgery only, n = 194), were selected for meta-analysis. Pooled hazard ratios revealed that the PORT cohort showed sustained superiority in both PFS and OS over the surgery-only cohort after GTR of the tumor. These results were consistent with those of a subgroup analysis that focused on grade 2 and 3 intracranial SFT. However, no significant improvement was observed in MFS with PORT addition. Conclusion. The present study underscores the importance of PORT in enhancing the PFS and OS of patients with intracranial SFT after GTR. These findings suggest that PORT should be considered an effective treatment strategy for all patients with intracranial SFT, irrespective of the extent of resection.
INNV-05. DEVELOPMENT OF A LABEL-FREE PLASMONIC OPTICAL BIOSENSOR FOR INTRAOPERATIVE DETECTION OF TUMOR TISSUE IN GLIOBLASTOMA
Authors: Víctor García-Milán, Alfredo Franco, Margarita Estreya Zvezdanova, Sara Marcos, Rubén Martín-Láez, Fernando Moreno, José L Fernández-Luna, Carlos Velásquez
Journal: Neuro-Oncology (2024)

Abstract Safe maximal resection of patients with glioblastoma remains a surgical challenge due to the invasive nature of the tumor and the difficulty in distinguishing tumor margins during resection. Several tools are currently used for this purpose, such as, confocal laser endomicroscopy and fluorescence-guided surgery. In this context, biosensors based on plasmonic technology using the extraordinary optical transmission (EOT) phenomenon can help to distinguish between tumor and surrounding tissue based on their optical properties. We developed a biosensor utilizing EOT through a nanostructured gold matrix with 220 nm diameter holes and conducted a prospective study in 35 GBM patients. Paired samples of tumor and peritumoral tissue were collected during surgery. Each sample’s optical imprint was analyzed, revealing significant differences in refractive indices (RI). Tumor tissue showed higher RI values (1.350, IQR 1.344–1.363) compared to peritumoral tissue (1.341, IQR 1.339–1.349) with a p-value of 0.0047. The receiver operating characteristic (ROC) curve indicated the biosensor’s ability to differentiate the tissues (AUC = 0.8779, p &amp;lt; 0.0001). An optimal RI cut-off point of 0.003 was determined, with the biosensor achieving 81% sensitivity and 80% specificity. Our results indicate that this plasmonic technology-based biosensor could have a significant impact on the surgical treatment of glioblastoma by providing a label-free tool for tumor margin discrimination and improving the accuracy of glioblastoma surgery. Future research will focus on optimizing the nanoarchitecture of the biosensor to further improve its sensitivity and specificity, as well as exploring its applicability to other cancer types by analyzing the biomarkers responsible for the different RIs of the footprints.
BIOM-12. ALLIANCE A071401: GENOMICALLY GUIDED PHASE II TRIAL OF ABEMACICLIB IN PATIENTS WITH GRADE 2/3 MENINGIOMAS HARBORING SOMATIC NF2 OR CDK PATHWAY ALTERATIONS
Authors: Priscilla Brastianos, Katharine Dooley, Susan Geyer, Elizabeth Gerstner, Timothy Kaufmann, A John Iafrate, Maria Martinez-Lage, Mohammed Milhem, Mary Welch, Thomas Kaley, Jan Drappatz, Amy Chan, Priya Kumthekar, Carlos Kamiya Matsuoka, Roy Strowd, Adam Cohen, Kurt Jaeckle, Lindsay Robell, Rajiv Magge, Joo Yeon Nam, Nicholas Blondin, Nawal Shaikh, Ian Rabinowitz, Alissa Thomas, Daniel Cahill, Sandro Santagata, Frederick Barker, Evanthia Galanis
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with meningiomas that have progressed after surgery and/or radiation have limited treatments. Loss of NF2 and CDKN2A/B are common in higher-grade meningiomas and promote meningioma progression. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance A071401, a genomically-driven phase II trial in recurrent or progressive meningiomas. METHODS Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR); the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided ≥85% power to detect a PFS6 ≥41.5% (vs. null 15%; alpha=0.02), and ≥89% power to detect RR ≥20% (vs. null 2.5%; alpha=0.021). RESULTS Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received abemaciclib. The observed PFS6 rate in the first 24 evaluable pts was 54% (95% CI 33-75%), thus the study met PFS6 endpoint. Of all 35 evaluable pts, median PFS was 7.6 months (95% CI 3.6-17.1 months), estimated 6-month PFS was 55% (95% CI 40-75%) and estimated 6-month OS was 88% (95% CI 77-100%). No objective responses were observed. Of the 36 pts who started treatment, two had a grade 4 adverse event at least possibly related to treatment which included ALT elevation(1), AST elevation(1) and vomiting(1). Patients with NF2 alterations (n=24) had favorable PFS6 outcomes (58%, 95% CI 37-78%) compared to those with CDK (n=4, 25%, 95% CI 1-81%) and CDK+NF2 alterations (n=7, 29% 95% CI 4-71%), (Fisher’s Exact p=0.036). CONCLUSIONS Abemaciclib was well-tolerated and resulted in improved PFS6, meeting the trial’s co-primary endpoint. Abemaciclib warrants further investigation for the treatment of patients with progressive meningiomas.
IMMU-07. THE IMMUNE LANDSCAPE OF PEDIATRIC BRAIN TUMORS: A TRANSCRIPTOMIC ANALYSIS
Authors: Stephen Frederico, Itay Raphael, Michal Nisnboym, Sakibul Huq, Brent Shlegel, Chaim Sneiderman, Sydney Jackson, Anya Jain, Brian Rood, Ian Pollack, Eugene Hwang, Dhivyaa Rajasundaram, Gary Kohanbash
Journal: Neuro-Oncology (2024)

Abstract Despite standard-of-care therapy, pediatric brain tumors are now the leading cause of cancer-related death in children, highlighting an urgent need for the development of new treatments. Immunotherapy is actively being evaluated as a therapeutic approach to pediatric brain tumors, however, more research is needed to reveal additional antigenic targets that exist in these malignancies. In this study, our team performed a transcriptomic analysis of pediatric brain tumor RNA sequencing data within the Children’s Brain Tumor Network (CBTN) to identify intra and extracellular antigens that are highly expressed across major tumor types. Interestingly, our team observed that most tumors had high gene expression of a group of antigens that were unique to that specific tumor type. Specifically, our analysis revealed that diffuse midline gliomas (DMGs) highly expressed the extracellular antigens CA9, CTCFL, and ST8SIA1, whereas atypical rhabdoid tumors (ATRTs) highly expressed MUC1 and TEK. Other tumors that displayed high gene expression for a variety of antigenic targets included H3-wildtype high-grade gliomas (HGGs), and ependymomas (EPNs). Strikingly, we observed minimal difference in antigen expression in primary tumors when compared to patient-matched recurrences. Beyond antigen expression, we evaluated the expression of antigen processing machinery (APM) which includes major histocompatibility complexes (MHCs). Our findings revealed that DMGs had the lowest level of APM expression, however, these tumors uniquely expressed high levels of the immune checkpoints ADORA2A, CD276, and KLRC1. Contrarily, ATRTs showed a high expression of immune checkpoints CD274 (PD-L1), PVR, and CD80. Other tumors included in our analysis had unique expression patterns of antigen, as well as APM and immune checkpoints. Our findings illustrate that pediatric brain tumors have distinct expression patterns of antigens, APM, and immune checkpoints that are specific to tumor type, emphasizing diverse, rather than general, immunotherapeutic approaches must be considered for childhood brain tumors.
EXTH-07. UNRAVELING THE ROLE OF SHH SIGNALING PATHWAY IN RETINOBLASTOMA
Authors: Yanxin Pei, Xiao Liu
Journal: Neuro-Oncology (2024)

Abstract Retinoblastoma (RB) is a pediatric cancer affecting the retina, often requiring surgical removal of one or both eyes due to the limited effectiveness of current treatments. There is an urgent need for advanced therapeutic strategies capable of effectively eliminating tumors, thereby obviating the need for surgical removal of eyes in affected children. Achieving this goal requires a deeper understanding of the cellular and molecular mechanisms governing RB initiation and progression. Using a transgenic mouse model, we identified the crucial role of the Shh signaling pathway in Rb1 mutation-induced tumorigenesis, highlighting its potential as a novel therapeutic target for RB treatment. We have observed frequent overexpression of Shh signaling proteins (SHH, GLI1, and GLI2) in human RB, correlating with aggressive clinicopathological features. GLI2 overexpression is necessary for Rb1 deletion-induced RB tumor initiation in mouse retinal progenitor cells (RPCs). These mouse intraocular tumors accurately replicate human RB at both cellular and molecular levels. Additionally, Shh pathway activation extends to normal retinal cells adjacent to human RB tumors, suggesting the involvement of Shh signaling in RB-microenvironment interactions. Importantly, our studies have identified a novel small molecular inhibitor targeting the Shh pathway, effectively inhibiting RB growth in vitro and in vivo by targeting both tumor cells and the tumor microenvironment (TME). The proposed research aims to provide unprecedented insights into the role of SHH signaling pathway in RB initiation and progression and the supporting communication network between RB tumors and TME. These outcomes have the potential to treat RB effectively while improving the well-being of young individuals with RB and those at risk of RB.
CSIG-31. ANNEXIN A7 ALTERNATIVE SPLICING IN GLIOMA STEM CELLS FACILITATES THE DEGRADATION OF EGFR BY PHOSPHORYLATING TYROSINE RESIDUES EXCLUSIVE TO PROTEIN ISOFORM 1
Authors: Aran Merati, Sindhu Nair, Rajani Rajbhandari, Nicholas Johnson, Markus Bredel
Journal: Neuro-Oncology (2024)

Abstract The majority of GBMs express aberrant receptor tyrosine kinase (RTK) activity, which are canonically endocytosed and degraded. This process is disrupted in GBM to promote receptor recycling and resulting in hyperactive RTK signaling. Exon six of Annexin A7 (ANXA7) can be alternatively spliced to yield two distinct protein isoforms through its inclusion (I1) or exclusion (I2). We investigated ANXA7 isoform differences for epidermal growth factor receptor (EGFR) trafficking fates in PDX glioma stem cells (GSCs). We demonstrated that ANXA7 exon skipping supports the impaired endosomal trafficking of RTKs to favor recycling in GBM. JX14 GSCs were made to overexpress ANXA7-I1 with lentivirus to conduct immunofluorescence experiments measuring EGFR-ANXA7 colocalization (Pearson) with markers of the endocytic pathway for the early endosomes (EEA1), recycling endosomes (Rab4/Rab11), and lysosomes (LAMP1). EV and I1 cells were also incubated with siRNA targeting both ANXA7 isoforms to determine the impact of ANXA7 loss on endosomal EGFR trafficking. Interestingly, we found drastic differences in endosomal EGFR trafficking in I1 expressing cells. EGFR colocalized with EEA1 in both EV and I1 cells (R2=0.01336, P&amp;gt;0.6275). In EV cells, EGFR was recycled via fast/slow recycling endosomes demonstrated by Rab4/Rab11 colocalization while I1 did not (R2=0.9267, P&amp;lt;0.0001). Furthermore, I1 cells and not EV preferentially degraded EGFR as seen by LAMP1 colocalization (R2=0.9398, P&amp;lt;0.0001). On the other hand, ANXA7 siRNA KD in I1 cells impaired EGFR sorting via a 40% increase (P&amp;lt;0.0010) in total EGFR protein and a 40% reduction (P&amp;lt;0.0001) in colocalization with EEA1 to prefer recycling again while EV cells were unaffected. I1 overexpression significantly reduced EGFR signaling through degradation, which is driven by the phosphorylation of I1-exclusive tyrosine residues in phosphomimetic (p&amp;lt;0.01) and non-phosphorylatable protein mutants. I1-induced reduction in EGFR signaling suggests a new therapeutic vulnerability for GSCs by potentially reducing tumorigenicity or improving the efficacy of EGFR inhibition.
DDEL-17. INTRA-TUMORAL CONVECTION ENHANCED DELIVERY OF DEXAMETHASONE REDUCES INFLAMMATORY SIGNATURES AND EXTENDS SURVIVAL IN GBM MODEL
Authors: Nicholas Dadario, Damian Teasley, Liang Lei, Nathaniel Rolfe, Nathan Winans, Corina Kotidis, Nadine Khoury, Nina Yoh, Julia Furnari, Colin Sperring, Pavan Upadhyayula, Nkechime Ifediora, Nelson Humala, Aayushi Mahajan, Wenting Zhao, Brian Gill, Peter Sims, Peter Canoll, Jeffrey Bruce
Journal: Neuro-Oncology (2024)

Abstract Dexamethasone is the most widely utilized drug for glioblastoma (GBM). However, systemic delivery of dexamethasone in GBM patients is associated with significant side effects and increasing doses with worse survival. Convection-enhanced delivery (CED) can deliver high doses of immunotherapy directly into the tumor microenvironment (TME) while avoiding systemic toxicity. Here, we report that high doses of dexamethasone can be delivered locally by CED without side effects and increase survival in a GBM model along with reduced inflammatory myeloid signatures. We investigated CED of dexamethasone treatment on survival(n=40), adverse side effects, and the immunological TME through peripheral analyses, liquid chromatography–mass spectrometry, and histology in a preclinical syngeneic mouse model. Additionally, we assessed the transcriptional responses of human GBM slices and stem-cell-derived human microglia after steroid treatment through bulk and single-cell RNA sequencing. We found that 7-day treatment with CED of dexamethasone produced a significant survival advantage in glioma-bearing mice compared to non-treated control(p=0.03). Systemic dexamethasone achieved low levels of drug in the TME and caused dysregulated blood glucose, blood counts, and peripheral organ weights, while high CED doses avoided these side effects(p&amp;lt; 0.05 each). Steroid treatment of acute GBM slices and lipopolysaccharide-activated microglia in-vitro both reversed inflammatory myeloid signatures associated with poor survival and recurrence on RNA sequencing analyses. We demonstrate the preclinical efficacy of delivering high local doses of dexamethasone in a GBM model through CED and observed prolonged survival along with reduced adverse inflammatory myeloid signatures. No side effects were demonstrated after chronic CED treatment of dexamethasone while systemic delivery achieved poor tumor penetration and caused known hematologic and metabolic side effects supporting the potential to optimize the clinical use of this therapy. CED of dexamethasone provides us a new treatment paradigm to locally control inflammatory signatures in the glioma TME in a controlled fashion.