bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-01. NF1 MUTATION DRIVES NEURONAL ACTIVITY-DEPENDENT OPTIC GLIOMA INITIATION
Authors: Pan Yuan , Hysinger Jared , Schindler Nicki , Cobb Olivia , Guo Xiaofan , Yalçın Belgin , Anastasaki Corina , Mulinyawe Sara , Ponnuswami Anitha , Scheaffer Suzanne , Ma Yu , Chang Kun-Che , Xia Xin , Toonen Joseph , Lennon James , Gibson Erin , Liau Linda , Goldberg Jeffrey , Monje Michelle , Gutmann David 
Published: June 2021

Abstract
Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic gliomas) during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1 optic glioma to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing optic nerve activity via light deprivation prevents tumor formation and maintenance. By manipulating environmental light to modulate optic pathway (retinal) neuron activity, we show that Nf1 optic glioma initiation depends on neuronal activity during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacologic inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce optic glioma incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.
LGG-05. GENERATION OF NOVEL MOUSE MODELS FOR BRAF V600E MUTANT GLIOMAGENESIS TO GAIN MECHANISTIC INSIGHTS INTO TUMOR FORMATION AND PROGRESSION
Authors: K. Petritsch Claudia , Barrette Anne Marie , Park Jong-Whi 
Published: June 2021

Abstract

Background
The BRAF V600E mutation occurs in ~ twenty percent of histologically diverse pediatric gliomas and is the second most common mutation in pediatric low-grade gliomas (LGG). BRAF V600E expression in LGG with balanced CDKN2A is associated with a higher rate for progression than for BRAF V600E wildtype tumors, and despite adjuvant therapy, consisting of resection, radiation and chemotherapy. Progression invariably occurs in BRAF V600E mutant CDKN2A deleted gliomas, marking a high-risk group. Here, we aim to overcome the lack BRAF V600E mutant glioma models that allow for studies of stem and progenitor cells and the immune system ability to understand progression.

Methods
We develop novel immunocompetent, stem and progenitor cell-based mouse models for BRAF mutant gliomas, including genetically engineered mouse models (GEMMs), orthotopic glioma models derived from gliomas in GEMMs as well as in vitro models of those tumors. BRAF mutant mouse brains and cells were analyzed by immunofluorescence staining, flow cytometry, mass cytometry and RNA sequencing.

Results
Ongoing model development studies indicate that BRAF V600E mutant gliomas in murine brain exhibit very similar neuroanatomical preferences to human gliomas. The BRAF V600E mutation exacerbates the heterogenous cell cycling pattern of normal neural stem and progenitors and expands a symmetrically dividing progenitor population. Cellular plasticity rather than cellular lineage hierarchy drives the generation of a therapy resistant stem cell pool. Transcriptomic analyses of neuroglial stem cells with induced BRAF V600E expression provide insights into mechanisms for neoplastic transformation and progression.

Conclusion
Analyses of two independent BRAF V600E mutant mouse models provide novel insights into the role for tumor intrinsic factors, such as plasticity and stemness, and the tumor microenvironment in progression.
TMOD-03. A NOVEL MB GR3 TRANSGENIC MOUSE MODEL IS GENERATED BY MYCN AND P53 DEFECTS IN VENTRICULAR ZONE PROGENITORS.
Authors: Morcavallo Alaide , Barker Karen , Adachi Toma , Boult Jessica K R , Kwok Colin , da Silva Patricia Benites Goncalves , Okonechnikov Konstantin , Hitchen Luke , Robinson Simon P , Clifford Steven C , Pfister Stefan M , Kawauchi Daisuke , Chesler Louis 
Published: June 2021

Abstract
Medulloblastoma (MB) represents the most common embryonal tumour of the Central Nervous System in childhood. MB occurs in the cerebellum and molecular features dictate the classification into four subgroups. Although Group3 (Gr3) MB tumours are dominated by primitive progenitor-like cells, the cells of origin remain unidentified. Gr3 MB is associated with relatively common MYC family member amplification and overexpression, often combined with p53 pathway defects at relapse. Molecularly stratified treatment is not yet available, causing Gr3 MB and its subsequent relapse to often represent an unstoppable progressive disease. The limited understanding of Gr3 tumorigenesis and targeted therapy development is also due to the lack of faithful in vivo models and consequently, their use in preclinical studies. We have now developed a new germline genetically engineered mouse model (GEMM), harbouring MYCN amplification in a p53 inactive background (tamoxifen-inducible p53 activation, Trp53ERTAM). The purpose of the GEMM is to investigate the developmental significance of MYC aberration in putative Gr3 MB cells of origin and exploit it in preclinical studies. A LSL-MYCN-Luciferase strain was crossed with mice expressing Cre recombinase under the Blbp promoter and subsequently to Trp53ERTAM inducible mice. As result, the MYCN overexpression alone did not generate tumours, conversely to the combination of MYCN with p53 deregulation. Tumours arise exclusively in the hindbrain of homozygote mice, with a penetrance of 100% and a latency of ~135 days. Pathology report suggests tumours are Gr3 MB with large cell/anaplastic (LCA) histology. Preliminary transcriptional profiling data analysis reveals that tumours share molecular features with human counterparts, clustering with Gr3 MB. Ongoing analysis will explore the tumour cells of origin, followed by tumour progression alteration restoring p53 activity and blood-brain barrier integrity status. In conclusion, we have developed a MYCN/Trp53ERTAM Gr3 MB GEMM arising from ventricular zone progenitor cells and resembling human cancer characteristics.
OMIC-04. IDENTIFICATION AND CHARACTERIZATION OF CIRCULATING RNAS (CODING AND NONCODING) AND METABOLITES IN CEREBROSPINAL FLUID IN MEDULLOBLASTOMA PATIENTS
Authors: Lee Bongyong , Stapleton Stacie , Pokhrel Rudramani , Bettegowda Chetan , Jallo George , Perera Ranjan 
Published: June 2021

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children, and monitoring patients for treatment response and recurrence can be challenging with available current technologies in neuro-imaging and performing a biopsy to confirm response or recurrence carries risks, whereas cerebrospinal fluid (CSF) can be obtained with a little invasiveness. MB has altered cellular metabolism due to changes in gene expression, therefore, we hypothesized that any changes in MB cells lead to changes in cell-free transcripts and metabolites in CSF. To test this, we applied RNA-sequencing and mass spectrometry to analyze transcripts and metabolites including lipid in CSF from patients with different sub-groups of MB tumors (i.e., WNT, SHH, G3/4, G4, and unknown) and compared them to non-cancerous CSF. Tumor and sub-group specific transcriptomic and metabolic signatures were shown by unsupervised hierarchical clustering facilitating tumor type differentiation. By comparison with previously published tumor tissue RNA-seq data, we were able to identify a group of upregulated molecular signatures in both tumor tissue and CSF. We also identified a group of lipids that differentiate each MB sub-group from normal CSF, and Pathway analysis confirmed alterations in multiple metabolic pathways. Finally, we attempted to integrate RNA-seq data with lipidomics data, and results depict that the combinatorial analysis of CSF RNAs and metabolites can be useful in diagnosing and monitoring patients with MB tumors. (This research was conducted using samples made available by The Children’s Brain Tumor Network.)
OMIC-06. MOLECULAR SUBGROUPING OF MEDULLOBLASTOMA VIA LOW-DEPTH WHOLE GENOME BISULFITE SEQUENCING
Authors: Thompson Dean , Castle Jemma , Hicks Debbie , Clifford Steve , Schwalbe Ed 
Published: June 2021

Abstract

Introduction
International consensus recognises four molecular subgroups of medulloblastoma, each with distinct molecular features and clinical outcomes. The current gold-standard for subgroup assignment is DNA methylation microarray. There is an unmet need to develop platform-independent subgrouping assays which are both non-proprietary and compatible with rapidly-expanding WGS capacity in healthcare. Whole Genome Bisulfite Sequencing (WGBS) enables the assessment of genome-wide methylation status at single-base resolution. Previously, WGBS adoption has been limited by cost and sample quality/quantity requirements. Its application for routine detection of medulloblastoma subgroups has not previously been reported.

Methodology
Two datasets were utilised; 36 newly-sequenced low-depth (10x coverage) and 34 publicly-available high-depth (30x) WGBS medulloblastomas, all with matched DNA methylation microarray data. We compared platform concordance and identified molecular subgroups. Machine-learning WGBS-based subgroup classifiers were optimised and compared between platforms. Aneuploidy and mutation detection using WGBS was optimised and compared to microarray-derived estimates where possible. Finally, comprehensive subgroup-specific DNA methylation signatures were identified.

Results
We optimised a pipeline for processing, quality control and analysis of low-depth WGBS data, suitable for routine molecular subgrouping and aneuploidy assessment. We demonstrated the suitability of fresh-frozen and FFPE DNA for WGBS, and, using downsampling, showed that subgroup calling is robust at coverages as low as 2x. We identified differentially methylated regions that, due to poor representation, could not be detected using methylation microarrays. Molecular subgroups of medulloblastoma assigned using WGBS were concordant with array-based definitions, and WGBS-derived classifier performance measures exceeded microarray-derived classifiers.

Conclusion
We describe a platform-independent assay for molecular subgrouping of medulloblastoma using WGBS. It performs equivalently to current array-based methods at comparable cost ($405 vs $596) and provides a proof-of-concept for its routine clinical adoption using standard WGS technology. Finally, the full methylome enabled elucidation of additional biological heterogeneity that has hitherto been inaccessible.
RARE-01. ASSESSING THE SYMPTOM DIAGNOSTIC INTERVAL FOR CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMOURS
Authors: Crowell Cameron , Crooks Bruce , Walling Simon , Boileau Kelly , Bowes Lynette , Rutledge Robert , Kulkarni Ketan , McNeely Daniel , Erker Craig 
Published: June 2021

Abstract

Background
Diagnostic delays in pediatric neuro-oncology is a subject of distress for families and providers. We aimed to evaluate the symptom diagnostic interval (SDI) and influencing variables for children with CNS tumors.

Methods
This retrospective study analyzed 210 patients diagnosed from 2001–2018 and managed at the tertiary care facility in Halifax, Canada. SDI was defined as time from first symptom until tissue diagnosis or, if not available, imaging diagnosis. Non-parametric tests were used to compare SDI between groups.

Results
Median SDI was 12.4 weeks (IQR 4.3–30), longer than 7 other studies of 1308 children reporting medians of 4.5–10 weeks (p &lt; 0.01). Most common tumors and their median SDI included low-grade glioma (LGG) (n=97, 46%; 17.9 weeks), medulloblastoma (n=31, 15%; 8.7 weeks), high-grade glioma (HGG) and DIPG (n=23, 11%; 5.6 weeks), and ependymoma (n=13, 6%; 13.6 weeks). The most common initial reported symptom included headache (n=63; 30%), nausea/vomiting (n=27, 18%), seizure (n=24, 12%), and visual impairment (n=13, 6.3%). Patients aged 0–3 years had a shorter SDI than patients 10 years and older (SDI 8.7 vs 14.6 weeks; p = 0.03). Tumor category showed longer SDI for LGG versus HGG (p = 0.003), DIPG (p = 0.02), medulloblastoma (p = 0.03) and other embryonal tumors (p = 0.03). Longer SDI was not associated with increased risk of disease progression for LGG (p = 0.93), medulloblastoma (p = 0.89), or ependymoma (p = 0.5). No difference in SDI was found with regard to diagnosis era, ethnicity, socioeconomic status, or distance to the tertiary care facility.

Conclusion
SDI at our centre is longer than previously reported studies. SDI is linked to tumor biology and its relevance within specific tumor groups deserves further investigation given it doesn’t appear to predict tumor progression/recurrence, yet families and providers feel distress when delays in diagnosis are perceived.
RARE-19. NETWORK AND DEEP LEARNING INFERENCE IN SINGLE CELL RNA SEQUENCING REVEAL DETAILED TRANSCRIPTIONAL SIGNATURES CONGRUENT WITH MOLECULAR UNDERSTANDING OF ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Prince Eric , Trudeau Tammy , Chatain Oscar , Chee Keanu , Vijmasi Trinka , Staulcup Susan , Donson Andrew , Foreman Nicholas , Hankinson Todd 
Published: June 2021

Abstract
Adamantinomatous Craniopharyngioma (ACP) is a highly morbid, cellularly heterogeneous pediatric tumor arising in the sellar/suprasellar region of the brain. This cellular heterogeneity makes ACP an ideal candidate for study using single-cell RNA-sequencing (scRNA-seq). We collected a 10,000 cell scRNA-seq dataset on the 10X v3 platform, from 6 unique patients. Using the industry standard Seurat software package, we identified 34 unique cell clusters. By crossing the results of two separate expert curated cellular reference atlases (Azimuth and scHCL), we determined that 33 of these cell types were immune-related (e.g., T cells, monocytes, etc.) or histologically related (e.g., glial cells). The remaining 2,048 cells were inferred to be ACP driver cells. Rigorous statistical testing of third-generation graph topology-based network enrichment methods utilizing the Reactome database supported this conclusion. In order to identify effective antitumor therapies, it is critical to understand the temporal evolution of tumor cell behavior. Computational solutions that describe the potential lifecycle of tumor cells have been derived using scRNA-seq datasets. Using a well-established method, Monocle3, we generated a potential model of temporal evolution of the ACP driver cell population. To identify a specific transcriptional “point-of-no-return” for ACP driver cells, which may help define a rational target for intervention, we created a custom probabilistic Deep Learning framework in the form of a Convolutional Variational Autoencoder (CVAE). By applying this CVAE to our data, we identified 31 anomalous transcripts, each of which was aberrantly active at all times or demonstrated a temporal pattern of anomalous activity. Strikingly, this small list – representing roughly 0.15% of the protein coding genome – aligns closely with extant data describing the molecular behavior of ACP. This work provides a novel transcriptome benchmark for comparison of in vitromodels, a deeper understanding of ACP heterogeneity, as well as a generalizable approach for scRNA-seq analysis.
EPCT-05. A PHASE 1/2 STUDY OF AVAPRITINIB FOR KIT- OR PDGFRA-MUTANT PEDIATRIC RELAPSED/REFRACTORY SOLID TUMORS
Authors: Chi Susan , Hsieh Antony , Foley Megan , Shi Hongliang , Swamy Preethi , Rodstrom Jill , Rudoltz Marc 
Published: June 2021

Abstract
Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; targeted therapies achieve response rates of only ~15%. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT mutations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) mutations. Two-year overall survival is &lt;10% for pediatric patients with diffuse intrinsic pontine glioma, often driven by PDGFRA mutations. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid tumors. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 &lt;2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM). CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for activity against CNS tumors. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA based on an overall response rate ³84% with 59% response durations &gt;6 months, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. The objectives of this 2-part phase 1/2 multicenter, open-label study, anticipated to enroll 31 patients from Q3 2021, are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients with KIT/PDGFRA-mutant solid R/R tumors. Eligible patients are aged 2 to &lt;18 years with no alternative treatment options. Part 1 will enroll ≥6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥25 patients at the recommended modeled avapritinib dose from Part 1; primary endpoint is overall response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.
EPCT-23 PRE-CLINICAL STUDY OF FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING AND PANOBINOSTAT FOR DIFFUSE INTRINSIC PONTINE GLIOMA TREATMENT
Authors: Wei Hong-Jian , Pouliopoulos Antonios , Yoh Nina , Tazhibi Masih , McQuillan Nicholas , Zhang Xu , Szalontay Luca , Gartrell Robyn , Pavisic Jovana , Zhang Zhiguo , Feldstein Neil , Becher Oren , Zacharoulis Stergios , Konofagou Elisa , Wu Cheng-Chia 
Published: June 2021

Abstract
Diffuse intrinsic pontine glioma (DIPG) is the lethal high-grade brain tumor in children with no effective treatment options to date. Despite excessive clinical trials, the prognosis remains poor, with a median overall survival (mOS) of less than 1 year. Genomic studies of DIPG tissue have identified highly recurrent mutations in genes encoding histone H3 resulting in the substitution of lysine to methionine at position 27 (K27M), which is found in approximately 80% of DIPG. Recent drug screening studies identified the histone deacetylase (HDAC) inhibitors panobinostat as a highly effective drug against DIPG in vitro. However, due to the poor Blood-Brain Barrier (BBB) penetration of systemic administration, to enhance the delivery of panobinostat to improve treatment efficacy is needed. Focused ultrasound (FUS) has been shown to be able to safely and non-invasively open BBB to enhance drug delivery. Hence, in this study, we hypothesize that FUS-mediated BBBO (BBBO) can enhance the delivery of panobinostat for a therapeutic benefit in DIPG. Herein we established the syngeneic DIPG model by intracranially injecting mouse DIPG cells (PDGFB+, H3.3K27M, p53−/−) and used FUS and microbubbles to open BBB and enhance the panobinostat delivery. Magnetic resonance (MR) imaging was utilized to evaluate BBBO and tumor progression. We first demonstrated that FUS-mediated BBB-opening is safe and feasible to mice with DIPG tumors by MR imaging and passive cavitation detection. Moreover, this DIPG cell line is very sensitive to panobinostat in in vitro cytotoxicity assay. The combined treatment of FUS-mediated BBBO and panobinostat showed benefits in both local control and overall survival. The current results demonstrated FUS could increase the treatment efficacy of panobinostat to DIPG animals may be due to the increase of targeted delivery of systemic panobinostat to DIPG tumors in brainstem.
Predictors of Enrollment of Older Smokers in Six Smoking Cessation Trials in the Lung Cancer Screening Setting: The Smoking Cessation at Lung Examination (SCALE) Collaboration
Authors: Eyestone Ellie , Williams Randi M , Luta George , Kim Emily , Toll Benjamin A , Rojewski Alana , Neil Jordan , Cinciripini Paul M , Cordon Marisa , Foley Kristie , Haas Jennifer S , Joseph Anne M , Minnix Jennifer A , Ostroff Jamie S , Park Elyse , Rigotti Nancy , Sorgen Lia , Taylor Kathryn L 
Published: June 2021

Abstract

Significance
Increased rates of smoking cessation will be essential to maximize the population benefit of low-dose CT screening for lung cancer. The NCI’s Smoking Cessation at Lung Examination (SCALE) Collaboration includes eight randomized trials, each assessing evidence-based interventions among smokers undergoing lung cancer screening (LCS). We examined predictors of trial enrollment to improve future outreach efforts for cessation interventions offered to older smokers in this and other clinical settings.

Methods
We included the six SCALE trials that randomized individual participants. We assessed demographics, intervention modalities, LCS site and trial administration characteristics, and reasons for declining.

Results
Of 6285 trial- and LCS-eligible individuals, 3897 (62%) declined and 2388 (38%) enrolled. In multivariable logistic regression analyses, Blacks had higher enrollment rates (OR 1.5, 95% CI 1.2,1.8) compared to Whites. Compared to “NRT Only” trials, those approached for “NRT + prescription medication” trials had higher odds of enrollment (OR 6.1, 95% CI 4.7,7.9). Regarding enrollment methods, trials using “Phone + In Person” methods had higher odds of enrollment (OR 1.6, 95% CI 1.2,1.9) compared to trials using “Phone Only” methods. Some of the reasons for declining enrollment included “too busy” (36.6%), “not ready to quit” (8.2%), “not interested in research” (7.7%), and “not interested in the intervention offered” (6.2%).

Conclusion
Enrolling smokers in cessation interventions in the LCS setting is a major priority that requires multiple enrollment and intervention modalities. Barriers to enrollment provide insights that can be addressed and applied to future cessation interventions to improve implementation in LCS and other clinical settings with older smokers.

Implications
We explored enrollment rates and reasons for declining across six smoking cessation trials in the lung cancer screening setting. Offering multiple accrual methods and pharmacotherapy options predicted increased enrollment across trials. Enrollment rates were also greater among Blacks compared to Whites. The findings offer practical information for the implementation of cessation trials and interventions in the lung cancer screening context and other clinical settings, regarding intervention modalities that may be most appealing to older, long-term smokers.