bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-60. Development and implementation of a complementary diagnostic tool to detect targetable pathways in pediatric glioma patients
Authors: Nobre Liana , Levine Adrian , Milos Scott , Johnson Monique , Laxer Benjamin , Ryall Scott , Siddaway Robert , Tabori Uri , Hawkins Cynthia 
Published: June 2022

Abstract
Pediatric Low grade gliomas are mainly driven by MAPK alterations including mutations in BRAF (BRAF fusions and BRAFV600) and FGFR. This has led to the study of BRAF, MEK and more recently FGFR inhibitors resulting in variable responses. We hypothesize that differing levels of RAS_MAPK coupled with alternate pathway activation may be driving this variability. To address this, we designed a custom NanoString assay that integrates proteomic and transcriptomic profiling of 4 key cancer-related, actionable pathways (MAPK, PI3K-AKT-mTOR, JAK-STAT, and NFkB) with robust results on formalin-fixed paraffin embedded tissue, including archival samples up to approximately 15 years old. We validated this assay using 15 gold standard cell lines with defined changes in each pathway including both isogenic activating mutations and perturbation with inhibitors. These findings were confirmed using data from the Cancer Cell Line Encyclopedia. The panel was further validated using a cohort of 40 low grade glioma samples with available RNAseq data where the RNA expression signatures had high concordance between assays. We have currently run the assay on over 200 surgical tumor samples, including 206 gliomas, 15 ependymomas, 11 medulloblastomas, 14 high grade gliomas and 10 control normal brain specimens. Findings indicate significant variability in pathway activations between tumors, although PLGG overall have higher MAPK activation scores than control tissue and other tumor types, a subset of these tumors have increased activity in PIK , JAK and NFKB pathways, underscoring the importance of integrating transcriptomic and proteomic information in precision oncology treatments. Finally, single cell RNA sequencing data from pilocytic astrocytomas demonstrates significant heterogeneity in pathway activation states within the tumor cells, as well as high pathway activations in some tumor associated microglia. This raises further research questions regarding the role of tumor heterogeneity in treatment failures and the impact of targeted therapies on the tumor immune microenvironment.
LGG-61. Cerebrospinal fluid as a source for liquid biopsy in pediatric gliomas
Authors: Nobre Liana , Johnson Monique , Siddaway Robert , Sheth Javal , Ryall Scott , Ku Michelle , Lyn Rodney , Stucklin Ana , Zapotocky Michal , Tabori Uri , Hawkins Cynthia 
Published: June 2022

Abstract
Central nervous system neoplasms are currently the leading cause of morbidity and mortality among childhood cancers, gliomas account for 50% of these cases. The last decade has seen a massive growth in our understanding of the genetic underpinnings of these cancers, including the discovery of multiple diagnostic, prognostic and therapeutic markers. However, molecular characterization of these tumours requires a biopsy, with no added therapeutic benefit particularly in unresectable tumors. Liquid biopsy is a minimally-invasive alternative to biopsies which enables molecular characterization to diagnose, monitor response to therapy, and potentially predict progression/recurrence. We here present the results of a customized capture based NGS panel including 21 commonly altered genes present in pediatric and AYA gliomas coupled with low pass whole genome as a diagnostic and monitoring liquid biopsy tool. To assess for common fusions, exonic and intronic regions of specific genes are covered to capture different breakpoints. To establish the sensitivity and specificity of this assay we have used a commercially available control (SeraseqR) with 18 known mutated genes of interest and a in house control sample with two additional mutations. Samples with low ctDNA concentration (10 ng) and a limit of detection as low as 0.5% variant allele frequency, had a sensitivity of 83% and specificity of 100%. At higher concentrations (30 ng of ctDNA) we achieved a sensitivity and specificity of 100 %. We are currently finalizing the validation steps ctDNA samples extracted from CSF collected intra-surgically, through ventricular shunt or lumbar puncture. Twenty-two samples have been tested with additional 40 samples in processing. Driver alterations were identified in 16/22 samples, with additional 3/4 samples having concordant CNV alterations between tumor and CSF. This work supports further implementation of CSF use as a minimal invasive source of diagnostic and monitoring sample in children and adolescent patients with gliomas.
LGG-62. Weight change in pediatric patients treated with MEK inhibitors: a retrospective cohort study
Authors: Hyun Bahng Hye , Malvar Jemily , Chi Yueh-Yun , Framson Celia , Robison Nathan 
Published: June 2022

Abstract
BACKGROUND: MEK inhibition is an emerging treatment strategy in pediatric tumors characterized by activation of the Ras-Raf-MEK-ERK pathway, including low-grade glioma (LGG) and neurofibromatosis 1 (NF1)-associated tumors. Preliminary clinical experience suggests that MEK inhibitors (MEKi) may be associated with weight gain in children, which has not been a reported toxicity in adults. METHODS: 35 patients &gt; 1 and &lt; 21 years old treated at CHLA with MEKi between October 2013 and May 2019 were identified. Data was collected at t = 0 (baseline), t = 3 months, t = 6 months, t = 12 months, and t = 24 months, as well as pre- and post-treatment time points. Weight change was categorized as no change (change in Z-score [-0.25, +0.25]), weight gain (change in Z-score &gt; 0.25), and weight loss (change in Z-score &gt; -0.25). RESULTS: Weight gain and weight loss were seen in 11 (34.4%) and 8 (25%) patients, respectively, after 6 months on therapy. Weight gain reversed in 4 out of 5 patients with post-treatment data. There was no clear association between weight outcome and hypothesized covariates (including hypothalamic location and NF1 status). Notably, significant weight gain was seen across baseline weight spectrum, including patients who had underweight and severely overweight BMI percentiles at baseline. CONCLUSION: Our findings preliminarily suggest that MEK inhibition may be associated with clinically significant weight change, especially weight gain, in a subset of children and young adults. Reversal upon drug cessation suggests a causal relationship. Further prospective and mechanistic investigation is needed.
MEDB-03. Medulloblastoma cerebrospinal fluid reveals hypoxic indicators (metabolites and lipids) and cancer-specific RNAs
Authors: Lee Bongyong , Mohamad Iqbal , Pokhrel Rudramani , Murad Rabi , Yuan Menglang , Stapleton Stacie , Bettegowda Chetan , Jallo George , Eberhart Charles G , Garrett Timothy , Perera Ranjan J 
Published: June 2022

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. There remains an unmet need for diagnostics to sensitively detect the disease, particularly recurrences. Cerebrospinal fluid (CSF) provides a window into the central nervous system, and liquid biopsy of CSF could provide a relatively non-invasive means for disease diagnosis. There has yet to be an integrated analysis of the transcriptomic, metabolomic, and lipidomic changes occurring in the CSF of children with MB. CSF samples from patients with (n=40) or without (n=11; no cancer) MB were subjected to RNA-sequencing and high-resolution mass spectrometry to identify RNA, metabolite, and lipid profiles. Differentially expressed transcripts, metabolites, and lipids were identified and their biological significance assessed by pathway analysis. Multivariate analysis method DIABLO (R package mixOmics) was used to integrate the molecular changes characterizing the CSF of MB patients. Differentially expressed transcripts, metabolites, and lipids in CSF were discriminatory for the presence of MB but not the exact molecular subtype. One hundred ten genes and ten circular RNAs were differentially expressed in MB CSF compared to normal representing TGF-β signaling, TNF-a signaling via NF-kB, and adipogenesis pathways. Tricarboxylic acid cycle and other metabolites (malate, fumarate, succinate, α-ketoglutarate, hydroxypyruvate, N-acetyl-aspartate) and total triacylglycerols were significantly upregulated in MB CSF compared to normal CSF. Although the transcriptomic, metabolomic, and lipid signatures in CSF to differentiate MB subgroup separation was challenging, we were able to identify a group of omics signatures that could separate cancer from normal CSF. Metabolic and lipidomic profiles both contained indicators of tumor hypoxia. Our approach provides several candidate signatures that deserve further validation, including the novel circular RNA circ_463, and insights into the impact of MB on the CSF microenvironment.
MEDB-05. Survival and prognostic factors in childhood medulloblastoma: A China single center experience from 2006 to 2015
Authors: Liang zhuangzhuang , Cao liangliang , Zhao yang , Wang baocheng , Tian shuaiwei , Wang jiajia , Ma jie 
Published: June 2022

Abstract
OBJECTIVE: Medulloblastoma (MB) is a malignant embryonal tumor that develops especially in childhood, with overall survival (OS) at 5 years of up to 70%. The aim of the study is to explore the clinical profile and outcome among the histo-molecular subgroups in Chinese children. METHODS: A total of 93 patients of MB who underwent surgical treatment at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2006 to December 2015. The clinical profile, treatment, and survival patterns are discussed. The relevant statistical analysis was done using SPSS software, version 21.0. RESULTS: At the most recent follow-up date, 15 (16.1%) had been lost to follow-up，78 cases were tested for RNA-seq, of which 54 cases were successful, and 24 cases failed the quality control due to sample quality problems.The male-to-female ratio was 2.4:1, and the patients’ mean age at diagnosis was 5 years (ranged from 4 months to 11 years).The estimated 5-year overall survival and progression-free survival, based on Kaplan-Meier analysis, were 55.1% ± 5.6% and 40.9% ± 5.7%.Multivariate survival analysis showed that progression -free survival were significantly affected by extent of surgery (P=0.026) and postoperative radiotherapy(P＜0.001).Preoperative metastasis (P=0.032) and postoperative radiotherapy (P=0.001) had a significant influence on overall survival. While，the molecular subtypes showed no statistically significant differences in 5-year PFS and 5-year OS. CONCLUSION: Extent of resection of MB and postoperative radiotherapy were the important clinical prognostic factors for survival. In the future, we will continue to expand cases and study the clinical characteristics and prognostic risk factors of different molecular types of medulloblastoma in Chinese children,and to improve the survival rate of children with medulloblastoma.
MEDB-07. Long-term medical and functional outcomes of medulloblastoma survivors: a population-based, matched cohort study
Authors: Coltin Hallie , Pequeno Priscila , Liu Ning , Tsang Derek S , Taylor Michael D , Bouffet Eric , Nathan Paul C , Ramaswamy Vijay 
Published: June 2022

Abstract
BACKGROUND: Most medulloblastoma survivors suffer from late treatment-related sequelae. There are no population-based studies examining such late effects in a dedicated cohort of medulloblastoma survivors. METHODS: Using a provincial pediatric cancer registry, all 5+ year medulloblastoma survivors diagnosed between 1987-2015 in Ontario, Canada were identified and matched to cancer-free population controls based on age, sex, and geographical location. Cases were followed from the index date (five years from latest of diagnosis, or relapse or subsequent malignancy prior to age 18 years) until December 31, 2020 or censorship (death, or relapse or new cancer after age 18 years). Clinical data were linked to administrative health databases to estimate cumulative incidences and cause-specific hazard ratios (HR) of mortality, hospitalizations, strokes, hearing loss requiring a hearing aid, and receipt of homecare services between cohorts, accounting for matching and competing risks. RESULTS: We identified 230 cases [65.7% female; median diagnostic age: 7y, interquartile range (IQR) 4-10; median attained age: 24y, IQR 18-31] and 1150 controls. One hundred eighty-seven (81.3%) received craniospinal irradiation. Ten-year survival probability after index was 92.4% in cases and 99.4% in controls (HR 21.5, 95% CI 9.8-54.0). Cases were at higher risk for hospitalizations (HR 3.4, 95% CI 2.7-4.3), stroke (HR 45.6, 95% CI 12.8-289.8), hearing loss (HR 96.3, 95% CI 39.7-317.3), and requiring homecare services (HR 7.9, 95% CI 5.8-10.9). By 10 years after index, 4.8% (95% CI 2.2-9.0) of survivors had experienced a stroke compared to 0.1% (95% CI 0.01-0.7) of controls. CONCLUSIONS: Survivors of childhood medulloblastoma experienced an increased risk of mortality and serious morbidity compared to population controls. Consideration for mitigation strategies or early interventions in preventing neurovascular sequelae and hearing loss is warranted, as are dedicated supports for survivors.
MEDB-10. Comparing pediatric medulloblastoma with and without spinal metastasis
Authors: Tang Phua Hwee , Nisa Sameema 
Published: June 2022

Abstract
AIM: To compare pediatric medulloblastoma with and without spinal metastasis
METHODOLOGY: Pediatric medulloblastoma cases from 1999 to 2021 were retrospectively reviewed in this Institutional Review Board approved study. Imaging reports, presence of spinal drop metastases at diagnosis, degree of tumor excision, treatment given and survival status were captured.
RESULTS: Brain and spine imaging at diagnosis was available in 54 medulloblastoma patients with no drop metastasis and in 7 with drop metastasis. Largest tumor dimension at presentation is 4.54 ± 0.94 cm with those with drop metastasis, similar to the 4.43 ± 0.94 cm in those without drop metastasis (p = 0.79). For the 54 medulloblastomas with no drop metastasis, 44 (81%) were completely excised, 9 (17%) partially excised and there was no follow up for 1. For the 7 medulloblastomas with drop metastasis, 3 (43%) of the primary tumours were completely excised, 3 (43%) partially excised and there was no follow up for 1. Post operative chemo/radiotherapy was given to 48 of the 54 with no drop metastasis, not given for 1 with no information available for 5. Chemo/radiotherapy was given to 6 of the 7 with drop metastasis with no information available for 1. At 1 year follow up of the 54 with no spinal drop metastasis at diagnosis , 42 remain tumour free, 3 have tumour, 4 are deceased and 5 are lost to follow up. At 1 year follow up of the 7 with drop metastasis, 2 are free of tumour, 2 have tumour and 3 are lost to follow up. Higher percentage of medulloblastomas without drop metastasis are completely excised (p&lt;0.01). No significant difference between postoperative chemotherapy/radiation rates between groups
CONCLUSION: Most medulloblastomas do not have spinal drop metastasis at diagnosis and complete excision is more frequently in those without drop metastasis.
MEDB-12. Severe developmental abnormalities and proliferative cerebellar lesions induced by combined activity of Wnt signalling and loss of SMARCA4
Authors: Göbel Carolin , Holdhof Dörthe , Schoof Melanie , Schüller Ulrich 
Published: June 2022

Abstract
Almost all medulloblastomas (MB) of the WNT subgroup are characterized by hotspot mutations in CTNNB1, and mouse models have convincingly demonstrated the tumor-initiating role of these mutations as well as the tumor origin in the dorsal brain stem. Around 20 % of WNT MB additionally carry SMARCA4mutations, but the functional role of these alterations is mostly unknown. We therefore amended previously described Blbp-cre::Ctnnb1(ex3)Fl/+mice by the introduction of a floxed Smarca4 allele. In contrast to existing literature, Blbp-cre::Ctnnb1(ex3)Fl/+ mice had a maximum life span of only 17 days, even after breeding into two different genetic backgrounds (C57BL/6J and 129S2/Sv). The mice displayed a severe developmental phenotype including a thinned cerebral cortex, hydrocephalus, missing cerebellar foliation and layering as well as non-proliferative cell accumulations in brain stem and cerebellum. An additional homozygous loss of SMARCA4 even resulted in prenatal death for most mice and caused big proliferative lesions in the cerebellum at embryonal day 14.5. These lesions appear to originate from SOX2-positive progenitor cells in the cerebellar ventricular zone. In a next experiment, cells isolated from this region will be characterized in vitro and will be transplanted orthotopically to evaluate their neoplastic potential in vivo. Altogether, we hope to elucidate how a loss of SMARCA4 and mutations of Ctnnb1 cooperate during hindbrain development and tumor formation within this region.
MEDB-15. Dynamic chromatin alteration induces oncogenic hijacking by essential transcriptional factors during SHH medulloblastoma tumorigenesis
Authors: Shiraishi Ryo , Cancila Gabriele , Kumegawa Kohei , da Silva Patricia , Chapman Owen , Wanchen Wang , Jami Maki , Hoshino Mikio , Pfister Stefan , Chavez Lukas , Maruyama Reo , Ayrault Olivier , Kawauchi Daisuke 
Published: June 2022

Abstract
Medulloblastoma is a malignant brain tumor that occurs in the cerebellum, most frequently in children. Medulloblastoma is molecularly classified into four major groups, and therapies are now being developed according to the nature of these groups and subgroups. However, there are currently no effective molecularly targeted drugs for most of these groups. In recent years, we have been analyzing the genomes of medulloblastomas to identify genetic mutations involved in tumorigenesis. Among them, mutations in chromatin modifiers are frequently detected in medulloblastoma, suggesting the importance of alterations in the epigenome in tumor development. However, it remains unclear how epigenomic changes are involved in tumorigenesis. Here, we have used the SHH-group medulloblastoma (MB-SHH) mouse model to understand the epigenomic changes during tumor development and identify new therapeutic targets for medulloblastoma. To this end, we utilized an Atoh1-EGFP:Ptch1+/- mice that specifically label cerebellar granule cell progenitors (GNPs) that are known to be the cellular origin of MB-SHH, preneoplastic (PNCs) and tumor cells with EGFP during MB-SHH formation. Following FACS-based collection of EGFP-positive cells, comparative ATAC-seq analysis revealed that the open chromatin regions dynamically changed during transformation of GNPs into PNCs with enrichment of nuclear factor I (NFI) binding motifs. Cut & Tag analysis on these cells showed that NFI proteins bound chromatin regions that become more accessible during tumorigenesis, suggesting that NFI could play an important role in tumorigenesis after the epigenomic changes. Indeed, CRISPR-engineered in vivo somatic deletion of Nfia and/or Nfib prevented hyperplasia formation, confirming their essential role in tumor initiation. Knockdown of either NFIA or NFIB in patient-derived xenograft models also attenuated tumor growth. Thus, our study has uncovered a novel oncogenic mechanism that contributes to the development of MB-SHH tumors via alterations of accessible chromatin and aberrant DNA binding of NFI transcription factors.
MEDB-17. Re-irradiation for recurrent medulloblastoma in a matched cohort: Advantageous especially in patients without resection
Authors: Adolph Jonas E , Tippelt Stephan , Tschirner Sebastian , Gaab Christine , Mikasch Ruth , Mynarek Martin , Rutkowski Stefan , Warmuth-Metz Monika , Bison Brigitte , Pfister Stefan M , Witt Olaf , Pietsch Torsten , Kortmann Rolf-Dieter , Dietzsch Stefan , Timmermann Beate , Fleischhack Gudrun 
Published: June 2022

Abstract
INTRODUCTION: Radiotherapy with craniospinal irradiation (CSI) is an important part of initial treatment for medulloblastoma in most children. Radiotherapy after recurrence is currently not widely used. This analysis aims to evaluate whether re-irradiation (RT2) may show survival benefits. METHODS: Data for patients with recurrent medulloblastomas from the German HIT-REZ studies was gathered. Patients with RT2 at 1st recurrence were matched by propensity score to an equal number of patients without radiotherapy. Matching variables were sex, initial therapy, time to recurrence, metastatic stage and therapy at 1st recurrence and radiotherapy at subsequent recurrences. The matched cohort was analysed regarding PFS and OS after 1st recurrence. RESULTS: From a cohort of 240 pre-irradiated patients, 106 patients were matched. Patients with RT2 showed improved median PFS [21.0 months (95%-CI: 17.5 – 27.6)] and OS [37.5 months (CI: 30.0 – 59.4)] compared to control patients [(PFS: 12.0 months (CI: 8.1 – 17.7) / OS: 20.1 months (CI: 14.5 – 44.8)]. When stratifying by resection at recurrence (36.8% resected), a survival advantage for RT2 was found in patients without resection in PFS [19.6 (CI: 14.9 – 31.5) vs. 8.0 months (CI: 5.4 – 14.4)] and OS [41.9 (CI: 30.0 – 59.4) vs. 13.3 months (CI: 8.1 – 36.7)]. However, no advantage was found after resection [PFS: 22.5 (CI: 17.5 – 50.4) vs. 19.1 months (CI: 14.1 – 34.3) / OS: 32.3 (CI: 27.6 – NA) vs. 48 months (CI: 23.4 – NA)]. CSI was used in 6 patients without differences in survival to focal RT2. Median PFS after first irradiation was 32.5 months, after RT2 20.9 months. No patients with RT2 were alive past 10 years after 1st recurrence.CONCLUSION: Patients with recurrent medulloblastoma show benefits from RT2 in median PFS and OS. However, no advantage for RT2 was found when resection was also applied at recurrence. Cure after treatment with RT2 was not found in our cohort.