bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-41. DECIPHERING PEDIATRIC LOW-GRADE GLIOMA TRAJECTORIES: DEEP LEARNING-BASED VOLUMETRICS FOR PATIENTS UNDER SURVEILLANCE
Authors: Pardo Juan Carlos Climent , Zapaishchykova Anna , Boyd Aidan , Tak Divyanshu , Mahootiha Maryamalsadat , Ye Zezhong , Vajapeyam Sridhar , Bandopadhayay Pratiti , Nabavizadeh Ali , Familiar Ariana , Poussaint Tina Young , Aerts Hugo , Haas-Kogan Daphne A , Kann Benjamin H 
Published: June 2024

Abstract

BACKGROUND
Pediatric low-grade gliomas (pLGGs) have heterogeneous clinical presentations and prognoses. Given the morbidity of treatment, suspected pLGGs are surveilled without treatment, though the natural histories of these tumors have yet to be systematically studied.

METHODS
We conducted a pooled, retrospective study of pLGG patients diagnosed between 1992 and 2020 from two sources (Dana-Farber Cancer Institute/Boston Children’s Hospital and the Children’s Brain Tumor Network), who were surveilled untreated for at least one-year post-diagnosis and who had linked clinical data and longitudinal MRI available. We applied a validated pLGG deep learning segmentation algorithm to longitudinal T2-weighted MRIs and calculated the 3-dimensional volumes at each timepoint. We evaluated individual tumor trajectories, treatment initiation, and clinical risk factors for radiographic progression and regression (defined as volumetric change &gt;=25% and &lt;=-25% respectively) with univariable and multivariable logistic regression. Unsupervised time-series K-means and density-based spatial clustering with dynamic time wrapping were conducted to uncover volumetric phenotypes and a statistical time-series algorithm with auto-regressive integrated moving average was evaluated to predict future volumetric changes.

RESULTS
Of 1774 scans from 129 patients (median follow-up of 4.0 years), baseline tumor median volume was 5.8cm3 (range: 0.01-108.1), with 33 cortical (25.5%), 21 brainstem (16.2%), and 21 (16.2%) cerebellar locations. At the last follow-up, 33.8% of tumors progressed, 35.8% were stable, and 30.2% had regressed. Treatment was initiated for 46.5% of the tumors, of which 70.4% underwent surgery. Risk factors such as adolescent age, larger baseline volume size, cortical location and symptomatic presentation were most associated with progression (p&lt;0.05 for each). Clustering revealed three distinct volumetric phenotypes with diverging natural histories, corresponding to progression, stability or regression. The forecasting showed average root-mean-squared error values of &gt;1cm3 at testing.

CONCLUSIONS
Deep learning auto-segmentation enables longitudinal, volumetric tracking of pLGG, yielding novel insights into the clinical trajectories of untreated tumors on surveillance.
LGG-44. CLINICAL AND MOLECULAR TUMOR CHARACTERISTICS OF ‘HIGHER RISK’ PEDIATRIC LOW-GRADE GLIOMAS
Authors: Rijsdijk Tiago , Lammers Julie A S , Hoving Eelco W , Wesseling Pieter , Tops Bastiaan B J , Kester Lennart , Meijer Lisethe , van Meeteren Netteke A Y Schouten- , Kersbergen Karina J , van der Lugt Jasper , Hoogendijk Raoll , Kranendonk Mariette E G 
Published: June 2024

Abstract

BACKGROUND
CNS WHO grade 1 pediatric low-grade gliomas (pLGGs) have an overall excellent survival. A small but relevant proportion of these patients, however, suffer from severe disease burden reflected in recurrent progression, metastasis or even death. To unravel clinicomolecular tumor characteristics that identify these ‘pLGG-higher risk’ patients we retrospectively analyzed clinical and molecular data of 223 patients from our center.

METHODS
All tumors were classified using histology, DNA methylation profiling and whole transcriptome analysis (RNA sequencing), with whole exome or panel DNA sequencing in a subset of cases, revealing a driver alteration in 100% of cases. Progression of disease was defined as continuous tumor growth upon treatment or need for multiple treatments. The effect of clinical and molecular variables on progression free survival was analyzed with the univariate and multivariate cox proportional hazard model.

RESULTS
The median follow-up of the entire cohort was 3,4 years. In univariate analyses the risk of progression significantly decreased with age (in years) at diagnosis (HR 0.92,p&lt;0.001). For tumor location using hemispheric tumors as reference, chiasm/suprasellar LGGs showed a significantly higher risk of progression (HR 2.96,p&lt;0.001). Type of molecular driver and sex was not associated with progression. In a multivariable model including age, location and driver, there was no longer a significant effect on progression for age but the effect of chiasm/suprasellar location remained intact. Furthermore, NF1 (HR 0.37,p0.02), and posterior fossa LGG (HR 0.24,p0.03) were both significantly associated with a lower risk of progression.

CONCLUSIONS
Our multivariate results show that the ‘pLGG-higher risk’ patients were characterized by a tumor in the chiasm/suprasellar location, while molecular driver (at least so far) did not affect risk of progression. Future work will focus on extending the cohort and integrating other multiomic data enabling to compose a prediction model for higher risk pLGG.
MDB-01. A POSITIVE FEEDBACK LOOP BETWEENLNC-HLX-2-7, HLX, AND MYC STRONGLY PROMOTES GROUP 3 MEDULLOBLASTOMA
Authors: Katsushima Keisuke , Joshi Kandarp , Yuan Menglang , Batish Mona , Stapleton Stacie , Jallo George , Seal Sudipta , Taylor Michael D , Wechsler-Reya Rober J , Eberhart Charles G , Perera Ranjan J 
Published: June 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&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&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.
MDB-12. NANOPORE SEQUENCING AS A CUTTING-EDGE TECHNOLOGY FOR MEDULLOBLASTOMA CLASSIFICATION
Authors: Filser Mathilde , Torrejon Jacob , Merchadou Kevin , Girard Elodie , Bourneix Christine , Lemaître Elisa , Brillet Riwan , Wong Jennifer , Gentien David , Rapinat Audrey , Servant Nicolas , Vasiljevic Alexandre , Bertozzi Anne-Isabelle , Raimbault Sandra , Tauziède-Espariat Arnault , Lhermitte Benoit , Faure-Conter Cécile , Icher Céline , Berger Claire , Maurage Claude-Alain , Bodet Damien , Meyronet David , Uro-Coste Emmanuelle , De Carli Emilie , Forest Fabien , Palenzuela Gilles , Chotard Guillaume , Gauchotte Guillaume , Sudour Hélène , Mansuy Ludovic , Deparis Mariana , Machet Marie-Christine , Faisant Maxime , Entz-Werle Natacha , Varlet Pascale , Leblond Pierre , Michalak-Provost Sophie , Houdemont Stéphanie Proust , Rigau Valérie , Doz François , Bourdeaut Franck , Delattre Olivier , Ayrault Olivier , Masliah-Planchon Julien 
Published: June 2024

Abstract

INTRODUCTION
Medulloblastoma (MB) is one of the most prevalent embryonal malignant brain tumors, divided into four distinct molecular subgroups (WNT, SHH, group 3, and group 4) with its individual prognosis. A more extensive classification of MB has recently been provided, identifying numerous subtypes, some with poor prognosis, leading to a significant number of patients succumbing to the disease while many survivors experience long-term side effects, highlighting the need for efficient subgrouping methods. Distinct genome-wide DNA methylation profiles characterize each MB subgroup, and the advent of Nanopore DNA sequencing has positioned itself as a reliable technique for comprehensive copy number and methylation profiling.

MATERIAL AND METHODS
We evaluated the ability of Nanopore sequencing to provide clinically relevant methylation and copy number profiles of MB, on a discovery cohort of 45 frozen MB samples, benchmarked against the gold standard EPIC array, and subsequently validated on a cohort of 116 MB samples.

RESULTS
The majority of MB in both the discovery cohort (43/45; 95.6%) and the validation cohort (110/116; 94.8%) were accurately subgrouped by Nanopore sequencing. Flongle flow cells for 18 MB allowed for a more rapid and cost-effective analysis, with 94.4% (17/18) being correctly classified. Additionally, Nanopore sequencing allowed us to correctly subtype 24/30 (80.0%) within MB groups.

DISCUSSION
We provided proof of concept that Nanopore sequencing can subgroup MB using DNA extracted from formalin-fixed paraffin-embedded (FFPE) samples and cell-free DNA obtained from cerebrospinal fluid. This first large-scale study establishes the proof of concept that this modern and innovative technology is well-suited for MB classification. We confirm the use of Nanopore sequencing on circulating DNA and present an initial exploration of its application on DNA extracted from FFPE samples. Its ability to deliver quick and cost-effective results firmly establishes Nanopore sequencing as a game-changer in the field of MB classification.
MDB-19. THE 3D CHROMATIN LANDSCAPE OF MEDULLOBLASTOMA
Authors: Wu Stephanie C , Diaz Eduardo Ferreira Martins , Mileti Enrichetta , Bihannic Laure , Smith Kyle S , Rodríguez-González Francisco G , Sidiropoulos Nicos , Weischenfeldt Joachim , Northcott Paul A 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is a highly malignant childhood cerebellar tumor comprised of four molecularly and clinically distinct subgroups. Sporadic yet subgroup-specific genetic and epigenetic landscapes suggest that higher-order chromatin topology may contribute to distinct subgroup identities and disease biology. Herein, we investigated the 3D chromatin landscape of MB by performing genome-wide chromosome conformation capture (Hi-C) across molecular subgroups using a cohort of n=24 patient-derived xenografts and primary tumor specimens, aiming to elucidate regulatory mechanisms facilitated by genome organization.

METHODS
Integrative analyses were adapted to incorporate a wide variety of sample-paired datasets. Chromatin contact matrices generated from Hi-C allowed for the mapping of active/inactive compartments (A/B compartments), topologically associated domains (TADs), and distal pairwise chromatin contacts (loops). Topological insights of chromatin architecture were complemented with whole-genome sequencing, RNA-seq, ATAC-seq, DNA methylation, CTCF and histone modification (H3K27ac/H3K27me3) ChIP-seq datasets to dissect mechanisms of gene regulation.

RESULTS
Unsupervised analysis revealed that chromatin compartmentalization is subgroup stratified. Gene loci contained in subgroup-unique active compartments correspondingly exhibited subgroup-specific chromatin contact patterns, adopted open chromatin conformations, and remained transcriptionally active. As an example, LIN28B resides within a Group 3-specific ‘A’ compartment where its local topology displays higher complexity compared to that of other subgroups. This consequentially facilitates a Group 3-unique loop connecting the LIN28B promoter with a distal enhancer, resulting in subgroup-specific transcriptional upregulation. Targeted displacement of CTCF that anchors and stabilizes chromatin looping at the LIN28B locus was sufficient to alter its transcriptional activity. Using similar lines of investigation, mechanistic insights into the topological determinants of known enhancer-hijacking events, including GFI1, GFI1B and PRDM6, were resolved.

CONCLUSIONS
Pioneering this integrative approach centered on comprehensive Hi-C maps, our study provides a high-resolution blueprint of the 3D chromatin landscape defining MB subgroups, informing the mechanistic basis of recurrent driver gene activation, and disclosing putative subgroup-specific vulnerabilities.
MDB-31. THE CLINICAL SIGNIFICANCE OF SUB-TOTAL SURGICAL RESECTION IN CHILDHOOD MEDULLOBLASTOMA: A MULTI-COHORT ANALYSIS OF 1100 PATIENTS
Authors: Keeling Claire , Davies Simon , Goddard Jack , Ramaswamy Vijay , Schwalbe Edward C , Bailey Simon , Hicks Debbie , Clifford Steven C 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma patients with sub-total surgical resection (STR; &gt;1.5 cm2 primary tumour residuum) typically receive intensified treatment. However, the association of STR with poor outcomes has not been observed consistently, questioning the validity of STR as a high-risk disease feature.

METHODS
We collected extent of resection (EOR) data from 1110 patients (UK CCLG centres (n=416), published cohorts (n=694)), the largest cohort with clinico-molecular annotation assembled to specifically assess the significance of EOR to date. We performed association and survival analyses, assessing overall survival (OS) cohort-wide with reference to the consensus medulloblastoma molecular groups and clinico-molecular features.

RESULTS
STR was reported in 20% (226/1110) of the cohort and was enriched in patients (i) &lt;5 years at diagnosis (p=0.021), (ii) with metastatic disease (p&lt;0.0001) or (iii) with non-WNT tumours (p=0.047). In cohort-wide analysis, STR was associated with worse survival in univariable analysis (p&lt;0.0001), though, outcomes for patients with STR as their only risk-feature were as per standard-risk disease. Examination of specific disease contexts showed STR was prognostic in univariate analysis for patients (i) receiving cranio-spinal irradiation (CSI) and chemotherapy (p=0.016) and (ii) with Group 3 tumours receiving CSI (p=0.039). In non-metastatic CSI treated patients, STR was not prognostic, independent of CSI dose. Crucially, STR was not independently prognostic in multivariable analyses when considered alongside established clinico-molecular high-risk features.

CONCLUSIONS
In a cohort of 1100 molecularly characterised medulloblastoma patients, STR (n=226) predicted significantly lower OS in univariable analysis, but was not an independent prognostic factor. Our data suggest that maximal safe resection can continue to be carried out for patients with medulloblastoma and suggest STR should not inform patient management when observed as a sole, isolated risk feature. These findings provide necessary evidence to inform the selection criteria for forthcoming risk-adapted medulloblastoma clinical trials.
MDB-32. PRDM6 PROMOTES MEDULLOBLASTOMA FORMATION IN NEUROEPITHELIAL STEM CELLS AND IS A CHROMATIN REPRESSOR BY BINDING TO HISTONE H3 LYSINE 27 TRIMETHYLATION MARKS
Authors: Schmidt Christin , Cohen Sarah , Gudenas Brian L , Husain Sarah , Carlson Annika , Westelman Samantha , Wang Linyu , Phillips Joanna J , Northcott Paul A , Weiss William A , Schwer Bjoern 
Published: June 2024

Abstract
A substantial fraction of Group 4 MBs are characterized by enhancer hijacking through tandem duplication of SNCAIP, resulting in high expression of PRDM6, a putative transcriptional repressor and histone methyltransferase. PRDM6 is a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and its potential role as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.
MDB-38. AN INTEGRATED MODEL FOR RESISTANCE TO BROMODOMAIN INHIBITORS IN CHILDHOOD MEDULLOBLASTOMA
Authors: Choi Seung H , Lupien Leslie , Boynton Adam N , Bandopadhayay Pratiti , Prensner John R 
Published: June 2024

Abstract

BACKGROUND
Bromodomain inhibitors (BETi) have emerged as a potential treatment option for children with medulloblastoma, where hyperactivation of gene transcription by the MYC and MYCN transcription factors may lead to a transcriptional dependency. Yet, drug resistance limits the utility of these agents when employed as a monotherapy. We therefore sought to identify mechanisms of BETi resistance that inform rational development of multimodal therapy options.

METHODS
We used CRISPR screening of D458 medulloblastoma cells that have acquired resistance to the JQ1 inhibitor. We subsequently used small molecule inhibition and knockdown experiments to validate Menin as a target. Finally, we used RNAseq, ribosome profiling, and mass spectrometry to characterize transcriptional and post-transcriptional changes in D458 cells compared to D458 with JQ1 resistance.

RESULTS
In the setting of BETi resistance, we observed dependency on key transcriptional actors, such as MLL (KMT2A) and the Mediator complex, which we are now validating in mini-pool experiments. We further characterized aberrant MLL complex function through knockdown, small molecule inhibition, and RNA-sequencing of Menin, a critical MLL cofactor. Next, we were surprised to observe ribosome and proteosome genes as CRISPR dependencies in our initial screening of BETi-resistant cells, suggesting post-transcriptional regulation. Indeed, MYC, whose transcription is potently blocked by BETi, remained robust at the protein level in BETi resistance. We therefore performed integrated transcriptional, translational, and proteomic profiling to characterize gene regulation in BETi-resistance. We found that the BETi-resistant state leads to an “uncoupling” of transcriptional and post-transcriptional regulation for a subset of genes, leading us to test small molecule inhibitors of post-transcriptional processes in BETi-resistant medulloblastoma.

CONCLUSIONS
Taken together, our data inform an integrated model of BETi resistance based on both transcriptional and post-transcriptional mechanisms, suggesting new therapeutic angles that may be effective in combination with BETi therapies.
MDB-46. ARE RAB40 SMALL GTPASES DRIVERS OF MEDULLOBLASTOMA PATHOGENESIS?
Authors: Allen Joseph , Entwistle Susannah , Coyle Beth , Hume Alistair N 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma is the most common solid paediatric neoplasm and is among the leading causes of cancer-related deaths in children. Patients associated with high-risk molecular subgroups convey poor outcomes due to frequent relapse and metastasis, with two thirds of survivors experiencing life-changing developmental deficits. Poor patient outcomes and significant co-morbidities highlight an urgent need for specific, molecularly targeted therapies. The RAB40 subfamily of atypical small GTPases regulate cytoskeletal structure and cell adhesion via their ubiquitin ligase activity. Although previous studies have linked the RAB40 subfamily with cell invasiveness, their role in paediatric brain cancer remains undefined.

METHODS
Patient methylation and survival data from Cavalli et. al (2017) was analysed via the R2 Genomics Analysis and Visualisation Platform. RAB40 gene and protein expression were determined in eight in vitro models of medulloblastoma via qRT-PCR and western blotting. Cells were transfected with EGFP-Cas9 mRNA and RAB40-targeted CRISPR sgRNA and seeded singly using fluorescence-activated cell sorting. RAB40 knockout clones were identified via western blot and Sanger sequencing.

RESULTS
Patient data demonstrated that higher RAB40 gene expression correlates with worse outcomes in group 3 and 4 medulloblastoma. RAB40 genes were also significantly more highly expressed in high-risk groups 3 and 4 compared to low-risk WNT group medulloblastoma. RAB40 mRNA was enriched in cell lines derived from high-risk group 3 and 4 medulloblastoma relative to SHH controls. RAB40 knockout models were subsequently generated in HD-MB03, an in vitro model of metastatic Group 3 medulloblastoma using CRISPR/Cas9.

CONCLUSIONS
Our data supports the hypothesis that RAB40 small GTPases are enriched in high-risk medulloblastoma subgroups, and that their expression correlates with worse patient outcomes. We have generated knockout models which will be used to characterise the impact of RAB40 GTPases on cell growth, adhesion, invasiveness, and chemotherapeutic tolerance.
MDB-48. A SINGLE INSTITUTION EXPERIENCE OF CIPN MEASURED BY THE PED-MTNS IN CHILDREN AND ADOLESCENTS WITH MEDULLOBLASTOMA TREATED ON A TRIAL USING SIMILAR DOSING OF VINCRISTINE AND CISPLATIN FOR ALL PATIENTS
Authors: Richards Jill M , Olsen Monica R , Bendel Anne E , Gilchrist Laura S , Tanner Lynn R 
Published: June 2024

Abstract

BACKGROUND
Standard treatment for medulloblastoma in patients &gt;3 years of age consists of tumor resection, radiation and chemotherapy using vincristine, cisplatin, cyclophosphamide +/- CCNU. Vincristine and Cisplatin are known to cause chemotherapy induced peripheral neuropathy (CIPN). The prevalence of CIPN in children with non-CNS cancers can be measured using the pediatric-modified Total Neuropathy Score (ped-mTNS). The purpose of this observational, retrospective pilot design is twofold: to investigate the prevalence of CIPN in children with medulloblastoma receiving neurotoxic chemotherapy, and to examine the feasibility of using the ped-mTNS as a measurement tool in this population.

METHODS
Data was manually extracted from medical records and entered into a REDCap database for analysis. The percent of patients successfully tested and clinical inferences made from ped-mTNS testing results were used to determine feasibility and barriers to use. A total of 33 medulloblastoma patients &gt;3 years of age were treated from 6/2013 - 6/2021 at Children’s Minnesota. Of those, 18 received testing using the ped-mTNS during chemotherapy treatment.

RESULTS
During cancer treatment, 54.5% of the cohort of patients received ped-mTNS testing. The average age of children tested was 10.26 (4.39) years with a majority being male (79%), and non-Hispanic white race/ethnicity (89%). Of the tested participants, 61.1% had more than one measurement. For those patients tested at multiple timepoints, 72.7% demonstrated worsening ped-mTNS scores while on chemotherapy treatment. Therapists recorded inferences relating to neuropathy in 88.1% of testing occurrences with questions of accuracy recorded in 31.3% of testing occurrences. Barriers to use of results included confounding impairments that may occur as a result of the primary tumor, post-surgical changes, and radiation.

CONCLUSIONS
Using the ped-mTNS is feasible in children and adolescents with medulloblastoma. The ped-mTNS scores indicated that children with medulloblastoma, treated with Vincristine and Cisplatin, experience worsening neuropathy while undergoing chemotherapy treatment.