bluuebunny/crossref_metadata_2025_split huggingface dataset:
OTHR-28. Multi-institution analysis of tumor mutational burden and outcomes in pediatric CNS tumor patients
Authors: Parisi Rose , Patel Roshal , Rood Gavrielle , Bowden Acacia , Turco George , Korones David , Andolina Jeffrey , Comito Melanie , Barth Matthew , Weintraub Lauren 
Published: June 2022

Abstract
Pediatric CNS tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision making. Tumor mutational burden (TMB) has been correlated with decreased survival across cancer types. This study is the first to examine TMB and outcomes in pediatric CNS tumor patients across multiple academic medical centers. We conducted a retrospective analysis of 121 pediatric patients (61 female (50%)) with a median age of 9 diagnosed with a primary CNS tumor at Albany Medical Center, Roswell Park Comprehensive Cancer Center, Upstate University Hospital, or University of Rochester Medical Center from 2008 to 2021. Common tumor types included low-grade glioma (N=51), high-grade glioma (N=30), medulloblastoma (N=11), ependymoma (N=7), ganglioglioma (N=4), and 18 other CNS tumors. Seventy-one patients had driver-mutations, including TP53 inactivation (n=17), BRAF-KIAA1549 fusion (n=16), FGFR1 amplification (n=12), BRAF V600E mutation (n=12), NF1 loss (n=12), and H3F3A K28M mutation (n=6). TMB data was available for most patients (N=91), median TMB was 1 mutations/megabase (mut/Mb, range=0-132). There were 26 deaths observed; patients with high TMB (≥3 mut/Mb; N=35) as compared to patients with low TMB (&lt;3 mut/Mb; N=56) were more likely to have a death event, 43% (N=15) vs 9% (N=5), respectively. High TMB tumors were more frequently high-grade (77%) than low-grade (41%). High TMB tumors were more frequently treated with systemic therapy (86%) compared to low TMB tumors (70%). Tumor progression was more common in high TMB (71%) than in low TMB tumors (54%). This multi-institutional analysis suggests that high TMB is correlated with higher rates of progression and death as compared to low TMB tumors. Knowledge of these findings is critical for identifying patients who may benefit from alternative treatments, such as immunotherapies.
OTHR-29. Exploring delays in diagnosis for children with brain and spinal cord tumors: a neuro-oncologist, epidemiologist and national nonprofit establish a consortium to discover the nature and extent of the problem in the United States
Authors: Riley Kathy , Coven Scott , Cullen Jennifer 
Published: June 2022

Abstract
Childhood brain and spinal cord tumors are the second most common pediatric cancer and the leading cause of disease-related mortality among children between one and nineteen years of age (Johnson & Cullen, 2014). To date, literature fails to acknowledge the perceived delay in diagnosis from a caregivers’ and providers’ perspective as it relates to disparities of care for a child with a brain or spinal cord tumor. Delay in diagnosis is a term used widely to define the time interval from onset of symptoms to confirmed diagnosis (Mullen, Barr & Franco, 2021). Our experience in caring for children with CNS tumors has demonstrated a disconnect in perception of delay in diagnosis between caregivers and providers. Furthermore, to our knowledge, there is no standardized data collection tool to assess delays in diagnosis and to enable the exploration of their relationship to the patient journey from time of diagnosis through long-term outcomes of patients with brain and spinal cord tumors. Timing of diagnosis of a brain or spinal cord tumor in a pediatric patient may be a predictor of clinical outcomes (Wilne, Dineen, Dommett, Chu & Walker, 2013). Additionally, the length of time from symptom onset to diagnosis may exacerbate caregiver distress which, in turn, impacts clinical outcomes. Associated social determinants of health, perceptions of credibility (e.g., not being believed about symptoms), and negative interactions with health care providers may contribute to inequalities of healthcare related to delays in diagnosis. This presentation will explore themes and key factors contributing to delays in pediatric brain and spinal cord tumor diagnoses developed through the work of our consortium. The goal of our work is to develop metrics and survey items that will be used to quantify sources of delays to improve our understanding and promote greater timeliness in diagnoses (Scott, Walter, Webster, Sutton, &Emery, 2013).
OTHR-30. Multidisciplinary approach to childhood cancer bio-banking improves enrollment and enables better access to diagnostic and therapeutic studies
Authors: Zhukova Nataliya , Habarakada Dilru , Drinkwater Caroline , Danks Andrew , Xenos Chris , Kumar Beena , Haddad Lauren , Wood Paul , Cain Jason , Firestein Ron , Downie Peter 
Published: June 2022

Abstract
Despite the significant progress made in the multi-modal treatment of childhood malignancies over the last four decades with a concomitantly increased cure rates, the benefit is still largely limited to patients with leukemias, lymphomas and localized non-CNS solid tumors, leaving patients with high-risk non-CNS solid tumours and most CNS malignancies with minimal advancements. More research is critical to understand what drives these cancers and to investigate the best ways to deliver curative therapies. Translational research relies on patient-derived tissue samples, animal models and cell-cultures to understand the biological, genetic, and molecular mechanisms of disease. To facilitate patient care and outcomes, it is becoming increasingly important that paediatric clinical trials include tissue availability as part of eligibility criteria, making collection and storage of patient tissue a mandate of personalised medicine and a pillar of modern paediatric cancer medicine. Monash Children’s Cancer Biobank was established in 2011. Since 2017, a total of 64 patients were diagnosed with CNS malignancies across all grades, with an overall 69% of patients’ tissues being biobanked at the time of initial diagnosis. A co-ordinated, multidisciplinary approach to biobanking is crucial to the success of tissue acquisition. Through the combination of an educational forum, regular neuro-surgical multi-disciplinary meetings, and the early involvement of medical oncology and biobank staff, with our neurosurgical and clinical pathology colleagues, as part of patient management planning, the tissue acquisition for biobanking increased from 44% to 82% over the course of 5 years. This consequently led to a 100% enrolment to tissue-enabling studies, significantly improving identification of targetable molecular lesions, enrolment onto treatment clinical trials and identification of patients with cancer predisposition syndromes.
OTHR-39. Extraneural spreading of a diffuse leptomeningeal glioneuronal tumor in a child: patient-derived models show sensitivity to vinblastin and trametinib
Authors: Messiaen Julie , Claeys Annelies , Shetty Aniket , Spans Lien , Derweduwe Marleen , Uyttebroeck Anne , Depreitere Bart , Bempt Isabelle Vanden , Sciot Raf , Ligon Keith , Jones David , Jacobs Sandra , De Smet Frederik 
Published: June 2022

Abstract
Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare neoplasms of the central nervous system. We describe the generation of patient-derived models from a DLGNT that metastasized to the peritoneal cavity via a ventriculoperitoneal shunt in a child. The original tumor contained a KIAA1549:BRAF fusion with a chromosome 1p deletion and corresponded with methylation subclass DLGNT-MC-2 From a sample of ascitic fluid, metastatic tumoral cells could be extracted and expanded ex vivo into a long-term cell culture model. This patient-derived cell line (PDCL) showed mixed morphological phenotypes and expressed MAP2 and SYP. The KIAA1549:BRAF fusion was preserved and the PDCL still corresponded to the original methylation subclass DLGNT-MC-2. Whole-genome sequencing showed additional mutations potentially contributing to the malignant behavior of the tumor. Cytotoxic assays performed on the PDCL indicated high sensitivity to vinblastine and trametinib (MEK-inhibitor) and intermediate sensitivity to DRD/ClpP-modulators. The PDCL underwent viral transduction to induce GFP-fLux positivity and was intraperitoneally injected into immunocompromised mice. A mouse model could be generated, with the growth of a peritoneal tumor in a localized manner. The cells grown from the mouse tumor were again put into culture and were afterwards subjected to the same treatments as the PDCL. This confirmed a similar profile, with high sensitivity to vinblastin and trametinib and an intermediate sensitivity to the DRD/ClpP-modulators. In conclusion, we were able to generate patient-derived models from a metastatic DLGNT, which recapitulate the molecular characteristics of the original tumor. The models showed high sensitivity to vinblastin and targeted therapy with MEK-inhibition, but further studies are necessary to define the adequate treatment for this kind of tumor.
OTHR-45. Kids First Variant WorkBench: application to germline genomic discoveries in the Children's Brain Tumor Network
Authors: Guo Yiran , Costanza Jeremy , Botek Christophe , Brown Miguel , Higgins David , Zhu Yuankun , Farrow Bailey , Heath Allison , Resnick Adam , Ferretti Vincent 
Published: June 2022

Abstract
The Gabriella Miller Kids First Pediatric Research Program (Kids First) aims at facilitating researchers to uncover new insights into the biology of childhood cancer (CC) and structural birth defects (SBD). Kids First has two initiatives, i) whole genome sequencing of biospecimens from families with CC/SBD, and ii) establishing Kids First Data Resources. Kids First Data Resource Center developed the Kids First Data Resource Portal (KFDRP), a centralized platform to search, view, analyze, and identify currently accessible data from both Kids First and collaborative cohorts, incorporating omics and phenotypic information of 30 studies and 26,300 participants. A recently released KFDRP component is Variant WorkBench (VWB), enabling users to query, mangle, analyze and visualize genomic variants from participating cohorts, with the Children’s Brain Tumor Network (CBTN) being one of the cohorts. VWB supports programming languages such as Python, Spark, SQL and R for in-depth analysis in Apache Zeppelin notebooks. In addition to variant calls and phenotypic information, VWB hosts rich external variant annotations in the public domain, such as Cancer Hotspots, COSMIC and ClinVar. Users can also load additional databases (e.g. Human Gene Mutation Database/HGMD) within a notebook, import custom datasets as temporary query tables, export analysis outputs to local drives, visualize analysis results in multiple chart styles, display local figures, and save notebooks for sharing, further use and Cavatica projects. In an effort to screen tier 1 genes (n=578) from the most recent Cancer Gene Census provided by COSMIC in CBTN, we identified ~127,500 germline variants that are both rare and damaging, or that are already cataloged in the most recent version of ClinVar/HGMD. The whole process took less than one hour which is much faster than conventional methods. VWB enables efficient genomic variant analysis and discoveries in pediatric neuro-oncology research with advanced big data technology.
PATH-02. Using DNA methylation profiling to define tumor type and appropriate treatment: a case report and review of the literature of a rare CNS CIC altered sarcoma
Authors: Brodwater William , Wilson Yelena , Judd Alexis , Rush Sarah , Wright Erin 
Published: June 2022

Abstract
The utilization of methylation profiling is increasingly becoming part of the standard evaluation for high-grade malignancies. CNS primary tumors with CIC alteration are a recently recognized CNS tumor entity identified via DNA methylation profiling of primitive neuroectodermal tumors (PNET). PNETs have historically carried a poor overall prognosis; however, CNS tumors with CIC alteration have rarely been described in the literature and much remains to be discovered regarding the presentation, tumor characteristics, outcomes, and ideal treatment strategy to optimize survival in these patients. We describe the case of a 2-year-old Hispanic female with a CNS primary tumor with CIC alteration. This patient initially presented with a five-week history of fatigue, headaches, emesis, and right-sided muscle weakness and was found to have a right-sided supratentorial mixed solid and cystic mass. The initial diagnosis was consistent with a high-grade neuro-epithelial tumor based on histology and standard CNS tumor genetic markers. Due to poorly defined tumor characteristics, a sample was also sent for DNA methylation profiling. The profiling pattern was consistent with a CNS CIC altered sarcoma thereby significantly altering the treatment plan. Accurate diagnosis is critical in managing patients with cancer. DNA methylation profiling has contributed to diagnostic accuracy in these aggressive tumors; however, it also creates challenges with beginning treatment expediently due to the time required for processing and interpretation. This case illustrates the positive utility of DNA methylation to better characterize tumor types and the impact this has on both treatment as well as prognosis.
PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study
Authors: Delaidelli Alberto , Dunham Christopher , Santi Mariarita , Negri Gian Luca , Triscott Joanna , Zheludkova Olga , Golanov Andrey , Ryzhova Marina , Okonechnikov Konstantin , Schrimpf Daniel , Stichel Damian , Ellison David , von Deimling Andreas , Kool Marcel , Pfister Stefan , Ramaswamy Vijay , Taylor Michael , Korshunov Andrey , Sorensen Poul 
Published: June 2022

Abstract
BACKGROUND: International consensus and the 2021 WHO classification recognize eight molecular subgroups among Group 3/4 medulloblastoma (representing ~60% of medulloblastoma). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or other molecular parameters of high-risk for Group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk-stratification. PATIENTS and METHODS: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three Group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Risk stratification and prediction capability were computed utilizing uni- and multivariate survival analysis. Newly developed risk classifiers including TPD52 IHC were compared to state-of-the-art risk stratification schemes in terms of prediction error, area under the time-dependent receiver operating characteristic (ROC) curves and C-statistic. RESULTS: TPD52 IHC percentage positivity represents a significant independent predictor of early relapse and death for Group 3/4 medulloblastoma (HRs between 3.67-26.7 [95% CIs between 1.00-706.23], p = 0.05, 0.017 and 0.0058). Cross-validated survival models incorporating TPD52 IHC with clinical and molecular features (subgroup affiliation, MYC status) outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, interaction effect in multivariate analyses revealed that TPD52 immunopositivity could be a predictive indicator of poor response to chemotherapy (HR 12.66 [95% CI 3.53-45.40], p &lt; 0.0001), suggesting important implication for therapeutic choices. CONCLUSION: The current study adds an important asset to improve risk-stratification for Group 3/4 medulloblastoma. Integration of TPD52 IHC in classification algorithms significantly improves outcome prediction and can be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
PATH-07. Diagnostic and therapeutic value of cerebrospinal fluid biopsy in pediatric brain tumors
Authors: Li Shaoqun , Lai Mingyao , Cai Linbo 
Published: June 2022

Abstract
BACKGROUND: The application of cerebrospinal fluid (CSF) biopsy in brain tumors is valuable. This paper further explores the diagnostic and therapeutic value of CSF biopsy in pediatric brain tumors. METHODS: In this study, children with primary brain tumor aged ≤18 years old in Guangdong Sanjiu Brain Hospital were enrolled．CSF next-generation sequencing (NGS) tests were required for all included patients. The genetic mutations in these children were analyzed. RESULTS: A total of 12 pediatric brain tumors who underwent CSF NGS were included in this study. 9 patients were brainstem glioma and 3 were pilocytic astrocytoma. The mutated genes were detected in 67% (8/12) patients by CSF NGS. In brainstem glioma, the rate was 67% (6/9), and the most common genes were H3F3A (5/6, 83%) and TP53 (5/6, 83%). Other detected genes included EGFR, CDK4 and NF2. H3F3A mutation is of great significance for the diagnosis and treatment of brainstem glioma, and CDK4 and EGFR are valuable for the treatment. In pilocytic astrocytoma, the deteaction rate was 67% (2/3), and the genes included KIAA1549-BRAF fusion, FGFR1 and PTPN11 mutations. KIAA1549-BRAF fusion is of great value in the diagnosis and treatment of pilocytic astrocytoma, and FGFR is valuable in the treatment. CONCLUSIONS: Fluid biopsy of CSF for pediatric brain tumors may be an important supplement to histological diagnosis, especially when histopathology is not available. The results are significant for the diagnosis and treatment of pediatric brain tumors.
PATH-12. A new powerful tool to simultaneously deliver DNA methylation profile and driver fusions detection based on Nanopore Sequencing
Authors: Filser Mathilde , Hamza Abderaouf , Girard Elodie , Servant Nicolas , Renault Victor , Merchadou Kevin , Bourneix Christine , Varlet Pascale , Uro-Coste Emmanuelle , Tauziède-Espariat Arnault , Doz Francois , Bourdeaut Franck , Delattre Olivier , Masliah-Planchon Julien 
Published: June 2022

Abstract
The fast advances in molecular biology have led to the discovery of new genetic and epigenetic driver events that play a key role in the pathogenesis of central nervous system (CNS) tumors. These data showed the importance of molecular biology, and in particular methylation profiling and fusion detection, to complete the histological examination. Exploring all these complex genomic and epigenomic alterations with the technologies implemented in the routine diagnosis requires massive laboratory equipment. In addition, it could take weeks before getting data that could be important to adapt the diagnosis, prognosis, and to ultimately guide the treatment’s choice. We describe the innovative potential of a nanopore sequencing device to obtain fast and multiple information to characterize CNS tumors. Adaptive-sampling is a software-controlled enrichment unique method that allows simultaneous methylation profiling, copy number landscape assessment, and fusion gene detection. Thereby, this technology brings comprehensive molecular information that could be very important for CNS tumor classification in a very short delay (below one week) and with a relative low cost compared to the combined other molecular analysis needed to get the same information. We report ten cases of diverse CNS tumors with already known oncogenic structural variants such as YAP1-MAMLD1 fused ependymoma, CNS neuroblastoma with FOXR2 activation, CNS high-grade neuroepithelial tumor with BCOR and MEN1 alteration, and atypical teratoid rhabdoid tumors (ATRT). For these tumors, using adaptive sampling with the nanopore sequencing, we were able to detect fusion genes as driver events, while obtaining at the same time the methylation profile to corroborate the tumor classification. Our results with this combined approach, never described before, demonstrate its feasibility as a new extremely powerful tool and show remarkable perspectives for this technology to bring a fast and comprehensive tumor molecular characterization.
LINC-03. A single center retrospective analysis of current therapy and outcome of central nervous system tumors in children of Beijing
Authors: Li Miao , Du Shuxu , Sun Yanling , Gong Xiaojun , Liu Jingjing , Ren Siqi , Zhang Jin , Gao Wenchao , Li Shuting , Wan Lulu , Wang Yuan , Wu Yuefang , Liu Yan , Zhang Zhen , Tang Hong , Wu Wanshui , Sun Liming 
Published: June 2022

Abstract
OBJECTIVE: To explore the clinical characteristics, therapy and outcome in children with central nervous system (CNS) tumors in Beijing, China. METHODS: Clinical data of 1003 patients with newly diagnosed CNS tumors under the age of 15 years admitted to Beijing Shijitan Hospital between January 2017 and December 2021 were retrospectively analyzed. The diagnoses were confirmed by pathology and/or molecular tests. RESULTS: 34 patients were lost to follow up. Medulloblastoma (n=472), ependymoma (n=79), ETMR (n=59) and pinealoblastoma (n=19) were treated according to HIT-2000/2017, 5-year progression-free survival (PFS) and overall survival (OS) were 76.4 ± 2.3%/ 84.8 ±1.9% in MB, 88.8±3.7% /89.5±3.8% in ependymoma, 49.9±7.6%/59.6±10.7% in ETMR, and 3y-PFS/OS of 11.1±10.5%, 90.0±9.5% in pinealoblastoma. The detailed histology of 59 cases of embryonal tumors included 40 cases of CNS embryonal tumor, 9 neuroblastoma, 7 ETMR, and 3 rare tumors (Intracranial mesenchymal tumor with FET-CREB fusion, CNS high-grade neuroepithelial tumor with BCOR alteration, and Melanotic neuroectodermal tumor of infancy). Among 19 cases of pinealoblastoma, two contain DICER1 mutations. Atypical teratoid/rhabdoid tumors (n=36) were treated by EU-RHAB-Protocol with 3y-PFS/OS of 42.2 ± 9.4 % and 62.8 ± 9.5 %. For low-grade gliomas (n=153, 114 cases of OPG and 39 other non-STR/NTR or progressive cases) under SIOP-LGG 2004, 5y-PFS/OS rates were 77.6±5.2% and 92.4±3.2%; Comparatively, among 63 cases of high-grade gliomas, 19 cases survived with median survival of 52 months, 44 cases died. Choroid plexus cancers (n=13) were treated according to CPT-SIOP-2009 with 5y-PFS /OS of 68.4 ± 13.1 % and 64.8±14.3 %. Among 109 germ cell tumors, 5y-PFS/OS were 93.8±2.8% and 95.5±2.2%, respectively. CONCLUSION: The prognosis of CNS tumors are related to pathology, molecular type and individualized therapy. By international multicenter cooperation and adopting advanced protocols, the survival rates of pediatric CNS tumors can be significantly improved.