tbuckley/cabot-search huggingface dataset:
DIPG-57. INITIAL AND EARLY METASTATIC SPREAD IN DIPG AND DIFFUSE MIDLINE GLIOMA, H3 K27-ALTERED - REPORT FROM THE EUROPEAN SOCIETY FOR PEDIATRIC ONCOLOGY (SIOPE) AND INTERNATIONAL DIPG/DMG REGISTRIES
Authors: Thomas Perwein, Gerrit H Gielen, Michael Karremann, Brigitte Bison, Carin M Damen-Korbijn, Joshua N Baugh, Trent R Hummel, Courtney Blank, Veronica Biassoni, Marina Caballero Bellón, Elwira Szychot, Lyudmila Papusha, David T W Jones, Dominik Sturm, Marion Hoffmann, Silke Kullmann, Laura S Steffen, Thorsten Simon, Lea L Friker, Torsten Pietsch, Clemens Seidel, Matthias Eyrich, Moatasem El-Ayadi, Gunther Nussbaumer, Maura Massimino, Andres Morales La Madrid, Simon Bailey, André O von Bueren, Martin Benesch, Sophie E M Veldhuijzen van Zanten, Lindsey Hoffman, Christof M Kramm
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND We aimed to assess frequency, patterns and potential prognostic impact of initial and early dissemination in pediatric patients with diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma, H3K27-altered (DMG). METHODS 199 patients (age, 0-18 years) with DIPG/DMG and positive CSF cytology and/or metastases on MRI at diagnosis (Types 1-3) were identified within the SIOPE and International DIPG/DMG Registries. Data on metastatic first progression (PD) in DIPG/DMG (Type 4) were analyzed from the HIT-HGG-2007/2013 trials. RESULTS Dissemination at diagnosis was present in 5% of patients with DIPG/DMG (16.9% in non-pontine DMG). For all 199 patients with initially disseminated pontine (n=166) and non-pontine DMG (n=33), median overall survival (OS) was 10±0.5 months and progression-free survival (PFS) was 6.6±0.2 months. Tumor cells in the CSF without metastases on initial MRI (Type 1) were detected in 12 patients. Four patients had no primary tumor but primary extensive leptomeningeal dissemination resembling diffuse leptomeningeal glioneuronal tumor, molecularly confirmed as DMG, with aggressive course (Type 2). 183 DIPG/DMG patients were identified with primary tumor and metastases on MRI at diagnosis (Type 3). OS and PFS was superior in patients receiving additional treatment to radiotherapy (n=124), without significant differences between focal and craniospinal irradiation. Metastatic spread at first progression (Type 4) occurred in 32.1% (65.3% in non-pontine DMG) of 224 HIT-HGG patients with DMG and recorded PD. OS of patients with metastatic PD was inferior to local PD (median, 10.8±0.9 vs. 13.3±0.9 months, p=0.005), as was post-progression survival (median, 3.1±0.4 vs. 5.2±0.5 months, p=0.003). CONCLUSIONS We observed a propensity for early dissemination in (especially non-pontine) DMG. While additional treatment beyond radiotherapy seems beneficial, preventing dissemination at progression (e.g., by upfront CSI) may help to prolong survival of patients with DMG and possibly provide options for further therapy.
MDB-01. A POSITIVE FEEDBACK LOOP BETWEEN<i>LNC-HLX-2-7</i>, HLX, AND MYC STRONGLY PROMOTES GROUP 3 MEDULLOBLASTOMA
Authors: Keisuke Katsushima, Kandarp Joshi, Menglang Yuan, Mona Batish, Stacie Stapleton, George Jallo, Sudipta Seal, Michael D Taylor, Rober J Wechsler-Reya, Charles G Eberhart, Ranjan J Perera
Journal: Neuro-Oncology (2024)

Abstract Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma formation and progression. We have identified a lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) medulloblastomas. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, its host gene, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium oxide nanoparticle–coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40-50% in an intracranial medulloblastoma xenograft mouse model (p&amp;lt;0.01). Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy (p&amp;lt;0.01). Thus, the lnc-HLX-2-7–HLX–MYC axis is important for regulating G3 medulloblastoma progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs in children.
ETMR-01. BRAIN STEM TUMORS IN CHILDREN LESS THAN THREE MONTHS: CLINICAL AND RADIOLOGIC FINDINGS OF A RARE DISEASE
Authors: Danai Papangelopoulou, Brigitte Bison, Lars Behrens, Simon Bailey, Marc Ansari, Karoline Ehlert, Ofelia Cruz Martinez, Christof M Kramm, Andres Morales La Madrid, Andre O von Bueren
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brainstem gliomas account for 10-20% of all central nervous system pediatric neoplasms. Brain stem tumors in children less than three months old at diagnosis are extremely rare. Our aim is to study a retrospective cohort to improve the understanding of the disease course and guide patient management. METHODS This is a multicenter retrospective analysis across the European Society for Pediatric Oncology SIOP-E HGG/DIPG Working Group linked centers and included patients with a brainstem tumor diagnosed between 2009 and 2020 and aged less than 3 months at diagnosis. Clinical data was collected, and imaging characteristics were analyzed blindly and independently by two experienced neuroradiologists. RESULTS Five cases (female; n=4) were identified of which no patient received any therapy. The epicenter of 2 tumors was in the medulla oblongata alone and in the medulla oblongata and the pons in 3 cases. For patients with tumor in equal parts in the medulla oblongata and the pons (n=3) the extension at diagnosis involved the spinal cord; for the 2 patients with the tumor epicenter in the medulla oblongata alone (n=2) the extension at diagnosis included the pons (n=2) and the spinal cord (n=1). Biopsy was performed in one patient identifying a pilocytic astrocytoma. Two patients died rapidly. In one patient autopsy revealed a high-grade glioma (case 3). Three survivors showed either spontaneous tumor regression (n=2) or stable disease (n=1). The surviving patients were followed-up for 10, 7, and 0.6 years, respectively. One case had the typical imaging characteristics of a dorsal exophytic low-grade glioma. CONCLUSIONS No patient fulfilled the radiologic criteria defining a high-grade glioma. Central neuroradiological review and biopsy (if feasible) may provide useful information with regards to the patient’s management.
DIPG-58. TARGETING DISORDERED DNA METHYLATION IN DIPG TO CONSTRAIN VARIABILITY AND INDUCE IMMUNE SIGNALING
Authors: Ashley R Tetens, Allison M Martin, Antje Arnold, Orlandi V Novak, Adrian Idrizi, Rakel Tryggvadottir, Jordyn Craig-Schwartz, Athanasia Liapodimitri, Kayleigh Lunsford, Michael I Barbato, Charles G Eberhart, Adam C Resnick, Eric H Raabe, Michael A Koldobskiy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal pediatric brain cancer characterized by the histone H3 K27M mutation. The known downstream consequences of this mutation include loss of repressive chromatin marks, global DNA hypomethylation, and altered gene expression. METHODS We sought to investigate the role of epigenetic variability as a basis of DIPG cellular heterogeneity and plasticity by using Whole Genome Bisulfite Sequencing (WGBS). Existing methods of analysis of WGBS are limited in that they average/smooth methylation data and fail to capture intrinsic variability. We performed (WGBS) on 23 primary patient samples of DIPG and applied an analysis that captures the variability of DNA methylation reads to characterize methylation stochasticity. We then sought to modulate the epigenome pharmacologically using a DNA methyltransferase inhibitor and assessed changes through RNA-Seq and immunopeptidomics. RESULTS We find that DIPG has a marked increase in methylation stochasticity (quantified as methylation entropy). Additionally, while DIPG is globally hypomethylated, it retains DNA methylation at specific regulatory regions, such as bivalent promoters, and key genes, such as FOXG1, CXCR4, and KLF4. We sought to reverse these changes using the DNA methyltransferase inhibitor, decitabine, in 4 DIPG neurosphere cell lines. Treatment with decitabine reversed the entropy seen in DIPG and induced innate immune signaling and interferon signaling in DIPG cells. Using RNA-seq, we found that decitabine treatment dramatically alters gene expression, including activation of endogenous retroviral elements, activation of interferon signaling, de-repression of hypermethylated targets, and expression of putative neoantigens, such as PRAME and DAZL. Immunopeptidomics profiling of MHC Class I bound canonical and non-canonical peptides of DIPG cell lines after decitabine treatment also revealed decitabine-induced differences. CONCLUSIONS Taken together, our study finds that the methylome of DIPG is highly disordered but is also highly responsive to pharmacologic modulation by hypomethylating agents. Furthermore, hypomethylating drugs can increase the immunogenicity of DIPG, thus offering the potential for future combination with immunotherapy.
LMIC-08. NEUROSURGERY UTILIZATION RATE FOR PEDIATRIC LOW-GRADE GLIOMA: A SIMULATION-BASED ANALYSIS
Authors: Scott Boop, Nickhill Bhakta, Nancy S Bolous, Daniel Moreira
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The outcomes of pediatric low-grade glioma (pLGG) are markedly influenced by accessibility to neurosurgical services. Even when clinically recommended, neurosurgical interventions might not be feasible when there is scarcity in qualified medical professionals and preparedness of medical facilities, which is the case in many low- and middle-income countries (LMICs). To aid cancer control planning efforts and guide policy makers and clinicians to prioritize allocation of resources, accurate neurosurgical utilization rate (NUR) estimations are crucial. This study developed a model to estimate the NUR, to facilitate the approximation of neurosurgery needs for pLGG. METHODS A decision tree model was developed to assess the NUR in HICs and LMICs. Patients were classified into five groups based on the anatomic site of the tumor. For each type of cancer, patients had three surgical options, gross total resection, subtotal resection, and biopsy. Anatomic distribution and likelihood to perform surgical resection were retrieved from the literature for both HICs and LMICs. RESULTS Findings showed discrepancy in the anatomic distribution of pLGG in HICs and LMICs. Proportion of patients with cerebral hemisphere, cerebellum, OPHG/diencephalon, brainstem, and spine tumors and their likelihood to undergo surgical intervention were 34% | 28%, 32% | 27%, 17% | 4%, 12% | 3% and 5% | 4% in HICs, and 26% | 22%, 39% | 32%, 26% | 5%, 6% | 2% and 3% | 2% in LMICs, respectively. Overall, NUR in pLGG patients was 66% in HICs and 63% in LMICs. CONCLUSION Despite the limited resources in LMICs, the overall proportion of patients recommended to undergo a surgical intervention is comparable to HICs. For this need to be met, long-term planning need to take place at the policymaking level. It is possible to estimate the NUR for all pediatric CNS tumors following the same approach to more comprehensively estimate the neurosurgical needs of this patient population globally.
DIPG-11. PRECLINICAL EFFICACY OF B7-H3 CAR T CELLS IN COMBINATION WITH ONC206
Authors: Andrea Timpanaro, Edward Song, Matthew C Biery, Davina Lau, Michael Meechan, Leonel Elena-Sanchez, Linh Thuy Vo, Joshua Gustafson, Carl Koschmann, Matthew D Dun, Jessica B Foster, Michael C Jensen, Nicholas A Vitanza
Journal: Neuro-Oncology (2024)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric tumor of the pons affecting over 300 children in the U.S. each year. Chimeric antigen receptor (CAR) T cells are a targeted immunotherapy with remarkable clinical success against hematological malignancies and now are being investigated against central nervous system (CNS) tumors. B7-H3 is a surface antigen specifically expressed on nearly all DIPG but not on normal brain providing an attractive therapeutic window. Therefore, Seattle Children’s opened BrainChild-03 (NCT04185038), a first-in-human phase 1 trial of repeatedly dosed intracranial B7-H3 CAR T cells for children with DIPG. We found the highest planned dose (10x107 cells) to be tolerable and observed preliminary signals of efficacy. ONC206 is a small molecule ClpP-agonist and DRD2-antagonist derivative of ONC201 that is currently being evaluated on PNOC-023 (NCT04732065). Here, we set out to evaluate the combinatorial potential of these modalities. ONC206 effectively reduced DIPG tumor cell viability (IC50 = ~300 nM compared to ONC201 ~1400 nM) against four treatment-naïve patient-deriving DIPG models representing a range of molecular subtypes. Using multiple orthogonal systems, apoptosis of DIPG cells was confirmed. We found that ONC206 drives tumor cell mitochondrial dysfunction and upregulation of DR5, a cell-death receptor involved in the TRAIL pathway, whereas levels of B7-H3, DRD2, and ClpP remain constant. We previously published the efficacy of B7-H3 CAR T cells against DIPG, but here - using low effector:tumor (E:T) ratios (e.g. 0.5:1) of activated B7-H3 CAR T cells and low-dose ONC206 (e.g. 200 nM) - we found a significant in vitro combinatorial benefit against DIPG (p&amp;lt;0.01). Supportive biologic studies suggest this could be an additive benefit and in vivo studies are currently ongoing. Based on the clinical translation of B7-H3 CAR T cells and ONC206, we aim to further validate this combinatorial benefit to help future patients.
DIPG-94. PROTEOMIC AND BIOINFORMATICS ANALYSIS OF THE SURFACEOME AND EXTRACELLULAR MATRIX OF DIFFUSE MIDLINE GLIOMAS
Authors: Bryce Thomas
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Diffuse midline glioma (DMG) is a universally fatal pediatric brain cancer with a median overall survival of 9-11-months. The extracellular matrix (ECM) plays a significant role in regulating bidirectional communication between glioma cells and the niches of the tumor immune microenvironment (TIME); influencing expression of immunosuppressive cytokines and regulating immune cell infiltrations, all of which contribute to poor outcomes. DMG immunosuppression remains poorly understood but has implications for emerging immunotherapies such as CAR T cells. Using a sucrose gradient plasma membrane purification method coupled with quantitative high-resolution proteomics we have discovered a novel cancer-associated protein termed ‘Protein-J 4 (PJ-4)’. PJ-4 is an important component of the DMG-ECM that we believe contributes to immunosuppression. METHODS Expression of PJ-4 was validated by Immunoblotting, flow cytometry and immunofluorescences microscopy. CRISPR/dCas9 gene deletion and amplification of PJ-4 and its transcription factor are current being established using DMG patient-derived cell lines, and syngeneic DIPG models to help elucidate the biological significance of PJ-4 expression. RESULTS Immunofluorescences microscopy showed PJ-4’s translocation from the Golgi apparatus to the cell membrane is dependent neurosphere formation, hence the formation of an ECM. Further, PJ-4 demonstrated high affinity with pro-TGF-β and may serve to regulate its bioavailability in the TIME, suggestive of an immunomodulatory role. Immunohistochemistry analysis of our PJ-4, TGF-β and CD45 is currently underway using a constructed tissue microarray of healthy brain tissue samples and over 30 pediatric brain cancers to determine tumor specificity and correlation with immune cell infiltration. CONCLUSIONS Resistance to conventional therapies and a poor understanding of the TIME and ECM remains a significant challenge to the development of effective DMG therapies. The identification of PJ-4 as a cancer-associated constituent of the DMG-ECM may help us to develop strategies to that increase DMG response to standard-of-care radiation therapy, novel target agents and immunotherapies.
LGG-58. A MULTI-CENTER RETROSPECTIVE CASE SERIES OF SURGICAL OUTCOMES FOR INTRAVENTRICULAR JUVENILE PILOCYTIC ASTROCYTOMA
Authors: Timothy Woodiwis, Wade Pingel, Juan Vivanco-Suarez, Derek Li, Gabrielle Gray, Joan Malley, Joshua Shimony, Jeremy Greenlee, Brian Dlouhy, Jennifer Strahle, Nicole M Brossier
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Juvenile pilocytic astrocytoma (JPA) is a common pediatric grade I astrocytoma. Prognosis is excellent with gross total resection (GTR) and 10-year survival rates of up to 95%. However, undesirable outcomes may occur, such as when tumors are in poorly accessible locations. Intraventricularly tumors present a unique surgical challenge due to their midline location in a fluid filled space with any intraparenchymal invasion involving critical neurologic structures. Here we retrospectively describe the clinical features of intraventricular JPA neoplasms from two centers to highlight the challenges in caring for this uncommon presentation. METHODS We retrospectively searched the electronic medical record from 2000-2023 for patients with neurosurgical treatment for intraventricular JPA at two centers. Intraventricular location was verified by a neuroradiologist. Data were collected on demographics, pathology, tumor location, extent of resection, adjuvant therapies, reoccurrence, progression, and neurological deficit. RESULTS We identified 28 surgical treated patients with intraventricular JPA. Females were 15/28 (54%) of patients with a mean age of 11.2±6.4 years. Most tumors presented in the 4th ventricle 15/28 (53.5%), followed by 9/28 (32%) in 3rd ventricle locations, and 4/28 (14%) in lateral ventricles. GTR was achieved in 12/28 patients (43%) and STR in 16/28 patients (57%). Progression/recurrence was noted in 8/28 (29%) and the 5-year PFS was 56% (10/18). Adjuvant treatment was used in 11/28 (39%) patients and repeat surgery was required in 4/28 patients (14%). Chemotherapy in 8/28 (29%) patients and radiation in 4/28 (14%) patients. A pre/post-operative neurological deficit was noted in 10/28 (36%) patients. A BRAF protein fusion was noted in 7 patients and 1 patient demonstrated a v600E mutation (some molecular data not available). Average follow up was 92 months with no deaths. CONCLUSION We observed that intraventricular JPA tumors commonly undergo subtotal resection with frequent progression/recurrence. Subsequently, recurrent surgeries and adjuvant therapies can be necessary.
BIOM-10. EXAMINATION OF GROWTH DIFFERENTIATION FACTOR 15 (GDF15) EXPRESSION AS A POTENTIAL PROGNOSTIC BIOMARKER IN PEDIATRIC BRAIN TUMORS
Authors: Elizabeth Marlowe, Michael J Ferguson, Mark S Marshall, Daniel V Runco
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Childhood brain tumors remain a leading cause of death with significant treatment-related morbidity and mortality, including disproportionate rates of altered metabolism, neuropathy, and poor quality-of-life. Growth Differentiation Factor 15 (GDF15), a circulating cytokine released by tissue injury, mediates nausea, vomiting, and anorexia, and promotes tumor growth, angiogenesis, and metastasis in adult cancers, predicting worse progression-free survival in adults with low-grade gliomas. Despite adult cancer data, GDF15 remains unexplored in children. Published pilot data demonstrate higher circulating GDF15 in children with cancer compared to healthy controls, but GDF15 expression has not been studied in pediatric brain tumors. We present GDF15 tumor tissue expression with tumor type, grade, metastasis, and progression to inform future study of GDF15’s role in pediatric brain tumors. METHODS Single-center retrospective review of 64 pediatric brain tumor specimens collected through our Precision Genomics Program. GDF15 RNA expression (normalized to ß-actin tissue expression) was log-transformed. Mean GDF15 expression based on diagnosis was compared (using ANOVA) and two-sample t-tests were used to compare metastatic, progressive, and high-grade disease. RESULTS Highest mean GDF15 expression was seen in medulloblastoma (1.96+0.66, N=3) and lowest in low-grade glioma (0.79+0.26, N=27), but groups were not statistically different (p=0.29). GDF15 expression was higher in progressive (1.46+0.22) versus non-progressive disease (0.76+0.24, p=0.04). Although not statistically different, GDF15 expression was higher in high-grade (1.43+0.27) compared to low-grade (1.03+0.21, p=0.24) and metastatic (1.80+0.44) versus non-metastatic disease (1.06+0.17, p=0.08). CONCLUSIONS This ongoing work suggests variable GDF15 expression in different pediatric brain tumors and may suggest GDF15 mediates disease progression. GDF15 may play a role in metastatic or high-grade disease, but further study is needed with larger disease-specific cohorts. We demonstrate feasibility of utilizing existing genomic data and are pursuing further characterizing these potential differences through international public databases (i.e., Children’s Brain Tumor Network).
DIPG-61. ARGININE DEPRIVATION USING ADI-PEG20 IMPROVES SURVIVAL IN A SYNGENEIC DIFFUSE MIDLINE GLIOMA MOUSE MODEL
Authors: Dani Chattenton, Molly Brooks, Richard Perryman, Hamida Mussa, Maria Chatziathanasiadou, Nelofer Syed
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG-H3K27) presents a significant challenge in paediatric oncology, with a &amp;lt;10% two-year survival rate despite standard palliative radiotherapy. Tumour infiltration behind the blood-brain barrier hampers drug delivery, contributing to clinical trial failures. ADI-PEG20 exploits tumour metabolic vulnerabilities: lack of argininosuccinate synthetase and reliability on extracellular arginine for proliferation. This study investigates ADI-PEG20’s efficacy in a syngeneic DMG mouse model. METHODS Twenty C57BL/6J mice were intracranially injected with a DMG cell line (H1H3BK27M, DNp53, PDGFRAD642V, Acvr1G328V) and monitored via bioluminescence imaging from day 7. Weekly treatments began on day 10, comprising ADI-PEG20 (5 I.U.) alone, ADI-PEG20 with concurrent radiation (2 Gy), radiation alone, or saline (0.9%), with each group comprising n=5. Radiation was administered 24 hours post-drug treatment. Bioluminescence imaging was conducted twice weekly, with mice culled upon symptom onset. Immunohistochemistry was performed on brain tissue. RESULTS The combination and ADI-PEG20 monotherapy cohorts exhibited comparable median survival rates, both surpassing those of the radiation-only and saline groups, with the latter exhibiting the lowest median survival. A significant disparity in survival curves was observed overall (p&amp;lt;0.0001), confirmed by log-rank (Mantel-Cox) test. Pairwise comparisons revealed significant differences in survival curves between the combination and radiation-only (p=0.0066), ADI-PEG20 monotherapy and radiation-only (p=0.0018), and ADI-PEG20 monotherapy and saline (p=0.0062) groups. Minimal divergence in IVIS signal intensity was noted across groups. Histological examination via H&amp;E staining demonstrated marked tumour regression in mice treated with ADI-PEG20 ± radiation, contrasting with the persistent tumour mass evident in the radiation-only and saline cohorts, alongside discernible heterogeneity in cellular phenotypes within the ADI-PEG20 ± groups. CONCLUSIONS In conclusion, ADI-PEG20 shows promise as a therapeutic strategy for DMG, offering a significant survival advantage over radiation and saline. Ongoing efforts will elucidate its mechanistic underpinnings, explore its efficacy across diverse DMG models, and assess synergistic interactions with immune-based therapies.