bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPEN-11. CHARACTERIZATION OF THE SPATIAL ARCHITECTURE OF INTRATUMORAL CELL STATES IN PEDIATRIC HIGH-RISK EPENDYMOMA
Authors: Bruckner Katharina , Madlener Sibylle , Biagi Junior Carlos A O , Gabler Lisa , Senfter Daniel , Jeong Daeun , Jiang Li , Englinger Bernhard , Jaunecker Carola , Bilban Martin , Haberler Christine , Dorfer Christian , Rössler Karl , Kool Marcel , Berger Walter , Filbin Mariella G , Lötsch-Gojo Daniela , Gojo Johannes 
Published: June 2023

Abstract
By single-cell analyses, we previously uncovered distinct intratumoral transcriptomic ependymoma (EPN) cell states and developmental trajectories correlating with molecular subtype and biological behavior. However, the relation of these cell states to characteristic EPN tissue architecture and tumor microenvironment remains widely unknown. We aimed to characterize the spatial architecture and elucidate regulatory circuits in EPN via spatial transcriptomics (10X Visium) of tumor specimens matching our previously generated single-cell transcriptome data spanning all EPN subtypes (ZFTA, YAP1, PFA, PFB). We investigated whether spatially restricted cell-cell interactions correlate with our previously identified cell states. Analyses revealed distinct spatially resolved cell populations in supratentorial and posterior fossa EPN. All subgroups showed several (5-9) spatially discrete cell clusters. Via non-negative matrix factorization (NMF), cell-specific spatial clusters emerged correlating with previous single-cell programs. ZFTA EPN highly correlates with ZFTA-specific metaprograms whereas all other subgroups did not show ZFTA-specific gene expression. Explicit genes such as DLK1 are exclusively upregulated in ZFTA EPN indicating spatially distinct aberrant Notch pathway signaling. Interestingly, this subgroup revealed spatial zones with upregulation of metabolic genes and endothelial markers anti-correlating with a ZFTA-specific program. Ependymal and neuronal-precursor-like signatures were enriched in our unique YAP1 EPN sample in a spatially restricted pattern, whereas GFAP was ubiquitously expressed. PFA was characterized by a neural stem cell (NSC)-like niche accompanied by metabolic and immune-reactive gene signatures. PFB showed a similar cell niche associated with NSC-like and glial-progenitor-like genes enriched simultaneously, further highlighting the NSC characteristic of posterior fossa tumors. Ependymal signatures were absent in PFA and present in PFB indicating more differentiated cell populations in PFB. Summarizing, we confirm presence of distinct intratumoral cell states within ependymoma tissue and reveal their spatial organization. In depth analysis and functional validation in matched ependymoma models will enable interrogation of underlying tumor promoting signaling events driving intratumoral developmental trajectories.
METB-06. HIGH FREQUENCY OF CLINICALLY RELEVANT ALTERATIONS DETECTED BY INTEGRATED TUMOR AND GERMLINE GENE PANEL TESTING IN CHILDREN WITH CNS TUMORS – RESULTS FROM THE TEXAS KIDSCANSEQ STUDY
Authors: Lin Frank Y , Desrosiers Lauren , Mangum Ross , Reuther Jacquelyn , Mohila Carrie , Blessing Melissa M , Aldave Guillermo , Muzny Donna M , Bernini Juan Carlos , Gill Jonathan , Griffin Timothy , Tomlinson Gail , Vallance Kelly , Chintagumpala Murali M , Scollon Sarah , López-Terrada Dolores H , Fisher Kevin E , Roy Angshumoy , Plon Sharon E , Parsons D Williams 
Published: June 2023

Abstract

BACKGROUND
Tumor and germline alterations detected by sequencing have the potential to inform management of children with CNS tumors. Comparative clinical utility data for available molecular sequencing modalities are needed to optimize testing strategies.

METHODS
Cancer patients less than 18 years of age were eligible to enroll in the Texas KidsCanSeq (KCS) clinical genomics study at six Texas institutions. Blood testing was performed on all patients using a pediatric solid tumor targeted DNA panel (124 genes), which included 35 genes associated with known cancer predisposition syndromes. Tumor testing was conducted on high-risk or recurrent tumors using the same DNA panel as well as an 81-gene RNA fusion panel. Tumor variants were classified as being of strong (Tier 1) or potential (Tier 2) clinical significance following AMP/ASCO/CAP guidelines. Germline pathogenic (P) or likely pathogenic (LP) variants per ACMG/AMP guidelines were considered clinically relevant.

RESULTS
A total of 224 children with CNS tumors were enrolled, including 146 patients with high-risk or recurrent tumors. Tissues were sufficient for analysis from 132 tumors and 211 germline samples. Clinically relevant alterations were identified in 90 of 132 (68%) tumors tested. Of 50 with therapeutic implications, 21 (42%) were not known from prior clinical testing. Therapeutically relevant tumor variants most frequently involved BRAF (n=20), CDKN2A/B (n=16), SMARCB1 (n=9), PIK3CA (n=8), and NF1 (n=7). One high grade glioma (in a patient with Lynch syndrome) was found to be hypermutated (tumor mutation burden &gt;190 mut/Mb). Germline analysis detected P/LP variants in cancer predisposition genes in 25 of 211 (12%) patients tested, including 12 of 135 (9%) with high-risk/recurrent tumors.

CONCLUSION
Combined tumor and germline panel testing revealed alterations of clinical relevance according to consensus guidelines in approximately 70% of children with high-risk or recurrent CNS tumors.
METB-08. GENOMIC AND MOLECULAR PROFILING OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS: A SINGLE INSTITUTION ANALYSIS
Authors: Kline Cassie , Lin Fumin , Liou Angela , Kraya Adam , Cole Kristina , Fisher Michael , Li Marilyn 
Published: June 2023

Abstract

BACKGROUND
Molecular characterization has revolutionized management of pediatric central nervous system (CNS) tumors, with genomic sequencing for diagnosis and determination of actionable variants now largely considered standard of care. We report a single institution’s experience performing genomic sequencing for pediatric CNS tumors over nearly five years.

METHODS
Nucleic acid isolated from tumor tissue and paired normal specimens from patients at Children’s Hospital of Philadelphia (CHOP) undergoes paired next generation sequencing (NGS) and copy number analyses of 237 cancer genes and a fusion panel of more than 700 exons of 117 cancer genes (tumor only). All variants are tiered 1-4 according to known clinical significance. Descriptive statistics summarize clinical and molecular data and ensemble-based methods will be used to correlate molecular and clinical characteristics.

RESULTS
Between January 1, 2016 and June 30, 2020, 497 patients ≤ 21 years old with median age of 9.5 years (n=243 females; 49%) contributed to 539 cases across 25 CNS tumor subtypes. The most common diagnoses were pilocytic astrocytoma (n=118), medulloblastoma (n=49), and diffuse midline glioma (DMG; n=39). Clinically significant variants (tier 1,2) were detected in 91% of the patients. Most tumors demonstrated tier 1,2 single nucleotide variants (SNV)/insertions/deletions (n=263, 53%), most commonly in TP53&gt;BRAF&gt;H3F3A, and/or CNVs (n=310, 62%), most commonly gains of 7q&gt;7p&gt;1q. Thirty percent of tumors demonstrated tier 1,2 fusions (n=149), most commonly involving BRAF, NTRK2, or FGFR. Average tumor mutation burden in patients without germline predispositions was 3.5/Mbp (standard deviation 3.8). Germline/presumed germline pathogenic variants were found in 18% (90/497) of patients tested with most common germline alterations in TP53 followed by NF1 and APC.

CONCLUSION
A large, single site cohort of molecularly characterized CNS tumors demonstrate the clinical and biologic utility of real-time, institution-based genomic sequencing. Molecular findings in correlation with clinical characteristics and outcomes are underway.
METB-11. EXPANSION OF THE PEDIATRIC BRAIN TUMOR ATLAS: AN OPEN SCIENCE EFFORT OF CHILDREN’S BRAIN TUMOR NETWORK, KIDS FIRST DATA RESOURCE AND CHILDHOOD CANCER DATA INITIATIVE
Authors: Koptyra Mateusz , Farrow Bailey , Sullivan Catherine , Coleman Noel , Rathi Komal , Van Kuren Nicholas , Zhu Yuankun , Heath Allison , McGrory Stephanie , Kraya Adam , Guo Yiran , Brown Miguel , Huang Xiaoyan , Kim Meen Chul , Zhang Bo , Ennis Brian , Rokita Jo Lynne , Friedman Christopher , Mason Jennifer , Lilly Jena , Cuellar Ximena , Duros Trang , Nguyen Thinh , Drake Emmett , Helili Zeinab , Frenkel Beth , Trooskin Gerri , Familiar Ariana , Viswanathan Karthik , Beck Christopher , Hollawell Madison , Baubet Valerie , Madsen Peter , Kline Cassie , Patton Tatiana , Arya Kamnaa , Cardona Dani , Velasco Ryan , Santi Mariarita , Storm Phillip B , Resnick Adam C ,   Children’s Brain Tumor Network
Published: June 2023

Abstract
Pediatric central nervous system cancers are the leading disease-related cause of death in children and there is urgent need for curative therapeutic strategies for these tumors. To address the urgency, Children’s Brain Tumor Network (CBTN) has advanced an open science model to accelerate the research discovery for pediatric brain tumors. In first phase of Open Pediatric Brain Tumor Atlas (OpenPBTA) effort CBTN together with Pacific Pediatric Neuro-Oncology Consortium (PNOC) and Gabriella Miller Kids First Data Resource Center (KFDRC) created and characterized over 1000 clinically annotated pediatric brain tumors.
The second phase of the OpenPBTA, through resource awards and collaboration across KFDRC, the NCI Childhood Cancer Data Initiative (CCDI), Clinical Proteomic Tumor Analysis Consortium (CPTAC), Center for Cancer Research and partnered institutions and foundations has expanded molecular characterization for an additional 1900 pediatric brain tumor patients and their families. This includes the processing and characterization of &gt;8000 specimens across &gt;50 brain tumor diagnoses. This expansion builds off multimodal data including whole genome, RNA, miRNA and methylation sequencing, proteomics, lipidomics and/or metabolomics. Molecular data is linked to longitudinal clinical data, imaging data, histology images, and pathology reports.
The data deposition in the cloud-based environment of the NCI’s CCDI and KFDRC to provide near real-time integration, dissemination, processing, and sharing capability. The approach leverages the DRC platform’s cloud-based computational environment through CAVATICA portal shareable pipelines. Data can be explored via PedcBioPortal, a data visualization/analysis application integrating additional public and deposited datasets.
This OpenPBTA expansion released with no embargo provides one of the largest deeply characterized cohorts of samples and associated clinical data for &gt;3000 pediatric brain tumor patients. CBTN’s open-science, rapid-release model aims to accelerate pediatric biomarker and drug discovery research and supports clinical trial development on behalf of changing the outcome for kids with brain tumors.
HGG-02. METABOLIC TARGETING OF HIGH-GRADE GLIOMAS WITH MTAP LOSS
Authors: Subramaniam Bavani , Kritzer Bettina , Putnam Ethan , Cunningham Gary , Bhattacharya Surajit , Packer Roger , Bornhorst Miriam , Nazarian Javad 
Published: June 2023

Abstract
Malignant transformation of pediatric glioma is often associated with homozygous deletion of CDKN2A. With CDKN2A loss, MTAP which is in the same chromosomal location, 9p21, is homozygously deleted in a majority of HGGs and some LGGs. The MTAP gene codes for methylthioadenosine phosphorylase (MTAP) protein which plays an important role in methionine salvage pathway. Absence of MTAP results in accumulation of 5’-methylthioadenosine (MTA), de novo purine synthesis, and tumor cell dependency on protein arginine methyltransferase 5 (PRMT5) and its substrate provider, methionine adenosyltransferase II alpha (MAT2A). We hypothesize that drugs targeting PRMT5, MAT2A, and de novo purine synthesis, in combination with drugs targeting hyper-activated RAS/MAPK pathway, will be effective in inhibiting MTAP-null glioma growth. Patient-derived glioma cells were validated for MTAP loss using genome sequencing, RNA sequencing and western blot. MTA accumulation caused by MTAP loss was validated through high-performance liquid chromatography. Cells were subjected to monotherapy and combination drug therapy with PRMT5, MAT2A and de novo purine synthesis inhibitors, in addition to drugs targeting RAS/MAPK signaling pathway. Additionally, MTAP-null (MTAPnull) in vivo models are being developed.We show accumulation of MTA in MTAPnull cells compared to MTAP-wild type (MTAPWT) cells, caused by loss of MTAP that cleaves MTA to adenine and 5-methylthioribose-1-phosphate (MTR). Accumulation of MTA makes MTAPnull glioma cells more sensitive to MAT2A inhibitor AG-270 in comparison to MTAPWT cells. Additionally, dual-drug therapies involving MTA and AG-270 result in additive effect on MTAPnull cells and antagonistic effect on MTAPWT cells. De novo purine synthesis inhibitor and drugs targeting the RAS/MAPK pathways also exhibited cell growth inhibition of MTAPnull cells. Overall, metabolic targeting of HGGs bearing CDKN2A/MTAP loss is indispensable for targeted therapy and for minimizing toxicity towards surrounding normal cells lacking similar mutations.
HGG-04. INFANTILE HIGH GRADE GLIOMA: HONG KONG EXPERIENCE
Authors: Ning Lau Sarah Sau , Ku Dennis Tak Loi , Liu Pak Yin Anthony 
Published: June 2023

Abstract

OBJECTIVE
To review local infantile high-grade glioma (IHG) patients and their outcome.

BACKGROUND
Infantile high-grade glioma is diagnosed in patients less than 12 months of age. Studies have shown that it displays a more stable genome, and are usually single mutation driven. The most identifiable mutations are receptor tyrosine kinase (RTK) fusion, such as NTRK family, ROS1, ALK and MET. The current principal treatment remains to be surgery, but it is challenging for a complete resection due to hemispheric involvement. Chemotherapeutic drugs for IHG are still under debate, with targeted therapy showing efficacy in promoting tumour shrinkage. Despite being a challenging CNS tumour, the overall survival of IHG is superior to other paediatric high-grade gliomas. Result: We identified 7 IHG patients in our local data. Mean age of diagnosis was 3 months. There were 4 males and 3 females. Six patients had histological diagnosis of glioblastoma and 1 patient had diagnosis of anaplastic astrocytoma. One patient had her tumour located in infratentorial region. Three patients had multilobar involvement. NTRK fusion was found in 4 patients (NTRK fusion, ETV6-NTRK3 fusion and TPR-NTRK1 fusion). ALK fusion was found in 1 patient (HMBOX1-ALK). All patients underwent chemotherapy, with four patients switched to NTRK inhibitor afterwards. Surgery was performed at various time points for these patients. One patient passed away at 22 months of age at submission of this abstract.

CONCLUSION
A local review gives us more insight into the updated diagnosis, management and outcome of infantile patients diagnosed with high-grade glioma. Infantile high-grade glioma should be regarded as a unique tumour entity and a multidisciplinary approach is paramount in improving survival for this group of patients.
HGG-06. CHARACTERIZATION OF THE EFFECT OF THE ORAL IRON-MIMETIC GALLIUM MALTOLATE ON PEDIATRIC GLIOBLASTOMA GROWTH IN VIVO
Authors: Al-Gizawiy Mona M , Wujek Robert T , Zoss Casey J , Tanaka Ryuma , Mirza Shama P , Chitambar Christopher R , Schmainda Kathleen M 
Published: June 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is a highly aggressive CNS tumor that is associated with poor outcome. This dire prognosis is due in part to its poor response to the limited treatment options available. Iron and iron proteins play a key role in the growth of brain tumors, with our published studies showing that the ferrobiology of adult GBM can be exploited for therapeutic purposes. Here, we further elucidate the inhibitory effects of oral gallium maltolate (GaM) in pediatric GBM in vivo.

METHODS
Pediatric SJ-GBM2 cells were stereotactically implanted into the right striatum of male athymic rats. Advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison.

RESULTS
The sensitivity of the in vivo pediatric GBM xenografts to GaM was consistent with our previous in vitro work. Median overall survival was 21 days in the controls and 49 days in the treatment group (p=0.014). GaM-treated xenograft tumors grew significantly slower than control tumors (p=0.031). Histologically, xenograft tumors recapitulated the aggressive growth features of clinical specimens, such as invasive margins. Unlike adult GBM xenografts in our previous studies, pediatric GBM xenografts did not exhibit vessel normalization or a reduction in pro-angiogenic markers in response to GaM. Additionally, MIB-1% (p=0.6583) and mitotic index (p=0.7097) were not affected by treatment. Yet, transferrin receptor and H-ferritin expression patterns in GaM-treated tumors suggested cellular iron deprivation.

CONCLUSION
Monotherapy with GaM provides a significant survival benefit in pediatric GBM, and further studies are planned to optimize the benefit of GaM in pediatric GBM.
IMG-01. LONGITUDINAL FMRI OF VISUAL, AUDITORY AND MOTOR FUNCTION IN PEDIATRIC CRANIOPHARYNGIOMA AFTER TREATMENT WITH PROTON RADIOTHERAPY
Authors: Zou Ping , Hua ChiaHo , Uh Jinsoo , Conklin Heather , Merchant Thomas , Sitaram Ranganatha 
Published: June 2023

Abstract

INTRODUCTION
Craniopharyngioma accounts for approximately 4% of childhood central nervous system tumors and has a 5-year overall survival rate exceeding 90%. Survivors of childhood craniopharyngioma may experience neurologic sequalae, including visual and fine motor deficits, and subclinical hearing loss associated with tumor and treatment. Contemporary treatment includes radical surgery or more limited surgery and proton radiotherapy (PRT). Here we report on a longitudinal fMRI study probing visual, auditory, and motor function in pediatric craniopharyngioma patients. METHOD: The study (NCT01419067) was IRB approved and informed consent was obtained for each patient. Functional MR images were acquired at 4 time points: after surgery and before PRT (TP1), and 18-months (TP2), 36-months (TP3), and 60-months (TP4) after PRT. Data from a sensory survey fMRI task (visual: flashing checkerboard; auditory: dissonant ascending/descending pure tones; and sensory/motor: button pushing when stimuli were on) for 67 patients were analyzed at the 4 time points. The median age was 11.7 years (range 8.3-20.2 years) and the female/male ratio was 37/30.

RESULTS
Significant brain activation was seen in visual cortices, auditory cortices, and supplementary motor area (SMA) and motor cortices for all 4 time points. Over the time, visual and motor cortices showed minimum changes in activation; however, there was a small increase in SMA. For the auditory cortices, the activation volume in Heschl’s gyri increased bilaterally, and the lateralization index decreased (TP1: 70%; TP2: 46%; TP3: 39%; and TP4: 26%) due to larger increases in the right Heschl’s gyrus.

CONCLUSION
Increasing activation in Heschl’s gyri, especially on the right side, after PRT suggests decreasing efficiency in distinguishing tones in these patients. These findings may be associated with late effects involving the specific gyri or neuropathways affected by surgery or irradiation.
IMMU-02. CMV-EXPANDED T-CELLS IN GLIOBLASTOMA PATIENTS: TRANSLATIONAL RESEARCH
Authors: Kampers Linde F C , Rajabpour Golnaz , Bitar Michael , Schirrmacher Volker , Stücker Wilfried , Van Gool Stefaan W 
Published: June 2023

Abstract
Human cytomegalovirus (CMV) is a contributing factor to tumour expansion and progression in glioblastoma patients. Patient-derived non-modified CMV-specific T cells can be isolated, ex vivo re-stimulated with CMV and expanded before IV infusion. Adoptive T cell Therapy with expanded CMV-specific T cells and has been shown to improve GBM prognosis. We aimed to develop a CMV-specific T cell expansion protocol. PBMCs were isolated from blood of 12 healthy CMV-antibody positive donors and 9 patients (three glioblastoma patients, four prostate cancer patients, one pancreatic cancer and one rectal cancer patient). CMV-pulsed stimulating and responding PBMC (S:R ratio = 1:2) were cultured in RPMI supplemented with IL-21 and subsequent IL-2 addition for 9 days. Cell quality was ensured via cell surface staining and intracellular cytokine assays. Product sterility was tested with aerobic and anaerobic sterility assays, Endotoxin test and mycoplasma tests. Autologous CMV-specific T cells were successfully isolated from CMV positive donors and cancer patients. Ex vivo analysis of CMV-specific T cells after in vitro CMV restimulation and expansion resulted in 6.81 x 106 to 2.52 x 108 viable cells (Δ1.09 x 108 with Δ90% viability) with antigen-specific active T-cell frequencies ranging from 15.10% to 41.98% (median 38.39%) in healthy donors and 14.78% to 54.75% of total CD8+ T cells (median 31.42%) in cancer patients. A cell culture protocol was developed to expand autologous CMV-specific CD8+ T cells from patients. Product release criteria were defined as 1-2 x 107 cells per m2 body surface area with a &gt;50% viability rate and &gt;15% CMV-specific CD8+ T cells within the total T cell population. The translation of the cell culture protocol within a GMP setting is envisioned. The efficacy of such treatment has to be elaborated once the cell product is approved for medicinal use.
IMMU-03. IDENTIFICATION OF GENETIC BIOMARKERS TO PREDICT RESPONSE TO HSV-1 G207 AND POLIO:RHINOVIRUS IMMUNOTHERAPY
Authors: Thompson Eric , Kang Kyung-Don , Zhang Hengshan , Brown Michael , Stevenson Kevin , Friedman Gregory 
Published: June 2023

Abstract

BACKGROUND
The polio:rhinovirus chimera, PVSRIPO, and the herpes simplex virus, G207, are viral immunotherapies with promising results in Phase I trials of pediatric high-grade glioma (pHGG) and medulloblastoma. While some patients have durable responses, others have no benefit. The purpose of this study is to identify genes that putatively confer resistance to viral immunotherapy.

METHODS
A panel of medulloblastoma and pHGG cell lines were treated with either PVSRIPO or G207 and categorized into “sensitive” and “resistant” groups based viability. Flow cytometry was used to quantify cell receptor expression (CD111 for G207, CD155 for PVSRIPO). RNA sequencing was completed on treated resistant and sensitive cells.

RESULTS
D341 and D556 medulloblastoma had &lt; 50% viability at 72h (G207) and 24h (PVSRIPO) and were categorized as sensitive; D283 and D324 were categorized as resistant. There was a correlation between CD111 expression and cell viability (Spearman r=0.71) but no correlation between CD155 and viability. The number of significantly differentially expressed (DE) genes (adjusted p≤0.05) was significantly higher in sensitive compared to resistant medulloblastoma, both for enriched (mean 666.4±614 vs. 454.6±377.4, P=0.0422) and depleted (826.9±645.5 vs. 449±367.8, P=0.0167) genes after treatment. There were few shared DE genes between cells treated with PVSRIPO and G207: GCLM, LANCL2, and RBM3 were enriched while ADAMTS1 and VEGFA were depleted. Likewise, there were few shared DE genes enriched between medulloblastoma and pHGG cell lines treated with G207: GPSM2, CHECK2, SEPTIN2, EIF4G2, GCLM, GDAP1, LANCL2, and PWP1.

CONCLUSIONS
Genetic analysis demonstrates minimal overlap in DE genes between the two viral immunotherapies. PVRIPO and G207 infection resulted in significantly more DE gene expression in sensitive vs. resistant cells. GCLM and LANCL2 are enriched by both PVSRIPO and G207 and in medulloblastoma and pHGG. These genes may serve as potential biomarkers in predicting response to viral immunotherapy.