bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-10. AN UNUSUAL PRESENTATION OF BILATERAL OPTIC NERVE GLIOMA IN CROUZON SYNDROME
Authors: Na Brian , Wang Anthony C , Watterson Christopher Travis , Martinez-Agosto Julian A , Saitta Sulagna , Dutra-Clarke Marina , Hinkamp Franceska , Pineles Stacy L , de Blank Peter , Chang Vivian Y , Moore Theodore 
Published: June 2021

Abstract
Optic pathway gliomas (OPGs) are low grade gliomas intrinsic to the visual pathway, frequently associated with Neurofibromatosis Type 1 (NF-1). Bilateral OPGs without chiasmatic involvement are almost pathognomonic for NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month old male patient with craniosynostosis and Crouzon Syndrome, an autosomal dominant disorder caused by activating FGFR2 mutations associated with craniosynostosis and optic atrophy. The patient’s c.1032 G&gt;A pathogenic variant in FGFR2 is a variant known to affect splicing and results in a protein that lacks part of an important domain involved in ligand binding. Although FGFR1 mutations have been implicated in low-grade glioma through MAPK activation, FGFR2 mutations have not yet been described in OPGs, although they have been described in epileptogenic low-grade gliomas and mixed neuronal-glial tumors. Our patient presented with worsening vision in the setting of known Crouzon Syndrome. An eye examination revealed bilateral primary optic atrophy. Brain and orbital MRIs demonstrated fusiform dilation and STIR hyperintensity of the intraorbital segments of the optic nerves bilaterally with normal pre-chiasmatic optic segments. There were no other radiographic or physical stigmata suggestive of NF-1. Next generation sequencing and copy number analysis from peripheral blood were negative for variants in NF1. RNA based studies for NF1 aberrations are pending. Although follow up MRI scans demonstrated stable size of his OPGs, the risk of further visual deficit was considered significant due to his pre-existing optic atrophy and poor baseline visual acuity. Therefore, he was started on vincristine and carboplatin chemotherapy according to A9952, and induction therapy has been well tolerated. To our knowledge, this is the first patient with Crouzon Syndrome who has developed bilateral optic pathway gliomas. Orbital MRIs should be considered for these patients with worsening visual acuity not explained by other causes.
OMIC-05. PHOSPHOPROTEOMIC ANALYSIS IDENTIFIES SUBGROUP ENRICHED PATHWAYS AND KINASE SIGNATURES IN MEDULLOBLASTOMA
Authors: Leskoske Kristin , Garcia-Mansfield Krystine , Krishnan Aparna , Sharma Ritin , Rusert Jessica , Mesirov Jill , Wechsler-Reya Robert , Pirrotte Patrick 
Published: June 2021

Abstract
Medulloblastoma (MB) is classified into four molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3) and Group 4 (G4), each with different molecular profiles and patient outcomes. Subgroup heterogeneity and low mutational burdens have hindered the identification of actionable therapeutic targets, especially in G3 MB which has a particularly poor prognosis. Therefore, we took a (phospho)-proteomics approach to identify active pathways and potential therapeutic opportunities in twenty orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3 and G4 subtypes. Through our enrichment analysis, we identified processes and pathways specifically upregulated in each MB subgroup. We also utilized neural network derived kinase-substrate predictions and kinase activity scores inferred by a heuristic machine learning algorithm to further characterize phosphosignaling activity. We found that MB PDX models recapitulate many features of primary MB tumors including two distinct proteomic subtypes of G3. G3a was enriched for transcription, translation and MYC target genes while G3b was enriched for axon guidance and neurotrophin signaling pathways. Notably, both G3a and G3b contained higher abundance of mitochondrial proteins, suggesting altered tumor metabolism in G3 MB. SHH PDXs displayed increased NFκB and JNK-MAPK signaling. Group 4 MBs most closely resembled differentiated neuronal cells and were enriched for PKC and AMPK signaling as well as DNA repair pathways. In conclusion, we have provided a comprehensive proteomic and phosphoproteomic characterization of commonly studied MB PDX models and revealed new insights into subgroup enriched pathways and kinase activity in MB.
OMIC-07. FEASIBILITY AND UTILITY OF EPIGENOMIC PROFILING FOR CHILDHOOD CNS TUMORS IN HONG KONG
Authors: P.Y. Liu Anthony , Ho Ronnie S L , Li Kay K W , Chan Shing , Ku Dennis T L , Fu Eric , Luk Chung-Wing , Yau Jeffrey P W , Ling Siu-Cheung , Chung Brian H Y , Yang Wanling , Kan Amanda , Shing Matthew M K , Ng Ho-Keung , Chan Godfrey C F 
Published: June 2021

Abstract
Genome-wide DNA methylation profiling has emerged as an important diagnostic tool that complements histopathology for CNS tumors in children and adults. Literature describing its application in Asian countries is nonetheless limited. Herein, we report the feasibility and utility of adopting such platform for children diagnosed with CNS tumors in Hong Kong. A multi-institutional cohort (n=94, 97% of Chinese ethnicity) with CNS embryonal or high grade neuroepithelial tumors (HGNET) diagnosed in Hong Kong from 1996–2020 was assembled based on tissue availability. DNA was extracted from FFPE tumor material (median 301ng, range 13-1000ng), bisulfite converted and profiled with the Infinium Methylation EPIC BeadChip kit. Raw data were analyzed on the German Cancer Research Center MNP 2.0 classifier and through unsupervised dimensionality-reduction analysis (t-SNE) referencing a published CNS tumor reference dataset (GSE90496). The radio-histologic diagnosis included medulloblastoma (n=65), ATRT (n=9), pineal parenchymal tumors (n=7), ETMR (n=5), CNS-PNET (n=4) and other embryonal tumors/HGNETs (n=4). Methylation class could be assigned based on results from MNP 2.0 (calibrated score ≥ 0.9) in 62 patients (66%, including 2 clustering with control) and t-SNE in 22 (23%), while no-match was encountered in 10 (11%). Methylation-based analysis allowed confirmation of diagnosis and assignment of molecular subgroup in 64 patients (68%), confirmation of histologic diagnosis alone in 5 (5%) and resulted in revision/reassignment of diagnosis in 13 (14%). Among medulloblastoma samples that were assigned molecular tumor classes (n=57), 8 clustered with WNT-activated medulloblastoma, 13 with SHH-activated medulloblastoma, 10 with Group 3 medulloblastoma, 21 with Group 4 medulloblastoma, and 5 with non-medulloblastoma entities (high-grade gliomas=3, ETMR=1, ATRT=1). In conclusion, epigenomic profiling allowed refinement of disease classification for pediatric CNS tumors. Availability of such methodology in Asia sets the stage for international collaborations in molecularly-driven trials.
OMIC-11. SINGLE CELL RNA SEQUENCING FROM THE CSF OF SUBJECTS WITH H3K27M+ DIPG/DMG TREATED WITH GD2 CAR T-CELLULAR THERAPY
Authors: Mochizuki Aaron , Ramakrishna Sneha , Good Zina , Patel Shabnum , Chinnasamy Harshini , Yeom Kristen , Schultz Liora , Richards Rebecca , Campen Cynthia , Reschke Agnes , Mahdi Jasia , Toland Angus , Baggot Christina , Mavroukakis Sharon , Egeler Emily , Moon Jennifer , Landrum Kayla , Erickson Courtney , Rasmussen Lindsey , Barsan Valentin , Tamaresis John , Marcy Anne , Kunicki Michael , Celones Michelle , Ehlinger Zach , Kurra Sreevidya , Cornell Timothy , Partap Sonia , Fisher Paul , Grant Gerald , Vogel Hannes , Davis Kara , Feldman Steven , Sahaf Bita , Majzner Robbie , Mackall Crystal , Monje Michelle 
Published: June 2021

Abstract

Introduction
We are conducting a Phase I clinical trial utilizing chimeric antigen receptor (CAR) T-cells targeting GD2 (NCT04196413) for H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) and spinal cord diffuse midline glioma (DMG). Cerebrospinal fluid (CSF) is collected for correlative studies at the time of routine intracranial pressure monitoring via Ommaya catheter. Here we present single cell RNA-sequencing results from the first 3 subjects.

Methods
Single cell RNA-sequencing was performed utilizing 10X Genomics on cells isolated from CSF at various time points before and after CAR T-cell administration and on the CAR T-cell product. Output was aligned with Cell Ranger and analyzed in R.

Results
As detailed in the Majzner et al. abstract presented at this meeting, three of four subjects treated at dose-level one exhibited clear radiographic and/or clinical benefit. We have to date completed single cell RNA-sequencing for three of these four subjects (two with benefit, one without). After filtering out low-quality signals and doublets, 89,604 cells across 3 subjects were analyzed. Of these, 4,122 cells represent cells isolated from CSF and 85,482 cells represent CAR T-cell product. Two subjects who demonstrated clear clinical and radiographic improvement exhibited fewer S100A8+S100A9+ myeloid suppressor-cells and CD25+FOXP3+ regulatory T-cells in the CSF pre-infusion compared to the subject who did not derive a therapeutic response. In one subject with DIPG who demonstrated improvement, polyclonal CAR T-cells detectable in CSF at Day +14 demonstrated enrichment of CD8A, GZMA, GNLY and PDCD1 compared to the pre-infusion CAR T-cells by trajectory analysis, suggesting differentiation toward a cytotoxic phenotype; the same subject exhibited increasing numbers of S100A8+S100A9+ myeloid cells and CX3CR1+P2RY12+ microglia over time. Further analyses will be presented as data become available.

Conclusions
The presence of immunosuppressive myeloid populations, detectable in CSF, may correlate to clinical response in CAR T cell therapy for DIPG/DMG.
OMIC-12. PREVALENCE AND SPECTRUM OF GERMLINE PATHOGENIC VARIANTS IN CANCER PREDISPOSITION GENES ACROSS THE CHILDREN’S BRAIN TUMOR NETWORK (CBTN)
Authors: Vaksman Zalman , McQuaid Shelly , Bornhorst Miriam , Zhu Yuankun , Heath Allison , Waanders Angela , Cole Kristina , MacFarland Suzanne , Diskin Sharon 
Published: June 2021

Abstract
Germline variants are known to contribute to the pathogenesis of specific central nervous system (CNS) tumor subtypes; however, a large pan-pediatric brain and nervous system cancer germline susceptibility study has not been performed. To define the prevalence and spectrum of pathogenic variants in known cancer predisposition genes (CPGs; n=200), we analyzed whole genome sequencing (WGS) data from 880 pediatric subjects across 19 different cancer types in the Children’s Brain Tumor Network (CTBN). Data were aligned using BWA. Variants were called using GATK and annotated with SnpEff and ANNOVAR. After quality control, variants with a minor allele frequency (MAF) &lt; 0.1% in Gnomad 2.11 or ExAC were retained. Pathogenicity was assessed with American College of Medical Genetics (ACMG) guidelines using a lab-developed modification of ClinVar and InterVar. Automated pathogenic/likely pathogenic (P-LP) calls were manually reviewed by two cancer predisposition clinicians and a bioinformatician. Frequency of P-LP variants was assessed and gene burden testing was performed against Gnomad3.1 (without cancer samples) using Fisher’s exact test with Bonferroni adjustment. We observed 214 P-LP variants involving 190 unique individuals (21.6% of cohort). As expected, the most frequent variants were observed in NF1, NF2, and TP53(n=40 variants in 21% of individuals). ATM, TSC2 and CHEK2 variants (n=23) were observed in another 12% of individuals. An increased burden of P-LP variants was observed for 5 of these 6 genes (p = 1.7x10-25 to 1.4x10-2, CHEK2 p=5.5x10-2). We also identified 5 variants in BRCA2 (3 in high-grade glioma), 7 in REQC helicases (BLM, WRN, REQL4), and 16 variants in Fanconi anemia genes. Overall, cases harbored increased burden in P-LP variants in CPG genes (p=8.8x-18) and the subset of DNA repair genes (p=4.7x10-4). In conclusion we confirmed the association of variants in established predisposition genes while potentially identifying novel variants and genes associated in CNS tumors.
RARE-02. POLYAMINE PATHWAY INHIBITION IS A POTENT NOVEL THERAPEUTIC STRATEGY AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Khan Aaminah , Gamble Laura , Upton Dannielle , Yu Denise , Pandher Ruby , Mayoh Chelsea , Burns Mark R , Norris Murray D , Haber Michelle , Tsoli Maria , Ziegler David S 
Published: June 2021

Abstract
Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brainstem tumour, with a median survival of less than 1 year. Polyamines are intracellular polycations that control important aspects of cell growth and are often upregulated in cancer. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is a key driver of polyamine synthesis. We investigated the efficacy of polyamine pathway inhibitors as a therapeutic strategy against DIPG. We found that there were high over-expression levels of polyamine synthetic enzymes from DIPG primary patient samples and neurosphere cultures. Using alamar blue cytotoxicity and soft-agar clonogenic assays, we found that DFMO inhibited the proliferation of DIPG neurospheres. However, DIPG cells compensated for DFMO inhibition by increasing expression of the polyamine transporter SLC3A2 and subsequently uptake of polyamines. Addition of polyamine transporter inhibitor AMXT 1501 to DFMO led to synergistic inhibition of DIPG proliferation in vitro. Consistent with the in vitro results, the combination of DFMO and AMXT 1501 significantly prolonged the survival of mice bearing 3 different DIPG orthografts with at least 2/3 of the animals surviving up to 160 days. Addition of irradiation further improved the survival of mice treated with DFMO and AMXT 1501. Differential expression analysis showed that the polyamine transporter, SLC3A2, was significantly overexpressed in DIPG and other paediatric brain tumours including high grade gliomas compared with normal brain tissue. Our results suggest that DIPG tumours are exquisitely sensitive to polyamine inhibitors, and that dual blockade of polyamine synthesis and transport is a promising novel therapeutic strategy. AMXT 1501 is currently in clinical development, and following completion of an adult Phase 1 trial, a clinical trial of AMXT 1501 + DFMO for DIPG patients is planned through the CONNECT consortium.
RARE-03 CENTRAL NERVOUS SYSTEM TUMORS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1, A COHORT FROM A NATIONAL PEDIATRIC ONCOLOGY CENTER
Authors: Vandenput Kim , Meijer Lisethe , Schouten-van Meeteren Netteke 
Published: June 2021

Abstract
Approximately 15% of the children with Neurofibromatosis type 1 (NF1) develop a central nervous system (CNS) tumor, predominantly optic pathway glioma. However, other brain tumor types are also frequent, resulting in a heterogenous population regarding tumor type, symptoms and treatment. Even though many tumors are indolent, clinical deterioration or radiological progression requires surveillance and treatment. Pediatric oncology care in the Netherlands has been centralized into the Princess Máxima Center since June 2018, providing care for the majority of Dutch NF1 CNS tumor patients. This retrospective cohort study describes the course of disease in NF1 patients with a CNS tumor diagnosed between 2005–2020, based on data from patient files. The population consisted of 95 patients (48 males), median age at diagnosis 4.3 (range 0.8–17.2) and 12.6 (range 2.9–19.9) years at follow up, 27% familiar NF1, mostly nonsense or frameshift mutations. Neurological and/or visual symptoms were present in 64 (67.4%) patients. 63.6% of the tumors was in the optic pathway, 9.1% in the cerebellum. Biopsy in 19/95 revealed 1 ependymoma and 18 low grade glioma, with rarely additional molecular changes besides NF1. Kaplan Meier median PFS was 24 months (range 3–174.5, n=65) in symptomatic presenting patients, 34 months (range 5–165, n=20) in asymptomatic patients with abnormal ophthalmological and/or neurological exam and 67.3 months (range 7–130, n=10) in asymptomatic patients without abnormalities at exam. Treatment was indicated in 53 (55.8%), predominantly chemotherapy (n=49), with substantial toxicity. Carboplatin allergy was seen in 29/44 (65.9%) patients, peripheral neuropathy in 21/46 (45.7%) patients receiving vincristine, and 5/10 patients receiving irinotecan and bevacizumab ended treatment early due to toxicity. In conclusion: analysis of our extensive cohort of NF1 patients with a CNS tumor indicates the relevance of regular screening of NF1 patients without complaints and critical surveillance and systematical documentation of treatment toxicity.
RARE-09. POORLY DIFFERENTIATED CLIVAL CHORDOMA IN EXTREME YOUNG AGE; CASE ILLUSTRATION AND REVIEW OF LITERATURE
Authors: Altewerki Malak , AlRamadan Abdullah , AlHindi Hindi , AlShail Essam 
Published: June 2021

Abstract
Chordomas are rare tumors believed to be originated from notochordal remnants. Of all intracranial neoplasms, the incidence of cranial chordomas is less than 1%1. The youngest patient with an intracranial chordoma reported in the literature was a newborn in the first few days after birth9. Intracranial chondroma are more predominant in males compared to females1. The clinical features of intracranial chondroma in the pediatric age group commonly include increased Intracranial pressure, lower cranial nerves palsy, and torticollis2. There is no optimum treatment, however, surgical resection of the tumor followed by radiation therapy reported successful outcome3. This is a case of a poorly differentiated clival chordoma of a 23-month old boy. The clinical features, pathological, radiological findings, and surgical technique are discussed with an elaboration of the current review of the literature of clival chordoma in the extreme young age group. To the best of our knowledge, this is the youngest age of clivus chordoma reported in Saudi Arabia.
RARE-22. THERAPEUTIC TARGETING OF PURINE METABOLISM IN DIPG
Authors: Mersich Ian , Dasgupta Biplab 
Published: June 2021

Abstract
Diffuse intrinsic pontine glioma is a universally lethal disease primarily impacting pediatric patients. There are currently no targeted therapies increasing overall for patients with these tumors; therefore, our lab set out to elucidate metabolic dependencies in DIPG patient-derived cell lines with the ultimate goal of identifying novel therapeutic targets. Through untargeted metabolomics and gene expression analyses, we have identified the purine metabolism gene ATIC to be important for DIPG tumor cell survival and proliferation. Anti-folate drugs such as methotrexate target de novo purine biosynthesis and are used to treat other pediatric cancers; however, we have identified a small molecule inhibitor of ATIC that may offer clinical benefits over other inhibitors of this pathway. In vitro cell viability experiments have demonstrated DIPG cell lines are much more sensitive to the ATIC inhibitor relative to normal neural stem cells and glial cell lines. Furthermore, we have started in vivo studies on pre-clinical mouse models of DIPG with promising results. Treatment with the ATIC inhibitor has significantly increased overall survival relative to control and vehicle treated mice. The dosage we started at was well tolerated in these mice so we are following up on this in vivo work through dose-escalation studies as well as combination treatment strategies. Mechanistically, the ATIC inhibitor works differently than anti-folate compounds such as methotrexate; therefore we are also elucidating why cancer cells are much more sensitive to this compound.
RARE-23. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR: A CASE SERIES
Authors: Aaroe Ashley , Ou Alexander , McGovern Susan , Paulino Arnold , Johnson Jason , Huse Jason , Fuller Gregory , de Groot John , Walter Andrew , Zaky Wafik 
Published: June 2021

Abstract

Introduction
Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare diagnosis first incorporated into the WHO Classification of Tumors of the Central Nervous System in 2016. Though historically considered indolent, emerging evidence suggests that the biological behavior of these tumors may be further classified by molecular features of prognostic significance.

Methods
A retrospective review was conducted in accordance with IRB approval of patients with the histologic diagnosis of DLGNT. Demographic, clinical, and molecular data where abstracted from the medical record when available.

Results
10 patients were identified (M = 8, F = 2). Median age at diagnosis was 6 years (range 0.3–21 years), and the most common symptoms at diagnosis were related to obstructive hydrocephalus, for which 3 patients required CSF diversion. MRI findings included diffuse leptomeningeal thickening, nodularity, or coating of the subarachnoid or ependymal surfaces. Histologically, these tumors expressed variable features of neuronal and/or glial differentiation. Four patients (40%) were treated with radiation therapy (all craniospinal), which was upfront for 2 patients. Chemotherapy regimens used included temozolomide, carboplatin and vincristine and vinblastine. NTRK or BRAF-targeted therapy were used upon progression. At follow-up, 6/10 had stable disease (4/6 of whom were on second line therapy), 1 had partial response, 1 passed away from sepsis and 2 were lost to follow-up. The median progression-free survival for the four patients who developed disease progression was 26 months (range 12–34 months). Next generation sequencing of the tumor tissue performed using a high-multiplex PCR-based NGS panel detected BRAF-KIAA1549 (4 patients) and NTRK (1 patient) fusions.

Conclusions
DLGNT are rare tumors with scarce data about imaging characteristic and standard of care treatment. Our case series reinforces current literature that although these tumors appear low-grade, they can be clinically aggressive. Further study is needed regarding molecular diagnosis and profiling treatment strategies.