bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEDB-62. Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation
Authors: Chen Zhuoyao , Ioris Rafael , Richardson Stacey , Van Ess Ava , Vendrell Iolanda , Kessler Benedikt , Buffa Francesca , Busino Luca , Clifford Steven , Bullock Alex , D'Angiolella Vincenzo 
Published: June 2022

Abstract
Genomic studies in medulloblastoma have identified distinct disease subgroups: wnt/wingless (WNT), sonic hedgehog (SHH), and non-WNT/non-SHH, comprising group 3 and group 4. Alterations in WNT and SHH signalling form the pathogenetic basis for their subgroups, whereas those for non-WNT/non-SHH tumours remain largely elusive. Recent analyses have revealed recurrent in-frame insertions in the E3 ubiquitin ligase adaptor Kelch Repeat and BTB Domain Containing 4 (KBTBD4) in cases of group 3 and group 4 medulloblastoma. Critically, group 3 and 4 tumours with KBTBD4 mutations typically lack other gene-specific alterations, such as MYC amplification, indicating KBTBD4 insertion mutations as the primary genetic driver of these malignancies. Delineating the role of KBTBD4 mutations in medulloblastoma thus offers significant opportunities to understand its pathogenesis and exploit underpinning mechanisms therapeutically, however their function is currently unknown. Here, we show a novel mechanism in cancer pathogenesis whereby indel mutations in KBTBD4 drive its recognition of neo-substrates for degradation. We observe that KBTBD4 mutants promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. The degradation of CoREST promoted by KBTBD4 mutations diverts epigenetic programmes inducing significant alterations in transcription to promote increased stemness of cancer cells. Transcriptional analysis of &gt;200 human group 3 and 4 medulloblastomas by RNA-seq, highlights the presence of CoREST and stem-like signatures in tumours with KBTBD4 mutations, which extend to a further sub-set of non-mutant tumours, suggesting CoREST alterations as a novel pathogenetic mechanism of wide relevance in group 3 and 4. Our findings uncover KBTBD4 mutation as a novel driver of epigenetic reprogramming in non-WNT/non-SHH medulloblastoma, establishes a novel mode of tumorigenesis through gain-of-function mutations in ubiquitin ligases (neo-substrate recruitment) and identifies both mutant KBTBD4 and CoREST complexes as new druggable targets for improved tumour-specific therapies.
MEDB-78. Unified rhombic lip origins of Group 3 and Group 4 medulloblastoma
Authors: Smith Kyle , Bihannic Laure , Gudenas Brian , Gao Qingsong , Haldipur Parthiv , Tao Ran , Iskusnykh Igor , Chizhikov Viktor , Scoggins Matthew , Zhang Silu , Edwards Angela , Deng Mei , Glass Ian , Overman Lynne , Millman Jake , Sjoboen Alexandria , Hadley Jennifer , Mankad Kshitij , Onar-Thomas Arzu , Gajjar Amar , Robinson Giles , Aldinger Kimberly , Hovestadt Volker , Tillman Heather , Orr Brent , Patay Zoltán , Millen Kathleen , Northcott Paul 
Published: June 2022

Abstract
Identification and characterization of lineage-specific beginnings of distinct medulloblastoma (MB) subgroups is a fundamental challenge in the field. Genetically engineered mouse models and cross-species transcriptomics have provided mounting evidence of discrete, subgroup-specific developmental origins. Likewise, murine single-cell transcriptional atlases of cerebellar development have recently provided further clues into MB subgroup origins, particularly for poorly defined Group 3 and Group 4-MB. However, initial studies were underpowered to characterize rare populations and lacked robust validation, resulting in incomplete findings. Herein, we leveraged a large harmonized murine cerebellar atlas, targeted lineage enrichment, and integrative multi-omic strategies to deeply dissect MB origins. Isolation of spatially and temporally discrete developmental trajectories of key glutamatergic lineages born out of the murine upper rhombic lip provided an enhanced reference for mapping MB subgroup origins, especially for Group 3 and Group 4-MB. However, human-specific anatomic and cellular complexity, particularly within the rhombic lip germinal zone complicated murine-derived inferences. Further tumor-normal integrations using a novel single-cell atlas of the human fetal cerebellum, companioned with laser-capture micro-dissected transcriptional and epigenetic datasets, reinforced developmental insights extracted from candidate murine cerebellar lineages. Characterization of compartment-specific transcriptional signatures identified in the human upper rhombic lip implicated convergent cellular correlates of Group 3 and Group 4-MB, suggestive of a common developmental trajectory underlying their ancestry. Systematic imaging review and 3D summarization of a large clinical trial series of patient tumors, coupled with our advanced insights into developmental signatures, substantiated subgroup-specific tumor location patterns observed at diagnosis. Together, our results strongly implicate a common lineage trajectory of the upper rhombic lip as the probable origin of Group 3 and Group 4-MB. These important findings provide unprecedented opportunities to explore context-dependent mechanisms of MB pathogenesis and will foster generation of improved preclinical models that more faithfully recapitulate tumor biology.
QOL-06. What impact does a posterior fossa tumor in childhood have on motor procedural learning? Group performance depending on radiotherapy status and individual differences on a perceptivo-motor sequence learning task and a motor adaptative task (IMPALA prospective study)
Authors: Baudou Eloïse , Pollidoro Lisa , Tallet Jessica , Danna Jérémy , Pariente Jérémie , Chaix Yves , Laprie Anne 
Published: June 2022

Abstract
INTRODUCTION: Procedural memory (PM) is a skill learning system that allows, through training, the automatization of procedures and progressive improvement of performances. The aim of this work was to explore the impact of a posterior fossa tumor (PFT) on PM. We hypothesized that motor adaptation, depending on cortico-cerebellar system, was impaired in PFT survivors treated with and without radiotherapy, and motor sequence learning, depending on cortico-striatal system, was only impaired in PFT treated with radiotherapy. METHODS: We investigated PM in 60 participants from the IMPALA study (NCT04324450) divided into three groups: 39 cured from a PFT in childhood (22 irradiated (PFT+RT group) and 17 non-irradiated (PFT group)) and 21 healthy volunteers (Control group) matched on age, sex and handedness with the PFT+RT group. We used a visuo-motor learning test, the Serial Reaction Time task (SRTT) and a motor adaptation task (MAT) of backwards handwriting. ANOVA and mixed models were used for statistical analysis. RESULTS: SRTT performance analysis showed an effect of Block in specific sequence learning (F(1)48.70,p&lt;0.001) with a preserved specific learning in the three groups. However individual differences were observed with 7/22 patients in PFT+RT group and 4/17 in PFT group who did not have specific learning. MAT performance analysis showed an effect of interaction between Orientation (forward or backward) and Group for speed (F(2)15.58,p&lt;0.001), linearity (F(2)8.39,p&lt;0.001) and amplitude standard deviation (F(2)15.70,p&lt;0.001) traducing an impairment both in PFT+RT and PFT groups, more marked in the PFT+RT group. CONCLUSION: We showed impairment, predominantly on motor adaptation but also, at individual level, in motor sequence learning whose origin requires additional work. This study brings new insights on the long-term impact of a PFT in childhood on a rarely investigated part of memory that is PM.
SURG-07. The impact of early targeted therapy on the neurosurgical approach to pediatric low-grade glioma
Authors: Piatelli Gianluca , Pavanello Marco , Piccolo Gianluca , Rossi Andrea , Garrè Maria Luisa , De Marco Patrizia , Iurilli Valentina , Antonelli Manila , Gaggero Gabriele , Caruggi Samuele , Verrico Antonio , Crocco Marco , Milanaccio Claudia 
Published: June 2022

Abstract
We report two cases of pediatric low-grade glioma (pLGG) treated with vemurafenib, an oral BRAF-inhibitor: a 12-year-old girl with involvement of basal ganglia, hypothalamus, and diencephalic junction; a 3-year-old boy, with an optic pathway/hypothalamic glioma extending along the left optic tract and basal ganglia. Both received a biopsy and molecular analysis was performed in the girl’s tumor, showing BRAF V600E mutation. Therefore, instead of surgical removal planned by neurosurgeons, first-line treatment with vemurafenib was started: after one month 45% reduction of the mass according to RANO criteria was found, as well as better balance control and strong reduction of the right arm paresis; five months later, a 70% shrinkage was detected, stabilized to 76% after a year. The young boy first started chemotherapy with vincristine and carboplatin, but at the end of the induction phase the tumor had increased and ascites, hydrocephalus, and visual impairment occurred. Molecular testing showing BRAF V600E mutation on the initial tumor biopsy was obtained; therefore, the surgical option was postponed and therapy with vemurafenib started. After only three days, visual acuity and muscle tone improved; brain MRI showed a 34% reduction of the mass after one week, increased up to 65% after six months. Therefore, no ulterior surgery was necessary. In pLGG, the neurosurgical biopsy is essential to let an early and rapid molecular diagnosis of BRAF mutations and guide subsequent targeted therapies. Our cases demonstrate how a prompt radiological response to vemurafenib and the related clinical improvement can influence both therapeutic and surgical decisions, hopefully reducing the occurrence of second neurosurgery with associated risks of neurological sequelae. To our knowledge, this is the first report assessing such a quick shrinkage in pLGG treated with vemurafenib, highlighting the importance of an early investigation of BRAF status in all cases of LGG in children.
OTHR-08. Pediatric Neurologic Assessment in Neuro-oncology (pNANO) Scale: A tool to assess neurologic function for Response Assessment in Neuro-oncology (RAPNO)
Authors: Malbari Fatema , Erker Craig , Driever Pablo Hernáiz , Pillay-Smiley Natasha , Avery Robert A , Castellino Robert Craig , Schouten-van Meeteren Antoinette A Y N , Lenzen Alicia C , Brandsma Rick , Kramer Kim , Baxter Patricia A , Dhall Girish , Goldman Stewart , Wen Patrick Y , Prados Michael , Packer Roger J , Warren Katherine E , Nayak Lakshmi 
Published: June 2022

Abstract
Background: The Neurologic Assessment in Neuro-Oncology (NANO) scale, a standardized metric to objectively measure neurologic function in adult brain tumor patients, complements radiographic assessment in evaluating outcomes of neuro-oncology patients in clinical trials and clinical practice. Currently, there is no standardized measure for neurologic function in pediatric neuro-oncology patients despite their distinct clinical presentations and tumor locations. Therefore, we developed a dedicated pediatric NANO (pNANO) scale. Methods: An international group of pediatric neurologists and adult and pediatric neuro-oncologists convened bi-weekly over 5 months to draft the pNANO scale as an objective and quantifiable measure of neurologic function in children that can be administered during routine examination by pediatric-trained providers of any sub-specialty and be utilized together with other indicators to assess response in clinical trials. Results: Ten relevant domains of neurologic function were identified based on common pediatric brain tumor locations: gait, strength, cerebellar function, visual fields, visual acuity, facial strength, level of consciousness, extraocular movements, dysarthria and dysphagia. For each domain, developmental age appropriate levels of function were defined and categorized. Each domain, based on direct observation and testing during any routine neurological exam, can be used for longitudinal monitoring. Conclusions: The pNANO scale has been developed and aims to provide an objective metric of neurologic function for pediatric brain tumor patients. This scale will be tested for reliability, feasibility and inter-observer variability. Consistent evaluation of neurologic function using pNANO along with radiographic assessment will enable more comprehensive and standardized response assessment in pediatric neuro-oncology patients enrolled in clinical trials.
OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type
Authors: Keck Michaela-Kristina , Sill Martin , Wittmann Andrea , Kumar Piyush Joshi , Stichel Damian , Sievers Philipp , Wefers Annika K , Roncaroli Federico , Hayden James , McCabe Martin G , Kranendonk Mariëtte E G , Zapotocky Michal , Vasiljevic Alexandre , Schüller Ulrich , Sturm Dominik , Blattner-Johnson Mirjam , von Deimling Andreas , Korshunov Andrey , Sahm Felix , Perry Arie , Solomon David , Pfister Stefan , Jones David T W 
Published: June 2022

Abstract
Pediatric central nervous system (CNS) tumors differ substantially from their adult counterparts, are marked by considerable molecular and clinical heterogeneity, and diagnosis through histopathology alone can be challenging. Using DNA methylation-based CNS tumor classification in combination with copy number and RNAseq analysis, we identify a rare, novel pediatric CNS tumor type (n=32) which is characterized by focal high-level amplification and consecutive overexpression of one of the PLAG family genes – PLAGL1 or PLAGL2. It is epigenetically divergent from other known tumor types such as high-grade gliomas, medulloblastomas, embryonal tumors, or CNS sarcomas. The wide range of original histopathologic diagnosis rendered attests to their polyphenotypic nature in terms of morphology. We suggest that these tumors may arise from early to intermediate neural progenitor cells with some neuronal commitment. Using ChIPseq data, we show that both PLAGL1 and PLAGL2 act as transcription factors for: i) the oncogenic kinase RET, a potential drug target, that was overexpressed in our cohort; ii) components of the Wnt/β-Catenin pathway; iii) a set of imprinted genes, reported to regulate the imprinted gene network in mouse models, that was deregulated in the PLAGL-amplified tumors. Consequently, a 250-gene expression PLAGL-signature indicated dysregulation of imprinting control and differentiation/development as a prominent feature. We report differences regarding age and sex distribution between PLAGL1- and PLAGL2-amplified tumors and shed light on differences in clinical behavior and outcomes between these subtypes in male and female patients. PLAGL1-amplified tumors were more prevalent in school-age children and teenagers, while PLAGL2-amplified cases occurred in very young patients. Kaplan-Meier analysis showed a trend towards a more favorable outcome in patients with PLAGL1-amplified tumors and in female patients. Survival rates remained constant after 5 years with a five-/ten-year overall survival of 75% for PLAGL1, 24% for PLAGL2, 18% for male patients, and 88% for female patients.
LINC-21. PROGNOSTIC FACTORS AND SURVIVAL OF LOW-GRADE GLIOMAS IN CHILDREN AND ADOLESCENTS – A MULTICENTER STUDY IN PERU
Authors: Diaz-Coronado Rosdali , Hernández-Broncano Eddy , Casavilca-Zambrano Sandro , Campos-Sanchez Danny , Maza Ivan , Tello Mariela , Leon Esmeralda , Cañari Hernan , Custodio Javier , Ojeda-Medina Luis , Negreiros Tatiana , Cordova Olga , Mora-Alferez Pamela , Garcia-Leon Juan , Vasquez Liliana , Moreira Daniel , Qaddoumi Ibrahim 
Published: June 2022

Abstract
BACKGROUND: Low-grade gliomas (LGG) are the most common central nervous system (CNS) tumors in children. Peru is an index country for the Global Initiative for Childhood Cancer (GICC). As part of the Initiative, a multidisciplinary brain tumor team was formed in 2020 that includes five national reference centers: National Institute of Neoplastic Diseases, National Children’s Health Institute-San Borja, National Children’s Health Institute-Breña, Edgardo Rebagliati Martins National Hospital and Guillermo Almenara Irigoyen National Hospital. This multicenter study sought to evaluate the survival and prognostic factors of patients younger than 18 years diagnosed with LGG, an index cancer for the GICC. METHODS: A retrospective study included all patients diagnosed with LGG in the five centers between 2014 and 2018. We analyzed clinical characteristics, histology, and treatment modalities. We used the Kaplan-Meier method for survival. RESULTS: 194 patients were registered; 136 patients were included. M/F ratio was 1.2, mean age 7 years old. The most frequent location was infratentorial (42.2%), supratentorial (34.9%), optic/chiasm/sellar (11%) and brainstem (11.9%). The most frequent histological types were pilocytic astrocytoma (61%), diffuse astrocytoma (10.3%), oligodendroglioma (5.2%), and other low-grade neoplasms (23.5%). Surgery was performed in 109 patients (83.2%). Chemotherapy alone was used in 17 (12.5%), while radiotherapy in 20 (14.7%). Overall survival at 5 years was 82.9% (95% CI 73.3 - 89.4). Age younger than 3 years (p=0.002), diffuse histological type (p=0.04), and location in the brainstem (p=0.001) were factors associated with a worse prognosis. CONCLUSIONS: Within the framework of the GICC, this work is one of the first steps to understand the current context of pediatric CNS tumor care in Peru. Although the reported survival rate is about the GICC goal of 60%, further improvements in care are needed to increase survival to level closer to high-resource setting and decrease long term morbidity.
MODL-15. High-throughput combination drug screening identifies synergism between retinoic acid treatment and BCL-XL-inhibition in MYC(N)-driven medulloblastoma and neuroblastoma models
Authors: Seiboldt Till , Zeiser Constantia , Salem-Altintas Rabia , Nguyen Duy , Holland-Letz Tim , Peterziel Heike , Witt Olaf , Oehme Ina 
Published: June 2022

Abstract
PURPOSE: Despite remarkable improvements in childhood cancer survival, certain high-risk entities including malignancies of the nervous system still carry dismal prognoses. Retinoic acid (RA) treatment has long been administered in high-risk neuroblastoma patients and preclinical data suggest a benefit in applying retinoids in selected brain tumor entities. However, limited single-agent efficacy and developing treatment resistance provide a rationale for investigating improved combination treatments. METHODS: We assessed the RA sensitivity of 16 cell lines and patient-derived cultures of pediatric nervous system tumors from the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) registry. Bulk RNA sequencing was performed for five sensitive models undergoing RA treatment. All models were screened for drug sensitivity to 76 clinically relevant drugs alone and combined with RA. Beneficial hit combinations were further investigated for synergy, as well as their effect on differentiation and apoptosis by high-content fluorescence microscopy and caspase activity assay. Results from in vivo experiments are pending. RESULTS: Group 3 medulloblastoma and high-risk neuroblastoma models were most sensitive to RA treatment leading to significant changes in gene expression of apoptotic regulation. Drug sensitivity screening revealed similar patterns of response to combination treatments in MYC-driven Group 3 medulloblastomas and MYCN-amplified neuroblastomas. Apoptosis regulating BCL-XL-inhibitors (A-1155463, navitoclax) were identified as top hits across RA sensitive models, whereas epigenetic BET family inhibitor I-BET151 and histone deacetylase inhibitor entinostat suggested entity-specific combination benefits in neuroblastoma and medulloblastoma models, respectively. In both entities, combining RA with navitoclax was synergistic and significantly increased caspase-3 activity. The combination led to a morphological shift from differentiation under RA treatment to cell death. CONCLUSION: Exploring combinations for RA treatment in pediatric nervous system tumors, we found that MYC(N)-driven medulloblastoma and neuroblastoma not only share responsiveness to RA treatment, but also demonstrate enhanced vulnerability in combination with BCL-XL-inhibition resulting in increased apoptosis.
MODL-20. Metabolic rewiring support the onset of chemotherapy resistance in medulloblastoma
Authors: Bortolozzi Roberta , Mariotto Elena , Rampazzo Elena , Manfreda Lorenzo , Marchioro Chiara , Rruga Fatlum , Persano Luca , Viola Giampietro 
Published: June 2022

Abstract
Medulloblastoma (MB) is the deadliest brain tumor of childhood, intrinsically characterized by fast growth, high invasiveness, and resistance to treatments. With the aim to deepen the molecular basis of MB aggressiveness and recurrence, we established an in vitro model of MB resistance to chemotherapy, in which, a weekly exposure to a cocktail of chemotherapeutics commonly used in MB treatment (Vincristine, Etoposide, Cisplatin, Cyclophosphamide – VECC) induces the selection of cells that progressively acquire resistance to subsequent VECC treatments. Preliminary data on our model of MB resistance show that resistant cells induce the activation of the two main regulator of pentose phosphate pathway TKT and G6PD via the activation of Nrf2 transcriptional activity. Moreover, resistant cells show an increase in hypoxia inducible factor-1α (HIF-1α) together with an augmented expression of glycolytic enzymes HK1, PFKB-3, PDK1 and LDHA and increased glycolytic capacity. Interestingly, enrichment analysis on label free mass spectrometry data reveal that the most significant terms deriving from the upregulated proteins, that characterized resistant cells, were related to metabolic processes such as “carbon metabolism”, “fatty acid beta oxidation”, “tricarboxylic acid cycle” and “carboxylic acid catabolic processes”.Consistently with recent studies that highlight the relevance of metabolic plasticity of cancer cells in chemotherapy adaptation, our data suggest a metabolic uncoupling in which MB resistant cells, through the alteration of peculiar metabolic processes, may satisfy their altered energetic demands through alternative metabolic pathways. In this way, the generation of a new balance of intracellular metabolites finally provide increased resistance to external insults (i.e., chemotherapeutics) and a greater ability of detoxifying the intracellular compartments.