tbuckley/cabot-search huggingface dataset:
STEM-05. CREATING PATIENT-DERIVED TUMOROIDS TO INVESTIGATE RADIORESISTANCE IN PEDIATRIC BRAIN TUMORS
Authors: Marlène Deschuyter, Rémi Pelletier, Chinar Salmanli, Thibaut Wolf, Benoit Lhermitte, Damien Reita, Eric Guerin, Sophie Foppolo, Andrey Klymchenko, Monique Dontenwill, Sophie Martin, Natacha Entz-Werle
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain cancers are the most frequently diagnosed tumor types in pediatric and young adult populations. Unfortunately, they often carry a poor prognosis and face common challenges such as treatment resistances due to intra- and intertumoral heterogeneity. To fully understand the intrinsic and extrinsic mechanisms which might hinder proper care, there is an emerging need to develop precise models of brain tumors to understand resistances and to predict therapeutic responses. While tumor-derived primary cell lines are relatively easy to produce, fully replicate the complexity of tumors as they grow without interactions with and from the microenvironment. Therefore, the advent of organoid cultures represents a significant advancement in modelling development. Derived from this technology, tumoroids offer a promising solution for modeling 3D tumors and their complex microenvironment. METHODS We develop tumoroids from fresh biopsies and patient-derived tumor xenografts. These models were rigorously validated against to initial tumor using confocal microscopy, methylome analyses, metabolomics and single-cell RNAseq. To assess the intrinsic hypoxic environment and its spatial heterogeneity, characteristic of aggressive cancers, we employed fluorescent oxygen-sensitive dye loaded polymeric nanorods. RESULTS We successfully generated tumoroids using PDX of ependymomas (BT39) and it paired relapse (BT42), two H3.3 mutated high-grade gliomas (BT35 and BT69), one ganglioglioma (BT63) and directly from fresh biopsies of DIPG sample (BT140). Several passages were obtained after primary derivation, and cryopreservation demonstrating the stability of the models over time. Tumoroids displayed similar protein and omics markers as their parental tumors and harbored specific stem cell and neural progenitor markers. The methylation patterns were entirely preserved comparing 3D models and their parental tumors, and other multiomics and metabolic approaches confirmed the accurate reconstitution of tumor complexity. The study of oxygen-sensitive nanorods highlighted the heterogeneous oxygen gradient within tumoroids. CONCLUSIONS All these initial characterized tumoroids helped us to develop radioresistant paired models.
IMG-28. AUTOMATIC BRAIN TUMOR VOLUMETRIC ANALYSIS IN MAGNETIC RESONANCE IMAGING GENERALIZABLE TO PEDIATRIC NEURO-ONCOLOGY
Authors: Zhifan Jiang, Daniel Capellán-Martín, Abhijeet Parida, Xinyang Liu, None Van Lam, Hareem Nisar, Austin Tapp, María J Ledesma-Carbayo, Syed Muhammad Anwar, Marius George Linguraru
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The prognosis of brain tumors is variable in clinical practice if it only relies on human interpretation of magnetic resonance imaging (MRI). The automatic segmentation of brain tumors in MRI enables quantitative analysis in support of clinical trials and personalized patient care. We developed benchmarked deep learning-based tools that are generalizable to the volumetric quantification of various tumor types across diverse populations. METHODS We participated in the well-established international brain tumor segmentation challenge (BraTS 2023) and benchmarking competition. The challenge made available 4,500 multi-national brain tumor cases with multi-sequence MRIs, including pediatric high-grade gliomas (PED), i.e., high-grade astrocytoma and diffuse midline glioma, and adult gliomas, brain metastases (MET) and intracranial meningiomas (MEN). Each case comprises four MRI volumes: T1, contrast-enhanced T1, T2, and T2-FLAIR. Manual segmentations were provided to establish ground truth for enhancing tumor (ET), tumor core (TC), and whole tumor (WT). Our framework used a model ensemble strategy based on two state-of-the-art deep learning models: a convolutional neural network (nnU-Net) and a vision transformer (Swin UNETR) and was tested for broader applicability across multiple tumor types. The framework was trained on 99, 1,000, and 165 cases and validated on 45, 141, and 31 unseen cases for PED, MEN, and MET, respectively. Automatic segmentations were evaluated by lesion-wise volume overlap (Dice similarity score, DSC) and Hausdorff distance (HD). RESULTS In the evaluation on independent unseen test datasets, our automatic tool was ranked first for PED, third for MEN, and fourth for MET volumetric analysis. Our method resulted in PED lesion-wise DSC of 0.733, 0.782, 0.817 and HD (mm) of 75.93, 25.54, 24.18 for ET, TC, and WT, respectively. CONCLUSIONS These brain tumor volumetric analysis tools are readily available to be efficiently tested on diverse datasets. Automatic MRI analysis provides consistent quantitative data for multi-institutional protocols and clinical trials.
DIPG-77. SOMATIC<i>TP53</i>,<i>PIK3R1, NF1</i> OR<i>TERT</i> MUTATIONS ARE ASSOCIATED WITH INFERIOR CLINICAL OUTCOME IN H3K27M-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Thien Nguyen, Benjamin Lerman, Schuyler Stoller, Timothy Müller, Lion Comfort, Samantha Lyons, Lynette Holman, Calixito Hope Lucas Junior, Anu Banerjee, Alyssa Reddy, Nalin Gupta, Nicholas Whipple, Nicolas Gerber, Ana Stuecklin, Esha Areza, Rizo Marion, Truman Knowles, David Solomon, Andrea Franson, Carl Koschmann, Sonia Partap, Michelle Monje, Laura Prolo, Samuel Cheshier, Reuben Antony, Aashim Bhatia, Jessica Foster, Michael LaRiviere, Laura Maule, Andrea W Carrion, Cassie Kline, Sarah Bruningk, Javad Nazarian, Sebastian M Waszak, Sabine Mueller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND H3K27-altered diffuse midline gliomas (DMGs) have poor prognosis with no standard of care therapy beyond radiation (RT). While RT prologues survival, not all patients respond. Prior work has shown somatic TP53 mutations predict radiation resistance, and poorer outcomes. We report on a multi-center retrospective cohort study to identify molecular biomarkers of RT response in DMG patients. METHODS We performed retrospective chart reviews of patients with biopsy-proven H3K27M-altered DMG between 2013-2023 from six US medical centers and the DMG Center in Zurich. Patients with tumor genomic sequencing and completion of RT were eligible. Genomic alterations were evaluated for somatic mutations, fusions, and chromosomal instability. Cox proportional hazard models were used to evaluate associations between genomic alterations and survival. Multivariate analysis included all significant variables at P &amp;lt;0.1 in initial analysis, including age at diagnosis, tumor location, TP53 and PIK3R1 alterations. RESULTS 297 patients (135 female; median age 8.3years; range 0.2-71.4 years) were included. Median progression-free survival (PFS) and overall survival (OS) was 7.6months (95%-CI 6.9-8.6) and 14.0months (95%-CI 12.9-15.7). Univariate analysis identified TP53 or PIK3R1 status to be associated with shorter OS (TP53-mutant 12.5months vs. TP53-wildtype 17.5months; HR=1.5; 95%-CI (1.1-2.0), P=0.005); (PIK3R1-mutant 12.6months vs. PIK3R1-wildtype 14.5months; HR=1.9, 95%-CI (1.1-3.4), P=0.03). Multivariate analysis corroborated TP53 status association with shorter OS (HR=1.5; 95%-CI (1.2-2.0), P=0.003). Subgroup univariate analysis of pontine DMG patients showed reduced OS with TP53, NF1, or TERT mutations (TP53-mutant 11.9months vs. TP53-wildtype 15.2months; HR=1.6; 95%-CI (1.1-2.3), P=0.02); (NF1-mutant 8.4months vs. NF1-wildtype 13.6months; HR=2.3; 95%-CI (1.1-5.0), P=0.03); (TERT-mutant 8.5months vs. TERT-wildtype 13.6months; HR=2.5; 95%-CI (1.1-5.7), P=0.03). Subsequent multivariate analysis corroborated the association of TERT mutations with shorter OS in pontine DMG (HR=2.5; 95%-CI (1.05, 5.9), P=0.03). CONCLUSIONS This is one of the largest molecular characterized cohorts of H3K27M-altered DMG patients. DMGs with somatic TP53 or PIK3R1 mutations demonstrate inferior OS. Pontine DMG patients with somatic TP53, NF1 or TERT mutations demonstrate inferior OS.
DEI-04. RACE AND ETHNICITY DIFFERENCES IN TREATMENT-LIMITING TOXICITIES IN PATIENTS TREATED WITH MEK INHIBITORS
Authors: Benjamin I Siegel, AeRang Kim, Miriam A Bornhorst
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND MEK inhibitor (MEKi) therapies are used to treat pediatric low grade glioma (pLGG) and plexiform neurofibroma (PN). The toxicity profile reported in clinical trials have been favorable, but samples have been demographically homogeneous. In this study, we evaluate differences in treatment-limiting toxicities by race and ethnicity. METHODS This is a single-institution, retrospective study of patients treated with MEKi on the Sprint (NIH plexiform) trial or off-study for pLGG or PN from 2014 to 2023. Patient data was abstracted from clinical records. Treatment-limiting toxicity was defined as temporary hold, dose reduction, or discontinuation due to toxicity. RESULTS Fifty-eight evaluable patients received MEKi for PN (N=40) or pLGG (N=18), 5 of whom received multiple agents. Selumetinib was used in 44 cases, trametinib in 16, and binimetinib in 3. Median age was 11.0 years (IQR 7.7-14.5) and 37(64%) were male. Twenty-nine (50%) patients identified as White, 15(26%) Black, 6(10%) Asian, 4 (7%) Hispanic, and 4(7%) other/declined. Treatment-limiting toxicity occurred in 27(47%). Each demographic group had a similar rate of treatment-limiting toxicities; 52%(n=15) of White, 40%(n=6) of Black, 66%(n=4) of Asian patients, and 50%(n=2) of Hispanic patients. The most prevalent treatment-limiting toxicity was skin-related (N=10; 6 White, 1 Black, 2 Asian, 1 Hispanic) and included rash, paronychia, and impetigo. Other recurring toxicities were gastrointestinal (N=6, 5 White, 1 Black), edema (N=4, 1 White, 1 Black, 1 Asian, 1 Hispanic), cardiac (N=2, 1 White, 1 Black), and weight gain/loss (N=4, 2 White, 2 Asian). CONCLUSIONS Frequencies of treatment-limiting toxicities were similar across race and ethnicity. Dermatologic and gastrointestinal toxicity were more commonly seen in White patients relative to other adverse events. Findings should be interpreted with caution due to sample size, but support future efforts to understand demographic differences in MEKi toxicity.
EPEN-09. TARGETING EPHB2/ABL1 RESTORES ANTI-TUMOR IMMUNITY IN A PRECLINICAL MODEL OF EPENDYMOMA
Authors: Jun Ren, Zohreh Amoozgar, Taylor P Uccello, Yuhui Zhao, Pinji Lei, William W Ho, Sylvie Roberge, Peigen Huang, Dan G Duda, Lei Xu, Rakesh K Jain
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymoma (EPN) is a childhood brain cancer that is often resistant to cytotoxic therapies. Molecular profiling has led to a better understanding of unique EPN subtypes and revealed a critical role of EPHB2 in driving disease. With this in mind, new treatments for EPN are desperately needed and should be developed in a molecular subtype-specific fashion. METHODS We developed a syngeneic mouse model of EPHB2-driven genetically engineered EPN tumor cells. We performed transcriptomic profiling and analysis of EPHB2-driven murine EPN tumors and human EPN datasets to reveal multiple protein kinases as potential druggable targets. After identifying the tyrosine kinase inhibitor, Dasatinib, as a potentially effective FDA-approved agent, we measured changes in the murine microenvironment during EPN growth and after Dasatinib treatment. RESULTS We determined that Dasatinib inhibited the growth of EPN both in vitro and in vivo, through blocking EPHB2 and ABL1 signaling. Furthermore, we identified an increased frequency of immunosuppressive M2-like tumor- associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. However, treatment with Dasatinib reprogrammed the EPN immune microenvironment by polarizing TAMs toward an anti-tumor M1-like phenotype and increasing CD8 T cell activation. In addition, Dasatinib treatment induced complete regression of established EPN tumors in 78% of the animals and protected survivors against tumor recurrence. Depletion of CD8 T cells compromised the durability of response and reduced overall survival. CONCLUSION In conclusion, these data indicate that Dasatinib may be an effective therapy for EPHB2-driven molecular subgroup of EPN by activating the anti-tumor immune response and support further investigation of Dasatinib in clinical trials.
EPEN-03. THE MANAGEMENT OF PEDIATRIC AND ADOLESCENT SPINAL EPENDYMOMA; A 20-YEAR NATIONAL EVALUATION INVOLVING UNITED KINGDOM PEDIATRIC ONCOLOGY PRIMARY TREATMENT CENTERS ON BEHALF OF THE UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG)
Authors: Marwa Deghedy, Martin English, Helen Curry, James Nicholson, Patricia O’Hare, Anthony McCarthy, Lena Uzunova, Sarah Curry, Shaun Wilson, Mette Jorgensen, Dominic Thompson, Rachel Cox, Milind Ronghe, Mark Brougham, Rachel McAndrew, Victoria Lee, Simon Bailey, Colin Thorbinson, John Goodden, Susan Picton, Sandra Dias, Fozia Saeed, Kavitha Srivatsa, Timothy Ritzmann, Richard Grundy, John-Paul Kilday
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Pediatric spinal ependymomas account for approximately 1% of childhood CNS tumors. Most are myxopapillary ependymomas (MPEs). For symptomatic cases, maximal safe surgical resection is the accepted therapeutic standard. However, a role for adjuvant therapy is unclear, underpinned by low incidence rates, inadequate trial data and recent WHO upgrading of the MPE variant. This retrospective national service evaluation aimed to provide safety and outcome data, from which future management guidance could be developed. METHOD Children, teenagers and young adults diagnosed with a spinal ependymoma of any WHO grade since 2000 across 17 UK CCLG centres were evaluated. Patient demographics, therapies, adverse events, and outcomes were captured. RESULTS 102 patients were evaluated. Ten children had NF2 (median age 11 (7.6 – 14) years) with nine located in the cervicomedullary region. All ten patients were alive following surveillance (n=3) or surgical intervention (n=7) with an estimated median PFS of 5.4 (1.7 – 9.1) years. For the remaining 92 patients (median age 12 (0.7 – 19) years), 63% of tumors were lumbosacral, 73% demonstrated MPE morphology and 16% were metastatic. The median symptom interval was 4 (0 - 36) months. Progression or relapse was reported in 30/92 (33%), with a 5-year PFS of 62(+ 6)%, yet only 4 disease-related deaths occurred (mean follow-up 6.8 years; no MPEs). Across this non-NF2 cohort, gross/near total resection and upfront adjuvant radiotherapy independently reduced disease progression risk (p &amp;lt; 0.05). However, improved local control from early irradiation was not statistically proven when localized disease or MPEs were exclusively scrutinized. No radiotherapy-related high-grade toxicity was reported. DISCUSSION Pediatric spinal ependymomas are rare tumors demonstrating excellent survival, particularly MPEs. Maximal safe surgery and early adjuvant radiotherapy can improve local control rates, but European collaboration will be required to evaluate efficacy for certain tumor and clinical subgroups. Conclusions could support future national management guidelines.
DIPG-51. DIFFUSE MIDLINE GLIOMAS HIJACK MYELOID CELL POPULATIONS TO INITIATE AN ANTI-INFLAMMATORY TUMOR IMMUNE MICROENVIRONMENT
Authors: Dennis Serge Metselaar, Aimée du Chatinier, Annemieke Verbaan, Susanne Gamas-Vis, Piotr Waranecki, Cristian Ruiz-Moreno, Mariette Kranendonk, Hendrik Stunnenberg, Timothy Phoenix, Eelco Wieger Hoving, Marcel Kool, Michael Hananja Meel, Esther Hulleman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline gliomas (DMG) are universally fatal pediatric brain tumors, for which no effective treatment exists. These tumors are known for their “cold” non-inflammatory tumor-immune microenvironment (TIME), which is thought to be a major hurdle for immunotherapy efficacy. METHODS/RESULTS To further investigate the mechanisms that drive this cold environment, we allografted immunocompetent mice with Histone 3.3 Lysine 27 (H3.3K27M) and 3.1 Lysine 27 (H3.1K27M) mutant murine DMG tumors, created through intra uterine electroporation, and performed single-cell analyses on the tumors that developed. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq) we mapped the single-cell RNA and protein expression profiles of the TIME of these tumors and healthy pontine regions, with a dominant focus on the myeloid cell populations. Through differential expression and pathway enrichment analyses, we found that DMG-microglia populations upregulate anti-inflammatory pathways and, over time, are pushed out by infiltrating anti-inflammatory macrophages. We confirmed these findings in single-cell sequencing data from DMG patients, taken at diagnosis and at late stage disease. Next, we established microglia cultures in vitro, by differentiating monocytes from healthy donors into microglia. We discovered that treatment of these microglia with tumor-conditioned medium, taken from primary DMG cultures, diminished their pro-inflammatory potential after stimulation with lipopolysaccharides (LPS), as observed by cytokine release arrays that showed a strong downregulation of IL-6 and TNF-alpha release, amongst others. Subsequently, using a Seahorse metabolic analyzer, we found that glycoATP potential was diminished in DMG-primed microglia after LPS stimulation, further suggesting that DMG-excreted factors are responsible for blocking the pro-inflammatory potential of microglia. CONCLUSIONS Taken together, these findings increase our understanding on how DMG cells reprogram tumor-associated myeloid cells to generate an immune-cold TIME, which will aid the scientific community to find therapeutic solutions to reverse this phenomenon and improve the efficacy of immunotherapy in these devastating malignancies.
IMG-26. USING [18F]FET-PET/CT SCAN TO DIFFERENTIATE RADIONECROSIS FROM RECURRENCE/NEW TUMOURS: THE CASE OF A CNS SARCOMA
Authors: Chiara Pilotto, Elisa Coassin, Eugenio Borsatti, Francesco Tuniz, Enrico Pegolo, Serena D’Agostini, Cristina De Colle, Barbara Rombi, Marco Vindigni, Angelo Vitullo, Maristella Toniutti, Giorgia Tanzi, Maurizio Mascarin, Paola Elisa Cogo, Ilaria Liguoro
Journal: Neuro-Oncology (2024)

Abstract CASE REPORT A 5-year-old girl diagnosed with a posterior fossa standard-risk medulloblastoma underwent surgery followed by proton therapy (PT) 23.4 Gy(RBE) (1.8 Gy(RBE)/fr) to the craniospinal axis plus a boost of 30.6 Gy(RBE) (1.8 Gy(RBE)/fr) to the tumor bed and maintenance chemotherapy according to HIT-SIOP PNET 4 protocol. The patient remained disease-free for 4 years after the end of treatmen. MRI showed a new left temporo-occipital lesion 8x10x10 mm which was irradiated from cranial field during the craniospinal phase but outside of the boost area, consistent with inoperable recurrence. She was then re-irradiated with a second course of PT 50.4 Gy(RBE) (1.8 Gy(RBE)/fr) and subsequently started on temozolomide. Periodic MRI scans showed progressive reduction of the lesion for 10 months, when new lesion progression occurred within the re-irradiated fieled. Considering the stable clinical conditions of the patient, the minimal size of the lesion, and the uncertain nature between actinic damage or cancer, a watchful waiting approach was adopted. Few months later, the area increased. [18F]FET-PET/CT evaluation documented an uptake of the drug compatible with metabolically active lesion. A biopsy was performed, and histology showed a CNS sarcoma. Genetical testing excluded cancer predisposition syndromes. Chemotherapy with bevacizumab and irinotecan was started, but the MRI showed significant progression of the disease and the patient died 6 months after the diagnosis. CONCLUSION MRI is the main diagnostic method in the follow up of CNS neoplasms, but it has limitations in discriminating recurrences/secondary tumours and tissue changes due to previous treatments, particularly radiotherapy. Recently, the use of [18F]FET-PET/CT is being investigated, but literature is still poor in children and most cases refer to high-grade gliomas. It is desirable to study it further, as it may play a relevant role in differentiating equivocal cases, as in our patient.
ETMR-32. SUPRATENTORIAL NEUROEPITHELIAL TUMOR WITH PLAGL1 FUSION: A CASE REPORT
Authors: Abbey Rocco, Mary Beck, Michele McHugh, Ashley Lampe, Ashley Meyer, Andrea Ogle, Andrew Cluster, Nicole M Brossier, Sonika Dahiya, Mohamed S Abdelbaki, Stephanie Perkins, Jarod Roland, Margaret Shatara
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Supratentorial neuroepithelial tumor with PLAGL1 fusion has emerged as a novel subgroup within pediatric brain tumors. Despite its recent identification, critical aspects such as optimal clinical characteristics and management strategies remain elusive. This case report aims to contribute essential insights to the growing body of literature surrounding this enigmatic tumor entity, providing a detailed exploration of its clinical presentation and histopathological features. METHODS A retrospective chart review was conducted, and relevant data were analyzed. RESULTS An 11-year-old female presented with a two-week history of headaches, vomiting, lethargy, and decreased oral intake. Neuroimaging revealed a left frontal lesion with conspicuous mass effect and midline shift, prompting urgent craniotomy due to sudden onset altered mental status. Histopathological analysis revealed a hypercellular glial neoplasm characterized by perivascular pseudorosettes, scattered microcalcifications, microcysts, and areas of necrosis. Immunohistochemical staining revealed GFAP positivity in a substantial subset of tumor cells, rare dot-like positivity for EMA, and diffuse membranous and focal dot-like positivity for D240. Olig2 was mostly negative, indicating the absence of Oligodendrocyte lineage differentiation. The tumor exhibited an elevated Ki-67 proliferation index (approximately 20-30%). Fluorescence in situ hybridization (FISH) studies were negative for RELA, YAP1, and C19MC rearrangements. Targeted next-generation sequencing unveiled an EWSR1-PLAG1 fusion and methylation profiling classified the tumor as “Neuroepithelial tumors, PLAG1-fused” with high confidence. Given the morphological resemblance to anaplastic ependymoma, the therapeutic recommendation included focal irradiation (54 Gy) with proton therapy. The patient, now 12 months post-therapy, is showing favorable clinical outcomes. CONCLUSION This case report underscores the clinical and histopathological intricacies of supratentorial neuroepithelial tumors with PLAGL1 fusion. The identification of EWSR1-PLAG1 fusion and associated molecular alterations informs diagnostic considerations and treatment strategies for this novel entity, emphasizing the importance of continued research to enhance our understanding of its clinical behavior and optimal management approaches.