bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPEN-26. DRUG SCREENING IN PATIENT-DERIVED MODELS OF POSTERIOR FOSSA A EPENDYMOMA REVEALS NOVEL PHARMACOLOGICAL VULNERABILITIES
Authors: Larson Jon D , Finlay Darren , Murad Rabi , Lo Yan Yuen , Zhao Ming , Manuvel Antony Michealraj Kulandai , Kumar Sachin A , Pass Ian , Handley Charles , Wechsler-Reya Robert J , Taylor Michael D , Vuori Kristiina , Chavez Lukas , Jackson Michael 
Published: June 2024

Abstract
Ependymoma (EPN) is the third most common malignant intracranial pediatric brain tumor. The most common and aggressive EPN subgroup, posterior fossa ependymoma group A (PFA-EPN), occurs predominantly in younger children and has a 5-year progression free survival of only 33%. Despite progress in the molecular characterization and subtyping of EPN, the standard treatment remains surgery with adjuvant radiation therapy. There is currently no approved role for chemotherapy in PFA-EPN. As such, identifying novel therapies for PFA-EPN is an important unmet medical need. To define therapeutic sensitivities for PFA-EPN, we performed a drug screen on three patient-derived PFA-EPN cell lines. We found that PFA-EPN cell lines were sensitive to several clinically relevant drugs, most notably those targeting epigenetic regulators. This is of a particular interest as a common molecular feature of PFA-EPN is the global reduction of the repressive post-translational histone modification H3K27me3 due to transcriptional EZHIP overexpression or H3 K27M mutations. To further characterize our PFA-EPN cell lines, we performed optical genome mapping analysis, revealing previously undescribed structural variants affecting genes encoding proteins responsible for signaling and transcription. One PFA-EPN sample that showed profound sensitivity to EGFR inhibitors, also had a duplication of a genomic region containing the EGFR ligand encoding genes, AREG, BTC, EREG, and EPGN. We are currently working to validate these results in larger cohorts of PFA-EPN models. Collectively, these findings provide new clues on drugs, signaling and putative therapeutic targets in these rare yet aggressive tumors.
EPEN-29. IS THE OUTCOME OF SUPRATENTORIAL EPENDYMOMA WITH ZFTA FUSION REALLY POOR?
Authors: Smith Amy A , Lensing Shelly , Onar-Thomas Arzu , Leary Sarah , Fouladi Maryam , Foreman Nicholas K , Ellison David W 
Published: June 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.
EPEN-30. PROTON THERAPY FOR PEDIATRIC INTRACRANIAL EPENDYMOMA: A SYSTEMATIC REVIEW, META-ANALYSIS AND META-REGRESSION
Authors:   Amanda Cyntia Lima Fonseca Rodrigues
Published: June 2024

Abstract

BACKGROUND
Pediatric intracranial ependymoma (IE) represents a challenging subset of tumors necessitating tailored therapeutic strategies. Conventional treatments, including surgery and conventional radiation therapy, have shown limitations in achieving optimal outcomes, particularly in preserving neurocognitive function and mitigating long-term sequelae. Proton therapy (PT) has emerged with its ability to offer precise tumor targeting with reduced irradiation of healthy surrounding tissues.

METHODS
A systematic search was conducted using the electronic databases PubMed, CENTRAL, and EMBASE from inception through February 2024 following the PRISMA statement. Statistical analysis was conducted using R (R Foundation for Statistical Computing; Vienna, Austria) with the packages ‘meta’ and ‘metafor’. The random effects model of proportions was estimated using the generalized linear mixed-effects model (GLMM) method.

RESULTS
A total of 7 studies were included comprising 943 patients, with a mean age of 4 years, 543 boys (57.58%) and a mean dose of 56.94 Gy. The local control (LC) rate at 3 years was 83% (95% CI = 0.80 to 0.86, p=0.65) and a 5-year rate was 81% (95% CI = 0.72 to 0.89, p=0.35). Progression-free survival (PFS) was 75% at 3 years (95% CI = 0.68 to 0.82, p=0.17) and 71% at 5 years (95% CI = 0.56 to 0.87, p=0.07). Overall survival (OS) rates were notably high, with 93% at 3 years (95% CI = 0.89 to 0.97, p=0.11) and 85% at 5 years (95% CI = 0.83 to 0.87, p=0.96). Meta-regression analysis revealed that total dose significantly influenced 3-year OS (p=0.04), indicating a dose-dependent effect on survival rates.

CONCLUSIONS
This meta-analysis supports the effectiveness of PT through the outcomes LC, PFS and OS in pediatric IE. The significant correlation between total dose and 3-year OS underscores the importance of dose optimization in treatment planning. These findings highlight the importance of PT in pediatric neuro-oncology management, offering evidence-based guidance for enhancing therapeutic strategies and patient outcomes.
EPID-01. ESTIMATING THE BURDEN DUE TO BRAIN AND OTHER CNS TUMORS IN ADOLESCENTS IN THE UNITED STATES
Authors: Price Mackenzie , Neff Corey , Kruchko Carol , Waite Kristin A , Cioffi Gino , Cordeiro Brittany , Penas-Prado Marta , Gilbert Mark R , Armstrong Terri S , Barnholtz-Sloan Jill S , Ostrom Quinn T 
Published: June 2024

Abstract

BACKGROUND
Brain and other central nervous system (CNS) tumors in adolescents have unique biological and behavioral distinctions from both children and adults. As a result, they pose challenges to treatment and reporting. Here, we describe the epidemiology of brain and other CNS tumors in adolescents (ages 15-19 years) in the United States, including mortality, survival, and prevalence.

METHODS
The Central Brain Tumor Registry of the United States (CBTRUS) data (containing data from the CDC’s National Program of Cancer Registries (NPCR) and NCI’s Surveillance, Epidemiology and End Results (SEER) data) were used to calculate average annual age-specific incidence rates (AASIR) per 100,000 population overall and by sex and race/ethnicity. Average annual age-specific mortality rates (AASMR) per 100,000 population for deaths resulting from all primary malignant brain and other CNS tumors were calculated using mortality data from NCHS. NPCR survival data were used to calculate relative survival (RS). Estimated prevalence counts as of December 31, 2024 were estimated using incidence from CBTRUS and SEER, and survival from SEER.

RESULTS
AASIR for all brain and other CNS tumors among adolescents was 7.51/100,000. Tumors of the sellar region had the highest incidence (AASIR=2.74/100,000). Overall, incidence was higher for females and non-Hispanic White persons. Overall AASMR was 0.56/100,000. Total five-year RS was 92.0%. Tumors of the pituitary had the highest RS (five-years=99.9%) and glioblastoma had the lowest (five-years=16.4%). As expected, prevalence was highest for tumors of the sellar region (3,720 cases).

CONCLUSION
Incidence, prevalence, and survival patterns for brain and other CNS tumors vary between adolescents, adults, and children. An accurate statistical assessment of these tumors in adolescents is required to understand risk and impact on this unique population, and to serve as a reference for afflicted individuals, for researchers investigating new therapies, and for the clinicians who treat them.
EPID-04. CAUSES AND LONG-TERM COURSE OF OTOTOXICITY IN PEDIATRIC MEDULLOBLASTOMA AND EPENDYMOMA PATIENTS – CUMULATIVE PLATINUM AND COCHLEAR IRRADIATION DOSE MATTER
Authors: Öz Elif , Hardt Annika , Kortmann Rolf-Dieter , Schwarz Rudolf , Timmermann Beate , Bison Brigitte , Warmuth-Metz Monika , von Hoff Katja , von Bueren André O , Gerber Nicolas U , Fleischhack Gudrun , Pietsch Torsten , Pfister Stefan M , Sturm Dominik , Mynarek Martin , Rutkowski Stefan , Obrecht-Sturm Denise 
Published: June 2024

Abstract

BACKGROUND
Ototoxicity is a well-known side effect of treatment with platinum-containing chemotherapy and radiotherapy (RT). Nevertheless, precise dose-effect relationships are still lacking.

METHODS
Patients from the HIT2000 trial receiving first-line treatment for medulloblastoma (MB) or ependymoma (EPN) who were alive at last follow-up and had at least one audiogram prior to and after administration of chemotherapy with cisplatinum and radiotherapy were included into this study. Treatment details (incl. cochlear irradiation dose [CID]) and audiological outcome were analyzed. The ototoxicity was graded using the HIT scoring.

RESULTS
Courses of 101 patients were analyzed. Median audiology follow-up was 6 years [range: 1.0–18.1 years]. Ototoxicity grade ≥1 was documented for n=66 patients (65.4%). For n=27 this resulted in treatment modification. Univariable analyses revealed different proportions of ototoxicity (grade ≥1) regarding histology (CMB: 50/65, LCAMB: 3/3, DMB/MBEN: 8/12, EPN: 5/21; p&lt;0.001), tumor location (supratentorial: 3/9, infratentorial: 63/92; p&lt;0.001), metastatic status at diagnosis (M0: 46/77, M+: 20/24; p=0.003), radiation field (CSI: 59/75, local RT: 6/21, no RT: 1/5; p&lt;0.001), CID (continuous variable, p=0.001) and cumulative cisplatinum dose (continuous variable, p&lt;0.001). Certainly, disease specific parameters (histology/staging) were related to treatment intensity (cisplatinum/irradiation dose). Multivariable analyses confirmed the impact of cumulative cisplatinum dose (p=0.01) and CID (p=0.04). ROC-analyses allowed the definition of cut-offs for high risk of ototoxicity grade ≥1 (cisplatinum: 70mg/m2 BSA, CID: 37.5 Gy) and ototoxicity risk estimation, when applying doses above the respective cut-offs (cisplatinum dose increase by 1mg/m2 BSA results in 4% higher risk for ototoxicity grade ≥1; CID dose increase by 1 Gy results in 4.6% higher risk for ototoxicity grade ≥1).

CONCLUSIONS
Ototoxicity affects a majority of children receiving adjuvant treatment for MB and EPN. To avoid disabilities and negative effect on quality of live, dosage of cisplatinum and radiotherapy should be scrutinized and reduced whenever possible.
EPID-09. CONGENITAL CENTRAL NERVOUS SYSTEM NEOPLASMS: A RETROSPECTIVE REVIEW FROM THEMARGARET HACKETT FAMILY PROGRAM CONSORTIUM
Authors: Lopes Carolina , Mosher Amanda M , Papadakis Joanna E , Keusch Dylan , Largen Kelsey , Weber Daniel , Huang Jesse , Yamini Bakhtiar , Bauer David , Danielpour Moise , Sayama Christina , Baird Lissa 
Published: June 2024

Abstract

INTRODUCTION
Congenital intracranial neoplasms are a heterogeneous group of lesions that account for &lt;2% of pediatric CNS tumors. Current understanding of histopathologic and survival outcomes in this population is limited.

METHODS
Pediatric patients (&lt;3-years) with congenital neoplasms were retrospectively evaluated across five institutions. Demographic, prenatal care, clinical presentation, histopathologic characteristics, operative and adjuvant therapies, and survival outcomes were collected.

RESULTS
323 patients met inclusion. The mean age at diagnosis was 1.5-years. Six patients were conceived through IVF. Eleven families reported abnormal prenatal ultrasounds, although only six were diagnosed prenatally. The most common histopathologies included low-grade astrocytoma (30.6%), ependymoma (15.8%), ATRT (11.5%), medulloblastoma (8.0%), and high-grade astrocytoma (2.8%). 48.9% of patients had low-grade neoplasms, and a third of patients (33.1%) had high-grade tumors. Patients commonly presented with hydrocephalus (59.1%), emesis (34.7%), ocular abnormalities (20.4%), macrocrania (18.0%), lethargy (14.6%), developmental delays (12.7%), and irritability (11.8%). All patients received surgical resection: 55.4% received gross-total (GTR) and 20.4% received subtotal resection. Concurrent treatment with adjuvant therapies occurred in a subset of patients, with 52.9% of patients receiving chemotherapy, 27.2% undergoing radiation, and 6.2% participating in a clinical trial. Patients with low-grade tumors had a rate of 88% progression-free (PFS) at 1-year, 74% PFS at 3-years, and 64% PFS at 5-years post-operative. Patients with high-grade neoplasms had worse PFS, with estimates at 59%, 40%, and 37% at 1-, 3-, and 5-years, respectively. There was statistically significant differences in PFS between patients with high- and low-grade neoplasms (p&lt;0.0001).

CONCLUSIONS
This series consisted of very young pediatric patients across five participating institutions with diverse histopathologies that vary in frequency relative to the entire pediatric population. Lesions were rarely detected prenatally, despite their young age at diagnosis. GTR occurred in half of patients and subsequent management with adjuvant therapies was common in both sub-totally resected low-grade lesions and high-grade tumors.
METB-04. UTILITY OF OPTICAL GENOME MAPPING IN THE CHARACTERIZATION OF PAEDIATRIC CENTRAL NERVOUS SYSTEM TUMOURS: ANALYSIS OF A MONO-INSTITUTIONAL SERIES OF 26 CASES
Authors: alesi viola , Genovese Silvia , Russo Serena , Giovannoni Isabella , Barresi Sabina , Tancredi Chantal , Pedace Lucia , Lombardo Antonietta , Bontempo Piera , Agolini Emanuele , Calacci Chiara , Morgia Alessandra , Calvieri Giusy , Puggioni Chiara , Cardoni Antonello , Cacchione Antonella , Baldo Giada Del , Colafati Giovanna Stefania , Carai Andrea , Mastronuzzi Angela , Miele Evelina , Abeni Damiano , Locatelli Franco , Muda Andrea Onetti , Novelli Antonio , Alaggio Rita , Rossi Sabrina 
Published: June 2024

Abstract

BACKGROUND
Optical Genome Mapping (OGM) is a recent platform which enables the detection of genome-wide balanced and unbalanced structural rearrangements (SR), providing a genome complexity overview.

METHODS
This study explores OGM implementation in the context of paediatric central nervous system (CNS) tumours by analyzing a series of 26 cases.

RESULTS
OGM equaled Chromosomal Microarray Analysis in detecting aneuploidies and copy number alterations (CNA), and, although less sensitive than RNAseq in identifying gene-fusions (15/19), enabled the definition of their causative mechanism. The assessment of SR and CNA allowed the distinction of different groups. Amount and distribution of SR identified 4 groups: HIGH_SR with &gt;10 breakpoints (BP) distributed in ≥5 chromosomes (8 cases), SR_CHROMOTHRIPSIS with ≥10BP in &lt;5 chromosomes with the most affected chromosome presenting with &gt;10 BP (9 cases), and LOW_SR with &lt;10BP (9 cases). CNA non-associated with chromothripsis (nCthCNA) stratified the series in NO_nCthCNA, LOW_nCthCNA, INT_nCthCNA, HIGH_nCthCNA group, where the alterations were absent (9 cases), &lt;10 (9 cases), 10-49 (2 cases) and ≥50 (6 cases), respectively. nCthCNA directly correlated with the mean number of chromosomes harboring SR, i.e. 10.2 in HIGH_/INT_nCthCNA vs 2.5 in NO_/LOW_nCthCNA (p=0.001), and inversely with chromothripsis (9/18 in NO_/LOW_nCthCNA vs 0/8 in HIGH_/INT_nCthCNA, p=0.015).

CONCLUSIONS
High complexity groups associated with biological aggressiveness, with HIGH_nCthCNA including only high-grade tumours (p=0.004) and disease progression mostly occurring in HIGH_SR (6/7 cases vs 1/17, p&lt;0.001) and HIGH_nCthCNA (4/5 vs 2/12 cases, p=0.013). Low-complexity groups were enriched of low/intermediate-grade tumours (13/15 in NO_/LOW_nCthCNA vs 5/11 in INT_/HIGH_nCthCNA, p=0.024). SR_CHROMOTHRIPSIS cases were all low/intermediate-grade fusion-driven tumours, did not harbour TP53 mutations or high-impact CNA (0/9 vs 7/17, p=0.030), and did not progress (0/9 vs 7/16, p=0.030). This study suggests a possible value of OGM assessment of genome complexity in prognostication of paediatric CNS tumours.
METB-08. CIRCULAR EXTRACHROMOSOMAL DNA IS ASSOCIATED WITH POOR SURVIVAL IN CHILDHOOD CANCER TYPES
Authors: Sridhar Sunita , Chapman Owen , Dutta Aditi , Wang Shanqing , Kenkre Rishaan , Luebeck Jens , Bafna Vineet , Mesirov Jill P , Chavez Lukas 
Published: June 2024

Abstract

BACKGROUND
Circular extrachromosomal DNA (ecDNA) is a common form of oncogene amplification in aggressive cancers and a promising target for improved cancer therapy. The frequency and diversity of ecDNA has been described in different types of adult cancers and in selected childhood cancer types such as neuroblastoma and medulloblastoma. However, the frequency of ecDNA and its association with survival has not been comprehensively analyzed across the spectrum of pediatric cancers.

METHODS
We performed a pediatric pan-cancer study of ecDNA in which we mined large pediatric cancer genomics repositories and reconstructed ecDNA sequence structures from whole genome sequencing data.

RESULTS
We analyzed a retrospective cohort of 1684 tumor biopsies from 1506 different patients, covering all major childhood cancers, many of which occur exclusively in children, including rare embryonal tumor types. The fraction of patients with ecDNA-positive tumors was 10%, varying significantly by tumor type. Aggressive tumor types had particularly high incidences of ecDNA, including embryonal tumors with multilayered rosettes (n = 6, 67%), osteosarcoma (n = 55, 47%), rhabdomyosarcoma (n = 38, 39%), and neuroblastoma (n = 111, 30%). Survival analysis revealed that ecDNA amplifications are significantly associated with poor outcome. Furthermore, we catalogued known and potentially novel oncogenes that are recurrently amplified on ecDNA in pediatric cancers and showed that ecDNA often evolves during disease progression.

CONCLUSIONS
These results reveal childhood tumor types in which ecDNA is widely prevalent and highlight patient populations that could potentially benefit from future therapies targeting mechanisms of ecDNA biogenesis and function.
METB-10. GENOME-WIDE DNA METHYLATION PROFILING OF PRIMARY CELLS FROM PEDIATRIC BRAIN TUMORS IS AN INFORMATIVE TOOL TO ASSESS CELL CULTURE RELIABILITY AND IN VITRO SELECTION
Authors: Pedace Lucia , Abballe Luana , Pizzi Simone , Vinci Maria , Antonacci Celeste , Nardini Claudia , Patrizi Sara , Bufalo Francesca Del , Rossi Sabrina , Pericoli Giulia , Gianno Francesca , Besharat Zein Mersini , Tiberi Luca , Mastronuzzi Angela , Ferretti Elisabetta , Tartaglia Marco , Locatelli Franco , Ciolfi Andrea , Miele Evelina 
Published: June 2024

Abstract

BACKGROUND
Recent genomic and epigenomic profiling analyses have provided remarkable insights into biology of pediatric brain tumors (pBTs). Nonetheless, pBTs represent the deadliest childhood cancer worldwide and are associated with high morbidity. In vitro models of pBT are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor.

METHODS
We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples from medulloblastomas, high-grade gliomas, low-grade gliomas, ependymoma, and meningiomas. The cohort included 155 tumors and 86 pBT-derived cell cultures. For the analysis of pBT-derived cell cultures, we have considered the most significant variables: i) cultured medium (serum vs serum-free), ii) passages (late vs early), and iii) dimensionality (2D vs 3D cultures). As a complementary approach, the global relationships between the 241 samples based on the DNAm information were visualized using fast interpolation-based t-distributed stochastic neighbour embedding (t-SNE) and differentially methylated regions in tumors compared to cell models were identified.

RESULTS
Our findings showed that cell cultures cultured under stem-like cells enriching conditions (serum-free, 3D) and maintained in culture early passages are characterized by a higher degree of faithfulness to the parental tumors, in terms of methylation class and CNV profile, than the counterparts maintained in 2D cultures, in presence of serum, and maintained for extended passages. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration.

CONCLUSIONS
DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors.