bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-99. SPATIAL AND TEMPORAL DEVELOPMENT OF GLI2-DRIVEN MEDULLOBLASTOMA
Authors: Murad Najiba , Xu Zhenhua , Zhang Jiao , Gamachchige Prathibhani Ramawickrama , Schoof Melanie , Schüller Ulrich , Dlugosz Andrzej , Taylor Michael D , Pei Yanxin 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is a highly malignant tumor of the cerebellum predominantly affecting children. It can be classified into four major molecular subgroups: WNT, SHH, Group 3, and Group 4. Among these subgroups, the SHH subgroup MB, characterized by GLI2 amplification, is associated with a poor prognosis. However, while GLI2 alterations have been linked to SHH-MB, evidence demonstrating its role as an oncogenic driver in an animal model is lacking. Understanding the mechanisms underlying GLI2-amplified MB initiation and progression is crucial for developing improved therapeutic strategies.

METHODS
By utilizing transgenic mouse models, our study aims to elucidate the role of GLI2 in SHH-MB tumorigenesis and uncover the underlying mechanisms driving tumor formation. This research effort seeks to identify novel therapeutic targets for the treatment of this disease.

RESULTS
We discovered that overexpression of GLI2 in embryonic Math1+ granule neuron precursors (GNPs) led to tumorigenesis within the cerebellum, resulting in 100% mortality in the mice. Importantly, the cellular and molecular characteristics of these tumors faithfully recapitulated those found in human SHH-MB. Further analysis revealed that only Math1+ GNPs specifically between E13.5 and E15.5 are susceptible to GLI2-induced tumorigenesis, while overexpression of GLI2 in embryonic GFAP+ stem cell/progenitors failed to induce tumorigenesis. Additionally, our single-cell RNA-seq analysis unveiled the heterogeneity of Math1+ cells during cerebellar development. Furthermore, we demonstrated that the MAPK signaling pathway was involved in the tumorigenesis of embryonic Math1+ GNPs by preventing cell apoptosis.

CONCLUSIONS
Our findings establish a pivotal oncogenic role of GLI2 in SHH-MB tumorigenesis, with GLI2-driven tumors developing within a specific spatial-temporal window from a distinct cell population during cerebellar development. Targeting the MAPK signaling pathway holds promise in preventing tumorigenesis and progression of GLI2-amplified MB.
MDB-104. TARGETING Y BOX BINDING PROTEIN (YBX1) IN PEDIATRIC MEDULLOBLASTOMA
Authors: Carney Stephen , Hemenway John , Rajendran Ashmita , Hathaway Matthew , Nealy Eric , Paese Christian Bonatto , Tailor Dhanir , Malhotra Sanjay , Evans II Myron 
Published: June 2024

Abstract
Medulloblastoma is the most common malignant pediatric brain tumor, with some patients having abysmal survival despite an intense therapeutic regimen. A significant barrier to effective outcomes is cell-intrinsic resistance to chemo- and radio- therapy. Using a batch-normalized bulk RNA-seq dataset (GSE124814) comprised of 1350 MB samples and 291 normal cerebella, we reveal upregulation of Y-box binding protein 1 (YBX1) in MB compared to normal cerebellum. Further analysis of this dataset and others demonstrates a significant correlation between MYC and YBX1 expression in G3 tumors. Proteomics analysis also reveals higher YBX1 in G3 tumors characterized by hyperstability of MYC. Using a well-established ex vivo model, we demonstrate increased YBX1 expression as normal cerebellar progenitor cells transition to tumorigenic G3 MB stem-like cells. Deletion of YBX1 in these progenitor cells limits tumorigenesis suggesting a requirement for YBX1 in tumor initiation. We utilized an orthogonal pharmacogenetic approach to inhibit YBX1 and determine its effects on G3 MB tumor biology. Genetic depletion of YBX1 significantly reduced cellular proliferation and antagonized MYC expression in vitro. Orthotopic implantation of these YBX1KO G3 MB cells leads to increased tumor latency and animal survival. Transcriptomic analysis reveals a de-repression of neuronal target genes as well as suppression of MYC-activated genes. Evaluation of SU056, a YBX1 targeting small molecule, revealed both single agent efficacy as well as synergism with chemo- and radio- therapy. Further analysis revealed efficacy in SHH MB, even in tumors with mutant p53, suggesting cross-subgroup use for SU056. In silico docking identified binding of SU056 in the mRNA recognition domain of YBX1. Disruption of YBX1-RNA binding impacts the stability of known oncogenic transcripts, important for tumorigenesis and progression. Our findings corroborate previous identification of YBX1 as a chemoresistance factor and validate pre-clinical targeting of YBX1 to improve patient outcomes.
NFS-01. EXTREMELY RARE CASE OF CHILDREN WITH NIJMEGEN BREAKAGE SYNDROME AND MEDULLOBLASTOMA – A THERAPEUTIC CHALLENGE
Authors: Krawczyk Malgorzata A , Bien Ewa , Perek-Polnik Marta , Abdelbaki Mohamed S 
Published: June 2024

Abstract

BACKGROUND
Nijmegen Breakage Syndrome (NBS) is an autosomal recessive inherited disorder characterized by DNA repair abnormalities. It manifests with heightened sensitivity to radiotherapy (RT) and predisposes individuals to neoplastic diseases. Antineoplastic treatment in NBS patients is particularly challenging due to concurrent immune disorders, intense toxicities, and contraindications for RT. Hematologic disorders, especially lymphomas, are among the most prevalent malignancies in NBS patients. Solid tumors in NBS are extremely rare, with only two pediatric cases documented in the literature, both succumbing due to severe complications of treatment.

METHODS
A review and analysis of the medical documentation of a child with NBS and MB treated at the Department of Pediatrics, Hematology, and Oncology, Gdansk, Poland, were conducted.

RESULTS
A genetically confirmed NBS girl displaying typical phenotypic features presents symptoms at the age of 2 years, such as headaches, reluctance to walk, and drowsiness. Imaging confirmed a tumor in the left cerebellar hemisphere, measuring 40x33x30mm, displaying radiological features consistent with Medulloblastoma (MB). The patient underwent gross total resection of the tumor. The pathology revealed a desmoplastic type of MB with SHH activation, TP53 wild type, and ongoing molecular analysis. Postoperative imaging confirmed clinical remission, and cerebrospinal fluid examination was negative. Considering the substantial toxicities of chemotherapy in NBS patients and the contraindications for RT, the patient received chemotherapy with reduced cytostatic doses. Treatment was complicated by profound and prolonged myelosuppression and infections. Currently, after completing six cycles of chemotherapy, the patient is still in remission. To maintain remission and address NBS, the patient will receive allogeneic bone marrow transplantation from a 9/10 HLA-matched unrelated donor.

CONCLUSIONS
Managing patients with NBS, complicated by neoplastic diseases, is exceptionally demanding and necessitates an individualized multidisciplinary approach. Modern diagnostic and therapeutic methods enhance the prospects of reducing the toxicity of oncologic treatment, improving quality of life, and extending overall survival.
NFS-22. INVESTIGATING MALIGNANT TRANSFORMATION IN NF1 PEDIATRIC GLIOMAS USING AN IPSCS-DERIVED CEREBRAL ORGANOID MODEL
Authors: Tomasso Federica , Chong Wai Chin , Bhuvanendran Shivaprasad , Yadavilli Sridevi , Packer Roger , Nazarian Javad 
Published: June 2024

Abstract

BACKGROUND
Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor predisposition syndrome affecting 1 in 3000 children around the world. Although NF1 inactivation is recognized as the cause of low-grade glioma (LGG) development, little is known about subsequent genetic alterations that lead to malignant transformation. One of the limitations in understanding the molecular events underlying the malignant transformation of NF1 gliomas is the lack of appropriate NF1 preclinical models for its comprehensive profiling.

OBJECTIVE
Brain organoids have emerged as powerful in vitro models for studying the interaction between tumor cells and the tumor microenvironment. In this study, we present a novel cerebral organoid model, developed to investigate the molecular events leading to malignant transformation in NF1 pediatric gliomas.

METHODS
Induced pluripotent stem cells (iPSCs)-derived cerebral organoids were generated using NF1wt and NF1mut iPSCs, the latter reprogrammed from patients with plexiform neurofibromas (Carlos III Health Institute, Spain). Immunofluorescence analysis was performed at four different developmental stages to confirm their correct cytoarchitectural development and differentiation into heterogeneous cell populations. Furthermore, four mCherry-labelled isogenic glioma cells lines, RES 186 wild type, NF1-/-, CDKN2a-/-,NF1-/-/CDKN2a-/- were co-cultured with the developed cerebral organoids and their migration potential and invasiveness were compared using two-photon microscopy.

RESULTS/DISCUSSION
NF1mut cerebral organoids display ventricular-like zone at early stages of development (d15-d30), characterized by luminal Sox2+ neural stem cells surrounded by Tuj1+ immature neuron. These organized structures disappear at later stages, while progenitor cells start to differentiate into fully mature neurons and glial cells (d45-d60). Additionally, after 10 days of co-culture, all four RES186 isogenic cell lines infiltrated the organoid structure with different invasion patterns. The established organoid model will provide a platform for evaluating the impact of sequential mutational events on LGG transformation, taking into consideration the role exerted by the tumor microenvironment in supporting tumor cell invasion and migration.
NFS-23. ASSOCIATION OF LOCALIZED MAGNETIC RESONANCE IMAGING FEATURES IN ANTERIOR VISUAL PATHWAY WITH VISUAL ACUITY LOSS AMONG CHILDREN WITH NF1-OPG
Authors: Jiang Zhifan , Parida Abhijeet , Liu Xinyang , Tang Yucheng , Roth Holger R , Fisher Michael J , Packer Roger J , Anwar Syed Muhammad , Avery Robert A , Linguraru Marius George 
Published: June 2024

Abstract

BACKGROUND
Half of children with optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPG) are at risk for vision acuity (VA) loss. NF1-OPGs manifest along the anterior visual pathway (AVP), where the overall shape and volume from MRI have been recently associated with VA loss. To investigate the added value of localized features within the optic nerves (ONs) and chiasm, we propose an automatic deep-learning framework for VA loss prediction from volumetric and radiomic analysis of ONs, chiasm, and AVP.

METHODS
We collected MRIs of 60 children with NF1-OPG from Children’s National Hospital (CNH, GE platform) and 75 from Children’s Hospital of Philadelphia (CHOP, Siemens platform). MRI sequences included T1-, T2-weighted and T2-FLAIR. Experts annotated the AVP to establish ground truth. Neuro-ophthalmic evaluation identified VA loss (LogMAR &gt;= 0.2) in 52/135 children. Automatic AVP segmentation was performed using the Swin transformer network. ONs and chiasm were split through template-based registration. Brain volume, tumor location, child age, and 1,172 radiomic features were used to predict VA loss using support vector machines. Sequential feature selection associated with risk VA loss was done using sensitivity and univariate statistical tests (ANOVA). We compared predictions based on new ON and chiasm analysis with results based on AVP alone.

RESULTS
Balanced accuracy, sensitivity, specificity, and AUROC of VA loss prediction were 0.865, 0.882, 0.857, 0.899, respectively. Significant risk factors were maximal image intensity and gray level run length entropy in T2-FLAIR for ONs, and image intensity range in T2-FLAIR for chiasm. AUROC based on analysis of AVP alone dropped to 0.728 (p-value=0.028).

CONCLUSIONS
Deep learning-based analysis indicates an association of new localized MRI features in ONs and chiasm with VA loss, which show enhanced capability in predicting VA loss. This automated framework has the potential to accelerate and guide the treatment decisions for children with NF1-OPGs.
QOL-14. EPILEPTIC SEIZURES, ANTI-SEIZURE MEDICATIONS, AND NEUROCOGNITION IN SURVIVORS OF PEDIATRIC BRAIN TUMORS
Authors: de Licht Edvard Fine , Ideland Tova , Sigurdsson Gunnar , Anastasopoulou Stavroula , Olsson Ingrid Tonning 
Published: June 2024

Abstract

BACKGROUND
Younger age at diagnosis and cranial radiation therapy are associated with neurocognitive late complications in survivors of pediatric brain tumors (PBT). Less is known about the association between neurocognition and epileptic seizures, with the latter affecting 27% of 5-year survivors. This study aimed to explore whether epileptic seizures exacerbate neurocognitive late complications beyond treatment and demographic factors.

METHODS
Fifty-nine survivors of PBT who had experienced at least one epileptic seizure, and a control group of survivors matched on sex, age at diagnosis, and cancer treatment, all diagnosed at Skåne University Hospital, were included in the study. Demographic and clinical variables, along with neurocognitive measures of verbal and non-verbal reasoning, cognitive processing speed, working memory, and cognitive flexibility were collected from medical records. Neuropsychological scores, assessed on average 3.68 years after diagnosis, were transformed into z-scores employing age-adjusted norms (m=0, sd=1). Generalized linear models, controlling for increased intracranial pressure at diagnosis and tumor localization, were used to analyze the association between epileptic seizures, cumulative use of anti-seizure medications (ASM), and neurocognition.

RESULTS
Experiencing any type of epileptic seizures was associated with reduced processing speed (β = -0.91z, p&lt;0.01) and cognitive flexibility (β =-1.05z, p&lt;0.01). Treatment with one ASM was associated with reduced cognitive processing speed (β =-0.81z, p=0.03), and treatment with two or more ASM was associated with lower scores on measures of non-verbal reasoning (β =-0.81z, p&lt;0.01), working memory (β =-0.77z, p=0.01), processing speed (β=-1.26z, p&lt;0.01), and flexibility (β =-1.54z, p&lt;0.01).

CONCLUSIONS
Epileptic seizures and treatment with ASM were both associated with neurocognitive late complications. Optimal seizure management presents a potential modifiable factor for reducing cognitive burden in survivors of PBT.
QOL-19. THE SIBLING TOOLKIT: DEVELOPMENT OF A PSYCHOLOGICALLY-INFORMED TOOLKIT TO SUPPORT SIBLINGS OF CHILDHOOD CNS TUMOUR PATIENTS WITH LIMITED ACCESS TO FORMAL SERVICES
Authors: Verity Sarah J , Adey Claire , Dyson Tracy , Fifield Kate , Holman Natalie , Lewington Philippa , Marshall Kirsty , Owens Meghan , Samrai Amandeep , Tregay Jeni , Davies Kimberley , Martinez Phil , Mitchell Deborah 
Published: June 2024

Abstract

BACKGROUND
There is a recognised gap in service provision addressing the psychological and social needs of siblings of children with a diagnosis of brain tumour. In the absence of funding to provide direct psychological service provision for siblings, a project development group was established to identify and advance alternative methods of delivering support.

METHODS
Funding for a two year sibling-needs project was sourced from UK child brain tumour charity Tom’s Trust and led by the Neuro-Oncology psychology service at the Great North Children’s Hospital (Newcastle, UK). A development group was established of clinical psychologists and neuropsychologists representing nine UK hospital Trusts and one former school teacher. Following a comprehensive priorities exercise a toolkit was developed to support siblings of children with brain tumours. Significant further stakeholder involvement, including input from the regional Young People’s Advisory Group, resulted in positive revision to the initial draft.

RESULTS
A 39 page toolkit was produced for the use of any adult involved in the sibling’s life. This psychologically-informed toolkit provides guidance and support for a caring but potentially uninformed adult, such as a teacher, community leader, or member of the wider family, to be able to offer support to siblings. Guidance is included to help the adult talk about cancer, know what common issues siblings face, and to think about how to safely and appropriately undertake supportive work with this age group. The kit is associated with a website link, allowing toolkit users to download worksheets and resources for use with the sibling.

CONCLUSIONS
Early feedback on the published toolkit is highly positive, suggesting that the toolkit is considered ‘comprehensive’, ‘accessible’, and ‘practical’. We believe that this toolkit offers the potential to bridge some of the gap in service provision to siblings of a child with brain tumour.
QOL-26. SYTHESIS OF THE LITERATURE REVIEW ON PHYSICAL ACTIVITY IN PEDIATRIC NEURO-ONCOLOGY
Authors: YILDIZ Seda , TANRIVERDİ Müberra 
Published: June 2024

Abstract

BACKGROUND
Physical Activity plays a vital role in physical, social, phychological wellbeing of pediatric neuro-oncologic group. However, the researches investigating the effects of physical activity on this group have been sparse. The purpose of this study was to identify studies conducted about the effects of physical activity on this population.

METHODS
PRISMA statement conduct review was followed in electronic database of Journal of Neuro-oncology. Two authors (SY, MT) independently conducted systematic literature searches February 2024. Keywords/Mesh terms: “physical activity’’. Randomized controlled English clinical trials are included; Studies that were published as “review”, “protocol”, “books”, “news”, not reach full text and not related to physical activity excluded. After articles had been reached, used QUADAS-2 checklist for methodological quality.

RESULTS
29 articles were identified from 1721 articles, and 2 of them (published 2014-2023) were about pediatric age group. One of them was assessment (50%), while the other one was interventional study (50%). Assessment study was measured by using Bruininks-Osteretsky Test of Motor Performance, Second Edition (BOT-2) and online surveys. Interventional study analyzed the effects of aerobic exercises of three 90-minute sessions per week for 12 consecutive weeks primarily on cortical thickness, white matter, hippocampal volume and secondarily reaction time, accuracy across tests of attention, processing speed, and short term memory.

CONCLUSION
This abstract provides an initial scoping review of physical activity in pediatric neuro-oncology group. It demonstrates limited range of assessments, and interventions which highlights the lack of clinical evidence in this specific area. The results raise the need for further research in this field to help the development of physical activity guidelines for evaluation and physical activity methods in children with ataxia, and tumours expecially posterior fossa brain tumors. Investigation of different physical activity methods in a group of neuro-oncology children in need of support is major importance.
QOL-29. COGNITIVE DEVELOPMENT WITHIN TWO YEARS AFTER CRANIOSPINAL IRRADIATION IN CHILDREN TREATED FOR MEDULLOBLASTOMA: A COMPREHENSIVE ASSESSMENT USING AGE-APPROPRIATE SCALES
Authors: Satragno Camilla , Kieffer Virginie , Dufour Christelle , Martin Valentine , Sellami Noura , Lanfranchi Francesco , Bolle Stephanie 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma 5-years survival rates range from 50-95% across risk classes, underscoring the need to mitigate treatment-related neurocognitive deficits. This study evaluates cognitive outcomes within 2 years post-radiotherapy, considering treatment modalities and various influencing factors.

METHODS
We conducted a retrospective monocentric study on patients under 18 years old, treated at our hospital from 2007 to 2020, with histologically and molecularly confirmed medulloblastoma, who underwent craniospinal irradiation. Cognitive function was assessed within 24 months post-therapy using age-appropriate Wechsler scales to evaluate verbal comprehension, perceptual reasoning, working memory, and processing speed. Patients were categorized into two groups based on a threshold score of 80, indicating “neurocognitive normality” if scores were ≥80 in all domains or “neurocognitive deficient” if any domain scored &lt;80. Statistical analyses utilized SPSS for descriptive statistics and tests for categorical and continuous variables.

RESULTS
Among 100 selected patients, 91 completed the evaluations. The average age at diagnosis was 8.47 years, and at the onset of radiotherapy was 8.83 years. Forty-four patients (48%) scored ≥80 in all domains, indicating ‘neurocognitive normality,’ while 47 patients (52%) scored &lt;80 in at least one domain, classified as ‘neurocognitive deficient’. In the descriptive analysis identifying significant differences in the two groups, no significant differences were observed in age, WHO classification, risk class, or pre-surgical shunt. In contrast, significant differences emerged in posterior fossa syndrome frequency, kinetic (p=0.002) and static forms (p&lt;0.001) and in parental education level(p=0.025).

CONCLUSION
Our findings highlight the multifactorial nature of neurocognitive development in children with medulloblastoma within 2 years post-radiotherapy, identifying postoperative complications and the social environment as significant factors. Notably, specifics of radiotherapy and high-dose chemotherapy did not show a significant impact in this preliminary analysis. Future studies will further investigate the roles of various variables on neurocognitive outcomes, aiming to extend our understanding beyond two years post-radiotherapy.