tbuckley/cabot-search huggingface dataset:
ETMR-11. RECURRENT GENETIC ALTERATIONS IN EPIGENETICALLY DEFINED PINEOBLASTOMA SUBTYPES
Authors: Tobias Goschzik, Mathias Yuan, Elke Pfaff, Martin Mynarek, Evelyn Doerner, David T W Jones, Stefan M Pfister, Stefan Rutkowski, Torsten Pietsch
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Genome-wide methylation analyses recently revealed distinct epigenetic pineoblastoma (PBL) subtypes. The aim of the study was to shed further light onto the genetic characteristics underlying the pathogenesis of pineoblastoma subtypes. METHODS Cytogenetic alterations of tumor samples of 76 patients with a diagnosis of PBL confirmed by reference neuropathology and methylation-based subtyping were analyzed by high-resolution genome-wide molecular inversion probe analysis. Seventy-two cases were screened for mutations by next-generation DNA panel sequencing. Survival data of 49 patients were available. Patients ≥4y received postoperative RT followed by maintenance chemotherapy (n=42); infants (&amp;lt;4y) were primarily treated on RT-sparing regimens with intensified chemotherapy. RESULTS According to epigenetic consensus PBL subtypes (Liu et al., 2021), our cohort consisted of 48 PBL-miRNA1 (1A=40; 1B=8), 17 PBL-miRNA2, 4 PBL-MYC/FOXR2, and 7 PBL-RB1 samples. PBL-miRNA subtype tumors had characteristic alterations in microRNA-processing genes; DICER1 mutations (n=18) and homozygous deletions of the DROSHA locus (n=17) were most abundant, followed by DROSHA mutations (n=12). Most frequent cytogenetic aberrations in PBL-miRNA were whole chromosome (chr.) 7 gain (n=30) and chr. 14 loss (n=21). DICER1 mutations were significantly associated with chr. 14 loss (p&amp;lt;0.001). Twenty-one cases showed gains of chr. 14, 8 additional cases gains of the OTX2 oncogene (chr. 14q). In the miRNA subtypes we identified cases with polyploid cytogenetics (n=15). Of note, only one of the 8 patients with polyploid tumors and survival data died, while the remaining patients of the miRNA subtypes had a 5-year PFS/OS of 61.46±9.27/63.24±9.23% (14 of 35 died) after a median follow-up time of 5.52 years. However, this comparison did not reach statistical significance (p=0.25). CONCLUSION The epigenetically defined PBL-miRNA subtypes are characterized by distinct cytogenetic and mutational events. A possible prognostic role for a superior (e.g. polyploidy) or inferior outcome requires investigation in prospective clinical trials.
EPEN-21. EXPLORATION OF TUMOR SUPPRESSOR LATS1 LOSS IN POSTERIOR FOSSA GROUP A EPENDYMOMA WITH LOSS OF CHROMOSOME 6Q
Authors: Andrew M Donson, Andrea M Griesinger, Annaliese Calzadilla, Vladimir Amani, Enrique Grimaldo, Nicholas K Foreman
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Chromosome 6q loss (6q-) has recently been identified as an ultra-high-risk factor in posterior fossa group A ependymoma (PFA). This study seeks to pinpoint the biological mechanism underlying the aggressive biology of PFA 6q-. We hypothesize that loss of chromosome 6q gene large tumor suppressor kinase 1 (LATS1) in PFA 6q- results in increased Hippo pathway activity that drives malignant tumor progression. LATS1 is a key negative regulator of the Hippo pathway which may represent a novel therapeutic vulnerability in 6q- PFA. METHODS We are testing this hypothesis using genomic and transcriptomic analysis of PFA patient samples, and by gene knock-in and pharmaceutical interventions of LATS1 and Hippo pathway components in PFA 6q- models. RESULTS Tumor suppressor LATS1 shows reduced expression in PFA 6q- patient samples. Although complete loss of the entire 6q arm is common in PFA 6q-, partial loss of chromosome 6q is also observed, and in all cases this partial loss encompasses the LATS1 locus on chromosome 6q. We used lentiviral transduction to knock-in LATS1 in PFA 6q- cell lines to determine the effect on tumor growth. This demonstrated loss of viability that was specific for 6q- PFA cell lines versus 6q WT control cell lines. DISCUSSION Data point to LATS1 loss being a key driver of the aggressive phenotype of PFA6q-, implicating the Hippo pathway in PFA 6q- and potential for novel therapeutic strategies.
ETMR-07. OVEREXPRESSION OF THE PLAG-GENE FAMILY MEMBER PLAG1 DURING MURINE BRAIN DEVELOPMENT LEADS TO ABERRANT EXPRESSION OF IMPRINTED GENES AND THE FORMATION OF MIDLINE BRAIN TUMORS
Authors: Jan Vaillant, Michaela-Kristina Keck, Andrea Wittmann, Nina Hofmann, Philipp Sievers, Angela Chen, Jacob S Rozowsky, Mariella G Filbin, Rameen Beroukhim, Pratiti Bandopadhahay, David T W Jones, Lena M Kutscher
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The transcription factor PLAG1, ordinarily active during development, has been identified as overexpressed in several pediatric brain tumor entities, including H3 K27-altered diffuse midline glioma. Additionally, our group recently identified a novel type of embryonic CNS tumors with amplification of the related genes PLAGL1 and PLAGL2. How this aberrant PLAG family gene activation drives tumor formation is unknown. We hypothesize that aberrant activity of these transcription factors impedes normal differentiation, thereby fostering neoplastic transformation. METHODS To investigate this, we utilize transgenic mouse models engineered to exhibit targeted PLAG1 overexpression and loss of Trp53 during brain development. Following, we use bulk and single-cell RNA-seq to examine underlying mechanisms and are working on whole genome CRISPR-Cas9 screens to detect genetic dependencies in derived tumorsphere cultures. RESULTS We found that transgenic mice develop brain tumors in the midline. RNA-seq of these tumors suggests the activation of developmental (homeobox transcription factors) and imprinted genes e.g. H19 and Dlk1, the latter being similarly activated in pediatric CNS tumors with PLAGL1/2 amplification. Using single-cell RNA-seq of the resultant tumors, we compared the gene expression profiles of the tumor cells to a developmental mouse brain atlas. Tumor cells best correlated to radial glia stem cells and glioblasts, supporting the hypothesis of a developmental block caused by PLAG1 overexpression. A subpopulation of the tumor cells seemed to escape the radial glia cell state but were then ultimately locked in the OPC state. A similar mechanism was observed in H3 K27M diffuse midline gliomas. CONCLUSION Collectively, we provide evidence that PLAG1 overexpression drives pediatric brain tumor formation by inhibiting normal cellular differentiation. The ongoing CRISPR screen in PLAG1 and PLAGL1 overexpressing murine cell lines, ChIP-seq analysis of the murine tumors, and comparisons with human data and hNSC models aims to unveil the specific molecular mechanisms underlying tumor progression.
EPEN-24. 5FU SENSITIVITY IS MEDIATED THROUGH TRISOMY UCK2 EXPRESSION IN 1Q+ PFA EPN
Authors: Andrea Marie Griesingr, Annaliese J Calzadilla, Enrique Grimaldo, Andrew M Donson, Vladimir Amani, Angela M Pierce, Jena Steiner, Soudabeh Kargar, Natalie J Serkova, Kelsey C Bertrand, Karen D Wright, Rajeev Vibhakar, Todd Hankinson, Michael Handler, Holly B Lindsay, Nicholas K Foreman, Kathleen Dorris
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Nearly all children with gain of chromosome 1q (1q+) PFA ependymoma (EPN) will die, highlighting the urgent need to develop new treatment strategies for these patients. It has recently been shown that 1q+ creates a p53 mutant-like phenotype through trisomy expression of MDM4, a repressor of p53 signaling. This same study found toxic uracil analogs could reverse trisomy MDM4 effect on p53 and this was mediated through another 1q-trisomy gene UCK2. We and other have previously identified 5-fluorouracil (5FU) as an ependymoma specific inhibitor. In this study, we present the mechanism for 5FU sensitivity. METHODS In this study we utilize 1q+ PFA in vitro models to test the efficacy of combination radiation and 5FU in a preclinical setting. We measured p53 signaling through proteomic array and qRT-PCR for p21, a p53 response gene. RESULTS 5FU enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of UCK2 located on chromosome 1q in 1q+ PFA. Experimental down regulation of UCK2 resulted in decreased 5FU sensitivity in 1q+ PFA cells. Though not statistically significant, we did see prolong survival and decreased tumor burden in 1q+ PFA orthotopic patient-derived xenograft models treated with focal 2Gyx5days radiation and 5FU. CONCLUSION These results are the first to identify a 1q+ specific therapy approach in PFA EPN. Existing phase 1 studies in pediatrics have already established safety and dose of 5FU, providing a rapid translation into phase 2 trials for children both up front and at recurrence for 1q+ PFA.
LMIC-16. PRE-IRRADIATION CHEMOTHERAPY AND DELAYED RADIATION THERAPY IN INFANTS AND YOUNG CHILDREN WITH WITH CENTRAL NERVOUS SYSTEM EMBRYONAL TUMOURS
Authors: Maya Prasad, Venkata Ramamohan Gollamudi, Archya Dasgupta, Abhishek Chatterji, Ayushi Sahay, Vikas Singh, Prakash Shetty, Aliasgar Moiyadi, Arpita Sahu, Amit Chaudhuri, Kajari Bhattacharya, Sridhar Epari, Tejpal Gupta, Girish Chinnaswamy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Established strategies for infants and young children(IYC) with embryonal tumours of the central nervous system(CNSET) - autologous stem-cell rescue(ASCT) and intraventricular chemotherapy(IVCT) – are not universally available. We report the outcomes of IYC with CNSET treated using the strategy of surgery, pre-irradiation chemotherapy and delayed radiation. METHODS Children &amp;lt;3years diagnosed with CNSET- medulloblastoma(MB), atypical teratoid/rhabdoid tumour(ATRT), embryonal tumour with multilayered rosettes(ETMR), CNS primitive neuroectodermal tumours(PNET)- and pineoblastoma(PB),underwent standard evaluation and staging, maximal safe excision, pre-irradiation chemotherapy(cyclophosphamide, etoposide and carboplatin;CEJ) upto 36months of age and either ris-adapted craniospinal with boost or focal irradiation. We performed a retrospective intention-to-treat outcome analysis. RESULTS Of 117children &amp;lt;3years with CNSET treated January2011- December2022, 72 were treated with this strategy.The median age was 25months (range6-35), 49males,histology medulloblastoma-42(58%), ATRT-9(12.5%), PNET-8(11.1%), ETMR-8(11.1%) and PB-5(6.8%); 23(32%) metastatic.The median chemotherapy cycles were 6(range 1-15). 36 children went on to receive RT; CSI in 33 (20standard-dose,13reduced-dose) and focal in 3. At last follow-up, 27children are in remission, 43 have relapsed/progressed (9 received salvage treatment) and 2 died due to chemotherapy toxicity. The 3-year and 5-year event-free-survival(EFS) are 35% and 3-year and 5-year overall-survival(OS) are 41.8% and 40.2%. The 3-year EFS/OS for MB are 51.1%/ 62.8%,PNET 25%/25%,ATRT 11.1%/11.1%,ETMR 12.5%/12.5% and PB 0%. Only metastasis was prognostic in medulloblastoma (HR 2;95% CI 0.86-4.6 for EFS and HR 1.7;95% CI 0.67-4.5 for OS); age, molecular group and histology were not prognostic. Long-term follow-up (n=17) documented &amp;gt;grade2 late effects in all (endocrine-16, neurocognitive-8, vision-3, hearing -8 and neurological-10). CONCLUSION The use of moderate-intensity pre-irradiation chemotherapy is feasible and effective in infants and young children with CNSETs. Despite inferior outcomes compared to ASCT or IVCT,this strategy could be used in resource-limited settings.
ATRT-06. PEDIATRIC INI1-NEGATIVE ATYPICAL TERATOID RHABDOID TUMORS TREATED WITH TAZEMETOSTAT AS MAINTENANCE THERAPY IN THE RELAPSE SETTING: AN ITALIAN SINGLE-CENTRE EXPERIENCE
Authors: Olga Nigro, Veronica Biassoni, Elisabetta Schiavello, Michela Casanova, Luca Bergamaschi, Giovanna Gattuso, Nadia Puma, Giovanna Sironi, Valeria Colombo, Marta Giorgia Podda, Stefano Chiaravalli, Cristina Meazza, Filippo Spreafico, Andrea Ferrari, Monica Terenziani, Roberto Luksch, Maura Massimino
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Rhabdoid tumors are aggressive malignancies, primarily affecting children ≤3 years. Common sites of primary localization are kidney, central nervous system (atypical teratoid rhabdoid tumor -AT/RT-) or soft tissues. Although high-dose chemotherapy (HD-CT) with radiotherapy (RT) has significantly increased EFS and OS rates, more than 50% of patients diagnosed with AT/RT still die of tumor progression. METHODS From February 2021 to January 2024 three patients with AT/RT were treated with tazemetostat after first-line treatment (complete resection, CT, RT). RESULTS At diagnosis, patient 1 presented with a lesion in the lamina quadrigemina and a renal mass; patient 2 and 3 with a lesion in the posterior cranial fossa. Median age at diagnosis was 8 months (3-34 months). Patient 1 died due to the progression of the disease (OS 24 months); patient 2 ended treatment with tazemetostat on December 2023; for patient 3 the treatment is still ongoing. Patient 1 started tazemetostat at the end of first-line treatment, as maintenance therapy. Before starting treatment with tazemetostat, patient 2 performed a re-irradiation on the tumor bed; patient 3 performed surgery and then RT on a new-onset spinal lesion. Median time of treatment with tazemetostat was 9 months (6-12 months). Patient 1 showed an EFS of 9 months. EFS of patients 2 and 3 has exceeded this timepoint. For patient 2 the treatment is ongoing (in total 6 months of treatment), with a complete response of the disease (CR); patient 3 ended treatment after 12 months, with a CR. Tazemetostat was overall well tolerated. CONCLUSIONS Despite the small number of patients, we feel able to state that the use of tazemetostat as a single agent in the relapse setting could represent a therapeutic promise as maintenance therapy. Future studies with a larger number of patients are needed to confirm this hypothesis.
IMG-07. PEDIATRIC CRANIAL INCIDENTALOMAS: A SYSTEMATIC REVIEW UTILIZING MACHINE LEARNING
Authors: Anne M Cochrane, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The use of diagnostic neuroimaging in the care of pediatric patients continues to increase, leading to a rise in incidentally discovered lesions. The understanding of appropriate assessment and management of these findings is critical to providing comprehensive and timely care. This review aims to analyze the current literature to characterize diagnostic and prognostic characteristics of incidentally found brain tumors in pediatric patients. METHODS Using the guidelines under the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), Pubmed and Medline (NCBI) databases were searched using selected keyword combinations and machine learning-assisted software. Case reports, case series, and retrospective cohort studies published up to December 2023 were included. RESULTS A total of 20 studies encompassing 627 patients were included in the review. The most common indications for imaging were headache (204; 33%), seizures (96; 15%), and trauma (78; 12%). Of studies providing information regarding localization, lesions were found in the supratentorial region in 327 (52%) cases and infratentorial region in 190 (30%). Of studies reporting imaging characteristics, T1 hypointensity (183/302; 61%), T2 hyperintensity (410/497; 82%), and no contrast enhancement (58/97; 60%) were the most common findings. Four hundred and thirty (68%) patients were observed after diagnosis, 83 (13%) patients underwent surgical intervention at diagnosis, and 40 (6%) patients underwent surgery after observation. Of 91 patients with histopathology data available, pilocytic astrocytoma (19; 21%) was most commonly reported. CONCLUSION In this study, we provide a review of diagnostic characteristics of incidentally discovered brain tumors in the pediatric population. Management of such lesions has changed greatly over the past several decades, and risks of surgical intervention should be weighed against a more conservative management and interval monitoring approach. These results may help guide discussions regarding disclosure of findings and recommendations for additional clinical management.
EPEN-29. IS THE OUTCOME OF SUPRATENTORIAL EPENDYMOMA WITH ZFTA FUSION REALLY POOR?
Authors: Amy A Smith, Shelly Lensing, Arzu Onar-Thomas, Sarah Leary, Maryam Fouladi, Nicholas K Foreman, David W Ellison
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Survival of children with intracranial ependymoma is known to depend, in part, on the molecular group of the tumor. Previous studies have linked both PFA and ZFTA molecular group ependymomas to poor outcomes. As part of an unplanned analysis from ACNS0831, we explored outcomes for ZFTA supratentorial (ST) and PFA ependymomas. METHODS Patients were stratified by location, grade and extent of resection. Grade 2, ST tumors with no evidence of disease were observed only, N=37. All other patients were randomized to RT versus RT + maintenance chemotherapy or non-randomly assigned to RT + M if residual disease. A planned “as treated” analysis was performed by actual treatment received for randomized patients, excluding those who did not receive RT. Molecular groups were compared using two-sided log-rank tests stratified by study arms for all and randomized patients. Molecular characterization was achieved in 161/166 (97%) ST and 282/283(99.6%) PF. Among ST, 94% were classified ZFTA and 6% YAP1. Homozygous CDKN2A deletion was detected in 16 tumors, all ZFTA and WHO grade 3. Among posterior fossa ependymomas, 88% were classified as PFA and 12% as PFB. RESULTS There was no statistical difference in outcome according to treatment. Across all study arms, 5-year EFS was 69.6%+4.3 for ZFTA vs. 52.9%+3.4 for PFA (p=0.028). For the randomized cohort, 5-year EFS was 72.1+4.8 for ZFTA vs. 60.1+3.9 for PFA (p=0.076). For the randomized cohort with initial GTR/NTR, 5-year EFS was 74.1+5.1 for ZFTA patients vs. 61.0+4.2 for PFA patients (p=0.045). The 5-year EFS was 66.7+12.2 for ZFTA patients with CDKN2A deletion vs. 69.3+4.7 for ZFTA patients without CDKN2A deletion (p=0.232) CONCLUSION Children with ST ZFTA ependymomas have a significantly better outcome than those with PFA tumors. Homozygous deletion of CDKN2A was present in 12% of ST ependymomas but was not an indicator of poor outcome.
CP-16. PROTEOMIC ANALYSIS OF ADAMANTINOMATOUS CRANIOPHARYNGIOMA REVEALS A COMPLEX NETWORK OF ECM REMODELING
Authors: Aaron Knox, Stephen Medlin, Keanu Chee, Susan Staulcup, Eric W Prince, Todd C Hankinson, Siddhartha Mitra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Adamantinomatous craniopharyngiomas (ACPs) are the most challenging pituitary tumors in children. Despite their histological classification as benign, ACPs exhibit an aggressive clinical demeanor, posing challenges in management and conferring a suboptimal quality of life. The anatomical intricacies of ACPs often preclude complete surgical excision. The greatest morbidity of ACP is associated with damage to the hypothalamus - iatrogenically or through direct invasion, which may be dependent upon extracellular matrix (ECM) remodeling. We endeavored to describe the ECM components of ACPs and the protein milieu that may alter the ECM. METHODS High throughput imaging mass cytometry (IMC) alongside conventional histological staining methods. IMC offers unparalleled resolution in detecting ECM constituents, which may play pivotal roles in tumor pathophysiology and could represent novel therapeutic targets. We also employed SomaScan, an innovative, high-throughput, aptamer-based protein quantification platform. SomaScan utilizes Slow Off-Rate Modified Aptamers (SOMAmer Reagents) for the measurement of a broad spectrum of proteins within various biological fluids, including plasma and cyst fluid. RESULTS We identified prominent collagen tracts within ACP, which are further interspersed with areas of increased fibrosis surrounding wet keratin, suggestive of focal inflammatory response to cyst fluid. SomaScan identified elevated levels of proteins implicated in neutrophil degranulation. Neutrophil degranulation plays a significant role in ECM remodeling, a process critical to tumor progression and invasion. The association of neutrophils with ECM remodeling in ACPs suggests a potential mechanism through which these tumors might facilitate their own growth and invasion. The elevated protein markers of neutrophil degranulation may also serve as potential biomarkers or therapeutic targets, offering a novel approach to managing these tumors. CONCLUSIONS By integrating the data from IMC and SomaScan, our findings reveal a complex interplay between ACPs and the immune system, particularly highlighting the role of neutrophils in the tumor microenvironment.
IMG-06. IMAGING-BASED, TEMPORALIS MUSCLE THICKNESS AS A BIOMARKER IN CHILDREN WITH GLIOMAS
Authors: Anna Zapaishchykova, Divyanshu Tak, Zezhong Ye, Sridhar Vajapeyam, Ceilidh Smith, Kevin X Liu, Hugo J W L Aerts, Susan N Chi, Daphne A Haas-Kogan, Ali Nabavizadeh, Ariana Familiar, Sabine Mueller, Tina Y Poussaint, Benjamin H Kann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Sarcopenia, or lean muscle loss, causes morbidity and early mortality in pediatric cancer patients and survivors. Sarcopenic patients who are also obese have a particularly morbid metabolic condition that cannot be identified by body mass index (BMI) alone. Temporalis muscle thickness (TMT) on T1-weighted MRI provides a direct assessment of lean muscle mass. In this study, we determined how TMT was associated with nutritional and survival outcomes in children with gliomas using an automated deep-learning pipeline that calculates TMT on MRI and provides age-and sex-specific TMT percentiles (iTMT). METHODS We analyzed a cohort of 343 patients and 1,673 scans (244 low-grade gliomas(LGG) and 99 high-grade gliomas (HGG)) diagnosed between 2000-2023 at Boston Children’s Hospital/Dana-Farber Cancer Institute, who had linked longitudinal MRI and clinical data available. We calculated and compared age-adjusted iTMT, BMI, weight percentiles, and serum albumin. Sarcopenic obesity in glioma survivors was defined as sarcopenic iTMT (&amp;lt;5th %tile) and obese BMI (&amp;gt;95th %tile). RESULTS iTMT was significantly correlated with BMI (N=1,574 scans, Spearman r=0.34, p=4e-45) and weight (N=1,574 scans, r=0.21, p=1e-17), but not serum albumin (N=84 scans, r=-0.04, p=0.66) at any given time point. Of all patients, 113(36.4%) had sarcopenic obesity during at least one time point. For HGG patients, those with less than the median survival time (550 days) had significantly lower baseline iTMT (median: 6th %tile vs. 33rd %tile, p=0.01). For LGG patients, symptoms of malnutrition at diagnosis were associated with a trend toward lower iTMT (N=244, 19th %tile vs.28th %tile, p=0.07). CONCLUSION Our study demonstrates that iTMT is an independent biomarker for malnutrition and survival for pediatric gliomas and can identify patients with sarcopenic obesity. iTMT assessment on routine clinical MRI could be a practical way to monitor muscle status and guide supportive interventions in children with brain tumors.