bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-01. DEVELOPMENT OF A WEB-BASED CALCULATOR APPLICATION FOR PREDICTING SHORT- AND LONG-TERMSURVIVAL IN PEDIATRIC OPTIC PATHWAY GLIOMA: A POPULATION-BASED DATABASE ANALYSIS
Authors: Brown Nolan , Kuo Cathleen , Pennington Zach , Gendreau Julian , Givens Drew , Daniels David 
Published: June 2023

Abstract
Optic pathway gliomas (OPG) are generally low-grade lesions arising from the astrocytes of the visual pathway, most commonly of the optic nerves and chiasm. Uncertainty remains regarding the optimal management of this patient population. We sought to leverage population-level data from the Surveillance, Epidemiology, and End Results program database to develop a predictive calculator for overall survival (OS) amongst pediatric patients with OPG. A total of 1,052 patients who had been diagnosed with OPG were included. Multivariate cox proportional hazard model demonstrated patients of “other” race (hazard ratio [HR]=4.109, 95% confidence interval [CI] 1.076-15.694, p=0.039) exhibited a decreased overall survival, while patients with a median household income ≥$55,000 (HR=0.172, 95% CI 0.065-0.457, &lt;0.001) and those who underwent subtotal resection (HR=3.549, 95% CI 1.092-13.364, p=0.047) had a higher overall survival rate. An online, interactive survival prediction tool (https://spine.shinyapps.io/optic_glioma/) was created to estimate 5-, 10-, and 15-year overall survival probability as well as median survival months. C-index was 0.722 (95% CI 0.642-0.776) for the training set and 0.745 (95% CI 0.661-0.790) for the validation set. Good concordance between the predicted probability and the actual probability of the dataset was also observed. This calculator may serve as a useful clinical tool during patient counseling. Further investigations aimed at developing calculators of visual acuity preservation and progression-free survival are merited; progress toward this end will benefit from continued multicenter collaborations.
LGG-07. TARGETED THERAPY IN PEDIATRIC LOW-GRADE GLIOMAS; REAL WORLD DATA IN THE CONTEXT OF CONVENTIONAL TREATMENT MODALITIES
Authors: Sumerauer David , Trkova Katerina , Koblizek Miroslav , Kyncl Martin , Krskova Lenka , Benes Vladimir , Zapotocky Michal 
Published: June 2023

Abstract
Progressive inoperable pediatric low-grade gliomas (pLGG) are challenging and chemotherapy provides unsatisfactory long-term disease control. Majority of pLGGs harbor oncogenic MAPK pathway alterations. BRAF and MEK inhibitors were developed and available data suggest possible benefit in pLGG patients. Therefore, we aimed to evaluate efficacy and toxicity of dabrafenib in BRAF-V600E positive pLGG and trametinib in KIAA1549::BRAF fused or NF1-associated pLGGs. Retrospective review of patients with molecularly profiled pLGGs treated with MAPK inhibitors at our institutions was performed. Response to targeted therapies was evaluated using RAPNO criteria and volumetric analysis. Twenty-six patients were eligible for this study because they had either BRAF-V600E pLGG treated with dabrafenib (n=11) or KIAA1549::BRAF fused/NF1-associated pLGG treated with trametinib (n=15) outside clinical trials. Patients received targeted therapy because of radiological progression (n=18), clinical deterioration (n=2) or as an upfront approach (n=6). Overall response rate (ORR) of the whole cohort using RAPNO criteria was 46.1% (12/26). There was a discordance observed between RAPNO bidimensional and manual volumetric analysis in 7 patients (26.9%). Progression free survival (PFS) at 2 years for the whole evaluated cohort was 78.5%(95 CI, 63.2 to 97.4%). ORR of patients with BRAF-V600E pLGG was 64% (median time to response 2.6 months). Out of fifteen patients treated with trametinib, 33% achieved partial response (median time to response 6.6 months). In total, 6 patients experienced progression on therapy. Six patients were treated with vinca alkaloids and trametinib with no additional toxicity. All 15 patients experienced trametinib-related adverse event, grade III was reported in 6 (40%) of them. Altogether 11 patients (73%) required dose reductions or treatment interruptions. MAPK inhibitors represent novel treatment modality in pLGG patients with clinical benefit in proportion of patients. Nevertheless, patients may experience progression on therapy requiring further management.
LGG-08. TARGETED THERAPY IN BRAFV600E-DRIVEN PEDIATRIC GLIOMAS: UNCOVERING MECHANISMS OF RESISTANCE THROUGH A MULTI-OMIC APPROACH
Authors: Capogiri Monica , De Micheli Andrea , Berenjeno-Correa Ernesto , Postlmayr Andreas , Guerreiro Stücklin Ana Sofia 
Published: June 2023

Abstract
BRAFV600E is a key oncogenic mutation, detected in both pediatric low-grade gliomas and high-grade gliomas. Targeting the Ras-BRAF-MAPK pathway with BRAFV600E-specific inhibitors, such as Dabrafenib, is a therapeutic strategy increasingly used in clinical practice. However, therapy failure often emerges in patients, and the mechanisms driving drug resistance remain elusive. We apply a multi-omic approach to understand the evolution of BRAFV600E glioma cell lines and ex-vivo patient-derived cultures under BRAF inhibition. To recapitulate the clinical situation and decipher mechanisms of acquired resistance, we chronically expose BRAFV600E-positive glioma cells to a sublethal dose of Dabrafenib (IC20) and generate drug-resistant cell lines. We then profile the kinome (Pamgene microarray) and the transcriptome (bulk RNAseq) of resistant versus wildtype cells: in addition to reactivation of the Ras-BRAF-MAPK pathway, we observe increased activation and expression of PDGFRB and Src family kinases (SFK) in the Dabrafenib-resistant phenotype. To identify and track the longitudinal evolution of drug-resistant states, we further assess the evolution of glioma cell subpopulations under therapeutic pressure and profile consecutively collected samples (day 0; day 2; day 10; day 30 of treatment; and 10 days post-treatment) using single-cell transcriptomics (10x Chromium system, 10x Genomics). By profiling BRAFV600E glioma cells pre-, on- and post-treatment, we find that therapeutic pressure induces changes in cell subpopulations from early stages, and these changes are selected over time. Consistent with our kinome and bulk RNAseq findings, we confirm the role of PDGFRB in driving Dabrafenib resistance in a subset of cells. Furthermore, when off-treatment, the cells recapitulate the untreated status, indicating that resistance is a temporary, drug-dependent, phenomenon relying on the kinome rewiring. By dissecting the pro-survival role of the PDGFR/SFK axis upon Dabrafenib treatment, we will provide valuable mechanistic and therapeutic insights into targeted therapies for children with BRAFV600E gliomas.
LGG-13. GANGLIOGLIOMA DEEP TRANSCRIPTOMICS REVEALS A CD34+ PRIMITIVE NEUROECTODERM NEURAL PRECURSOR-LIKE POPULATION
Authors: Regal Joshua , Guerra-Garcia Maria , Jain Vaibhav , Chandramohan Vidyalakshmi , Ashley David , Gregory Simon , Thompson Eric , Lopez Giselle , Reitman Zachary 
Published: June 2023

Abstract
Gangliogliomas are glioneuronal brain tumors that typically present in childhood or early adulthood. Though most often low-grade, new insights are needed to refine glioneuronal tumor classification and to identify therapeutic approaches, particularly for unresectable, high-grade, and/or recurrent disease. Gangliogliomas often possess a rare population of immature astrocyte-appearing CD34+ cells. CD34 is expressed in neuroectoderm neural precursor cells during embryogenesis. Neural cell CD34 expression is usually lost prior to birth. We hypothesized that CD34+ ganglioglioma cells represent tumor precursor/stem cells and closely resemble ganglioglioma cells of origin. To test this, we evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. Developmental trajectory analyses uncovered a neoplastic cellular hierarchy, with CD34+PAX6+SOX2+MSI1+PECAM1-VWF-DCN-COL1A2- cells being the most primordial and precursor to neuron-like and macroglia-like neoplastic cell states. Gene regulatory network inference of CD34+ ganglioglioma cells indicated TCF7L2/MEIS1-PAX6 and SOX2-mediated transcriptional programming, similar to that found during neuroectodermal/neural development in utero. Spatially-resolved transcriptomics revealed a neuroectoderm neural precursor-like tumor cell niche relatively devoid of vascular and immune cells. We used these high-resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ neural precursor-like cell-associated gene programs associate with gangliogliomas compared to other brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy - identifying CD34+ neuroectoderm neural precursor-like tumor-initiating cells, corresponding regulatory transcriptional programs, cell signaling pathways, and associated immune cell states. These findings may facilitate improved ganglioglioma tumor classification, diagnosis, and therapeutic investigations.
LGG-21. FGFR1 GENE MUTATION AS A POTENTIAL RISK FACTOR FOR SPONTANEOUS INTRACRANIAL HEMORRHAGE IN PEDIATRIC LOW GRADE GLIOMA PATIENTS
Authors: Lebert Brittany , Campion Stephani , Wagner Aaron , Gonzalez-Vega Maxine , Aguilar-Bonilla Ana , Smith Amy 
Published: June 2023

Abstract
The Fibroblast Growth Factor Receptor 1 (FGFR1) gene is the second most altered gene in pediatric LGGs and has been associated with poorer prognoses. A recent study suggested a link between the FGFR1 mutation and spontaneous intracranial hemorrhage in pediatric LGG patients, an event that can be detrimental to cognitive development and, in some cases, even fatal. The current study aimed to further confirm this link by following 49 pediatric LGG patients treated at the Arnold Palmer Hospital for Children from 2007-2022 and investigating the occurrences of spontaneous intracranial hemorrhage. We accessed their treatment course, clinical outcome, radiographic findings, and pathological findings. Genetic analysis was performed as part of their standard of care at the time of tumor resection or biopsy. Of the forty-nine pediatric LGG patients we followed, eight (16.3%) experienced spontaneous intracranial hemorrhage. Five of these eight patients (62.5%) had an FGFR1 mutation. Out of the forty-nine patients, only six of them had an FGFR1 mutation, and five out of the six (83.3%) experienced spontaneous intracranial hemorrhage at some point during treatment. The one patient that did not experience hemorrhage lacked a classic FGFR1 mutation and presented with a variant of unknown significance that has yet to be regarded as pathogenic. These findings are consistent with the aforementioned study and are significant because, to date, little is known about the tumor-specific risk factors for these spontaneous intracranial hemorrhages. Understanding the risk factors could help clinicians better predict these occurrences and potentially prevent their devastating effects.
MDB-03. DFMO AS A TREATMENT STRATEGY IN GROUP 3 MEDULLOBLASTOMA
Authors: Shahab Shubin , Roggeveen Christianna , MacDonald Tobey , Kenney Anna 
Published: June 2023

Abstract
Medulloblastomas, the most common malignant brain tumor in children, are subdivided into 4 major molecular subgroups. Among these, Group 3 medulloblastomas have one of the worst prognoses. We have recently identified the LIN28B pathway as being critically important in Group 3 medulloblastoma growth in vitro and in vivo. There are few targeted inhibitors of the LIN28B pathway and none are currently in clinical practice. Recently DFMO has been identified as an indirect inhibitor of the LIN28B-let-7 axis through its inhibition of polyamine biosynthesis. Another recent study identified ornithine, a precursor to polyamines, as being upregulated in MYC amplified Group 3 medulloblastoma. Importantly, DFMO has been demonstrated to achieve high concentrations in brain tumors in a rat glioma model with minimal systemic toxicity. Based on this we hypothesize that DFMO would be attractive agent for Group 3 medulloblastoma treatment as it would inhibit both polyamine synthesis and LIN28B and potentially achieve high tumor concentrations. Here we demonstrate that treatment with increasing concentration of DFMO leads to significant reduction in Group 3 medulloblastoma viability, increased apoptosis and reduced levels of LIN28B and its downstream targets. We are currently investigating whether this drug can effectively inhibit in vivo tumor growth in orthotopic xenograft models of Group 3 medulloblastoma.
MDB-07. MYC AND TGFΒ PROMOTE GROUP 3 MEDULLOBLASTOMA TUMOR RESISTANCE THROUGH DEREGULATION OF KDM2B TARGETS
Authors: Qadeer Zulekha , Westelman Samantha , Johnson Mackenzie , Grele Shane , Hou Elise , Hendrikse Liam , Wang Linyu , Husain Sarah , Beytagh Mary Clare , Schmidt Christin , Huang Miller , Taylor Michael , Weiss William 
Published: June 2023

Abstract
Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at &lt;50%, few recurrent mutations, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some MB tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We hypothesize that the TGFβ pathway and MYC contribute to the intrinsic resistance of G3MB through deregulation of key genes and pathways. We previously established humanized models for SHHMB by introducing MYCN or PTCH1 deletions into neuroepithelial stem cells (NESC) derived from normal human induced pluripotent stem cells (hIPSCs). In this study, we transduced NESCs with TGFb effectors activated in G3MB alone and/or in combination with MYC, prioritizing combinations observed in patients. Excitingly, both MYC and TGFβ effectors drove tumor formation in vivo with the combination of TGFβ effectors with MYC leading to more aggressive tumors. We next found that NESCs expressing MYC with either TGFβR1 or TGFβ1 showed resistance to clinical TGFβR1 inhibitors, compared to cells driven by either TGFβR1 or TGFβ1 alone. To decipher mechanisms of resistance, we integrated CUT&RUN to probe for MYC genomic localization and relevant histone PTMs with RNA-seq analysis and discovered a subset of genes upregulated in MYC and TGFb-driven lines that are targets of the histone demethylase KDM2B. Loss of function mutations in KDM2B occur in G3MB patients, indicating that KDM2B deregulated genes are critical in G3MB. We postulate that epigenetic remodeling via MYC and recruitment of other MYC-interacting cofactors to KDM2B targets culminates in transcriptional changes that lead to aggressive disease. Overall, our studies provide important insight on identifying new therapeutic avenues for patients with MYC and TGFβ driven G3MB.
MDB-10. EPIDEMIOLOGICAL PROFILE OF MEDULLOBLASTOMA IN MOROCCO: A 2-YEAR RETROSPECTIVE STUDY
Authors: Erefai Ouassima , Sennani Sara , Soulaymani Abdelmajid , Mokhtari Abdelrhani , Hami Hinde 
Published: June 2023

Abstract
Medulloblastoma is a malignant, invasive embryonal tumor of the central nervous system. This pathology is the leading malignancy in children, accounting for 30% of central nervous system pediatric tumors. This study aimed to present the epidemiological profile of medulloblastoma in Morocco. It was a retrospective study including all children aged 0 to 16 years and diagnosed with medulloblastoma at the pediatric hematology-oncology department of the children’s hospital in Rabat (Morocco) over two years, from January 1, 2021, to December 31, 2022. A total of 12 patients were included in the study, 7 boys and 5 girls (M/F ratio 1.4). The mean age was 9 ± 3 years. The majority (91.7%) of children were over 5 years of age. Only one child was aged 18 months. over half of the patients were from a rural areas. Most cases were living over 30 Km from the center. Among them, 40% were more than 150 km. A low socio-economic level was reported by 75% of the families. Two children were born to consanguineous parents. A familial cancer history was noted in 41.7% of patients. Clinical symptoms were dominated by headache (83.3%) and vomiting (66.7%). Regarding treatment, two patients were treated with surgery and seven with a combination of surgery, radiotherapy, and chemotherapy. During the period of study, there were no cases of death. A good outcome was noted in 91.7% of patients. Only one child received palliative care. Childhood cancer in general, and medulloblastoma in particular, is on the rise in Morocco. Given the scarcity of publications on this type of cancer in our country, a national registry is necessary for the monitoring and appropriate management of this disease.
MDB-11. AN ONLINE CALCULATOR USING MACHINE LEARNING FOR PREDICTION OF SURVIVAL IN PEDIATRIC PATIENTS WITH MEDULLOBLASTOMA
Authors: Kuo Cathleen , Brown Nolan , Lim Jaims , Monteiro Andre , Recker Matthew , Ghannam Moleca M , Gendreau Julian , Li Veetai , Reynolds Renée 
Published: June 2023

Abstract

OBJECTIVE
Medulloblastoma is the most common malignant intracranial tumor affecting the pediatric population. Despite advancements in multimodal treatment over the past 2 decades yielding a &gt;75% 5-year survival rate, children who survive often have substantial neurological and cognitive sequelae. The authors aimed to identify risk factors and develop a clinically friendly online calculator for prognostic estimation in pediatric medulloblastoma patients.

METHODS
Pediatric patients with a histopathologically confirmed medulloblastoma were extracted from the Surveillance Epidemiology and End Results database (2000-2019) and split into training and validation cohorts in an 80:20 ratio. The Cox proportional hazards model was used to identify the univariate and multivariate survival predictors. Subsequently, a calculator with those factors was developed to predict 2-, 5-, and 10-year overall survival as well as median survival months for pediatric medulloblastoma patients. The performance of the calculator was determined by discrimination, calibration, and decision curve analysis (DCA).

RESULTS
A total of 1,739 pediatric patients with medulloblastoma met the prespecified inclusion criteria. Fourteen variables, including age, sex, race, ethnicity, median household income, county attribute, laterality, histology, anatomical location, tumor grade, tumor size, surgery status, radiotherapy, and chemotherapy, were included in the calculator (https://spine.shinyapps.io/Peds_medullo/). The concordance index was 0.757 in the training cohort and 0.762 in the validation cohort, denoting clinically useful predictive accuracy. Good agreement between the predicted and observed outcomes was demonstrated by the calibration plots. The DCA curves indicated that the developed model has a good clinical prognostic benefit for pediatric medulloblastoma patients.

CONCLUSION
An easy-to-use prognostic calculator for a large cohort of pediatric patients with medulloblastoma was established. Future efforts should focus on improving granularity of population-based registries and externally validating the proposed calculator.
MDB-12. TRANS-SPECIES ANALYSIS OF REPLICATION-REPAIR DEFICIENT (RRD) MEDULLOBLASTOMA AND RESPONSE TO IMMUNE-CHECKPOINT INHIBITION: AN IRRDC REPORT
Authors: Das Anirban , Fernandez Nicholas R , Levine Adrian , Smith Kyle , Wang Evan , Galati Melissa , Aamir Zoya , Chung Jill , Negm Logine , Crump Owen , Trinh Quang , Nunes Nuno M , Bianchi Vanessa , Stengs Lucie , Edwards Melissa , Stein Lincoln , Bouffet Eric , Taylor Michael , Northcott Paul , Ramaswamy Vijay , Hawkins Cynthia , Tabori Uri 
Published: June 2023

Abstract

BACKGROUND
Replication-repair deficiency (RRD) stemming from mismatch repair and polymerase-proofreading gene defects (MMRD/PPD) lead to hypermutant childhood cancers, most frequently brain tumors. While medulloblastoma is reported, the clinical, genomic and immune landscape remains unknown.

METHODS
We analysed the genome, methylome, transcriptome (bulk, single-nuclei) and immune-microenvironment of the largest cohort of RRD-medulloblastoma patients enrolled by the International RRD Consortium, and correlated these to clinical outcomes. RRD mice-models were used to preclinically assess response to immunotherapy.

RESULTS
RRD-medulloblastoma (n=40) were enriched for anaplasia (55%) and localised disease (85%). Methylation/nano-string-based subgrouping failed to classify 40%, while the remaining clustered with the SHH-subgroup. Copy-number changes were notably infrequent (&lt;20%). All tumors harboured hypermutation and microsatellite instability in contrast to non-RRD controls (p&lt;0.0001). Pathogenic variants were frequent in POLE/POLD1 (80%), TP53 (48%) and SHH-pathway genes (PTCH1, SUFU, SMO: 56%). Interestingly, some tumors additionally had glioma-driver alterations (ATRX, NF1: ~50%), similar to RRD cerebellar glioblastoma, but distinct from both non-RRD medulloblastoma (n=791) and hemispheric glioblastoma (n=733) controls. Moreover, although bulk-transcriptome matched non-RRD SHH-medulloblastoma, single-nuclei analyses suggested an earlier cell-of-origin potentially explaining the heterogenous phenotypes resulting from the driver mutations. Uniquely, immune analyses (gene expression and immunohistochemistry) demonstrated high intra-tumoral CD8 T-cell infiltration.
Three-year progression-free survival was 60%. Outcome was worse for RRD-medulloblastoma harbouring TP53-mutation (p=0.04) and failing subgroup-classification (p=0.004). Nestin/Cre MSH2-/- POLE;p.S459F mice developing medulloblastoma recapitulated human disease and demonstrated response to anti-PD1 monotherapy. Recurrent/progressive human tumors including those harbouring TP53-mutations exhibited radiological responses to anti-PD1 monotherapy, which was associated with prolonged ongoing survival in comparison to those not treated with checkpoint-inhibitors (p=0.02).

CONCLUSIONS
Hypermutant RRD-medulloblastoma reveal heterogenous phenotypes due to unique spectrum of driver mutations and an early cell of origin. Their immune-hot microenvironment allows successful salvage treatment with checkpoint-inhibitors for those failing chemo-radiation, including the high-risk SHH/TP53-mutant and unclassified subgroups.