tbuckley/cabot-search huggingface dataset:
NIMG-15. RAPID EARLY PROGRESSION AFTER SURGERY ON PRE-RADIATION PLANNING MRI FOR IDH-WILDTYPE GLIOBLASTOMA
Authors: Jonathan Sackett, Khadija Ahmed, Tim Struve, Luke Pater, Norberto Andaluz, Jonathan Forbes, Rekha Chaudhary, Lalanthica Yogendran, Soma Sengupta, John Breneman, Gavin Udstuen, Kyle Wang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Use of pre-RT planning MRI for glioblastoma (GBM) is inconsistent and not required by many clinical protocols. We performed a detailed volumetric analysis of rapid early progression (REP) on pre-RT planning MRI’s, hypothesizing that REP is associated with worse survival and more accurately risk stratifies than extent of resection. METHODS Patients with IDHwt GBM who had resection (biopsy-only patients excluded) and pre-RT planning MRI ≥2 weeks after postop MRI were included. MRI’s were reviewed by a neuroradiology fellow and attending who measured in 3 dimensions new/increased contrast-enhancing disease between postop and pre-RT MRI. REP was defined as disease ≥1cm in 2 dimensions or ≥0.5cc. Extent of resection was scored 1: gross total (GTR, &amp;gt;95%); 2:near total (NTR, 90-95%); 3:subtotal (STR). The primary endpoint was survival (OS). Cox proportional hazards model analyzed association with age, resection extent, MGMT+ status, short course RT (a surrogate for performance status), and REP. RESULTS The final cohort included 77 patients (median age 63), with 9 (12%) receiving short course RT. Surgical extent was GTR in 42 (55%), NTR in 16 (21%), and STR in 19 (25%). REP occurred in 41 patients (53%), with a rate of 29% after GTR, 75% after NTR, and 90% after STR. Age (p=0.24, HR 1.02/yr), short course RT (p=0.64, HR 1.2), and surgical extent (p=0.49, HR 1.1) were not significantly associated with OS on univariate analysis. MGMT+ and REP were associated with survival on both univariate and multivariate (MGMT+ p=0.002, HR 0.4; REP p=0.005, HR 2.3) analyses. Median OS was 1.3 years vs. 1.9 years with vs without REP. CONCLUSIONS REP occurs frequently, adds a “growth rate” variable, and is a better prognostic factor than extent of resection. These data have implications for clinical trial design and support pre-RT planning MRI’s as standard of care.
CTNI-39. UPDATE ON GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Andrew Lassman, Brian Alexander, Donald Berry, Nicholas Berry, Meredith Buxton, Howard Colman, Hui Gan, John de Groot, Macarena de la Fuente, Jan Drappatz, Francois Ducray, Benjamin Ellingson, Gary Gordon, Emma Hyddmark, Adam Johnson, Mustafa Khasraw, Eudocia Lee, Michael Lim, Anna McGlothlin, Ingo Mellinghoff, Tom Mikkelsen, Phioanh Nghiemphu, James Perry, Ashley Powell, Erik Sulman, Krik Tanner, Sarah Untch, Michael Weller, Patrick Wen, Antje Wick, Alfred Yung, Timothy Cloughesy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 platform trial designed to rapidly identify and confirm experimental therapies that improve overall survival for approval along with their associated biomarker signatures. GBM AGILE is a collaboration between academic investigators, patient organizations, and industry to support new drug applications for newly diagnosed (ND) and recurrent glioblastoma. METHODS The primary objective of GBM AGILE is to identify therapies that improve the overall survival in patients with ND or recurrent glioblastoma. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. GBM AGILE operates under a Master Protocol allowing multiple drugs to be evaluated simultaneously and over time against a common control. New experimental therapies are added as information about promising new drugs is identified, while therapies are removed as they complete evaluation. Six investigational arms have been included to date. Along with an adaptive trial design, shared control arm and operational processes, GBM AGILE continues to incorporate new design and operational elements. One recent design element added to the Master Protocol for consideration for future arms is an extended evaluation period, of up to 11 months, for arms that reach maximum sample size in Stage 1 (Stage 1: learn most responsive signature) without having reached a decision for futility or graduation. Allowing data to mature and additional events to accumulate may increase the ability of the trial to detect efficacy, and if appropriate, for an arm to graduate to Stage 2 (Stage 2: confirm activity in graduating signature). Using improved and flexible processes, GBM AGILE continues to serve as a global trial that supports the efficient and rapid incorporation and evaluation of new experimental therapies for patients with glioblastoma. NCT number: NCT03970447.
BIOM-18. MAPPING TUMOR HABITATS IN IDH-WILD TYPE GLIOBLASTOMA: INTEGRATING MR IMAGING, PATHOLOGIC, AND RNA DATA FROM IVY GLIOBLASTOMA ATLAS PROJECT
Authors: Ji Eun Park, Ho-Su Lee, Dongjun Lee, Shinkyo Yoon, Sang Woo Song, Young-Hoon Kim, Chang Ki Hong, Jeong Hoon Kim, Ho Sung Kim
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND To identify biologic correlates and spatially validate intratumoral subregions (tumor habitat) using diffusion-weighted and dynamic susceptibility contrast-imaging on a comprehensive pathology map of the isocitrate dehydrogenase (IDH)-wild type whole glioblastoma sample using the Ivy Glioblastoma Atlas Project (Ivy GAP). METHODS Complete data of 20 patients with 168 slides of IDH-wild type glioblastoma were obtained from the IvyGAP (http://glioblastoma.alleninstitute.org/). On MRI, tumor habitats were defined using voxel-wise clustering of apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) maps for contrast-enhancing lesion (CEL) and peritumoral non-enhancing lesion (NEL). On pathology slides, normalized areas of leading edge (LE), infiltrating tumor (IT), cellular tumor (CT), hypervascular lesion (CThypervascular), and perinecrotic lesion (CTperinecrotic) were obtained. Gross specimen pictures were co-registered on MRI images for co-localization and correlation between MRI tumor habitats. Pathologic areas were calculated using Pearson’s correlation coefficient. RNA sequencing of 67 RNA-seq samples was assessed using 4 Neftel subtypes and further correlated with pathology. RESULTS Six tumor habitats were correlated: hypervascular, hypovascular cellular, and hypovascular hypocellular habitats for CEL and NEL. CT was strongly correlated with hypovascular cellular habitat in CEL (C2, r = 0.238, p =.005). IT was strongly correlated with hypovascular cellular habitat in NEL (C5, r = 0.294, p =.017). CThypervascular was correlated with hypervascular habitat in NEL (r = 0.195, p =.023). CTperinecrotic was correlated with imaging necrosis (r = 0.199, p =.005). Astrocyte-like subtypes were positively correlated with IT (r = 0.256, p &amp;lt;.001), while mesenchymal-like subtypes were positively correlated with CTperinecrotic area (r = 0.246, p &amp;lt;.001). CONCLUSION Pathologically matched tumor subregions were cellular tumor with hypovascular cellular habitat in CEL and infiltrative tumor with hypovascular cellular habitat in NEL. Identification of the most aggressive tumor portion, and infiltrative tumor portion using non-invasive imaging can be achieved using MRI tumor habitats.
EPCO-21. ELUCIDATING THE FUNCTIONAL RELEVANCE OF ATRX-DEFICIENCY IN H3.3-G34-MUTANT DIFFUSE HEMISPHERIC GLIOMA
Authors: Annette Alexandra Machado, Prit Benny Malgulwar, Jason T Huse
Journal: Neuro-Oncology (2024)

Abstract Diffuse hemispheric gliomas (DHGs) account for 30% of aggressive cerebral tumors in children and young adults, exhibiting abysmal outcomes. Co-existing recurrent mutations in H3.3 histones at residue G34 (H3.3-G34R/V mutation) and concurrent inactivating mutations in TP53 and α-thalassemia/intellectual disability-X-linked gene (ATRX) implicate a coordinated molecular effort to drive oncogenesis. ATRX, a core component of the SWItch/Sucrose Non-Fermentable chromatin remodeling complex, regulates the incorporation of histone H3.3 into chromatin sites across the genome to maintain epigenome integrity. Yet, it is unclear how ATRX loss combines with H3.3-G34R/V mutations to influence cellular phenotype and dysregulate neuro-developmental programs. We propose that ATRX deficiency coordinates with key oncogenic partners by inducing oncogenic transcriptional programs and neuro-developmental pathways in DHGs. To investigate this, we employed CRISPR-editing to model H3.3-G34R followed by ATRX knockdown (ATRX-KD) in a TP53 mutant (TP53-mut) human-induced pluripotent stem cell (h-iPSC) line, developing an isogenic system to map contributions to epigenetic dysfunction made by specific molecular alterations. Upon differentiation of our h-iPSCs to neural stem cells (NSCs), we found unique transcriptional profiles associated with each genetic alteration, with upregulation of forebrain progenitor genes driven by ATRX-loss. Hierarchal clustering of normalized transcript counts revealed gene signatures from each model driving unique functional pathways, with the ATRX-KD and the triple mutant (TP53-mut, ATRX-KD, H3.3-G34R) signatures enriched for neural development pathways. Additionally, both signatures were associated with published transcriptional profiles of G34-mutant DHGs, emphasizing the disease relevance of our models. Further, time-course analysis using cerebral organoids uncovered distinct morphological changes with each alteration, with the triple mutant exhibiting impaired differentiation at later time points. These latter findings suggest that ATRX deficiency transcriptionally influences early neuronal differentiation, effects further refined by H3.3-G34 mutation. To conclude, our innovative models demonstrate the involvement of ATRX in neuro-developmental and differentiation phenotypes, illuminating underlying molecular features of aggressive DHGs.
CTNI-67. AI BASED PREDICTION OF CLINICAL TTFIELDS RESPONSE IN GLIOBLASTOMA PATIENTS (RETROSPECTIVE ANALYSIS)
Authors: Sied Kebir, Sarah Wilms, Katharina Wenger, Almuth F Kessler, Martin Pröscholdt, Biyan N Harapan, Stefanie Quach, Andreas F Hottinger, Bogdana Suchorska, Teresa Schmidt, Christoph Oster, Ulrich Sure, Christoph Kleinschnitz, Björn Scheffler, Martin Glas
Journal: Neuro-Oncology (2024)

Abstract RESEARCH QUESTION Accurate and individualized prediction of response to therapies is central to precision medicine and a major goal in neuro-oncology. An extension of overall survival (OS) and progression-free survival (PFS) was observed in patients treated with tumor treating fields (TTFields) plus maintenance temozolomide compared to those treated with maintenance temozolomide alone and TTFields have become an integral part of the treatment of glioblastoma. To identify patients who benefit most from TTFields, we aim to implement a state-of-the-art machine learning approach to create a model capable of identifying responding patients early in treatment. METHODOLOGY In this retrospective analysis, patients with IDH-wildtype glioblastoma treated with TTFields, in addition to RT and temozolomide, as first-line therapy are included. Clinical data and MRI raw data (in DICOM format) are collected. The preprocessing of the MRI data includes reorientation, bias field correction, registration, segmentation, and intensity normalization. This is followed by the extraction of a Radiomics signature. The latter, along with the clinical data, is trained using various machine learning models. The model validation occurs on an independent test cohort. Data collection from various neuro-oncological centers across Europe is ongoing. RESULTS So far, data from 134 TTFields patients and 131 control patients have been collected. Initial results, providing detailed insights into the model architecture and performance, will be presented at the time of the SNO meeting. CONCLUSION This study has the potential to optimize the treatment of glioblastoma patients by using machine learning to allow the early identification of patients that respond to first line therapy.
CNSC-09. OTOSYPHILIS MIMICKING A VESTIBULAR SCHWANNOMA
Authors: Ruham Alshiekh Nasany, Juan Blaquier, Macarena de la Fuente, Carolina Benjamin, Eric Mellon
Journal: Neuro-Oncology (2024)

Abstract Vestibular schwannomas are common nonmalignant primary brain tumors representing up to 80% of the cerebellopontine angle (CPA) tumors. Their diagnosis is made radiographically in most cases with the presence of an enhancing mass along the 8th nerve complex. The United States is experiencing a surge in the number of recorded syphilis cases with an approximate 80% increase since 2018 according to the CDC, after reaching an all-time low in the year 2000. Syphilis can involve the Central Nervous System (CNS) in its early, late, and latent forms, and in its early stages it typically presents in the form of meningitis which can be accompanied by cranial neuropathies especially of the nerves II, VII, and VIII. We present a case of a 35-year-old man who presented with subacute onset unilateral left-sided hearing loss and dizziness that did not respond to prescribed steroids. Magnetic resonance imaging (MRI) revealed an enhancing mass in the left cerebellopontine angle presumed to be a vestibular schwannoma. The patient was subsequently planned for radiosurgery, however, MRI done during the procedure revealed that the mass was of a smaller size. The patient was referred to neuro-oncology and work up included cerebrospinal fluid (CSF) analysis that showed 3 white blood cells, normal protein and glucose, and negative VDRL. Cytology, flow cytometry, and inflammatory markers were negative. However, the Treponema pallidum antibodies were positive confirming otoshyphilis. The patient was treated accordingly with a course of Penicillin G with near resolution of the enhancement of the 8th nerve complex. His hearing remained impaired on his initial follow up, however, his facial weakness near resolved. This case brings up an important diagnostic question in cases of presumed schwannomas where patients would be otherwise treated solely based on the MRI appearance, especially given the re-emergence of syphilis.
NCOG-29. HIGHER HYPOTHALAMIC RADIATION DOSE AND FEMALE GENDER ARE RELATED TO HIGHER SELF-REPORTED FATIGUE
Authors: Bryan Neth, Eva Alden, Ugur Sener, Joon Uhm, Stacy D’Andre, Terry Burns, Adam Amundson, David Routman, Daniel Trifiletti, Sujay Vora, Anita Mahajan, Nadia Laack, Paul Brown, William Breen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Fatigue is among the most common symptoms managed by patients with cancer. Hypothalamic pituitary axis dysfunction has an established role in a subset of patients with fatigue. Our primary aim was to longitudinally assess the impact of hypothalamic radiation exposure to patient self-reported fatigue. METHODS We included a sample of patients who received radiation therapy treated at a single institution from 2014-2024. The PROMIS-10 questionnaire (“How would you rate your fatigue on average,” scale 1-5) was used in standard clinical practice, with measures from 6 time points over 2 years. We performed descriptive statistics. Linear mixed models were used to assess the impact of hypothalamic radiation dose on fatigue scores. Mixed models were controlled for gender, age, time, tumor category (CNS vs. non-CNS), and modality (photon vs. proton). Models were fit with random intercepts for each Patient ID. RESULTS 1092 patients (43% female) with a median age of 54 years (range: 18-92) were included. Most patients were treated for CNS cancer (76%), with about 50% each photon and proton. Median hypothalamus radiation dose was 1306 cGy (range: 0.01-6138). Mean baseline fatigue (2.4) increased after treatment (2.7) remaining elevated at 3- and 6-months post-treatment (2.6, 2.5), returning near baseline at 1- and 2-years post-treatment (2.4, 2.3). Higher radiation dose (Estimate (SE): 0.014 (0.006), p=0.0266) and CNS cancer treatment (0.11 (0.051), p=0.0319) were significant predictors of higher fatigue in the mixed model. Male patients (-0.16 (0.042), p=0.0001) and time (-0.003 (0.0016), p=0.0398) were associated with lower fatigue. Age and treatment modality were not significant predictors of fatigue. CONCLUSIONS We found that higher hypothalamic radiation dose was related to more self-reported fatigue, which peaked by 6 months. This effect was seen more prominently in female patients and those treated for CNS disease. Treatment modality and age did not influence fatigue scores.
TMOD-02. PATIENT-DERIVED GLIOBLASTOMA ORGANOIDS AS REAL-TIME AVATARS FOR ASSESSING RESPONSES TO CLINICAL CAR-T CELL THERAPY
Authors: Xin Wang, Meghan Logun, Yusha Sun, Stephen J Bagley, Nannan Li, Arati Desai, Daniel Y Zhang, MacLean P Nasrallah, Emily Ling-Lin Pai, Bike Su Oner, Gabriela Plesa, Donald Siegel, Zev A Binder, Guo-li Ming, Hongjun Song, Donald M O’Rourke
Journal: Neuro-Oncology (2024)

Abstract Patient-derived tumor organoids have been increasingly leveraged for disease modeling and preclinical studies, but rarely in real-time to aid with the interpretation of patient treatment responses in the clinical setting. Whether tumor organoids can be applied to mirror clinical activity in patients and even to predict responses for personalized medicine remains uncertain. We recently demonstrated promising early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma (clinical trial identifier: NCT05168423). Determination of meaningful clinical efficacy, in particular for CAR-T cell therapy, may take months to manifest. Given this challenge, real-time analysis of patient-derived glioblastoma organoids (GBOs) could help to provide early assessment of clinical efficacy and guide patient management. We analyzed six sets of GBOs generated on the same timeline as the production of patients’ CAR-T cell products. GBOs demonstrated the presence and retention of both targeted tumor-associated antigens EGFR and IL13Rα2 by immunohistochemistry. These GBOs were then treated with the same autologous CAR-T cell products received by patients in our phase 1 study in parallel with patient treatment. CAR-T cell treatment led to target antigen reduction assessed by immunohistochemistry and flow cytometry. Furthermore, we confirmed cytolysis of tumor cells in GBOs by cleaved caspase-3 immunostaining and by co-culture in the Axion Maestro Cellular Impedance platform. Importantly, the degree of cytolysis ex vivo significantly correlated with CAR-T cell engraftment detected in patients’ cerebrospinal fluid (CSF) for all six patients. Furthermore, cytotoxic activity of CAR-T cells as measured by TNFα, IL-2, and IFNγ release kinetics in GBOs mirrored cytokine levels in patient CSF samples over time. Our findings highlight a unique trial design and suggest GBOs as a valuable platform for real-time assessment of CAR-T cell bioactivity and for insights into immunotherapy efficacy.
RADT-42. DISSEMINATED TUMORAL AMYLOIDOSIS OF THE CRANIAL NERVES IN THE ABSENCE OF SYSTEMIC DISEASE: CASE REPORT
Authors: Aubrey Rogers, Robert Heller
Journal: Neuro-Oncology (2024)

Abstract Tumoral amyloidosis, characterized by tumor-like deposits without systemic disease, is rare in the central nervous system. Most often located in the periventricular white matter, tumoral amyloidosis typically consist of immunoglobulin light chains (AL). While prior reports describe cases of tumoral amyloidosis isolated to the trigeminal nerve, we report herein a first known case of diffuse cranial nerve involvement. The patient is a 43-year-old man who presented with left trigeminal dysesthesias, which led to self-excoriation and erosion of the left naris. On exam, he had absent sensation in the V1-V3 distributions, left trochlear nerve palsy, and bilateral abducens nerve palsies. Imaging demonstrated significant thickening of the left trigeminal nerve and diffuse cisternal contrast enhancement of the other cranial nerves, including the oculomotor, abducens, facial, and glossopharyngeal nerves. Work-up began with a lumbar puncture that found elevated protein with otherwise benign results, including flow cytometry. He was therefore recommended to undergo open biopsy of the left trigeminal nerve and cavernous sinus. Pathology from this surgery demonstrated congo red- positive AL amyloid deposits. Following this pathologic diagnosis, he subsequently underwent a full workup for systemic amyloidosis including bone marrow biopsy, abdominal fat pad biopsy, and a PET CT scan. Biopsy of a long nodule was negative for amyloidosis. Systemic amyloid testing did not demonstrate non-CNS sites of amyloid deposition. Medical therapy with daratumumab, cyclophosphamide, bortezomib, and dexamethasone was started but then discontinued due to ineffectiveness. He underwent radiation treatment of 4500 cGy to the left cavernous sinus where the tumoral amyloidosis was most severe. He has had no further progression of his disease. Tumoral amyloidosis of the cranial nerves remains a rare and poorly-understood disease. Prior reports have described the disease isolated to the trigeminal nerve. This report raises attention to this diagnosis in cases of rare multi-nerve involvement and suggests that radiation may be a useful first-line treatment.
NIMG-89. MULTI-THRESHOLD VOLUMETRIC MAPPING OF18F-FLUOROETHYLTYROSINE POSITRON EMISSION TOMOGRAPHY (18F-FET PET) IMPROVES TUMOR DETECTION IN PRIMARY MALIGNANT BRAIN TUMOR PATIENTS
Authors: Shaun Grega, Andrew Gauger, Matthew Larson, Kathryn Nevel, Wendy Territo, Mark Green, Michael Veronesi
Journal: Neuro-Oncology (2024)

Abstract PURPOSE The purpose of this study was to determine whether additional volumetric measurements yielded significant prognostic information than typically reported tumor-to-brain ratio thresholds (TBRmax) alone for accurately distinguishing progressive disease from treatment induced changes. METHODS Hybrid 18F-FET PET/MRI was obtained on pathology confirmed high-grade glioma in sixty patients from August 6th, 2022 to March 9th, 2023 at one US institution. We compared the diagnostic accuracy of various TBR thresholds and volumetric measurement combinations in identifying progressive disease. Specifically, we assessed TBR &amp;gt;1.6, 2.0, 2.5, 3.0, 3.5, 4, 4.5, and 5.0 alone and in combination with volumetric measurements greater than 1 mL. Survival data for all patients were analyzed using Kaplan-Meier curves. RESULTS Our analysis revealed that TBR &amp;gt; 2.5 and &amp;gt;1 mL yielded the highest diagnostic accuracy (100%) in distinguishing progressive disease from treatment induced changes. This was followed by the combination TBR &amp;gt;2.0 and &amp;gt;1 mL (98%), TBR &amp;gt; 2.5 alone (98%), TBR &amp;gt; 2.0 alone (86%), TBR &amp;gt;1.6 and &amp;gt;1 mL (84%), and TBR &amp;gt;1.6 alone (77%). TBR &amp;gt;3.0, 3.5, 4.0, 4.5, and 5.0 with and without volumetric measurements showed accuracies of 100%. Kaplan-Meier survival analysis showed significant results for all thresholds: TBR &amp;gt;1.6 alone (p = 0.047), TBR &amp;gt;1.6 and 1 mL (p = 0.003), TBR &amp;gt; 2.0 alone (p = 0.019), TBR &amp;gt;2.0 and &amp;gt;1 mL (p &amp;lt; 0.001), TBR &amp;gt;2.5 alone (p &amp;lt; 0.001), and TBR &amp;gt;2.5 and &amp;gt;1 mL (p = 0.002). CONCLUSION Our findings suggest that although TBRmax &amp;gt; 2.5 alone continues to be a reliable metric for distinguishing progressive disease from treatment induced changes, TBRmax &amp;gt;2.5 when volume is greater than 1 mL shows the greatest accuracy in detecting disease progression. Understanding the volumetric contribution to static FET TBRmax is important for tumor response assessment at TBRmax thresholds above 1.6 TBRmax.