tbuckley/cabot-search huggingface dataset:
DIPG-67. RE-IRRADIATION PRACTICES AND OUTCOMES IN PATIENTS WITH DIPG/DMG: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
Authors: Natasha Pillay-Smiley, Aaron Webster, Adam Lane, Cynthia Hawkins, Tim Hassall, James Leach, Blaise Jones, Kathleen Dorris, Jordan R Hansford, Mohamed Zaghloul, Sylvia Cheng, Trent R Hummel, Lindsey M Hoffman, Katherine E Warren
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Given that radiation therapy is the only treatment modality demonstrated to result in any clinical benefit for children with DIPG, re-irradiation therapy has been explored as a treatment option for progressive DIPG. Several studies suggest re-irradiation is feasible, and may lengthen survival for children with progressive DIPG. However, any re-irradiation benefits are unclear and no standard of care (dose, fractionation, volume, timing, clinical status) has been defined. The aims of this study are to evaluate re-radiation therapy practices for children with progressive DIPG/DMG and to define a historical cohort of children with DIPG/DMG who have received re-radiation (re-XRT) for progressive DIPG/DMG. METHODS Data was extracted from the International DIPG Registry, and analyzed with descriptive statistics. RESULTS Of 1214 patients in the iDIPG Registry, 113 receiving re-XRT. Patients were diagnosed between 2002-2022, with the majority of patients diagnosed over the last decade. Of those 113 patients with specified data, at re-irradiation, n=68 (60%) received photon and n= 4 (4%) were treated with proton radiation. The median dose at re-XRT was 25 Gy (20-30 IQR) in 10 fractions (10-14 IQR). Time between initial XRT and re-XRT was 41.5 weeks (29.5-54 weeks). OS from diagnosis was 18 months (range, 15-23 mo); OS from re-XRT was 6 months (range, 4-10 mo). CONCLUSIONS Re-radiation therapy for children with DIPG/DMG is becoming a more common practice and appears to have OS benefit, with post-progression OS of 6 mo comparing favorably to historical data of 2.3 mo. [Cooney T et al, Neuro Oncol 2017] Efforts are underway to define patient selection and tolerability. Data extraction from the SIOPE DIPG/DMG Registry is also ongoing; data from both registries will be collated and uniformly presented.
LGG-27. LOWER GRADE GLIOMA (LGG) IN INFANTS. ANALYSIS OF 25 NON-NF1 PATIENTS
Authors: Marta Perek-Polnik, Monika Drogosiewicz, Iwona Filipek, Ewa Swieszkowska, Magdalena Tarasinska, Joanna Trubicka, Wieslawa Grajkowska, Pawel Kowalczyk, Maciej Ciolkowski, Elzbieta Jurkiewicz, Bozenna Dembowska-Baginska
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Infants constitute approximately 5% of all pediatric LGG. This group is identified as having aggressive course and worse prognosis as compared to older children. No specific therapeutic guidelines are yet available for this specific age group. AIM: Retrospective analysis of infants diagnosed and treated for LGG. METHODOLOGY: 25 patients treated between 2001-2023 were analyzed for: sex, age, tumor location, pathology, treatment and outcome. NF1 patients were excluded. RESULTS There were 13 boys and 12 girls, aged 3 months-11 months, median 6 months. 12 had optic chiasm tumors, 6 of visual pathway, 3 had tumors of posterior fossa, 2 of pineal region and 1 spinal tumor. Pathology was available for 16 children revealing Pilocytic astrocytoma in 9, Pilomyxoid astrocytoma in 6, ganglioglioma in 1. Resection as first line treatment was performed in posterior fossa and spinal locations, in 4 cases of visual tracts tumors. All patients were treated with chemotherapy with a maximum of 6 subsequent episodes in a patient with visual pathway tumor. MEK inhibitors were given to 3 pts (in 2 discontinued due to cardiotoxicity). Radiotherapy was applied in 5 (older than 4 years). Twenty two patients are alive, from 4 months to 22 years 4 months (median 8 years 11 months) from diagnosis. Three patients died (midline tumors) 2 from electrolyte disorders and 1 from radiation related cerebral bleeding with observation time of 3, 10, 9 years. Among children with visual tract tumors 5 are blind, 3 have impaired vision. Five patients with very good response to first line treatment have excellent quality of life. Ten patients are disabled, requiring help in everyday life. CONCLUSIONS The risk of disability or death is highest in infants of all LGG patients, those who respond the first line treatment have very good quality of life.
ATRT-16. MAPPING THE DISORDERED METHYLOME IN ATRT
Authors: Ashley R Tetens, Kayleigh E Lunsford, Athanasia Liapodimitri, Jordyn Craig-Schwartz, Tyler Findlay, Eric H Raabe, Michael A Koldobskiy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical Teratoid Rhabdoid Tumor (ATRT) is an aggressive pediatric brain tumor driven by inactivation of the chromatin regulator SMARCB1, with remarkably few other mutations. SMARCB1 loss leads to epigenetic dysregulation which plays a pivotal role in ATRT development and progression, and DNA methylation profiling has distinguished molecular subgroups of this disease. However, studies that provide a static view of the epigenome may not capture epigenetic variability that drives cellular plasticity and heterogeneity. Mapping epigenetic variability is crucial to understanding the phenotypic plasticity of this tumor and its ability to evade therapeutic interventions in the clinic. METHODS We performed whole genome bisulfite sequencing (WGBS) on 22 ATRT samples, 4 normal fetal brain controls, and 1 hindbrain neural stem cell control, and applied a novel analytic pipeline (InformME) to generate DNA methylation potential energy landscapes encapsulating epigenetic stochasticity. This characterizes mean methylation as well as methylation entropy. We identified key genes and regulatory regions with the most stochastic methylation signatures. RESULTS We find that ATRT exhibits a globally destabilized epigenome, with markedly elevated methylation entropy (a measure of variability/disorder). Methylation discordance mapped to key regulatory regions including bivalent promoters, quiescent chromatin regions, and enhancers, and specific genes, with an enrichment for targets of the Polycomb repressive complex 2 and regulators of pluripotency and differentiation. CONCLUSIONS The disordered methylome of ATRT could play a critical role in the tumor’s ability to evade therapies. Mapping the targets of epigenetic instability can identify targets for intervention. Moreover, strategies to constrain epigenetic variability may have therapeutic benefit by limiting the number of epigenetic states available to cancer cells.
CP-07. FEASIBILITY, TOLERABILITY AND FIRST EXPERIENCE OF INTRACYSTIC TREATMENT WITH PEGINTERFERON ALFA-2A IN PATIENTS WITH CYSTIC CRANIOPHARYNGIOMA
Authors: Cora Hedrich, Priya Patel, Lukas Haider, Tracey Taylor, Elaine Lau, Roxanne Hook, Christian Dorfer, Karl Roessler, Natalia Stepien, Maria Aliotti Lippolis, Hannah Schned, Clara Koeller, Lisa Mayr, Amedeo A Azizi, Andreas Peyrl, Bienvenido Ros Lopez, Alvaro Lassaletta, Julie Bennett, Johannes Gojo, Ute Bartels
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Craniopharyngiomas (CP) is a life-long chronic disease predominantly affecting young children. Consequently, the developing brain is particularly sensitive to therapies such as surgery or radiotherapy. Hence, therapies allowing to avoid or delay intensive therapies provide substantial benefit. Intracystic injection of interferon alfa-2a or -2 has emerged as frequently applied treatment based on advantageous risk-benefit ratio with good effects leading to cyst shrinkage. Unfortunately, the original drug is worldwide no longer available. To overcome this shortage we performed an elaborate pharmacological review, identifying peginterferon alfa-2a (Pegasys®) as best currently available alternative drug for intracystic treatment of CP patients. METHODS Within an international collaboration we set up a novel protocol for intracystic peginterferon treatment. Based on the protocol five patients were treated with intracystic peginterferon alfa-2a for cystic CP. After initial CP cyst-aspiration peginterferon alfa-2a was injected once per week via an Ommaya reservoir. One treatment course was six weeks accompanied by regular response assessment with MRI (3-6 weeks). Side effect, safety and therapeutic effects were analyzed. RESULTS Age of patients ranged from 4 to 54 years (4 pediatric patients &amp;lt;12 years, 1 adult patient). Intracystic therapy with peginterferon alfa-2a was generally well tolerated throughout the treatment course and resulted in cyst shrinkage in all cases. Cyst leakage was observed in one case highlighting the importance of testing cyst permeability before starting intracystic treatment courses. CONCLUSIONS Taken together, intracystic treatment with peginterferon alfa-2a was feasible and effective being comparable to prior intracystic interferon protocols for cystic CP being of potential clinical benefit for this severely affected patient cohort. Our experience in this small cohort indicated the potential of this treatment modality, which should be further investigated within a larger trial cohort.
DIPG-72. CREATION, CHARACTERIZATION AND CATALOGUING NEXT-GENERATION DIPG PATIENT-DERIVED CANCER CELL LINES: THE DIPG C3 PROJECT
Authors: Sonam Bhatia, Thomas Quinn, Kin-Hoe Chow, Jayne Vogelzang, Aniket Shetty, Smitha Yerrum, Michelle Monje, Eric Raabe, Mariella Filbin, Esther Hulleman, Keith L Ligon, Katherine Warren
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Preclinical studies of diffuse intrinsic pontine glioma (DIPG) have increased significantly over the past 15 years due to the development of DIPG disease-specific tools including cell lines and animal models. We now know that DIPG is a molecularly heterogeneous tumor. While &amp;gt;80% of these tumors have H3K27M alterations, partner mutations can vary. Many DIPG cell lines used for pre-clinical assessments of new therapies have not been fully characterized, therefore, comparing preclinical results across studies has been impeded. We sought to Create, Characterize and Catalogue DIPG cell lines and animal models with the aim of expanding contemporary resources and providing a public database for DIPG researchers. METHODS Existing DIPG cell lines in the Center for Patient-Derived Models (CPDM) were utilized; additional patient-derived cell lines were created in CPDM, and obtained from collaborators. The assembled collection was characterized by whole genome (WGS) and RNA-sequencing (RNAseq). RESULTS To date, we have 21 growth-verified DIPG models with the majority grown as 3D neurospheres in-vitro and capable for long-term culture. Fourteen (14) of these patient-derived models were genomically verified with WGS and RNA-seq platform. Data will be made publicly available to researchers on cBioPortal. CONCLUSIONS Systematic characterization and cataloguing of pre-clinical DIPG models is important to allow more stringent comparison across studies and ensure their utility and impact. These DIPG-specific tools can thus be used in applications such as drug discovery and testing.
MDB-97. INVESTIGATING THE IMMUNOMODULATORY ROLE OF V-DOMAIN IG SUPPRESSOR OF T-CELL ACTIVATION IN AN AGGRESSIVE MURINE MODEL OF PEDIATRIC MEDULLOBLASTOMA
Authors: Natalia Andrea Munoz Perez, Juliana Pensabene, Kirsten Moziak, Rita Yazejian, Xingxing Zang, David M Loeb, Allison M Martin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Efforts to treat relapsed medulloblastoma patients with immune checkpoint inhibitors aim to enhance T-cell recognition and elimination of tumor cells. However, significant barriers to treatment efficacy include low numbers of infiltrating effector T-cells and paucity of PD-L1 expression in the tumor microenvironment. Thus, identifying alternative immune checkpoints on the predominant immune cells that infiltrate tumors represents an attractive therapeutic alternative. METHODS Medulloblastoma tumor cells (mCB MYC DNp53) are orthotopically implanted into the right cerebellum of C57/BL6J mice. Once moribund, tumors are harvested and analyzed by flow cytometry. For in vitro studies, tumor cells are co-cultured at increasing concentrations with naïve splenic CD4+ T-cells, CD3/CD28 beads, and rIL-2 for 5 days and then analyzed by flow cytometry. RESULTS Flow cytometric analysis of tumors reveals an abundance of CD45highCD11bhigh tumor-associated macrophages (TAMs), CD45intCD11bint tumor-associated microglia, and CD4+FoxP3+Treg cells. Across all three immune populations, we observe high expression of the inhibitory immune checkpoint, V-domain Ig Suppressor of T-cell Activation (VISTA), with the highest MFI observed on Mø-like TAMs (n=9 tumors; p&amp;lt;0.05). Compared to sham controls, infiltration of Mø-like TAMs is specific to the tumor and express higher levels of MHCII than Mg-like cells (n=14 tumors, 6 sham; p &amp;lt;0.05). Additionally, we find that medulloblastoma tumor cells (mCB MYC DNp53) express VISTA’s binding partner, VSIG3. Tumor cells co-cultured with CD4+ T-cells can inhibit T-cell proliferation in vitro. Preliminary results suggest that addition of 2ug/mL of anti-VISTA blocking antibody (13F3) can rescue proliferation. CONCLUSIONS Tumors are highly infiltrated by VISTA+ T-regs and TAMs. These TAMs upregulate MHCII, suggesting that they are presenting antigen in the context of an inhibitory molecule. Furthermore, our in vitro results warrant further investigation into the role of the VISTA/VSIG3 axis in inhibiting T-cells and supports blocking VISTA as a potential strategy to promote T-cell activation and an anti-tumor response.
IMG-05. USING CONVOLUTIONAL NEURAL NETWORKS TO IDENTIFY COMMON MOLECULAR ALTERATIONS IN PEDIATRIC BRAIN TUMORS
Authors: Taylor Free, Jonathon Moore, Michael Taras, Shankar Ganapathy, Gayathri Sreedher, Erin Wright
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Artificial intelligence (AI) and deep learning have had increased uses in healthcare. Initial studies have shown it is possible to predict multiple tumor types in adults and children using convolutional neural networks (CNN), a form of deep learning, using MRIs. In pediatric CNS tumors, molecular alterations are used in both diagnosis and treatment decisions. This project aims to verify that we can use deep learning to help diagnose and molecularly classify primary pediatric CNS tumors. Previously, we used Recurrent Health’s platform to predict high vs. low grade CNS lesions to &amp;gt;95% recall and 85% precision in pediatric patients. The objective of this study is to validate the AI’s ability to predict common genetic alterations with 90% accuracy. METHODS This retrospective study evaluated patients (ages 0-21) with histologically confirmed primary CNS tumors that underwent BRAF molecular analysis. We collected demographic data: age, tumor location, and presence of BRAF mutations/fusions. The data was divided into a training and validation set (80%/20% split). To determine the viability of models, we will measure specificity, sensitivity, and F1 Score (Sorenson-Dice coefficient) for predicting genetic alterations. Model score confidence was achieved through K-fold cross-validation and statistical power analysis with a finite population coefficient to determine the appropriate sample size. RESULTS Our retrospective test included 136 patients with multiple scans for training, model validation and testing. The CNN was able to predict presence of BRAF fusions with &amp;gt;95% recall/sensitivity, &amp;gt;76% precision/specificity and F1/accuracy &amp;gt;87% while predicting BRAFV600 mutations with &amp;gt;75% recall/sensitivity, &amp;gt;95% precision/specificity and F1/accuracy &amp;gt;85%. These metrics indicate strong discrimination in classification. CONCLUSIONS Preliminary data suggests the accuracy of the model in identifying the presence of BRAF mutations, providing a potential opportunity for a non-invasive tool to help aid in diagnosis and help guide initiation of targeted therapy.
ATRT-13. NOVEL ACYLFULVENE LP-184 SYNERGIZES WITH RUCAPARIB TO KILL AT/RT CELLS
Authors: Abigail Tindall, Abby Kwon, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical Teratoid Rhabdoid Tumor (AT/RT) is a pediatric brain cancer with survival rates of less than 40%. Illudins are a novel class of DNA-damaging alkylating agents. LP-184, an investigational synthetic acylfulvene analog currently in a first-in-human Phase 1 trial, exhibits enhanced ability to penetrate the brain and damage DNA in tumor cells. We hypothesized that LP-184 would synergize with PARP inhibitors such as rucaparib which inhibit DNA repair. The combination of these therapies could be a promising treatment option for AT/RT. METHODS We tested LP-184 against the AT/RT cell lines BT37, CHLA06, CHLA05, and CHLA266. Cell viability assays were conducted by flow cytometry. Immunofluorescence was performed to visualize CC3 and BrdU. Western blots were performed to determine c-PARP and p-RB protein levels. Synergy experiments were performed using cell growth inhibition as the readout and quantified using the SynergyFinder online computational tool. RESULTS LP-184 suppressed AT/RT proliferation at nanomolar concentrations as measured by BrdU immunofluorescence and pRB western blots (BrdU BT37 p=0.0001, CHLA06 p=0.0001, CHLA05 p=0.033 50 nM concentration of LP-184 compared to DMSO control). Furthermore, LP-184 showed strong synergy with the PARP inhibitor rucaparib. Viable cell count was reduced by as much as 80% in combination compared to DMSO control (BT37 p=0.0001, CHLA06 p=0.0002, CHLA05 p=0.0077). Combination therapy decreased proliferation as measured by immunofluorescence and confirmed by pRB western blots (BrdU BT37 p=0.0004, CHLA06 p=0.0033, CHLA05 p=0.0154 compared to DMSO control). LP-184 and rucaparib induced apoptosis as measured by cleaved caspase 3 (CC3) and cPARP western blots (BT37 p=0.0002, CHLA06 p=0.0117, CHLA05 p=0.0001 %CC3+ compared to control). Survival studies in vivo are underway to test single agent and combination therapies of LP-184 and rucaparib in AT/RT. CONCLUSION LP-184 and rucaparib together could provide a compelling clinical option for patients with this poor-prognosis brain tumor.
METB-03. SOLID PEDIATRIC TUMORS IN MICE REVEAL MODEL-SPECIFIC GLOBAL DNA METHYLATION AND CNV PROFILES CORRESPONDING TO HUMAN COUNTERPARTS
Authors: Melanie Schoof, Tuyu Zheng, Martin Sill, Roland Imle, Nina Hofmann, Kati Ernst, Dominik Vonficht, Chun Ho Chan, Alessia Cais, Tim Holland-Letz, Andreas Postlmayr, Ryo Shiraishi, Wanchen Wang, Alaide Morcavallo, Michael Spohn, Carolin Göbel, Judith Niesen, Levke-Sophie Peter, Alicia Eckhardt, Franck Bourdeaut, Zhi-Yan Han, Yanxin Pei, Najiba Murad, Fredrik J Swartling, Jessica Taylor, Richard J Gilbertson, Matthias Dottermusch, Kornelius Kerl, Rainer Glass, Jiying Cheng, Martin A Horstmann, Peter Nollau, Gerrit Wolters-Eisfeld, Haotian Zhao, Dominik Sturm, Louis Chesler, Simon Haas, William A Weiss, Paul A Northcott, Lena M Kutscher, Ana Guerreiro Stücklin, Olivier Ayrault, Julia E Neumann, Daisuke Kawauchi, David Jones, Stefan M Pfister, Kristian Pajtler, Ana Banito, Ulrich Schüller, Marc Zuckermann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The analysis and comparison of global DNA methylation patterns has become a gold standard in modern neuropathology. For human central nervous system (CNS) tumors and other cancers, the research community has collected thousands of methylation profiles, leading to the discovery and definition of numerous molecularly distinct tumor types and subtypes. Although reliable preclinical mouse models are essential for the understanding of tumor development and the validation of therapeutic approaches, such DNA methylation analyses have so far not been systematically performed for murine tumors owing to technical limitations. METHODS We employed the Illumina Bead Chip 285k mouse methylation array to profile ~500 samples covering 90 different mouse models representing 33 pediatric solid tumor types, including CNS tumors and sarcomas from 18 laboratories. We compared DNA methylation profiles of these models between each other and to human CNS tumors, performed immune cell deconvolution and conducted an in-depth analysis of copy number variants (CNVs) during tumor evolution. RESULTS Unsupervised clustering showed that mouse models form groups of their presumed tumor types. Using a tailor-made cross-species analysis based on syntenic CpG sites, we found that most tumors also group with their corresponding human counterparts. Immune cell deconvolution revealed distinct tumor microenvironments that showed clear similarities to human tumors. We further identified recurrent, model-specific CNVs that are syntenic to genomic aberrations in respective human tumors, suggesting an essential role of CNVs during tumor initiation or maintenance. CONCLUSION We provide a global resource of well characterized pediatric solid cancer models representing numerous different tumor types. Our comparative analyses reveal novel molecular model characteristics and validate their reliability as human disease models. Our data provide new biological insights into immune composition, tumor cell identities and tumor development by identifying model-specific CNV profiles.
ETMR-12. INFANTILE CENTRAL NERVOUS SYSTEM JUVENILE XANTHOGRANULOMA WITH SOMATIC<i>CSF1R</i> MUTATION - RESPONSIVE TO IMATINIB MONOTHERAPY
Authors: Valerie Martinez-Torres, Kayla Etienne, Long Di, Andrew Rosenberg, Sakir Gultekin, Aditi Dhir, Heather J McCrea, Bradley Gampel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Juvenile xanthogranuloma (JXG) of the central nervous system(CNS) is a rare non-Langerhans cell histiocytosis typically affecting children and young adults. CSF1R mutations have been reported for peripheral JXG but have not previously been reported in CNS JXG. Treatment of CNS JXG relies on maximal safe surgical resection followed by cytotoxic chemotherapy, radiotherapy and/or molecular targeted therapy involving MAPK signaling pathway. Imatinib has been effective in treating tenosynovial giant cell tumor with CSF1R mutations. METHODS Case Report RESULTS A 3 month old male presented with fever, lymphadenopathy, and macrocephaly (45.5cm, 99.97%) with bulging fontanelles. Head ultrasound revealed dilated ventricles and brain MRI demonstrated multiple dural-based masses, the largest measuring 6.6 x 5.3 x 5.7 cm was located along the right tentorium and caused obstructive hydrocephalus. Patient underwent right frontal endoscopic third ventriculostomy and choroid plexus cauterization to treat hydrocephalus and right parietal craniotomy to resect the superficial dural-based mass for tissue diagnosis. Pathology was most consistent with a JXG that harbored a somatic CSF1R (NM_001288705.3) mutation. DNA Methylation profiling was unmatched. PET scan was negative for non-CNS lesions. Due to the multiple masses on presentation, the surgical risks of resection of the largest lesion, as well as having a targetable mutation, we opted for medical therapy. As Pexidartinib, a selective CSF1R inhibitor, was not available for infants, patient was started on liquid imatinib 340 mg/m2/day monotherapy. Three months after initiation of imatinib, the smaller parietal lesions resolved and after six months, the largest mass continued to shrink (6.3 x 2.9 x 2.9 cm). Treatment has been well tolerated without adverse events or drug interruptions. CONCLUSION This is the first report of CNS JXG with a CSF1R mutation. Importantly, it demonstrates that imatinib is a potentially safe and effective form of monotherapy for this rare disease.