tbuckley/cabot-search huggingface dataset:
DIPG-69. IN-VITRO DETERMINATION OF 5-AMINOLEVULINIC-ACID-TREATMENT EFFICACY IN PATIENT-DERIVED DIPG MODELS
Authors: Martin Stano, Bettina Kritzer, Andreas Hierlemann, Javad Nazarian, Mario Matteo Modena
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse Intrinsic Pontine Glioma (DIPG) presents a significant clinical challenge due to its inoperable nature and poor response to current treatments. Sonodynamic Therapy (SDT) is a non-invasive therapy that combines low-intensity ultrasound stimulation with a sonosensitizing agent. 5-Aminolevulinic Acid (5-ALA) as a sonosensitizer has yielded positive outcomes in in-vivo glioblastoma models, and a clinical trial (NCT05123534) for DIPG patients is currently ongoing. 5-ALA is a precursor of Protoporphyrin IX (PpIX), which preferentially accumulates in cancer cells and generates cytotoxic reactive oxygen species upon activation by ultrasound or light. Our work is aimed at investigating the accumulation of PpIX in in-vitro DIPG patient-derived cell models to predict the efficacy of 5-ALA SDT treatment. METHODS Patient derived DIPG cell lines (H3K27M, P53 mutant and wild type) were used to create three-dimensional spheroids. The spheroids were dosed with 5-ALA for 4 hours, and PpIX accumulation was quantified by measuring its fluorescence intensity within the cells. The spheroids were then exposed to controlled light stimulation as an in-vitro proxy for SDT. RESULTS We confirmed the uptake of 5-ALA and subsequent PpIX accumulation in all patient-derived DIPG spheroids. Light exposure of 5-ALA treated DIPG spheroids resulted in reduced viability of the tumor models, while 5-ALA itself did not show cytotoxic effects. The extent of PpIX accumulation and cytotoxicity upon PpIX light activation varied among DIPG models with higher sensitivity of p53 wild type cells. Further studies incorporating a larger number of DMG cells with p53 alterations are underway. CONCLUSIONS These findings indicate that SDT using 5-ALA as sonosensitizer may offer clinical benefits for treatment of DIPG, however treatment efficacy could vary considerably between patients. In vitro evaluation of PpIX accumulation and sensitivity to activation could potentially provide a means to stratify patients and to identify those most likely to benefit from 5-ALA-mediated SDT.
DIPG-19. SURGICAL STATUS IN THE ERA OF NEW MOLECULAR DIAGNOSTICS: INSIGHTS FROM A SINGLE-CENTER CASE SERIES REPORT IN CHINA
Authors: Juan Li, Ruyu Ai, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2024)

Abstract The therapeutic value of surgery for DIPG has been a subject of controversy. Surgical biopsy provides valuable information on molecular markers of brain gliomas, aiding in further personalized treatment. This retrospective study aimed to elucidate the real-world application of surgery in Diffuse Intrinsic Pontine Glioma (DIPG) in the era of new molecular diagnostics. This study from Guangdong Sanjiu Brain Hospital investigates the surgical landscape in the treatment of Diffuse Intrinsic Pontine Glioma (DIPG) amid the new molecular diagnostics era (Jan 2017 to Feb 2023). Among 184 cases, 58.6% underwent surgery. Notably, 97.2% were introduced to surgery, with 65.8% opting for open surgeries and 34.2% utilizing the Rosa robot. Patients aged 18 and above showed a higher surgery rate (78.3%) than those below 18 (49.1%), revealing a significant difference (P&amp;lt;0.05). The median time from surgery to radiotherapy varied between open (19 days) and stereotactic biopsy (7 days). Complications included increased cranial nerve dysfunction in 20 open biopsy cases. All 108 patients received pathological diagnoses, with 79 having diffuse midline gliomas. Targeted therapy based on second-generation sequencing was administered to seven patients, involving drugs like ribociclib and rigosertib. The study concludes that compared to a decade ago, there is an increased willingness among oncologists to perform brainstem surgery, especially in older patients. Stereotactic biopsy, with fewer side effects, allows swift initiation of radiotherapy. Obtaining lesion tissue during surgery holds promise for new treatments and future research.
PATH-09. CNS EMBRYONAL TUMOUR WITH<i>ZNF532</i>:<i>NUTM1</i> FUSION: A RARE NEW CNS TUMOUR TYPE
Authors: Christine Haberler, Hannah Schned, Leonhard Müllauer, Maria Schmook, Philipp Sievers, Kenneth Aldape, Abdullaev Zied, Katja von Hoff, Pascal Johann, Johannes Gojo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Rare embryonal and sarcomatous CNS tumours represent a diagnostic and therapeutic challenge. In the latest WHO 2021 several new tumour types, defined by molecular alterations, have been introduced. Some of these tumours have molecular counterparts outside the CNS e.g. CNS tumour with BCOR alteration or CIC-altered sarcoma.We report a CNS tumour with unusual histological and molecular features. METHODS/RESULTS A 3-year-old boy presented with a 5x3 cm sized tumour in the left lateral ventricle, which was removed at an external institution. After treatment with 1 cycle carboplatin/etoposide the patient presented at our clinic with leptomeningeal dissemination across all CNS compartments. Therapy was switched to HIT-MED Guidance augmented by intraventricular therapy. Histology showed a highly cellular tumour composed of small uniform cells with round nuclei, distinct nucleoli and a scant cytoplasm. The cells were arranged sheet-like without discernible background. Mitotic figures were conspicuous. Immunohistochemically, expression of Olig2, Chromogranin A, NCAM, BCOR and EGFR was present; synaptophysin and SOX10 were positive in a fraction of cells. DNA methylation profiling using the DKFZ and the Bethesda CNS tumour classifier did not match with any methylation class. Archer FUSIONPlex panel revealed a ZNF532::NUTM1 fusion, which was confirmed by RNA sequencing, leading to the diagnosis of a CNS embryonal tumour NEC with ZNF532::NUTM1 fusion. CONCLUSIONS NUTM1 fusion oncogenes, including among other fusion partners ZNF532, are drivers of aggressive NUT carcinomas. Furthermore, NUTM1 can be a fusion partner in CIC-rearranged sarcoma. The present case neither qualified as carcinoma nor sarcoma. As no clear response was evident after 3 cycles of HIT-MED Guidance therapy was switched to the Scandinavian Sarcoma Protocol. A similar case showing embryonal morphology has been recently reported (PMID 37203791). In conclusion, the spectrum of NUTM1-rearranged tumours is expanding and rare unclassifiable CNS embryonal tumours should be checked for NUTM1 immunopositivity/rearrangement.
DIPG-86. INVESTIGATING THE TUMOR ENVIRONMENT AND SIGNALING DEPENDENCIES DRIVING DIFFUSE MIDLINE GLIOMA TUMOR INITIATION, PROGRESSION, AND RESISTANCE: A COMPREHENSIVE APPROACH LEVERAGING BULK MULTIOMICS DECONVOLUTION AND SINGLE-CELL OMICS VALIDATION
Authors: Palak Patel, Scott Ryall, Bharti Kukreja, Andrei Turinski, Robert Siddaway, Michael Brudno, Arun Ramani, Sanja Pajovic, Brian Kalish, Cynthia Hawkins
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse Midline Glioma (DMG) is a incurable tumor affecting children. Recent genomic investigations have identified a recurrent H3K27M mutation which induces global alterations in histone methylation patterns and DNA methylation. These epigenetic modifications hint at pivotal roles in DMG pathogenesis, yet effective therapeutic strategies remain elusive, with median survival rates stagnant at approximately one year. This shortfall stems from two main factors: 1) Inadequate multiomics studies hindering our understanding of DMG evolution and tumor progression, and 2) Limited comprehension of the tumor microenvironment in DMG. METHODS To elucidate DMG’s clonal evolution, we adopted a comprehensive multi-region sampling approach, acquiring 33 specimens from seven patients. Whole-exome and transcriptome sequencing, alongside DNA methylation profiling, were performed. Additionally, we generated one of the most extensive single-cell multiomics datasets (&amp;gt;300,000 cells from 21 additional samples), with a focus on pre- and post-treatment, and dissemination effects in DMG. RESULTS Our analysis delineated a tumor-promoting microenvironment characterized by hypoxia and pro-inflammatory conditions, nurturing genomic alterations and specialized biological processes such as proliferation and epithelial-mesenchymal transition. Notably, a majority of immune cells exhibited M1-like polarization, bolstering pro-inflammatory programs within the tumor milieu. Subclones within the DMG cohort demonstrated dissemination potential, often exhibiting up-regulation of NOTCH, P53, and WNT beta-catenin signaling pathways. These findings suggest that DMG clones harboring dissemination capabilities outside the pons acquire additional phenotypic features, possibly mediated by epigenetic or transcriptional alterations, contributing to enhanced migratory and aggressive behaviors. CONCLUSIONS Our study unveils the parallel evolution of DMG at genetic, epigenetic, and transcriptional levels, unveiling novel subclonal phenotypes governing tumor behavior. Crucially, we identify critical environmental shifts such as hypoxia and inflammatory changes, coupled with specialized signaling programs, driving dissemination and resistance phenotypes. These insights may pave the way for generating accurate genetically mouse models and targeted therapeutic interventions to combat this challenging malignancy.
ETMR-09. HEALTH-RELATED QUALITY OF LIFE OF CHILDREN, ADOLESCENTS AND ADULTS AFTER DIAGNOSIS OF CHILDHOOD-ONSET MENINGIOMA
Authors: Katharina Wagener, Julia Beckhaus, Carsten Friedrich, Hermann L Müller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningiomas are rare intracranial tumors in childhood. Childhood-onset meningiomas differ from their adult counterparts in terms of frequency, molecular features and clinical presentation. There is limited data on health-related quality of life (HRQoL) of pediatric meningioma patients. The aim of this study was to analyze the HRQoL of pediatric or adult patients after completion of treatment for childhood-onset meningioma. Further, the influence of disease-specific characteristics on HRQoL, fatigue or functional capacity was analyzed. METHODS In this cross-sectional study, the HRQoL of 8 pediatric and 27 adult meningioma patients from the clinical trials HIT-ENDO, KRANIOPHARYNGEOM 2000/2007 and KRANIOPHARYNGEOM Registry 2019 was assessed. The validated questionnaires EQ-5D-Y, EQ-5D-3L, PedsQL Generic Core Scale, EORTC QLQ-C30 and QLQ-BN20 were used. Patients’ fatigue and functional capacity were scored using the EORTC QLQ-C30, the PedsQL Multidimensional Fatigue Scale and the FMH questionnaire. Exploratory data analysis was performed using univariate, bivariate and multivariate analyses (α=0.05). RESULTS The HRQoL was assessed in median 10 (IQR: 5-17) years after diagnosis. The mean HRQoL value was 86 (IQR: 79-92) for pediatric and 75 (IQR: 67-92) for adult patients using the PedsQL Generic Core Scale or EORTC QLQ-C30 questionnaire, respectively. Most limitations were reported in emotional function and fatigue. The median functional capacity of patients was at the 90th (IQR: 65-90) percentile. HRQoL was lower in adults with neurofibromatosis type 2 or at older age (p=0.009) and higher HRQoL after progressive disease. Age at diagnosis, WHO grade, residual tumor, use of radiotherapy, tumor location, tumor entity (meningioma vs. craniopharyngioma), degree of disability, or time since diagnosis did not affect HRQoL in adults. CONCLUSION The median HRQoL of childhood-onset meningioma patients indicates that it is comparable to the healthy normal population. Nevertheless, HRQoL is a construct that can be influenced in many ways. Further research on HRQoL is warranted.
EPEN-22. ZFTA FUSION ONCOPROTEINS DRIVE ONCOGENESIS THROUGH ASSEMBLY OF BIOMOLECULAR CONDENSATES
Authors: Srinidhi Varadharajan, Amir Arabzade, Hazheen K Shirnekhi, Siri Ippagunta, Nic Laboe, David Gee, Erik Emanus, Alisha Kardian, Aaron H Phillips, Swarnendu Tripathi, Abbas Shirinifard, Becky Petersen, Sharon King, Daniel Stabley, Aaron Pitre, George Campbell, Cheon-Gil Park, Adam D Durbin, Jun Qi, Kelsey Bertrand, Michael D Taylor, Paul A Northcott, Benjamin Deneen, Aseem Z Ansari, Richard W Kriwacki, Stephen C Mack
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymomas continue to be an aggressive brain tumor entity without targeted therapies. The highly recurrent fusion oncoprotein (FO), ZFTA-RELA, is known to be associated with about 70% of supratentorial ependymomas. While recent studies have highlighted that the fusion protein is involved in aberrant DNA binding and subsequent oncogenic gene expression, the precise mechanisms underlying the transcriptional dysregulation remain elusive. METHODS Using super-resolution and lattice-sheet microscopy, we demonstrate that ZFTA-RELA forms dynamic liquid-like nuclear condensates. ZFTA-RELA condensates recruit co-factors like Med1, and Brd4 and are associated with the transcription of ependymoma oncogenes (Notch1 and Ccnd1). We leveraged machine learning models trained on FOs in other cancers to identify critical intrinsically disordered domains (IDRs) within ZFTA-RELA. A series of mutagenesis experiments were conducted to determine IDRs important for condensate formation, transcription, and tumor initiation. We also performed NMR spectroscopy to unravel the protein structure of ZFTA-RELA zinc finger binding domains. RESULTS We demonstrate that transcriptional condensate formation of ZFTA-RELA is an important cellular phenotype that is tightly linked with oncogenic transcription and tumor initiation. Further, we identify key residues within the zinc finger domain of ZFTA that are required for DNA binding of oncogenic target genes and condensate formation. Deletion of the key IDRs within ZFTA-RELA disrupts condensates and abolishes transcriptional activation and tumorigenesis. We also show that condensate formation is an underlying feature found across all other ZFTA-fusion oncoproteins, providing a model to understand how ZFTA FOs drive cancer. CONCLUSION Our studies provide mechanistic insights into the biophysical and structural basis of ZFTA fusion oncoproteins. These findings provide a framework to develop druggable strategies through targeting ZFTA FO zinc finger domains or disruption of oncogenic condensates.
ETMR-08. DECODING TUMOR-NEURONAL COMMUNICATION IN PEDIATRIC BRAIN TUMORS: INSIGHTS FROM ETMR 3D MODEL REVEALING MECHANO-SIGNALING DYNAMICS AND THERAPEUTIC OPPORTUNITIES
Authors: Nicolas Sterbies, Flavia Watusi de Faria, Nicole Riedel, Daniel Münter, Lea Altendorf, Carolin Göbel, Clara Inserte, Rajanya Roy, Christian Thomas, Ulrich Schüller, Jan M Bruder, Kornelius Kerl
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Exploring tumor-neuronal interactions is essential for comprehending brain tumor proliferation, chemotherapy resistance, and patient survival. While glioma research has made significant strides, our understanding of tumor-neuronal interactions in pediatric brain tumors, notably Embryonal Tumors with Multilayered Rosettes (ETMRs), remains limited. METHODS To elucidate tumor-neuronal interactions in ETMRs, we developed a 3D model by co-aggregating the human ETMR cell line BT-183 with human induced pluripotent stem cells (iPSCs) and allowing them to mature into forebrain organoids for 30 days, forming ETMR-forebrain organoids (ETMR-FBO). We further employed single-cell RNA sequencing to compare the gene expression profile of healthy forebrain organoids (FBO) with the ETMR-FBOs. Additionally, we conducted immunohistochemistry of 3D model sections for comparative evaluation and spatial transcriptomics of murine and human primary ETMR samples. RESULTS Our integrated dataset of 48,764 cells of healthy FBOs (n = 4) and ETMR-FBOs (n = 6) revealed that ETMR tumor cells impeded the neuronal differentiation of the FBO cells. The ETMR-FBOs exhibited a significant enrichment of neuro-stem cells (67% vs 49%), accompanied by a reduction of more differentiated neuronal cells. Comparative trajectory analysis confirmed a blockage of neuronal maturation/differentiation in ETMR-FBOs compared to controls without ETMR cells. Immunohistochemistry further confirmed an enrichment of SOX2-positive/synaptophysin-negative neuronal progenitors in the organoid areas closest to the tumor border. Additionally, we identified upregulated extracellular matrix-related pathways, particularly integrin and YAP/TEAD signaling, in the neuro-stem cell compartment of ETMR-FBOs. This implies a tumor-specific mechano-signaling mechanism influencing the neuronal differentiation state of the tumor microenvironment. CONCLUSION Our findings suggest that mechano-signaling-related tumor-neuronal interactions in ETMR contribute to the formation of an immature neuronal niche. Targeting mechano-signaling may hold promise for innovative therapies by disrupting tumor architecture and enhancing susceptibility to chemotherapy.
MDB-94. RADIOMICS-BASED DECISION SUPPORT FOR PEDIATRIC MEDULLOBLASTOMA RISK STRATIFICATION ON MULTI-PARAMETRIC MRI
Authors: Kartik Reddy, Abhishek Midya, Farid Hajibonabi, Martin Halicek, Eswar Damaraju, Adam Goldman-Yassen, Sheila McThenia, Robert C Castellino, Claire Mazewski, Anant Madabhushi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is the most common pediatric brain malignancy. Accurate risk stratification is crucial for prescribing appropriate therapy. However, current risk stratification into standard or high-risk groups is limited in scope and does not accurately address the unique biological behavior of each specific tumor, with approximately 30% of children diagnosed with MB suffering from treatment failure. We developed a radiomic tool to more accurately risk stratify children with MB. METHODS We collected 1.5T/3T MRI (Siemens, Philips, or GE scanners) and clinical data from 80 patients with MB treated at Children’s Healthcare of Atlanta. Radiomic features that quantify textural heterogeneity including first and second order statistics, Haralick’s features from Gray Level Co-occurrence Matrices, and CoLIAge were extracted from tumor volumes segmented by a board-certified radiologist from multi-parametric MRI data including Apparent Diffusion Coefficient (ADC), T2, and post-contrast T1 sequences. Continuous survival models were built using the Cox proportional hazard method with 70% of the data for progression free survival (PFS) and overall survival (OS) using the 5 most predictive features obtained by univariate analysis after removing correlated features within the training data. RESULTS We developed three models with T1, T2, and ADC separately to evaluate predictive power of radiomic signatures. Three models for predicting MB OS delivered Harrel’s concordance indices (C-index) of 0.72 and 0.61 (T1); 0.70 and 0.65 (T2); and 0.80 and 0.76 (ADC) for training and test, respectively. C-indices for PFS were 0.70 and 0.69 (T1); 0.73 and 0.67 (T2); and 0.63 and 0.61 (ADC). CONCLUSIONS Our preliminary results show the feasibility and efficacy of our approach for predicting MB OS and PFS. Future studies will build an integrated model combining T1,T2, ADC, and other clinical information for predicting MB OS and PFS using a large multi-center validation cohort.
ETMR-13. MARROW-ABLATIVE CONSOLIDATION CHEMOTHERAPY WITH AUTOLOGOUS HEMATOPOIETIC PROGENITOR CELL RESCUE (HDCT) DECREASES THE DEVELOPMENT OF CHOROID PLEXUS CARCINOMA (CPC)-SPECIFIC RELAPSE IN HIGH-RISK TP53-MUTATED (GERMLINE OR SOMATIC) YOUNG CHILDREN WITH NEWLY DIAGNOSED CPC
Authors: Maxim Yankelevich, Diana S Ozorio, Wafik Zaky, Lucie Lafay-Cousin, Ashley Margol, Stephanie Toll, Michael Prados, Sharon L Gardner, Derek Hanson, Lina Quiroz, Javier E Fox, Sabine Mueller, Jonathan L Finlay
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND CPC are childhood cancers in which the loss of TP53 function defines unfavorable disease. CPC-free survival rates have remained poor in patients with TP53 mutations and recent data revealed CPC-free survival of 29% with a non-marrow-ablative chemotherapy strategy. Previously reported results of the “Head Start” (HS) HDCT approach were limited by small patient numbers and incomplete TP53 mutation data. Consequently, the role of HDCT in TP53-mutated CPC remains unclear. METHODS We have analyzed data on TP53 status, CPC-free survival and second cancers from the largest cohort of patients who received initial therapy with the intent of undergoing HDCT. RESULTS Twenty-seven children with CPC received HS-like induction chemotherapy and 23 completed HDCT consolidation. Somatic or germline TP53 mutations were identified in 17 patients, 4 exhibited TP53 wild type (TP53wt); TP53 status remained untested in 6. Five-year CPC-free survival was 66% for patients with TP53 germline mutations (n=12), 40% for those with somatic tumor TP53 mutations (n=5) and 50% with confirmed TP53wt (n=4). Among patients with germline TP53 mutations, only 4/12 experienced CPC recurrences, 4 died from secondary cancers and 4 are currently alive. The 5-year CPC-free survival for 23 patients who underwent HDCT was 52%. All six survivors with TP53 mutations had undergone HDCT, and 5/6 avoided irradiation. Eight/12 patients with TP53 germline mutations and Li-Fraumeni Syndrome (LFS) developed second malignancies, including 6 patients in HDCT group and the remaining 2 patients who did not undergo consolidative HDCT. CONCLUSIONS Our data indicate that HDCT consolidation is associated with improved CPC-free survival compared with historical reports in children with TP53 mutated CPC. The ultimate development of second cancers affects outcomes for those with LFS, irrespective of HDCT treatment. These data justify the inclusion of HDCT in the prospective international trial under development for young children with newly diagnosed TP53 mutated CPC.