bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-20. DELINEATING MEDIATORS OF ONCOGENESIS IN FOXR2-EXPRESSING DIFFUSE MIDLINE GLIOMAS
Authors: Tsai Jessica , Cejas Paloma , Coppola Marissa , Wang Dayle , Patel Smruti , Wu David , Arounleut Phonepasong , Wei Xin , Zhou Ningxuan , Syamala Sudeepa , Dubois Frank , Pelton Kristine , Vogelzang Jayne , Sousa Cecilia , Baguette Audrey , Chen Xiaolong , Condurat Alexandra , Dixon-Clarke Sarah , Zhou Kevin , Lu Sophie , Gonzalez Elizabeth , Chacon Madison , Digiacomo Jeromy , Kumbhani Rushil , Novikov Dana , Tsoli Maria , Ziegler David , Dirksen Uta , Jager Natalie , Balsubramanian Gnana Prakash , Kramm Christof , Nathrath Michaela , Bielack Stefan , Baker Suzanne , Zhang Jinghui , McFarland James , Getz Gad , Aguet Francois , Jabado Nada , Witt Olaf , Pfister Stefan , Ligon Keith , Hovestadt Volker , Kleinman Claudia , Long Henry , Jones David , Bandopadhayay Pratiti , Phoenix Timothy 
Published: June 2023

Abstract

BACKGROUND
Diffuse midline gliomas (DMGs) are a universally fatal brain tumor of childhood. While histone mutations are a critical tumor initiating event, they are insufficient to drive gliomagenesis. Histone mutations co-occur with somatic alterations in other pathways including TP53, MAPK, and MYC signaling. However, the mechanisms through which these pathways are activated have not been fully elucidated.

METHODS
We applied an integrative approach using transcriptomics, epigenetics, proteomics, in vitro cancer models, and in vivo mouse models to systematically evaluate how FOXR2 mediates gliomagenesis.

RESULTS
We have recently found that a subset of DMGs aberrantly express FOXR2, a forkhead transcription factor. FOXR2 is both sufficient to enhance tumor formation, and necessary for FOXR2-expressing DMGs. While FOXR2 indeed enhances MYC protein stability, FOXR2 exerts oncogenesis through MYC-independent functions and specifically hijacks E26-transformation specific (ETS) transcriptional circuits and FOXR2 DNA-binding is highly enriched at ETS motifs. We have performed proteomic and phospho-proteomic analysis of FOXR2-expressing human neural stem cells to identify proteins and phospho-sites that are highly enriched in FOXR2-expressing cells.

CONCLUSION
Taken together, this study elucidates how FOXR2 interacts with ETS transcription factors to mediate oncogenesis in FOXR2-expressing diffuse midline gliomas.
DIPG-27. DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) CHALLENGE: FROM GENE EXPRESSION PROFILE TO DRUG
Authors: Scilimati Antonio , Armenise Domenico , Baldelli Olga , Centonze Antonella , Derri Davide , Ferorelli Savina , Miciaccia Morena , Solidoro Roberta , Perrone Maria Grazia 
Published: June 2023

Abstract
Diffuse intrinsic pontine glioma (DIPG) accounts for 80% of pediatric brainstem tumors and about 10-20% of all central nervous system tumors in childhood. Despite the adoption of aggressive therapeutic approaches, DIPG remains the leading cause of cancer-related mortality in childhood: prognosis is still poor with more than 90% of affected children dying within 18-24 months from the diagnosis.1 Decades of clinical attempts involving more than 200 trials evaluating different conventional cytotoxic drugs, targeted drugs and studies with radiation dose escalating and new radio sensitizing agents, have failed to improve the overall survival of children with DIPG. Since available drugs have proven no benefits hereto for DIPG, it is fundamental to gain insights into the gene expression profile of DIPG patients and speed up the discovery of novel therapeutics for this dismal malignancy. Only the compound ONC201 was discovered to reduce DIPG tumors size in DIPG H3K27M mutated and now is in phase III clinical trials.
Given the complex molecular mechanisms underlying DIPG, it would be necessary to fully utilize gene expression profiles to build a fully knowledge of DIPG-related genes and pathways. Preliminarily, the gene expression profile of eight pediatric DIPG samples and two primary pontine tissue samples was downloaded and analyzed starting from the Gene Expression Omnibus (GEO) database2. The GEO data were used to evaluate the differentially expressed genes (DEGs) in the pediatric DIPG samples. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathways of DEGs were enriched, integrated, and analyzed to find out genes and signaling pathways involved in the biological and clinic-pathological features of DIPG. More data are being to be added to our meta-analysis.
DIPG-33. P16 IMMUNOHISTOCHEMICAL EXPRESSION AS A SURROGATE ASSESSMENT OF CDKN2A ALTERATION IN GLIOMAS LEADING TO PROGNOSTIC SIGNIFICANCES
Authors: Geyer Lucas , Wolf Thibaut , Chenard Marie Pierre , Cebula Helene , Schott Roland , Noel Georges , Guerin Eric , Pencreach Erwan , Reita Damien , ENTZ-WERLE Natacha , Lhermitte Benoit 
Published: June 2023

Abstract
CDKN2A is a tumor suppressor gene encoding for p16 protein. Its homozygous deletion is a central prognostic factor for numerous brain cancers. This deletion can be detected by several techniques. Up to now, immunohistochemistry (IHC) using p16 antibody is not recommended as a surrogate test. This study aimed to evaluate to what extent IHC levels of p16 expression may provide information about CDKN2A homozygous deletion. A retrospective study was conducted in 173 gliomas comprising 50 circumscribed low-grade MAPK-altered gliomas, 18 pediatric diffuse high-grade gliomas (HGG), and 105 adult-type diffuse gliomas of all grade, using p16 IHC and CDKN2A fluorescent in situ hybridization. Survival analyses were performed to assess their prognostic impact. Three patterns of p16 expression were observed: absence of expression, focal expression and overexpression. The prognostic impact of p16 overexpression was dependent on the tumor drivers. Indeed, it was associated to a better prognosis in MAPK-induced tumors, but to a worse survival in IDH-wild-type glioblastomas. CDKN2A homozygous deletion present in all type of high grade pediatric or adult gliomas was significantly linked to a worse outcome in the entire population. Regarding specifically to H3K27-altered gliomas, no significant prognostic impact was observed, probably related to the small size of our population. Nevertheless, this p16 lost expression was rarely reported in this pediatric population. The lost expression was observed in 7/9 H3K27M-mutants and in 6/8 wild-type cases. Its implication should be considered more largely and is probably opening the path for therapies targeting the p16 pathway in this population. Regarding the IHC technique itself, beyond the association between absence of p16 protein expression and the CDKN2A loss (p&lt;0.001), this technique seems to have a strong sensitivity and a high negative predictive value. These data suggest that p16 IHC might be a pertinent test to detect cases harboring CDKN2A homozygous deletion.
DIPG-39. SIGNALING NETWORKS IN PEDIATRIC-TYPE DIFFUSE HIGH GRADE GLIOMAS
Authors: Herbst Sophie A , Ahn Ryuhjin , Agnihotri Sameer , Zapotocky Michal , White Forest M 
Published: June 2023

Abstract
Pediatric-type diffuse high grade gliomas are aggressive brain cancers in children which to date lack effective treatment options and remain largely understudied. Even though genomic markers including histone H3 K27M and G34R mutations have been identified, their functional implications on signaling networks remain to be described. Phosphoproteomics might be able to uncover activated signaling pathways which could open up new paths for treatment. Here we analyzed formalin-fixed paraffin-embedded (FFPE) sections from K27M mutated, G34R mutated and histone H3 wild type patient tumors (n = 14) using phosphoproteomics. Our workflow not only enables the comprehensive characterization of phosphoserines and threonines but also of phosphotyrosines which, despite being rare modifications (0.1-1% of all phosphorylations), are known to play an important role in cancer. We found that signaling networks were distinct between the different tumor subtypes. For phosphotyrosines, tumor subtype accounted for the largest source of variation in the data (44% of variance) as determined by principle component analysis. The separation by subtype could also be seen from serine and threonine phosphoproteomics and proteomics, but was not as striking as for the phosphotyrosine data. Differential abundance analysis, partial least squares discriminant analysis and self-organizing maps revealed deregulated signaling networks between subtypes. The most downregulated pathway in K27M compared to wild type tumors was enriched for proteins involved in the epigenetic regulation of gene expression (FDR&lt;5%), which is in accordance with the remodeling of the epigenome taking place in K27M mutated tumors. In addition, we could identify signaling networks (e.g. EGFR signaling) which were activated in a few individual patients independent of their subtype and might be targetable. Our study provides insights into the signaling landscape of pediatric-type diffuse high grade gliomas. Recognizing deregulated signaling networks across subtypes and in individual patients could offer new avenues for personalized therapy.
DIPG-54. UPDATED FINDINGS FROM THE PHASE IB STUDY OF UNESBULIN (PTC596) IN CHILDREN WITH NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG): A REPORT FROM THE COLLABORATIVE NETWORK FOR NEURO-ONCOLOGY CLINICAL TRIALS (CONNECT)
Authors: Lazow Margot , Baxter Patricia , Stanek Joseph , Rodriguez Diana , Kumar Shiva Senthil , Palmer Joshua , Leach James , Mikael Leonie , Thomas Diana , Fuller Christine , Boué Daniel , Pierson Christopher , Breneman John , Li Xiao-Nan , Salloum Ralph , Ashley David , de Blank Peter , Hwang Eugene , Leary Sarah , Plant Ashley , Fisher Michael , Chi Susan , Crabtree Dorothy , Murali Mythili , Weetall Marla , Rance Mark , Maliakal Pius , Baird John , D’Silva Dhiren , O’Keefe Kylie , Leonard Jeffrey , Stewart Clinton , Mardis Elaine , Fouladi Maryam , Drissi Rachid 
Published: June 2023

Abstract
BMI-1 represents a potential therapeutic target in pediatric HGG given its role in self-renewal and DNA-damage signaling, high expression levels in these tumors, and resultant proliferation blockade, mitotic abnormalities, and radiosensitization when modulated by unesebulin, a microtubule polymerization inhibitor. This phase Ib study sought to determine the recommended phase 2 dose (RP2D) and pharmacokinetic (PK) profiles of unesbulin administered concurrently with radiotherapy and as maintenance therapy in children with newly-diagnosed DIPG or HGG, as well as assess intratumoral PKs and target inhibition within a surgical cohort. As previously reported, the established RP2D from the dose-finding cohort (parts A [capsule] and C [tablet]), consisting of 27 patients (median age: 9 years; 18 with DIPG, 9 with HGG) is 200mg/m2 twice weekly. Eleven additional patients (5 with DIPG, 6 with HGG) have been enrolled in an expansion cohort (part D [tablet]), with no dose-modifying toxicities to date. Among 38 total patients, most common drug-related grade 3/4 adverse effects observed are neutropenia (49%), leukopenia (31%), and elevated ALT (18%). Pharmacokinetic profiles are comparable between capsule and tablet formulations, and corroborate adult data. Genomics correlatives are underway on 13 biopsy and 5 autopsy specimens (2 paired samples). Five patients (median age: 5 years; 4 with DIPG, 1 with HGG) have enrolled in the surgical cohort (part B [tablet]) at the RP2D. PK analyses performed on the first three samples confirm intratumoral unesbulin exposure. In summary, the RP2D of unesbulin at 200mg/m2 twice weekly concurrent with and post-radiotherapy is feasible and well-tolerated, with evidence of blood-brain barrier and tumor penetrance. Survival outcomes as well as ongoing analyses of intratumoral BMI-1 pathway inhibition in surgical cohort samples, plus comprehensive molecular profiling (focusing on BMI-1 and cell cycle signaling) of biopsy and autopsy specimens from the entire cohort, will be shared at time of presentation.
METB-02. DECIPHERING THE CELLULAR HETEROGENEITY OF INFANT-TYPE HEMISPHERIC GLIOMAS USING SINGLE-NUCLEI MULTI-OMICS
Authors: De Micheli Andrea J , Zápotocký Michal , Cavalli Florence M G , Guerreiro Stücklin Ana S 
Published: June 2023

Abstract
Infant-type hemispheric gliomas (IHGs) have recently been recognized as a new tumor entity. Compared to other types of pediatric gliomas, most IHGs distinctively harbor a fusion in a cluster of receptor tyrosine kinase (RTK) genes: the NTRK family, ROS1, ALK, or MET. Clinically, IHG patients appear to be associated with better outcomes compared to older children with high-grade tumors. While large-scale genomic studies have helped uncovered the complex molecular landscape and clinical features of IHGs, little is known about the underlying biology – specifically how tumor heterogeneity may explain the spectrum of clinical presentations and progression of the disease. Using single-nuclei multi-omic (RNA/ATAC-seq) profiling, we assembled a comprehensive atlas of IHG tumor cells from a cohort of patients spanning different age groups and RTK fusion subtypes. We measured that tumor single-nuclei transcriptomes clustered into distinct subpopulations and contained genes expressed by the normal brain cell lineages. Data integration with single-cell atlases from the developing brain allowed us to rank tumor cell subpopulations according to their developmental stage, with age- and fusion-specific differences. Using trajectory inference and gene expression velocity modeling, we describe a hierarchical and dynamic organization between subpopulations, potentially illustrating the role of phenotypic plasticity in glioma formation. Moreover, we measured in fragments of open chromatin a cell-type specific enrichment of binding sites for transcription factors known to regulate brain cell maturation. Taken together, our multi-modal atlas describes the cellular and functional heterogeneity of IHGs, paving the way towards a greater understating of its unique biology and clinical consequences.
METB-04. THE MOLECULAR CHARACTERIZATION INITIATIVE (MCI): A CLINICAL AND GENOMIC RESOURCE FOR THE PEDIATRIC BRAIN TUMOR COMMUNITY
Authors: Leary Sarah , Thomas Diana , Cottrell Catherine , Wang Yu , Rudzinski Erin , Ramirez Nilsa , Hawkins Douglas , Fouladi Maryam , Mardis Elaine 
Published: June 2023

Abstract

BACKGROUND
The Molecular Characterization Initiative (MCI) sponsored by the National Cancer Institute (NCI) as part of the Childhood Cancer Data Initiative provides free clinical molecular testing with return of results to treating institutions.

METHODS
The MCI was activated as an optional sub-study of the COG Project:EveryChild registry, eligibility screening, biology and outcome study. Eligibility for subjects with central nervous system (CNS) tumors included newly diagnosed benign and malignant tumors in subjects &lt; 25 years. Clinical testing included exome sequencing of paired tumor/normal; DNA methylation array for CNS tumor classification; and targeted RNA sequencing for fusion detection. Required specimens were tumor (snap frozen, FFPE block or slides) and whole blood. Quality control confirming presence and percentage of tumor was confirmed by central pathologist. Minimum nucleic acid yield included 300ng DNA (frozen, 700ng from fixed tissue) and 500ng RNA.

RESULTS
In the first 10 months since activation 3/21/2022, 867 CNS subjects from 149 COG institutions have enrolled in the MCI, of which 675 (78% of enrolled) have submitted both required tumor and blood specimens. Adequate nucleic acids were extracted from 592 specimens (88% of submitted). For subjects with adequate nucleic acids, DNA exome and methylation classification results were returned for 99%; RNA fusion analysis was returned for 93%. Median time to return of results was 19 days from receipt of tumor specimens. Only 16% of CNS subjects were also participating in screening for COG therapeutic studies, including medulloblastoma (7%), low-grade glioma (6%) and high-grade glioma (4%). Genomic and annotated clinical data are available within the NIH-sponsored repository, dbGAP, through controlled access request by academic investigators.

CONCLUSIONS
The MCI represents an unprecedented resource of genomic and clinical data that is readily available to improve clinical diagnosis and support pediatric brain tumor research.
METB-12. CLINICAL MONITORING OF MEASURABLE RESIDUAL DISEASE BY CELL-FREE DNA IN PEDIATRIC BRAIN TUMORS
Authors: Crotty Erin , Cole Bonnie , Paulson Vera , Lockwood Christina , Leary Sarah 
Published: June 2023

Abstract
Conventional response monitoring relies on imperfect tools like MRI and cerebrospinal fluid (CSF) cytology to detect measurable residual disease (MRD) in children with brain tumors. “Liquid biopsy” techniques provide a minimally-invasive method for MRD detection by identifying fragments of cell-free DNA (cfDNA) shed from tumor cells following cell death. Early detection of MRD has been proposed as a clinically actionable biomarker that may allow clinicians to reliably detect tumor versus treatment effect, intensify therapy prior to relapse, and minimize toxicity. Our center is currently evaluating low-pass whole genome sequencing (LP-WGS) in children with brain tumors receiving standard of care therapy for real-time MRD assessment. Following informed consent, patients are enrolled on the Seattle Children’s Hospital Tissue Banking and Biology Protocol, and CSF samples are collected prospectively by lumbar puncture during routine clinical care. LP-WGS is performed in a CAP/CLIA certified environment with return of results to the referring clinician. In addition to feasibility as a prognostic and predictive biomarker, correlative studies will investigate if neuroinflammatory and immunologic profiles change with the presence of MRD using CNS cytokine signatures, including CXCL-12, CCL-2, MMPs, CD163, and GFAP. Preliminary cfDNA studies of children with embryonal tumors suggest LP-WGS is both a sensitive and clinically valuable test to detect tumor-associated copy number variants (CNVs). Thirty of thirty-one (97%) of CSF samples from 17 patients demonstrated adequate cfDNA for LP-WGS testing. Key CNVs detected included monosomy 6, isodicentric chromosome 17, and amplifications of MYCN and TTYH1. Among 8 samples obtained at initial tumor staging, LP-WGS detected tumor in 7/8 (1 negative ATRT without CNVs), whereas only 2/8 were positive by cytology. Two samples acquired additional chromosomal alterations at progression beyond those observed in the original tumor. Future prospective clinical trials are warranted to determine how MRD will transform clinical care and patient outcomes.
RARE-02. OBSERVATIONAL REGISTRY STUDY OF TREATMENT PRACTICES AND LONG-TERM OUTCOMES OF CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 (NF1) AND PLEXIFORM NEUROFIBROMAS (PN) INITIATING SELUMETINIB IN REAL-WORLD PRACTICE IN THE UNITED STATES (US): STUDY DESIGN AND METHODOLOGY
Authors: Waanders Angela , Yohay Kaleb , Fang Shona , Wahlstrom Svea , Bornhorst Miriam , Meade Julia , Vallance Kelly , Rodriguez Randolph de la Rosa 
Published: June 2023

Abstract
Selumetinib (ARRY-142886, AZD6244) is an oral, allosteric MEK1/2 inhibitor approved in the US for children aged ≥2 years with NF1 and symptomatic, inoperable PN, based on results from the pivotal SPRINT study. Aims of the US Selumetinib Registry study [NCT05683678] include understanding treatment practices and assessing short- and long-term safety and effectiveness outcomes of selumetinib treatment in children with NF1-PN in real-world US practice. Clinical and non-clinical factors affecting outcomes will also be explored. This observational registry study of pediatric patients with NF1-PN will be conducted in up to 22 US centers. Eligible patients will be 2–18 years old at the time of selumetinib initiation (on/after April 10, 2020), and not currently participating in a clinical trial. Patients will be divided into three cohorts: Cohort 1 – treatment discontinued before enrollment, Cohort 2 – treatment initiated before enrollment and currently on treatment, Cohort 3 – treatment initiation intended within 3 months of enrollment. Patients will be followed for ≥36 and up to 60 months. Primary objectives are to describe patient demographics and disease characteristics (including diagnosis criteria and related manifestations, diagnostic tests and results, and PN-related morbidities), selumetinib treatment course, short- and long-term effectiveness and safety, and disease course and treatment following discontinuation. Key secondary objectives include measures of quality of life, pain and physical functioning before, during, and after selumetinib. Target enrollment is 200 patients with a 24-month enrollment period and will begin in 2023. The US Registry study will facilitate understanding of treatment practices and assess short and long-term outcomes of selumetinib for NF1-PN in a real-world setting.
RARE-05. MOLECULAR HETEROGENEITY OF PEDIATRIC CHOROID PLEXUS CARCINOMAS
Authors: Zaytseva Margarita , Papusha Ludmila , Yasko Ludmila , Karachunskiy Alexander , Novichkova Galina , Druy Alexander 
Published: June 2023

Abstract
BACKGROUND:
Choroid plexus carcinomas (CPCs) are rare aggressive pediatric tumors of the brain with no treatment standards. Genetic profiling of CPCs is often confined to possible association with Li–Fraumenisyndrome, though only about a half of CPCs develop fromsyndromic predispositions. Whole-chromosome gains and losses typical of CPCs reflect genomic instability of these tumors, but only partially explain the aggressive clinical course.
METHODS:
This retrospective study enrolled 25 pediatric patients with CPC, receiving treatment between January 2009 and June 2022. Molecular genetic testing was performed for 20 cases with available tumor tissue and encompassed mutational status, chromosomal aberrations and gene expression profiles. We analyzed several factors presumably influencing the outcomes, including molecular profiles and clinical parameters. The median follow-up constituted5.2 years (absolute range 2.8–12.6 years).
RESULTS:
All studied CPCs had smooth mutational profiles with the only recurrent event being TP53 variants, either germline or somatic, encountered in 13 cases. Unbalanced whole-chromosome aberrations, notably multiple monosomies, were highly typical. Inseven tumors, chromosome losses were combined with complex genomic rearrangements: segmental gains and losses or signs of chromothripsis. This phenomenon was associated with extremely low 5-year survival: 20.0±17.9% vs. 85.7±13.2%; p=0.009. Transcriptomically, the cohort split into two polar clusters Ped_CPC1 and Ped_CPC2 differing by survival: 31.3±17.8% vs. 100%; p=0.012.
CONCLUSION:
CPCs split into at least two molecular subtypes distinguished both genomically and transcriptomically. Clusterization of the tumors into Ped_CPC1 and Ped_CPC2 significantly correlates withsurvival. The distinction may prove relevant in clinical trials for dedicated and patient-oriented optimization of clinical protocols for these rare tumors.