tbuckley/cabot-search huggingface dataset:
EPCO-01. FROM HIERARCHY TO GEOGRAPHY: MULTI-CLONES DRIVE THE CELLULAR DIVERSITY AND EVOLUTION OF HUMAN MEDULLOBLASTOMA
Authors: Hailong Liu, Jiankang Li, Tao Jiang
Journal: Neuro-Oncology (2024)

Abstract We’ve curated a comprehensive multi-omics database of medulloblastoma (MB) serving as a resource to understand spatiotemporal organization and guide therapeutic strategies. Herein, our analysis encompasses single-nucleus transcriptome (n = 51), chromatin accessibility (n = 46), and spatial transcriptomic profiles (n = 31) from human MB samples and patient-derived xenograft lines spanning four subgroups, augmented by bulk RNA (n = 322), whole-genome short-sequencing (n = 279), and bisulfite sequencing (n = 300) from matched samples. We delineate the malignant cellular hierarchy, identifying MB cancer stem-like cells (MB-CSCs), cycling cells, and more differentiated populations. Gene signatures of different cell subpopulations strongly correlate to clinical outcomes, while spatial character of patient-derived materials emphasizes the geographically heterogeneous nature of MB. Examination of somatic copy number variants (CNVs) and transcriptional signatures at single-nucleus resolution reveals geographically defined subclones harboring distinct CNVs, suggesting a competitive agglomeration of co-existing multi-clones for MB. Alongside the trajectorial transition, we observe distinct chromosomal alterations in apical MB-CSCs compared to more differentiated cells, indicative of extensive subclone-primed spatiotemporal evolution. Further analysis of reagent-gene interactions of subclonal lineages contributes to predicting the druggable candidates for treatment optimization. Integration of spatial architecture data highlights the recapitulation of subclone-determined niches through colocation with identified malignant lineages and their own inflammatory or fibrotic adaptions. Taken together, this comprehensive database, comprising five or six kinds of datatypes on the same MB cases, facilitates combinatorial analyses across different genomic modalities, offering genetic and geographic insights into therapeutic advancements.
EPCO-02. HIGH CELLULAR PLASTICITY STATE OF HUMAN MEDULLOBLASTOMA LOCAL RECURRENCE AND DISTANT DISSEMINATION
Authors: Hailong Liu, Jiankang Li, Tao Jiang
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) is a heterogeneous pediatric brain tumor with variable clinical outcomes. Since current treatments facing limitations due to tumor resistance, less than 10% of relapsed patients survive beyond five years, with poorly understood recurrence mechanisms. To obtain cellular diversity and genetic characters in primary and recurrent MB, we conducted comprehensive analyses utilizing the single-cell/nucleus RNA sequencing (sc/snRNA-seq), snATAC-seq and spatial transcriptomics, complemented with bulk RNA sequencing and matched primary-recurrent whole exon profiles. SHH and Group_3 subgroups revealed distinct cellular subsets, including cycling, differentiated and quiescent tumor cells. Recurrent or disseminated MB displayed a dramatically different cellular ecosystem compared to primary tumors, with varying proportions of shared cell types. Local recurrence exhibited a higher enrichment of cycling tumor cells, while differentiated subset was notably present in disseminated lesions, indicating that local recurrences harbored the stronger proliferative capacity, whereas disseminations relatively well differentiated. Additionally, chromosomal alterations were assessed, reflecting distinct genetic subclones, such as chr7q gain and chr11 loss in Group_3 disseminations. Notably, the emergence of a subpopulation termed “high cellular plasticity (HCP)” during MB progression was noted, characterized by dynamic adaptability and stemness properties. As validated, HCP state was associated with increased chromatin accessibility, contributing to tumor recurrence and immune microenvironment remodeling. Functionally, inhibiting markers associated with HCP cells, such as PTPRZ1, efficiently suppressed MB metastasis in preclinical models. In conclusion, our findings fill the critical knowledge gaps in understanding the cellular diversity, chromosomal alterations and biological dynamics in MB recurrence and dissemination, offering potential therapeutic interventions.
PATH-28. KI-67 INDEX AS A PREDICTIVE MARKER OF MENINGIOMA RECURRENCE FOLLOWING SURGICAL RESECTION
Authors: Mark Mizrachi, Benjamin Hartley, Shahzaib Saleem, Eric Hintz, Yonah Ziemba, Jianyi Li, Anuj Goenka, Michael Schulder
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningiomas are the most common primary intracranial tumors in adults. Although benign in a majority of cases, they have a variable clinical course and may recur even after a thorough surgical resection. Ki-67, a nuclear protein involved in cell cycle regulation, has been widely studied as a marker of cellular proliferation in various cancers. Here, we investigate the Ki-67 index, as a predictive marker of meningioma recurrence following resection. METHODS The medical records of 451 patients with previously untreated cranial meningiomas who underwent resections from January 2011 to January 2021 at North Shore University Hospital (NSUH) were reviewed. Collected data included WHO grade, Ki-67 proliferative index, degree of resection - gross (GTR) vs subtotal (STR) - as judged by the surgeon, tumor location, and meningioma recurrence. This study was approved by the NSUH Institutional Review Board IRB 21-1107. RESULTS There were 290 patients with grade I, 154 with grade II, and 7 with grade III meningiomas. Higher WHO grades were associated with higher rates of recurrence, with rates of 11.4 %, 27.9 %, and 71.4 % for grades 1, 2, and 3, respectively, and subtotal resection corresponded to a higher rate of recurrence than total resection (34.3 % and 13.4 %, respectively). Higher WHO grades also correlated with higher Ki-67 scores (2.59, 10.01, and 20.71) for grades 1, 2, and 3, respectively. A multivariate logistic regression model identified Ki-67 and degree of resection as independent predictive variables for meningioma recurrence, with Ki-67 specifically predicting recurrence in the WHO grade II subset when analyzed separately for WHO grades I and II. CONCLUSION Our 10-year retrospective study suggests that the Ki-67 index is an important predictive marker for recurrence of intracranial meningiomas following surgical resection, particularly among patients with WHO grade II tumors. Our findings add to a growing body of data that support inclusion of Ki-67 index in the WHO grading criteria for patients with meningiomas.
NIMG-79. A RADIOMIC-RISK SCORE FOR SURVIVAL PREDICTION IN GLIOMA: A LARGE MULTI-INSTITUTIONAL RETROSPECTIVE VALIDATION STUDY
Authors: Gustavo Pineda, Michael Veronesi, Timothy J Stuhlmiller, Hope Lee, Sarah Ginn, Alaa Awawda, Zachariah Cole, Ankush Bhatia, Santosh Kesari, Manmeet Ahluwalia, Marwa Ismail, Pallavi Tiwari
Journal: Neuro-Oncology (2024)

Abstract Gliomas have dismal survival. Recently, radiomics has demonstrated success in developing non-invasive image-based biomarkers for survival prediction in gliomas. However, clinical applicability of radiomics-based biomarkers will ultimately require rigorous validation on large, multi-institutional data. This work attempts to evaluate a radiomic-based survival risk-assessment prognostic score on a multi-institutional cohort of Glioma patients. Our rationale is that optimizing and validating radiomic features that capture intensity-based textural variations and morphology-based changes (e.g., local curvature and global contour) on large multi-institutional cohorts can allow for robust risk assessment in Glioma. n=668 pre-operative T1w MRI scans for Glioma patients from 4 cohorts: University of California San Francisco “UCSF” (n=495), LUMIERE (n=86)), xCures (n=13), and Cleveland Clinic (CCF) (n=74) were analyzed. Subjects from UCSF, CCF, and xCures were used for training, whereas the LUMIERE cohort was used for hold-out testing. Following pre-processing, expert-vetted tumor segmentation into Edema (ED) and Enhancing tumor (ET) regions was performed. A total of n=1558 radiomic features were extracted from the tumor regions (779 per region), namely, 31 global contour, 20 curvature-based, 624 gradient co-occurrence statistics, and 104 Collage features. Cox regression model was employed to create a radiomic risk score (RRS) for every subject, which included radiomics features as well as on clinical and demographic variables (IDH, MGMT, sex, age), for survival analysis. RRS incorporated a total of 43 radiomic features, and the associated clinical and demographic variables (CDS), yielding significant differences between high and low risk groups in the training (RRS: p=0.043, HR = 2, CSD: p=0.0031, HR = 2.8) and testing sets (RRS: p=0.0096, HR = 1.8, CSD: p=0.0071, HR = 1.8). Combining RRS and CDS improved the OS prediction at group level (p=3.6e-6, 0.0011, HR=5.4, 2, for training and testing, respectively). Radiomics-based risk-stratification may be promising for reliable risk-stratification in glioma.
NIMG-76. INCORPORATING IMAGING FEATURES OF NORMAL BRAIN TO ENHANCE SPATIALLY DIFFERENTIATING TREATMENT-INDUCED EFFECTS FROM RECURRENT GLIOMA WITH AI
Authors: Jacob Ellison, Tiffany Ngan, Angela Jakary, Nate Tran, Joanna Phillips, Anny Shai, Annette Molinaro, Yan Li, Tracy Luks, Devika Nair, Javier Villanueva-Meyer, Mitchel Berger, Shawn Hervey-Jumper, Manish Aghi, Susan Chang, Janine Lupo
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Although AI-based approaches have been applied to discriminate between tumor recurrence (rTumor) and treatment-induced effects (TxE) from chemoradiotherapy in patients with recurrent glioma, these models typically either do not account for within-lesion mixtures of rTumor and TxE or generalize to independent test-sets with &amp;gt;80% accuracy. We hypothesize that incorporating imaging features of normal-appearing brain (NAB) into existing AI-based models that leverage tissue-samples with known locations on MRI and physiological imaging will significantly improve performance for distinguishing regions of TxE from rTumor and allow for visualization of rTumor beyond the T2-lesion. METHODS Using 254 pathology-confirmed tissue-samples with coordinates on diffusion-weighted, perfusion-weighted, and anatomical MRI from 135 glioma suspected of progression, we modified previously-developed binary, AI-based prediction models to learn multi-class targets consisting of rTumor, TxE, and contralateral NAB-regions (3/patient) with imaging signatures of CSF, white-matter, and grey-matter (659 total 10mm-isotropic samples). The multi-class ensemble model was trained with 4 unique repeats of constrained-5-fold-cross-validation and evaluated on a held-out test set (30 patients). This process was repeated 20 times, and the performance was compared to corresponding binary AI-based models. RESULTS NAB was easiest to distinguish from individual and combined classes (AUC-ROCs&amp;gt;0.98). Multi-class model performance for predicting TxE increased by 27% to 0.93±0.03 (p&amp;lt;0.00001) when discriminating between NAB and rTumor as compared to just rTumor with the binary models. While TxE vs rTumor alone was most difficult to predict with the multi-class model (AUC-ROC=0.73) achieving equivalent performance to binary models, there was 67% less variance in test performance. This approach allowed for the quantification of whole-brain probability maps of rTumor, TxE, and NAB along with a combined 3-channel colormap, facilitating the visualization of rTumor predictions beyond the T2-lesion. CONCLUSIONS Including NAB imaging features improved performance of AI-based models of rTumor/TxE, while expanding the predicted area to produce more interpretable whole-brain probability maps. Current work is evaluating their utility in prospectively guiding sampling of rTumor tissue and predicting survival.
NIMG-77. MRI PHENOMENON OF PUNCTATE ENHANCING LESIONS IN PATIENTS TREATED WITH IDH INHIBITORS
Authors: Michal Nisnboym Ziv, Mallika P Patel, Maria Minor, Margaret O Johnson, Kristen Batich, Justin Low, Madison L Shoaf, Mustafa Khasraw, Annick Desjardins, Henry S Friedman, David M Ashley, Katherine B Peters
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Magnetic Resonance Imaging (MRI) response assessment is essential in isocitrate dehydrogenase (IDH)-mutant gliomas and provides evidence of treatment efficacy. Ivosidenib, a mutant IDH1 inhibitor, and vorasidenib, a pan-mutant IDH inhibitor, may induce imaging stabilization or improvement. We describe an imaging phenomenon of punctate enhancing lesions in patients receiving ivosidenib or vorasidenib. METHODS From October 2020 to December 2023, we identified patients treated with IDH inhibitors who developed punctate enhancing lesions on imaging during their treatment course. We report their clinical and imaging characteristics. RESULTS In our cohort (n=5), patients age range was 29-47 years. Diagnoses included astrocytoma grades 2 (n=2) or 3 (n=1), and oligodendroglioma grades 2 (n=1) or 3 (n=1). Beside all having a prior resection, two had prior radiation therapy and temozolomide, one had prior temozolomide only and two were treatment-naïve. Before initiation of IDH inhibitor, all patients had some evidence of enhancement, albeit small (&amp;lt;1 cm) for most. Four patients received ivosidenib (500mg daily) and one received vorasidenib (40mg daily). The median time to develop punctate lesions from treatment initiation was 16 months (range 1-28 months). All but one lesion was &amp;lt; 1 cm and adjacent to the original tumor locations. Four had FLAIR correlation, and two had high DWI signal without associated restricted diffusion. Punctate lesions resolved on subsequent imaging, within 1-2 months, for all grade 2 tumors. Punctate lesions persisted in the grade 3 tumors, without further progression. Four patients remain on therapy. One discontinued treatment due to this enhancement, which resolved on subsequent imaging. CONCLUSIONS Punctate enhancing lesions may develop in patients on IDH inhibitors. We advocate for close interval imaging monitoring in these cases since they may not universally require treatment discontinuation. Future advanced imaging and tissue evaluations of punctate enhancement, to differentiate between inflammatory response and progression, would be of interest.
NIMG-34. CXCR4-TARGETED PET IMAGING OF CENTRAL NERVOUS SYSTEM LYMPHOMA AND GLIOMA USING [68GA]GA-PENTIXAFOR
Authors: Jan-Michael Werner, Erwin Tomasich, Anna S Berghoff, Adelheid Wöhrer, Nathalie L Albert, Marius E Mayerhoefer, Norbert Galldiks, Tatjana Traub-Weidinger, Marcus Hacker, Matthias Preusser
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Initial results suggest that PET imaging of the chemokine receptor CXCR4 is of considerable interest for differential diagnosis and theranostic approaches. Here, we summarized findings of CXCR4 PET imaging in an institutional series of lymphoma of the central nervous system (CNSL) and glioma. METHODS Twenty-three patients with CNSL and 16 patients with glioma (IDH-wildtype, n=9) underwent PET imaging using the CXCR4-directed tracer [68Ga]Ga-Pentixafor. In 18 patients, serial PET imaging was performed (range, 2-14 scans), resulting in a total of 104 PET scans. For evaluation, PET scans were classified as [68Ga]Ga-Pentixafor-positive and -negative visually, and the maximum standardized uptake value (SUVmax) was obtained from [68Ga]Ga-Pentixafor-PET. RESULTS Twenty-four of all 39 patients (62%) had at least one [68Ga]Ga-Pentixafor-positive PET (CNSL, 57%; glioma, 69%). [68Ga]Ga-Pentixafor-positive PET scans were more common in patients with IDH-wildtype gliomas (89%) than in IDH-mutant gliomas (43%). In patients with [68Ga]Ga-Pentixafor-positive PET, the average SUVmax was 6.4±4.0 in CNSL, and 3.4±1.0 in gliomas (P=0.155). Besides visualization of tumors, [68Ga]Ga-Pentixafor uptake was observed in two patients with radionecrosis. In four CNSL patients who had undergone methotrexate/cytarabine-based first-line therapy, serial PET revealed a significant reduction of SUVmax after chemotherapy completion (average decrease of SUVmax from 4.5±3.8 to 0.6±0.7; P=0.044). In three of those four patients, tumor progression has not been reached (range of time after the follow-up PET, 4-55 months); one patient deceased 44 months after the follow-up PET. In contrast, another patient with an increase in SUVmax from 6.9 to 11.0 after first-line treatment died one month after the follow-up PET. DISCUSSION [68Ga]Ga-Pentixafor PET seems to be of value for non-invasively visualizing and quantifying CXCR4 receptor binding. In CNSL, changes in [68Ga]Ga-Pentixafor uptake following therapy may indicate potential for response assessment. CXCR4-targeting radioligand therapies might be more promising in CNSL than in glioma.
NIMG-80. IMPACT OF KETOGENIC DIET ON MOLECULAR METABOLIC IMAGING WITH [18F]FDG AND [18F]DASA-23 POSITRON EMISSION TOMOGRAPHY IN A PATIENT WITH GLIOBLASTOMA
Authors: Lewis Naya, Seyma Bilgin, Corinne Beinat, Alexander Khalaf, Lawrence Recht, Chirag Patel
Journal: Neuro-Oncology (2024)

Abstract The standard-of-care for neuroimaging in patients with glioblastoma is contrast-enhanced MRI, which does not provide tumor metabolism information. Although [18F]FDG PET is used to image tumor metabolism in many solid organ cancers, it has limited benefit in atients with brain tumors due to the high level of glucose uptake in normal brain cells. [18F]DASA-23 is a novel PET radiotracer that assesses the levels of pyruvate kinase M2 (PKM2), a protein highly expressed in cancer cells, which undergo aberrant glycolysis. Despite [18F]DASA-23 having a higher tumor-to-background ratio (TBR) of standardized uptake values (SUVs) in the brain compared to [18F]FDG, both may be susceptible to altered carbohydrate metabolism in the setting of a ketogenic diet (KD). We report the case of a patient with glioblastoma on a KD, whose [18F]FDG and [18F]DASA-23 PET brain scans were limited in identifying disease progression (PD). Background was defined as the white matter contralateral to the tumor, at the level of the centrum semiovale, for TBR of SUVmax. A 39-year-old man was diagnosed with right temporal glioblastoma after previous diagnoses of grade 2 gliofibrillary oligodendroglioma (age 20) and grade 3 anaplastic oligodendroglioma (age 22). He began a KD after the glioblastoma diagnosis. 21 months later, TBR on [18F]DASA-23 PET was 1.38. One month later, surveillance brain MRI showed PD. Ten days later, TBR on [18F]FDG PET was 1.03. The patient died 15 months later. Despite MRI-based PD, the TBR of each radiotracer was not markedly elevated, although the [18F]DASA-23 TBR 1-month pre-PD was 34% greater than the [18F]FDG PET TBR 10-days post-PD. This may suggest a limitation of metabolic imaging by PET in the setting of a KD, and provide an opportunity to develop novel PET radiotracers that are not susceptible to the patient’s diet.
EXTH-32. DUAL TARGETING OF CD155/TIGIT AND PD-L1/PD-1 IMMUNE CHECKPOINTS POTENTIATES NATURAL KILLER CELL-MEDIATED CYTOTOXICITY IN MEDULLOBLASTOMA
Authors: Matthijs Monnikhof, Michael Schakelaar, Chris Meulenbroeks, Matthias Quist, Alicia Perzolli, Aimee Selten, Celeste Koster, Daniëlle Maassen, Alba Montoro Canelo, Maureen Fredriks, Vela Kaludjerovic, Jan Meeldijk, Emma Pijnappel, Heggert Rebel, Sven van Kempen, Sandra Crnko, Aniello Frederico, Pieter Wesseling, Friso Calkoen, Jasper van der Lugt, Toine ten Broeke, Marcel Kool, Niels Bovenschen
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) is one of the most prevalent pediatric brain malignancies and makes up approximately 20% of all primary brain tumors in children. Current treatment options are not curative for about 30% of patients and leave survivors with an impaired quality of life. Immune checkpoint inhibition can offer a novel targeted therapy but largely remains understudied in MB. The aim of this study was to determine whether immune checkpoint inhibition can be used as a novel targeted therapy in MB. We used MB cell lines, MB patient-derived xenograft (PDX) organoid models, and primary patient-derived MB tissue to study immune checkpoints and their blockade to target MB. We identified the expression of immune checkpoint protein TIGIT on immune cells and its high-affinity ligand CD155 in medulloblastoma patient-derived tissues, cell lines, and PDX MB organoids. In addition, while MB shows weak, if any, PD-L1 protein expression, we found that MB cells can upregulate PD-L1 expression upon stimulation by natural killer (NK) cells via interferon-γ as a putative immune evasive strategy. Subsequent immunotherapeutic interventions with FDA-approved antibodies Tiragolumab (anti-TIGIT), Durvalumab (anti-PD-L1), and their combination potentiated primary NK cell activation and killing of MB cell lines and PDX-derived MB organoids. These data propose a translatable and novel immunotherapeutic strategy for patients diagnosed with MB.
PATH-25. CONSENSUS RECOMMENDATIONS FOR AN INTEGRATED DIAGNOSTIC APPROACH TO NERVE SHEATH TUMORS ARISING IN THE SETTING OF NEUROFIBROMATOSIS TYPE 1
Authors: Carina Dehner, Andrea Gross, Alexander Lazar, Calixto-Hope Lucas, Markku Miettinen, Melike Pekmezci, Arie Perry, Martha Quezado, Fausto Rodriguez, Carlos Romo, Anat Stemmer-Rachamimov, David Viskochil
Journal: Neuro-Oncology (2024)

Abstract NF1-associated nerve sheath tumors exist on a morphologically and molecularly diverse spectrum. Criteria for diagnosing neurofibroma, atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP), and malignant peripheral nerve sheath tumor (MPNST) developed by consensus in 2017 were codified in recent WHO guidelines. However, incorporation of molecular strata should be formalized to aid in early identification and appropriate intervention for patients with lesions at increased risk for malignant transformation. Here, we assembled a multi-institutional expert pathology working group to review molecular literature and formalize classification recommendations. In collaboration with clinical/surgical, imaging, and pre-clinical working groups during the “Symposium on Atypical Neurofibroma: State of the Science” held April 2024, we reached consensus on a potential integrated diagnostic approach. Based on strong preclinical and clinical evidence, we propose CDKN2A homozygous deletion as a sufficient molecular feature for diagnosing ANNUBP and either SUZ12, EED, or TP53 inactivating mutations or significant aneuploidy as sufficient molecular features for diagnosing MPNST, even in the absence of high-grade histologic features. In the absence of MPNST-defining molecular alterations, we also recommend reclassifying “low grade MPNST” as “ANNUBP with increased proliferation”. To facilitate molecular characterization of concerning tumors, we recommend at least six core biopsies be obtained and divided into two cores per block at time of grossing. Worrisome immunohistochemical features including reduced SOX10 or S100 immunoreactivity, decreased CD34 lattice-like network, minimal p16 expression, loss of H3K27me3 immunoreactivity, p53 overexpression, and increased Ki-67 labeling can guide region selection. A comprehensive next-generation sequencing panel that includes copy number and zygosity assessment is the preferred single assay, though a combination of multiple molecular techniques may provide similar information. In the spirit of the prior 2017 consensus agreement, we hope this refined integrated diagnostic approach for NF1-associated nerve sheath tumors will continue to evolve alongside our understanding of the spectrum of these neoplasms.