bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEDB-53. Incidence of Hearing impairment in childhood Medulloblastoma Survivors treated in King Fahad Medical City KFMC Saudi Arabia
Authors: Mahmodi Mohammed Al , Mobark Nahla Ali , Almowanes Demah A , AlGhunaim Haya N , Kattan Nad E , Aljabarat Wael abdel Rahman , Alotabi Fahad , Rayis Mohammed , AlNaqib Zaid G , Balbaid Ali Abdullah O , Alharbi Musa 
Published: June 2022

Abstract
Medulloblastoma MB is the most common childhood CNS tumor treated with intensive multimodalities therapy Surgery, Radiation and Cisplatin chemotherapy which causing significant Hearing impairment (HI) with profound impact on child’s quality of life. METHOD: Retrospective study evaluating risk factors & (HI) incidence in childhood MB survivors treated in KFMC between 2010 and 2020. (HI) was graded using the National Cancer Institute (NCI) Grades (1-4) ALL patients received 6 weeks of Risk adapted CSI radiotherapy concurrent with daily oral Etoposide. patients were treated with 2 different Maintenance chemotherapy German HIT-MED MB protocol 8 Maintenance cycles (Cisplatin 70 mg/m² x 1d /lomustine/VCR) Cumulative dose of Cisplatin 560 mg/m2 KFMC MB SAPHOS protocol 6 Maintenance cycle alternating A&B. cycle A: Cisplatin 90 mg/m² x 1d & 3 weeks of daily oral Etoposide. cycle B: Cyclophosphamide x 2 d & Vincristine Cumulative dose of Cisplatin 270 mg/m2. RESULTS: At Median follow-up of 5 years total of 78 MB survivors, male predominance 66.7% Median age at diagnosis 82 months post end of therapy 28.2% maintain normal hearing while 71.8% had hearing decline compared with baseline audiology Median time of onset of hearing decline was 7 months after start of radiation therapy Significant (HI) (NCI grade 3/4) in 26.9% of patients, and 23.1% required hearing aid use NO statistically difference in incidence of significant (HI) in patients treated with HIT-MED protocol (26.7%) & patients treated with KFMC MB-SAPHOS protocol (27.1%) OR those treated as Average-Risk CSI radiotherapy 22.9% Vs High-Risk CSI radiotherapy (30.2%), patients age at diagnosis (&lt; or &gt; 5 years) does not affects HI incidence. CONCLUSIONS: significant hearing impairment incidence was not affected by Radiation doses OR cumulative Cisplatin dose. Our study will form base line for future studies to modify therapy related Toxicity and improve outcome of childhood MB in Saudi Arabia.
MEDB-59. A draft atlas of medulloblastoma cellular evolution under therapy
Authors: Wang Lin , Jung Jangham , Babikir Husam , Shamardani Karin , Kasahara Noriyuki , Müller Sabine , Diaz Aaron 
Published: June 2022

Abstract
How standard care shapes the cellular composition of recurrent medulloblastoma (MB), if therapy selects for specific tumor or immune cell types, is unknown. We report the pilot phase of our ongoing effort to profile human longitudinal MB specimens via single-cell transcriptomics and epigenetics. We profiled 11 diagnostic and eight recurrent specimens from 19 subjects via single-nucleus RNA sequencing (snRNA-seq), and four subjects via single-nucleus assay for transposase-accessible chromatin. Specimens from select subjects were also profiled to assess genome-wide enhancer activity via single-nucleus cleavage-under-targets and tagmentation. We found an upregulation of the DNA-damage response, RNA translation, WNT and NOTCH signaling in recurrent specimens. The percentages of stem-like cells increased by over two-fold at recurrence. We found that microglia and oligodendrocyte-lineage cells were the most abundant non-malignant tumor-associated cell types, representing 2%-10% of cells profiled. Microglia abundances were relatively stable across molecular subtypes, and when comparing primary to recurrent tumors. There was a moderate, but statistically significant, increase in oligodendrocyte abundance in SSH and WNT tumors, compared to Group 3/4 tumors. We compared gene expression in tumor cells with public snRNA-seq from developing human cerebella (PCW 9-21). Combined Group-3/4 cell analysis supports a common lineage hierarchy, with an enrichment for unipolar brush-cell and Purkinje-cell phenotypes found in Group-4 tumors. All Group-3/4 cases contained cycling cells expressing markers of PAX2+ interneuron progenitors, most cycling cells had this phenotype. All specimens contained populations of non-cycling granule-cell progenitor-like cells. We performed single-cell co-expression receptor/ligand analysis to infer paracrine signaling between tumor and non-malignant cell types. This identified both tumor cells and microglia as sources of growth factors, pro-inflammatory cytokines, and pro-apoptotic ligands. Non-malignant oligodendrocyte-lineage cells uniquely expressed IL6-family cytokines, pleiotrophin, and class-III semaphorins. These studies shed light on the cellular heterogeneity of MB and the effect of standard therapy in shaping composition at recurrence.
MEDB-61. Genetic alterations ofTP53 andOTX2 indicate increased risk of relapse in WNT medulloblastomas
Authors: Goschzik Tobias , Mynarek Martin , Dörner Evelyn , Aretz Stefan , Rutkowski Stefan , Pietsch Torsten 
Published: June 2022

Abstract
PURPOSE: This genetic analysis of WNT-activated medulloblastomas (WNT-MBs) aimed to re-evaluate the prognostic impact of TP53 mutations and to identify specific chromosomal aberrations as possible prognostic markers in a retrospective cohort of patients treated according to the protocols of the HIT medulloblastoma studies. PATIENTS AND METHODS: In a cohort of 191 patients with WNT-MBs, mutations in CTNNB1, APC, and TP53 were analyzed by Sanger and/or NGS panel sequencing. Chromosomal copy number aberrations (CNAs) were assessed by high-resolution, genome-wide molecular inversion probe technology (MIP), SNP6 array, and/or 850k methylation bead-array hybridization. Complete clinical data were available from 120 patients. RESULTS: Patients with WNT-MBs had a female predominance (1.4:1) and a median age of 13 years (range 3-69 years). CTNNB1 mutations were present in 92.2% of the samples, APC mutations in 6.8%. One CTNNB1 wildtype tumor gained WNT-activation due to a homozygous deletion of FBXW7. Monosomy 6 was present in 78.6%, but more frequent in children compared to adults. 16.1% of the tumor samples showed TP53 mutations, of those 60% with nuclear positivity for the p53 protein. A loss of heterozygosity at the TP53 locus on chromosome 17p13.1 was found in 40.7% (11/27) of TP53 mutant tumor samples and in 18.5% of the whole cohort (24/130 cases). Patients with tumors harboring TP53 mutations showed significant worse progression-free survival (PFS; p=0.001), but not overall survival (OS) and were enriched for chromosomes 17p (p=0.001), 10, and 13 losses. Gains of the OTX2 locus on chromosome 14q were also associated with poor PFS and OS (p=0.017 resp. p=0.006). Multivariate Cox regression analysis identified both genetic alterations as independent prognostic markers for PFS and OS. CONCLUSION: For ongoing and future de-escalation trials for patients with WNT medulloblastomas, we recommend to exclude patients with tumors carrying TP53 mutations or OTX2 gains.
MEDB-67. Subgroup specific analysis of cellular metabolism in medulloblastoma
Authors: Funke Viktoria , Walter Carolin , Melcher Viktoria , Wei Lanying , Sandmann Sarah , Varghese Julian , Jäger Natalie , Albert Thomas K , Schüller Ulrich , Kerl Kornelius 
Published: June 2022

Abstract
INTRODUCTION: Molecular subgrouping of Medulloblastoma (MB) has expanded our understanding of its biology and the impact on clinical parameters. However, detailed analysis of inter- and intratumoral heterogeneity on a metabolic level is currently lacking. Within this study, we aimed at improving our understanding of metabolic heterogeneity between the MB subgroups, between samples within these subgroups and how these differences affect prognosis. METHODS: We analyzed metabolic characteristics of four MB cohorts covering 1,804 samples in total. In 911 samples (ICGC and MAGIC cohort), we explored metabolic programs on RNA level. In two cohorts (ICGC and G3/G4 samples from the HIT cohort; n=1,035) we examined genetic alterations on DNA level. Furthermore, single-cell RNA-sequencing data of six samples were used to explore intratumoral metabolic heterogeneity. Inter- and intratumoral heterogeneity were correlated to clinical data. RESULTS: Using publicly available gene signatures, we discovered significant differences in metabolic gene expression comparing established MB subgroups. Three metabolically distinct clusters of G3/G4 samples could be defined by unsupervised analyses in two independent cohorts. We were able to confirm our finding of intertumoral metabolic differences on single-cell RNA level. Additionally, our analysis revealed the possibility of sample-specific metabolic features. On DNA level, we identified regulatory genes with known role in MB development to be predominantly associated with lipid metabolic processes. After all, lipid metabolism and metabolism of nucleotides in MB have prognostic value and correlate with the outcome of patients. CONCLUSION: Our data highlight the importance of metabolic properties in MB. We show the distinct metabolic signatures are clinically relevant and, thus, might provide opportunities for novel target-directed therapeutic options in the future.
MEDB-73. Lipid metabolism as a therapeutic vulnerability in BET inhibitor-resistant medulloblastoma
Authors: Lupien Leslie , Boynton Adam , Chacon Madison , Kumbhani Rushil , Gionet Gabrielle , Goodale Amy , Root David , Keshishian Hasmik , Robinson Margaret , Carr Steven , Bandopadhayay Pratiti 
Published: June 2022

Abstract
MYC-driven medulloblastomas are a particularly devastating group of pediatric brain tumors that exhibit resistance and continued progression despite standard of care treatments. Our preclinical work identified BET-bromodomain inhibitors as a potentially promising new class of drugs for children with medulloblastoma and other MYC-driven cancers, providing rationale to evaluate these agents in clinical trials. However, treatment with BET inhibitor (BETi) alone is unlikely to be sufficient to cure, with most tumors evolving to acquire resistance to single-agent targeted therapies. We applied an integrative genomics approach to identify genes and pathways mediating BETi response in medulloblastoma. These studies revealed that MYC-driven medulloblastoma cells with acquired resistance to BETi reinstate transcription of essential genes suppressed by drug and exhibit changes in cell state and new vulnerabilities not present in drug-sensitive cells. We now have a growing body of evidence showing that BET inhibition downregulates the expression of key lipid metabolism genes and metabolism-related signaling pathways, and that medulloblastoma cells with adaptive resistance to drug differentially express and exhibit preferential dependency on specific lipid metabolic genes and transcriptional regulators. Our studies explore the possibility of exploiting these metabolic vulnerabilities to overcome BETi resistance and provide a more efficacious upfront therapy.
MEDB-81. Combined inhibition of CDK11 and EZH2 results in regression of MYC-amplified medulloblastoma
Authors: Wang Dong , Veo Bethany , Pierce Angela , Venkataraman Sujatha , Vibhakar Rajeev 
Published: June 2022

Abstract
We explored an shRNA library screen on 20 cyclin-dependent kinases to establish cyclin-dependent kinase 11 (CDK11) as a critical mediator in MYC-driven medulloblastoma. The effect and molecular mechanism of CDK11 in the proliferation and growth of medulloblastoma were investigated in vitro. Pharmaceutic inhibitors and genetic depletion of CDK11 resulted in cessation of tumor growth in xenograft mouse models. Through combination chemical screening, we identified that 5-FU enhanced the apoptosis which induced by inhibition of CDK11 in medulloblastoma cells. In addition, we found CDK11 is a significant candidate kinase participating in the negative control of Wnt/b-catenin signaling. Down-regulation of CDK11 led to the accumulation of Wnt/β-catenin signaling receptor complexes through activation of transmembrane Frizzled (FZD) receptors which is suppressed by H3K27Me3. RNASeq and cut&run revealed that Cdk11 and mediator associated Cdk8 kinase regulate a common set of genes. Lack of Cdk8 and Cdk11 impaired Ezh2 recruitment and the establishment of histone H3 lysine 27 tri-methylation. We concluded that combined EZH2 and CDK8/CDK11 inhibitors treatment concurrently activated Wnt signaling may be an effective treatment for Group 3 medulloblastoma.
MEDB-83. A novel epigenetic nanotherapeutic strategy to induce medulloblastoma differentiation
Authors: Raju Praveen , Tylawsky Daniel , Vaynshteyn Jake , Gerwin Jeffrey , Heller Daniel , Snuderl Matija 
Published: June 2022

Abstract
The histone-lysine N-methyltransferase EZH2 is the catalytic component of the PRC2 complex and is overexpressed in several medulloblastoma subtypes. However, its role in medulloblastoma tumorigenesis has been shown to be context-dependent using genetic approaches. Furthermore, pharmacological approaches have been limited by the very poor blood-brain barrier (BBB) penetration of current EZH2 inhibitors in use. Using laser capture microdissection and RNA-Seq analysis of human nodular/desmoplastic SHH medulloblastoma FFPE tissue, we provide data for the spatial epigenetic heterogeneity of primitive/proliferative regions compared to nodular/mature regions. Bioinformatic analysis identifies ~120 differentially expressed genes between primitive and mature regions with enrichment for genes regulated by H3K4me3 and H3K27me3 or SUZ12. ChIP-Seq analysis shows striking differences in H3K27me3 enrichment between primitive and mature medulloblastoma cells including at the EZH2 locus. Utilizing a genetically-engineered mouse model of SHH medulloblastoma, we show that conditional EZH2 genetic ablation within medulloblastoma cells results in wide-spread tumor cell differentiation (n=31 mice; *p=2e-07). Conversely, conditional EZH2 (Y641F) activation in this GEM model prevents tumor cell differentiation. Notably, we have found that the CDNK2A (p16) locus is an important EZH2 target that regulates tumor cell differentiation. qRT-PCR analysis of SHH medulloblastoma in wild-type and Ezh2 knockout settings show significant reduction in Gli1 and CCND1 and increase p15 and p16 expression in Ezh2 knockout mice compared to Ezh2 wildtype mice (*p&lt;0.05). Importantly, genetic ablation of p16 conditionally in SHH MB EZH2 double knockout mice rescues the widespread tumor cell differentiation (n=9 mice; *p=3e-06) seen in Ezh2 single knockout SHH medulloblastoma mice. Finally, we developed a novel fucoidan-based nanoparticle strategy to deliver the EZH2 inhibitor (EPZ-6438) across the intact BBB of this GEM model to achieve significant extension of mouse survival (median 70 days compared to 19 days in control mice; *p=0.01, Mantel-Cox) with potential utility for other pediatric brain tumors.
MEDB-90. Iron Imbalance Can Potentiate Cisplatin Response in Pediatric Medulloblastoma by Regulating Ferroptosis
Authors: Kanchan Ranjana , Perumal Naveenkumar , Khan Parvez , Doss David , Venkata Ramakanth Chirravuri , Thapa Ishwor , Vengoji Raghupathy , Kaushal Jyoti , Siddiqui Jawed , Nasser Mohd Wasim , Batra Surinder , Mahapatra Sidhartha 
Published: June 2022

Abstract
Medulloblastoma (MB), the most common malignant pediatric brain tumor, is a leading cause of childhood mortality. Of the four primary subgroups, patients with group 3 tumors have the poorest prognosis. Loss of chromosome 17p is a high-risk feature associated with poor outcomes in group 3 tumors. We recently elucidated the tumor suppressive properties of a novel miR, miR-1253, on the terminal end of 17p. In further exploring its anti-neoplastic effects, we discovered that miR-1253 can disrupt iron homeostasis, causing oxidative stress and inducing lipid peroxidation. These concurrent events are capable of triggering an iron-mediated form of cell death called ferroptosis. Notably, our in silico interrogation of ferroptosis regulator genes (FRGs) in group 3 tumors revealed high expression of genes associated with iron transport and glutathione metabolism. These included mitochondrial iron transporters and GPX4, a critical regulator of ferroptosis. Restoration of miR-1253 expression in group 3 cell lines resulted in specific downregulation of ABCB7, an iron-sulfur cluster exporter, and GPX4. Consequently, cytosolic and mitochondrial labile iron pools rose, glutathione levels declined, and mitochondrial oxidative stress and lipid peroxidation were induced. These events were recapitulated by ABCB7 knockdown and potentiated cell death. Treating miR-1253-expressing cancer cells with cisplatin, a group 3 MB chemotherapeutic agent with ferroptotic properties, further elevated oxidative stress, depleted glutathione levels, and augmented lipid peroxidation, with added inhibitory effects on cell viability and colony formation. Treatment with a ferroptosis inhibitor (ferrostatin-1) lead to recovery from the cytotoxic effects of this combination therapy. Our studies highlight a novel mechanism for group 3 MB pathogenesis via ferroptosis regulation and provide a proof-of-concept for exploiting group 3 MB tumor vulnerability to iron imbalance as a novel treatment strategy.
NFB-02. Maternal high-fat diet exposure increases the proliferation and glial differentiation of the cells of origin for NF1-optic glioma
Authors: Zhang Kailong , Gutmann David , Brossier Nicole 
Published: June 2022

Abstract
Some pediatric cancers arise in the context of tumor predisposition syndromes caused by germline mutations in genes that regulate cell growth. The most common of these syndromes, Neurofibromatosis type 1 (NF1), results in the development of low-grade tumors of the optic pathway (optic pathway gliomas; OPGs) in ~15% of affected children. However, risk assessment for each individual child is difficult, as it is currently challenging to predict which children with NF1 will develop OPG. Emerging human population-based evidence has raised the possibility that patient-specific risk factors, including infant birth weight, may modulate the risk of glioma development. High-infant birth weight can be modeled in mice by maternal exposure to a high-fat high-sucrose (HFHS) diet. To address the hypothesis that maternal high-fat diet exposure will increase the risk of OPG formation through intrinsic effects on the putative tumor cell of origin, we evaluated the effect of maternal exposure to a HFHS diet on the proliferation and differentiation of these cells (neural stem cells within the third ventricular zone; TVZ NSCs). Progeny from obese dams (MatOb) exposed to HFHS diet during and preceding gestation demonstrated increased proliferation and glial differentiation of TVZ NSCs in vivo. Similar results were observed with gestational HFHS diet exposure (GE) that did not result in maternal weight gain, suggesting these effects were related to maternal diet rather than weight. These effects were not observed in NSCs from other regions of the brain, supporting the regional specificity of the effect of diet on these tumor-initiating stem cells. Finally, we found that maternal HFHS diet resulted in elevated levels of leptin and insulin, both of which increase the proliferation of TVZ NSCs. Taken together, these findings provide early experimental evidence that maternal environmental exposure affects developing neural stem cells relevant to the risk of glioma formation.
NFB-03. Neurological manifestations in children and adolescents with Neurofibromatosis type 1 - Implications for management and surveillance
Authors: Angelova-Toshkina Daniela , Holzapfel Johannes , Bette Stefanie , Decker Josua , Hellmann Fabio , Traunwieser Thomas , Huber Simon , Schimmel Mareike , Vollert Kurt , Bison Brigitte , Kröncke Thomas , André Elisabeth , Wieczorek Dagmar , Gnekow Astrid K , Frühwald Michael C , Kuhlen Michaela 
Published: June 2022

Abstract
INTRODUCTION: We aimed to (1) characterize the spectrum of clinical phenotypes of NF1 in a random pediatric population, (2) correlate genotype with phenotypic expression for those with a genetic diagnosis, and (3) explore radiological features of NF1 in the central nervous system (CNS) by radiomics analyses to predict clinical course. METHODS: We performed a database search in the hospital information system of the University Children′s Hospital between January 2017 and December 2020 for patients with NF1 and evaluated the clinical phenotype by retrospective chart review. RESULTS: 75 children/adolescents were identified with suspicion/clinical diagnosis of NF1 (median age 10.0 years (range, 1.1-22.6); 35 female), confirmatory revised “diagnostic criteria” were met in 57 patients at the last follow-up. Per number of documented items, major signs were detected as 73/75 café-au-lait macules, 31/63 freckling, 38/71 neurofibromas (thereof 21 plexiform neurofibromas), 18/43 optic pathway glioma, 5/66 Lisch nodules, and two patients with sphenoid dysplasia. Genetic analysis (31/75) identified pathogenic NF1 variants in 27 patients. In 20/66 cases a parent met diagnostic criteria. Cognitive symptoms included developmental delay (28/68), learning deficits (12/48), attention-deficit hyperactivity disorder (3/53), and behavior anomalies (7/63). Classical unidentified bright objects were seen in 29/43, other intracranial tumors in 7/43, and cerebrovascular abnormalities in 5/43. Analysis of imaging features of the CNS in these patients will involve lesion segmentation and radiomics features. Symptomatic/progressive low-grade glioma necessitated neurosurgical resection (4/25) and/or chemotherapy (12/25). In 10/25 neuropsychological functions were assessed by the German neuropsychological basic diagnostic instrument. Until June 30th, 2021, one patient died of progressive plexiform neurofibroma.
CONCLUSIONS: A wide range of neurological manifestations, including neuropsychological deficits, should raise the suspicion of NF1 in an unselected pediatric population. We expect imaging features of the CNS to better predict the clinical course and enhance decision-making.