bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEDB-60. Medulloblastoma with extensive nodularity mimics cerebellar development and differentiates along the granular precursor lineage
Authors: Ghasemi David R , Okonechnikov Konstantin , Tirier Stephan , Rademacher Anne , Mallm Jan-Philipp , Ernst Kati , Rippe Karsten , Korshunov Andrey , Pfister Stefan M , Pajtler Kristian W 
Published: June 2022

Abstract
BACKGROUND: Medulloblastoma with extensive nodularity (MBEN) represents a rare type of cerebellar tumors of infancy comprising two histologically distinct components that differ in cell differentiation and mitotic activity. Whereas some children suffering from MBEN experience disease recurrence, MBEN can also spontaneously differentiate and discontinue to grow. The underlying mechanisms of this variable biological behavior may offer insight into how embryonal tumors develop. METHODS: Fresh frozen and FFPE tumor tissue from nine MBEN-patients was subjected to multi-omics characterization including bulk sequencing, microdissection followed by RNA sequencing, single nucleus RNA-sequencing using the 10X Genomics- and SMART Seq. V2-protocols and spatial transcriptomics via RNAscope. RESULTS: All cases were molecularly classified as Sonic Hedgehog (SHH)-MB, and harbored somatic mutations within the SHH-pathway. After quality control, a total of ~30.000 cells were subjected to downstream analysis. Several non-malignant cell types, such as glial cells, were identified. In accordance with previous studies, we found only sparse immune infiltration. Unsupervised clustering identified cell clusters that differed in differentiation state and represented a continuum from embryonal-like cells with SHH-upregulation over intermediate cell states, to neuronal-like, postmitotic cells. Mapping to a single nucleus sequencing atlas of cerebellar development indicated that tumor cells reflected various stages of normally developing cerebellar granular precursors. Interestingly, one cluster of malignant cells with tumor-specific copy number alterations showed both transcriptomic features of astrocytes and embryonal cells. Using spatial transcriptomics, we were able to correlate different clusters of MBEN cells with distinct histologic MBEN compartments, with astrocyte-like tumor cells being located in the internodular compartment and in close proximity to mitotically active cancer cells. CONCLUSION: MBEN is formed by a continuum of malignant cell differentiation along the granular precursor lineage, with a subset of cells developing into cells that may represent tumor astrocytes. This differentiation process is reflected in the bicompartmental structure of MBEN.
MEDB-66. Investigating intra-tumoral heterogeneity of extrachromosomal DNA in SHH medulloblastoma
Authors: Chapman Owen , Sridhar Sunita , Wechsler-Reya Robert J , Chavez Lukas , Mesirov Jill P 
Published: June 2022

Abstract
Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive cancers, including medulloblastoma (MB), the most common malignant pediatric brain tumor. Our study’s aim is to better understand how ecDNA containing cells can potentiate malignant growth. EcDNA’s role in the development of treatment resistance and association with poor outcomes is hypothesized to arise from its contribution to intra-tumoral heterogeneity and its potential to promote oncogene dependency switching. To analyze the intra-tumoral distribution of ecDNA, we have now simultaneously analyzed the accessible chromatin and gene expression in single cells of a SHH medulloblastoma (MB) patient using multiome single-cell ATAC-seq and gene expression (10X Genomics). Whole genome sequencing (WGS) of this tumor previously revealed a heterozygous somatic TP53 mutation and two distinct ecDNAs: a 3.2Mbp amplicon comprising 3 regions of chr1 and another 4.5Mbp amplicon comprising 23 segments originating from chr7 and chr17. We then used multimodal analysis to describe the tumor cell types, gene expression, variant signatures and estimate ecDNA copy number in the medulloblastoma tumor sample. We identified 12 distinct clusters in the human tumor, 5 of which were determined to be normal non-tumor [OSC1] cells, as identified by specific cell type markers, and 7 of which were determined to be tumor cells. Enrichment of ecDNA was restricted to only one of these tumor clusters. In addition, we also performed the same multiome single-cell analyses in an orthotopic xenograft mouse model derived from this SHH MB patient tumor. In the PDX, 17 clusters were identified, all of which were determined to be tumor cells and enriched for ecDNA. Our preliminary results indicate that tumor cells with ecDNA in the human tumor (particularly the ecDNA enriched cluster) almost exclusively account for [OSC2] the cells in the corresponding PDX, emphasizing the aggressiveness of ecDNA containing cells.
MEDB-76. Evaluating the B7-H3 checkpoint in Medulloblastoma
Authors: Moziak Kirsten , Picarda Elodie , Perez Natalia Muñoz , Galbo Phillip , Zheng Deyou , Zang Xingxing , Martin Allison 
Published: June 2022

Abstract
BACKGROUND: There is currently no curative therapy for recurrent/refractory MB. Novel approaches to MB include immunotherapy, such as targeting the immune checkpoint molecule B7-H3. B7-H3 is implicated in tumor metastasis and is highly expressed in MB. This study explores the effects of genetically knocking down B7-H3 in a murine model of recurrent/refractory medulloblastoma. METHODS: Murine MB cells were transduced with a CRISPR/Cas9 lentivirus to create a B7-H3 knockout. Knockout population was sorted twice via FACS by the AECOM flow cytometry CORE and confirmed by western blot and flow cytometry. Three healthy clones were used in subsequent studies, and compared to the wild type and the scramble control. IncuCyte live imaging technology was used to evaluate spheroid growth. Matrigel Boyden chambers were used to evaluate migration. Bulk RNA-seq was performed by the Yale University Core. RESULTS: B7-H3 knockout was successful in the murine MB model. Morphological differences were noted in the B7-H3 knockout cells. Spheroid formation assays show one of the clones with statistically slower growth kinetics compared to controls. Migration results are pending. RNA seq revealed similar clustering amongst knockouts, separate from controls with an enrichment in genes of morphologic development, WNT signaling and amoeboid migration. CONCLUSIONS: The morphologic changes in the B7-H3 knockouts suggest a potential growth differential. Although in vitro growth assays have shown mixed results regarding the effect of knocking out B7-H3 in spheroid formation, B7-H3 has been more directly implicated in migration and immune signaling. If migration is impaired, this will suggest that B7-H3 enhances malignant and metastatic potential in MB. Functional in vivo immune studies in syngeneic mice will investigate immune mediated effects of B7-H3 knockout in this tumor. If our studies support a role for B7-H3 in the development of MB, it may have important clinical implications, particularly for relapsed patients.
MEDB-80. CDK8 promotes stemness of MYC-driven medulloblastoma
Authors: Wang Dong , Veo Bethany , Pierce Angela , Venkataraman Sujatha , Vibhakar Rajeev 
Published: June 2022

Abstract
Cyclin-dependent kinase 8 (CDK8) belongs to the transcription-related cyclin dependent protein kinase family. CDK8 and cyclin C associate with the mediator complex to regulate gene transcription. Although CDK8 has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in medulloblastoma remains largely unknown. Here, we demonstrate how CDK8 plays an essential role in maintaining stemness and tumorigenicity in medulloblastoma stem cell. CDK8 inhibition suppresses stem cell associated signaling in medulloblastoma cells and inhibits tumor cell self-renewal. Additionally, CDK8 is amplified in MYC-driven medulloblastoma, is positively correlated with c-MYC expression in human medulloblastoma specimens and associates with poor survival in patients. Using cut&run assay, we found CDK8 associates with MED1 to activate transcription of MYC target genes. CDK8 attributes to MYC-driven transcriptional programs mediating DNA repair. Pharmaceutic inhibitors and genetic depletion result in cessation of tumor growth in xenograft mouse models and increase in apoptosis and DNA damage. Collectively, our studies establish the selective inhibition of CDK8 inhibition as a viable therapeutic strategy in MYC-driven medulloblastoma.
MEDB-88. BAF60C/SMARCD3-mediated novel neurodevelopmental epigenomic program promotes metastatic dissemination in medulloblastoma
Authors: Zou Han , Poore Bradley , Brown Emily , Hu Zhongliang , Li Xuejun , Pollack Ian , Friedlander Robert , Hainer Sarah , Taylor Michael , Hu Baoli 
Published: June 2022

Abstract
Normal brain development relies on precise genetic and epigenetic spatiotemporal regulation of gene expression. How dysregulation of neurodevelopment relates to medulloblastoma, the most common pediatric brain tumor, remains elusive. Here, we uncovered a novel neurodevelopmental epigenomic program that regulates Purkinje cell migration in developing cerebellum is hijacked to induce tumor metastatic dissemination in medulloblastoma. Integrating publicly available datasets with our in-house data, unsupervised analyses revealed that BAF60C/SMARCD3, a subunit of SWI/SNF chromatin remodeling complex, promotes tumor cell migration in vitro and metastasis in vivo. Based on analyzing the single-cell RNAseq data of cerebellum developmental trajectory in mice and humans, aligning with the medulloblastoma patients’ datasets, we found that BAF60C/SMARCD3 regulated DAB1-mediated Reelin signaling is involved in Purkinje cell positioning during cerebellum development and medulloblastoma metastasis by orchestrating the cis-regulatory elements (CREs) at the DAB1 gene locus. Analysis of spatiotemporal gene expression and chromatin architecture in the human and mouse cerebellum demonstrated that transcription activity of the BAF60C/SMARCD3-DAB1 circuit is downregulated in a mature state of cerebellar development, however, is upregulated in metastatic medulloblastoma. We further identified that a core set of transcription factors, enhancer of zeste homolog 2 (EZH2) and nuclear factor I X (NFIX), bi-directionally control BAF60C/SMARCD3 transcriptional regulation by coordinating with the CREs at the BAF60C/SMARCD3 gene locus to form a chromatin hub during developing cerebellar development and medulloblastoma metastatic dissemination. Highly expressed BAF60C/SMARCD3 activates the Reelin/DAB1 signaling pathway downstream Src kinase, which was validated in the pair-wised primary and metastatic tumors from medulloblastoma patients. Preclinical medulloblastoma mouse models revealed that inhibiting Src activity reduces tumor cell migration and metastatic dissemination at a lower and safe dose. Together, these data deepen our understanding of how the developmental program influences disease progression and provide an opportunity for the development of therapeutics for this devastating brain cancer in children.
NFB-17. "Optic Pathway findings in children with Neurofibromatosis type-1 (NF-1)
Authors: Roka Kleoniki , Kokkinou Eleftheria , Gavra Maria , Tsina Efthymia , Mparka Konstantina , Zarafonitis Georgios , Kosma Konstantina , Makrythanasis Periklis , Tzetis Maria , Chasiotou Maria , Kanaka-Gantenbein Christina , Pons Roser , Kattamis Antonis 
Published: June 2022

Abstract
BACKGROUND/OBJECTIVES:Optic-pathway-glioma(OPG) represents the most common central-nervous tumor in children with neurofibromatosis type-1(NF1), occurring at an incidence of 15-20%. It is estimated that 1/3 of NF1 patients(pts) with OPG will need treatment. DESIGN-METHODS:We performed a retrospective-review of all NF1-pts examined in the First Hellenic Multidisciplinary-Clinic – Center of Expertise for Neurocutaneous-disorders. Gender, age, MRI-radiological and ophthalmological findings, presence of OPG, management and outcome were analyzed. RESULTS:Since the establishment of the Clinic in 2016, 198pts with clinical diagnosis of NF1 based on NIH1988-criteria were evaluated and of them, 165(73 females, median age:5.5y, range:0.3-17.1y), who had imaging studies were included in this analysis. Eighty three pts(50.3%) had NF1-positive genetic-testing and 45NF1-family-history(27.3%). Imaging-findings from optic pathway were found in 55/165pts(28females). Percentage of pts with findings were 51.7% for &lt;3y, 45.4% for 3-5y, 34.7% for 5-10y and 8.5% for &gt;10y, respectively. The median age of their first brain-MRI imaging was 2.82y. Upon 1stMRI-imaging, 70.9% presented thickness of the optic nerves(ON)(25,4%bilateral, 20% optic chiasm,18.1% right ON, 10.0% left ON), 14.5%ON-tortuosity, 38.1%OPG(43,5% in the optic-chiasm) and 34.5% contrast enhancement. Of notice, 14pts presented an OPG after a median follow-up time of 1.79y. According to LGG2004-protocol indications for treatment, only 15/55pts had to be treated(27,2%, 5pts with family history, 33.3% between 5-10y). Severe vision-loss with need for immediate start of treatment upon 1stMRI imaging was found in 4pts, of whom 75% had family-history and first evaluation after the 5th year of age. Of notice, only 2pts&lt;3y had to receive treatment, one with family-history and one with symptoms(diencephalic syndrome). CONCLUSIONS: Pts with NF1 should be followed by a multidisciplinary-team. Management should be individualized and imaging-studies can be limited to patients at high-risk. Positive family-history may be a negative prognostic factor for OP lesions.
QOL-02. Paediatric medical traumatic stress in children with cancer and their parents: Differences in levels of posttraumatic stress symptoms
Authors: Klašnja Sandra , Hausmeister Ivana Kreft , Kavčič Marko , Masten Robert 
Published: June 2022

Abstract
Paediatric medical traumatic stress (PMTS) is a set of children’s and their parents’ psychological and physiological responses to pain, injury, serious illnesses, and other experiences with the medical environment. Paediatric cancer patients have the highest prevalence of PMTS as the illness involves a set of stressors that trigger many negative psychological reactions. Posttraumatic stress symptoms (PTSS) are one of the most common psychopathologies among cancer patients. We examined the incidence of PMTS in children with cancer and their parents due to coping with a serious illness and treatment complications. We analysed the following risk factors for PTSS: selected groups of individuals, medical interventions, complications, and treatment modalities. The study involved 183 parents of 133 children and 63 children and adolescents who were treated between 2009 and 2019 at Clinical Department of Paediatric Haematology and Oncology of Paediatric Clinic in Ljubljana. We collected the data using The Intensity of treatment rating scale 2.0 [IRT-2], PTSD checklist for Children/Parent [PCL-C/PR], The PTSD Checklist for DSM-5 [PCL-5] and The Child PTSD Symptoms Scale for DSM-5 [CPSS-5]. PMTS is frequently present in both, children and their parents, regardless of the cancer type, treatment duration, treatment outcome, and child’s age. Mothers, patients with relapse, patients who were diagnosed after age 5, patients with more intensive treatment, and parents of the latter are at higher risk for PMTS occurrence. Additionally, we found a decreasing trend of traumatic responses after five or more years post cancer diagnosis and that parents are more traumatized than children. Our findings will contribute to the systematic prevention of PMTS and medical trauma and to endeavour to use trauma-informed care.
QOL-12. Relaxation technique of imagery based story telling reduces manifestation of anxiety in children and adolescents undergoing brain tumor surgery
Authors: Goßler Christina , Schweitzer Tilmann , Krauß Jürgen , Andres Oliver , Rueckriegel Stefan Mark 
Published: June 2022

Abstract
Children and adolescents undergoing surgical resection of brain tumors are prone to marked psychologic burden. Especially fear of surgery and its consequences like pain or neurologic sequelae is an important issue. Techniques of relaxation might reduce the intensity of the experienced anxiety and therefore might improve quality of life. In this study, we aimed at determining the effect of a standardized imagery story telling on experienced anxiety as quantified by the questionaire KAT III and cardiac frequency (CF) before and after intervention at two time points (before and after surgery). 12 patients (age: 6-17 years) undergoing brain tumor resection were included in the study. KAT III-scores and CF were determined and compared before and after interventions using a dependend t-test. Mean KAT III-score before first intervention was 0.23 (SD: 0.23), while it was 0.15 (SD: 0.21) after (p = 0.11). Mean KAT III-score before second intervention was 0.11 (SD: 0.13), after: 0.05 (SD: 0.9), p = 0.07. Mean CF before first intervention was 77.1 (SD: 10.3), after: 68,36 (SD: 6.8), p = 0.003. Mean CF before second intervention was 71.67 (SD: 9.57), after: 65 (SD: 8.72), p = 0.003. CF was significantly lower post-interventionally after the first and the second intervention. KAT III-score showed a trend to be lower post-interventionally after the second intervention. Hence, our study points at an efficacy of the deployed relaxation technique of imagery story telling in children and adolescents undergoing brain tumor surgery, although it was limited by a small patient number. Further studies with larger patient numbers and a comparison of randomized intervention vs. non-intervention groups are warranted.
QOL-21. Language development and outcomes in pediatric brain tumor
Authors: Janke Kelly , Paltin Iris , Schofield Hannah , Sy Megan , Kearns Zoe 
Published: June 2022

Abstract
RATIONALE: Pediatric brain tumor (PBT) survivors are at risk for speech (e.g., articulation, prosody, fluency) and language (e.g., vocabulary, grammar, narratives, pragmatics) difficulties, though group outcomes vary with study design and individual risk factors (Hodges et al 2020). This study characterizes language functioning for clinically referred PBT survivors diagnosed in early childhood, a time of rapid language development and vulnerability. METHODS: Participants were 98 PBT patients (56 supratentorial) diagnosed by age 6 (M = 43.8 months, SD 24.4) who received tumor-directed intervention (surgery, chemotherapy, and/or radiation). Age at neuropsychological evaluation (2019 – 2022) was 2-19 years (M = 9.1, SD 4.1). Patients were 56% male, 73.5% White, and fluent English speakers. Verbal IQ, naming, working memory, fluency, comprehension, syntactic and phonological processing, and parent-reported functional communication outcomes were assessed. Rates of weak performance (1 SD&lt;Mean) were compared to the expected base rate of 16%. RESULTS: Group means significantly diverged from age-expected performance in all domains except fluency. IQ correlated with most language measures, age at diagnosis (r .280, p .010), and time from diagnosis (r -.276, p .012). Weakness was identified on at least 1 verbal subtests for 71.4% of the full sample and most (57%) patients with IQ&gt;84. Patients with NF1 (n=15) or treatment-related hearing concerns had lower reported functional communication. Naming difficulty was associated with supratentorial tumors; there were no other significant differences by tumor type or location. While functional communication correlated with several measures, weaknesses on performance-based and parent-report measures only corresponded for 44.6% of the sample. CONCLUSIONS: Language weaknesses are prevalent following early childhood PBT diagnosis. IQ and functional communication measures are useful indicators of risk, but more detailed and higher-level language measures are needed, particularly for cognitively intact patients. Additional implications and research needs will be discussed.
QOL-31. A psychosocial support program for young adult childhood cancer survivors in Austria: a qualitative evaluation study
Authors: Pletschko Thomas , Krottendorfer Kerstin , Schlifelner Juliana , Schwarzinger Agathe , Fohn-Erhold Verena , Weiler-Wichtl Liesa , Kienesberger Anita , Leiss Ulrike 
Published: June 2022

Abstract
PURPOSE: Many adolescents and young adult (AYAs) childhood cancer survivors face disease- or therapy-related late-effects, which limit their participation in various areas of daily life. AYAs are often left alone in our health care system and many worry about their ability to cope with long-term sequelae and some are even lost to follow up. Therefore, in the present study a targeted aftercare program was developed and evaluated with the goal of facilitating three important “life skills”: (1) self-perception, (2) social interaction and conflict management as well as (3) self-conscious communication of support needs. METHODS: A total of n=13 participants (19.2-30.2 years, mean age: 22.8 years) completed a three-day aftercare seminar, at the end of which each participant wrote a reflection letter (“letter to my future self”), elaborating on observed effects of the seminar, applicability of the given information in daily life and the direct impact of the seminar on their individual circumstances. The reflection letters were analyzed using qualitative content analysis. RESULTS: All target life skills were mentioned in the reflection letters. The participants reported individual benefits from the program especially with respect to self-perception and self-confidence, giving and taking feedback, and acceptance of personal strengths and weaknesses. Moreover, the feeling of “not being alone” was associated with the survivors’ experience of emotional and social support. CONCLUSIONS: This evaluation highlights the potential of a one weekend aftercare seminar to address important life skills that are known to positively influence health behavior in AYAs. The detailed description of the seminar can serve as a basis for making this kind of aftercare accessible for other people in similar circumstances.
SURG-08. 5-Aminolevulinic acid (5-ALA)-guided resection of pediatric brain tumors
Authors: Schwake Michael , Bruns Ann-Katrn , Müther Michael , Stummer Walter 
Published: June 2022

Abstract
BACKGROUND: 5-Aminolevulinic acid (5-ALA)-guided resection of gliomas in adults enables better differentiation between tumor and normal brain, allowing a higher degree of resection, and improved patient outcomes. In recent years, several reports have emerged regarding the use of 5-ALA in other brain tumor entities, including pediatric brains tumors. Since gross total resection (GTR) of many brain tumors in children is crucial, the role of 5-ALA-guided resection requires elucidation. METHODS: A systematic literature review of EMBASE and MEDLINE/PubMed databases revealed 20 eligible publications encompassing 186 5-ALA-guided operations on pediatric brain tumors. To reduce bias, publications were revised independently by two authors. RESULTS: 5-ALA-guided resection enabled the surgeons to identify the tumor more easily and was considered helpful mainly in cases of glioblastoma (GBM, 21/27, 78%), anaplastic ependymoma WHO grade III (10/14, 71%), and anaplastic astrocytoma (4/6, 67%). In contrast, cases of pilocytic astrocytomas (PAs) and medulloblastomas 5-ALA-guided surgery did not show consistent fluorescent signals and 5-ALA was considered helpful only in 12% and 22% of cases, respectively. Accumulation of fluorescent porphyrins seems to depend on WHO tumor grading. In case fluorescence signal was considered helpful, it was associated to a greater degree of resection. One study showed an association between visible fluoresce signal and concentration of protopophyrin IX (PPIX) concentration. A threshold of 4μg/ml was required in order to visualize the fluorescence signal. The rate of adverse events related to 5-ALA was negligible, especially new postoperative sequelae. CONCLUSION: 5-ALA could play a role in resection of malignant, contrast enhancing, supratentorial pediatric brain tumors. At present, we are conducting a prospective phase I-II multicenter clinical trial to evaluate side effects and feasibility of 5-ALA guided surgery