bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEDB-50. Assessment of cellular radiosensitivity and DNA repair in medulloblastoma cell lines and patient-derivded xenograft slice cultures
Authors: Feyerabend Simon , Rieckmann Thorsten , Riepen Britta , Oetting Agnes , Christiansen Sabrina , Schoof Melanie , Hardt Annika , Köcher Sabrina , Neumann Julia , Schwarz Rudolf , Mack Norman , Schwalm Benjamin , Federico Aniello , Milde Till , Kool Marcel , Schüller Ulrich , Rutkowski Stefan , Petersen Cordula , Rothkamm Kai , Mynarek Martin , Struve Nina 
Published: June 2022

Abstract
Medulloblastoma (WHO grade 4) is the most common malignant brain tumor of childhood. Despite the high importance of radiotherapy for disease control, the mechanisms underlying response and resistance to radiotherapy are incompletely understood. Therefore, we assessed the radiosensitivity and DNA repair capacity of medulloblastoma cell lines in-vitro and of patient-derived xenograft (PDX) models ex-vivo. Cell survival after irradiation of seven medulloblastoma cell lines displaying different subgroups was assessed via colony formation assay (DAOY, UW228, UW473, SJMM4, ONS-76, HDMB-03, D283). The ONS-76 and the mouse SJMM4 cell line were the most radioresistant strains (surviving fraction after 6 Gy (SF6): 0.33 and 0.31, respectively), followed by UW473, UW 228 and DAOY cells (SF6 0.16-0.21). The non-WNT/non-SHH-activated cell lines HDMB-03 and D283 cells demonstrated profoundly higher cellular radiosensitivity (SF6 &lt;0.05). Analysis of residual (24h after irradiation) DNA double-strand breaks (DSB) as assessed by co-localized γH2AX/53BP1-foci demonstrated a significant correlation between DSB repair capacity and cellular survival. To use a more reliable pre-clinical model for medulloblastoma, we further examined DNA repair foci in ex-vivo irradiated slice cultures of PDX models MED-113 (SHH) and NCH2194 & HT028 (Gr. 3). Immunofluorescence analyses of frozen sections demonstrated non-hypoxic (pimonidazole-negative) and proliferating (EdU-positive) cells at the outer rim of the tumor slices. Two hours after irradiation all three PDX models showed a strong increase in 53BP1-foci, clearly indicating DNA damage induction. Most radiation-induced DSB were repaired after 24h. In a first radiosensitization approach, we treated the HT028 model with the PARP inhibitor olaparib (1µM ± 2Gy irradiation). Twenty-four hours after treatment the sample displayed a strong increase in the amount and size of 53BP1-foci, indicating compromised DNA repair. Further in-vitro and ex-vivo investigations with the aim to predict individual radiosensitivity and effective radiosensitization strategies are ongoing.
MEDB-51. Impact of residual tumor on outcomes in children and adolescents with medulloblastoma in the German HIT-cohort
Authors: Wolgast Stella , Obrecht Denise , Mynarek Martin , Bison Brigitte , Schwarz Rudolf , Pietsch Torsten , Kortmann Rolf-Dieter , Warmuth-Metz Monika , Rutkowski Stefan 
Published: June 2022

Abstract
INTRODUCTION: To date, a historical threshold of 1.5cm2 extent of resection (EOR) of the primary tumor is used for risk stratification in pediatric medulloblastoma (MB). METHODS: Data of n=348 patients with MB included into the German HIT-MED studies and registries from 2000-2017 were retrospectively analyzed. Kaplan-Meier statistics and Cox regressions were calculated to determine the influence of EOR, histological and molecular subtype, MYC/N-amplification and presence of metastases at first diagnosis on overall and progression-free survival (OS/PFS). ROC curves were calculated aiming at identifying a new EOR cut-off. RESULTS: Median age at diagnosis was 6.8 [0.1-20.5] years. After initial surgery, residual tumor (R) ≥1.5cm2 was present in 129/348 patients (37%). 57% presented with additional metastases. In most cases, classic histology was found (71%, DMB/MBEN: 20%, LC/AMB: 9%). Molecular subtype was nonWNT/nonSHH in 68% (Group 4: 37%, Group 3: 31%), WNT in 6% and SHH-activated types in 26% of evaluated cases (n=208). MYC/MYCN-amplification was present in 5 and 4%, respectively. 41/348 patients received additional surgery, resulting in 73% GTR (not reported: n=22). EOR had no significant impact on OS/PFS (GTR: 5y-OS/PFS 69.9±3.4/57.6±3.7%, STR: 5y-OS/PFS 71.4±4.1/56.2±4.5%, p=0.6/0.8; Cox: p=0.2/0.4; median follow-up 8.4 [0.1-18.0] years). ROC curves did not identify a significantly improved limit for outcome-relevant EOR cut-off. Analyses confirmed less favorable OS/PFS for patients with metastatic disease (p=0.04/p&lt;0.05), LC/AMB (p&lt;0.05/p&lt;0.05), Group 3 (p&lt;0.05/p&lt;0.05), and MYC-amplification (p&lt;0.05/p&lt;0.05). Cox regression confirmed an increased risk for Group 3 (OS: HR=4.74, p&lt;0.05, PFS: HR=2.90, p&lt;0.05) and M+ (PFS: HR=2.69, p&lt;0.05). DISCUSSION: No distinct influence of EOR &lt;/≥1.5cm2 on OS/PFS in pediatric MB was detected. The relevance of EOR and the historical limit of 1.5cm2 should be further investigated in distinct MB subtypes and in context of other risk factors.
MEDB-85. Transcriptional complexes as resistance drivers to BET inhibition
Authors: Boynton Adam , Lupien Leslie , Kumbhani Rushil , Gionet Gabrielle , Chacon Madison , Goodale Amy , Root David , Keshishian Hasmik , Robinson Margaret , Carr Steven , Bandopadhayay Pratiti 
Published: June 2022

Abstract
BET-bromodomain inhibition (BETi) is a promising therapeutic strategy to target MYC-driven cancers, including Group 3 medulloblastoma, a deadly childhood brain tumor. We have shown that BET inhibitors exhibit preclinical efficacy against MYC¬-amplified medulloblastoma, providing motivation to evaluate this drug class in early phase clinical trials. However, our work has also found that MYC-amplified medulloblastoma cells can acquire resistance to BETi, suggesting that curative responses for this disease will require combination therapy. To guide the development of such combination therapies, we have focused our efforts on elucidating the mechanisms through which medulloblastoma cells acquire resistance to BETi. We found that medulloblastoma cells can develop tolerance to BETi by reinstating the expression of cell-essential “rescue genes,” which include bHLH transcription factors, cell-cycle regulators, and anti-apoptosis genes. This transition to the resistant cell state is mediated through changes in chromatin structure including the upregulation of H3K4me3 promoters. Our preliminary results suggest that BETi-resistant cells maintain mRNA transcription and protein translation of important mediators of resistance. Importantly, we observe that BETi-resistant medulloblastoma cells are more dependent on specific protein complexes involved in transcriptional regulation. This project explores the mechanisms through which these transcriptional regulators help maintain transcription of rescue genes that drive BETi resistance and evaluates the potential of targeting these drivers of BETi resistance. These results will help guide the development of combination approaches to improve the efficacy of BETi for the treatment of MYC-driven medulloblastoma.
NFB-08. TRAM-01: A Phase 2 study of trametinib for pediatric patients with neurofibromatosis type 1 and plexiform neurofibromas
Authors: Kiaei Dorsa Sadat , Larouche Valérie , Décarie Jean-Claude , Tabori Uri , Hawkin Cynthia , Lippé Sarah , Ellezam Benjamin , Ospina Luis H , Théoret Yves , Desjardins Léandra , Métras Marie-Élaine , Sultan Serge , Cantin Édith , Routhier Marie-Ève , Mailloux Chantal , Bertrand Marie-Claude , Caru Maxime , Vairy Stéphanie , Legault Geneviève , Bouffet Éric , Ramaswamy Vijay , Coltin Hallie , Lafay-Cousin Lucie , Hukin Juliette , Erker Craig , Jabado Nada , Dehaes Mathieu , Perreault Sébastien 
Published: June 2022

Abstract
BACKGROUND: Plexiform neurofibromas (PN) are found in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PN but limited data has been reported on its efficacy within a clinical trial. METHODS: This ongoing multicenter phase II trial includes patients with pediatric low-grade glioma and PN. The primary objective for PN was to evaluate the overall response rate based on RECIST 1.1 criteria after daily oral trametinib administration for eighteen 28-day cycles. The volumes of PN were centrally quantified using a new semi-automatic 3D segmentation method. RESULTS: As of January 1, 2022, 45 patients with PN were enrolled in the study. Twenty-eight completed treatment and were available for analysis. For these patients, the median age was 11.4 years (range 0.7-19.8) including 16 males (57.1%). The majority did not receive prior systemic therapies (71.4%). The median volume of PN at baseline was 49.5 cm3 (range 2.6 to 469). Among the 28 patients, 25 (89.3%) completed 18 cycles as planned. One patient discontinued due to adverse reaction, one patient refused to continue treatment and one patient discontinued treatment based on physician decision. Median duration of treatment was 15.9 months (range 4.6 to 16.8). Median duration of follow-up was 29.7 months (range 17.7 to 38.1). A total of 32 PN were available for volumetric analysis. Using RECIST evaluation, the overall response rate was 24.1%. Volumetric assessment demonstrated an overall response rate of 60.7% and 62.5% of PN showed a decrease of more than 20% in volume. Median decrease in volume was -30% (range -93.5 to 14.3). Twenty-seven patients (93.1%) had durable response without progression (lasting ≥1 year). CONCLUSION: We report outcome and volumetric quantification of PN treated with trametinib within a large clinical trial. Based on the current results, trametinib appears effective and offers durable response.
NFB-18. Integration of single-nuclei RNA-sequencing and spatial transcriptomics to define the complex tumor microenvironment of NF1-associated plexiform neurofibroma and highly-aggressive malignant peripheral nerve sheath tumors
Authors: Amani Vladimir , Donson Andrew , Riemondy Kent , Fu Rui , Willard Nicholas , Gilani Ahmed , Norris Gregory , Griesinger Andrea , Harris Faith , Grimaldo Enrique , Foreman Nicholas 
Published: June 2022

Abstract
During formation of plexiform neurofibroma (PN), a complex tumor microenvironment (TME) develops, with recruitment of other cell types being critical for growth and progression. Approximately 10% of PN can undergo transformation into malignant peripheral nerve sheath tumors (MPNST) which is a substantial cause of mortality in older teenagers and young adults. We sought to apply single cell transcriptomic analysis to PN and MPNST to provide a clearer understanding of the complex TME and how this contributes to transformation and disease progression. Due to the cohesive cellularity of PN, single-cell RNA-sequencing is difficult and may result in a loss of detection of critical cellular subpopulations. Single-nuclei RNA-sequencing (snRNA-seq) is an alternative approach that can be applied to fibrous and bulk frozen tissues, such as NF1-associated PN. Our initial snRNA-seq analysis of PN indicates that PN have a TME comprised of a variety of cellular subpopulations, with the predominant fraction being fibroblast-like cells. snRNA-seq analysis of MPNST also shows high cellular heterogeneity, including distinct fibroblast-like subpopulations distinct from PN fibroblast clusters, increased proliferating populations and antigen presenting cells. MPNST cluster separately from PN, suggesting an evolutionary shift in tumor biology. We are currently validating our findings using Visium spatial transcriptomic profiling, allowing us to apply TME architectural context to the PN and MPNST subpopulations identified by snRNA-seq. These techniques provide a deeper understanding of the complex cellular heterogeneity of human PN and MPNST that has not previously been used to describe the TME of these tumors. The mechanisms of tumorigenesis and malignancy described can provide targets for novel therapies ultimately benefitting patients with these devastating tumors of childhood and early adulthood.
QOL-07. The importance of an onco-fertility program for pediatric neuro-oncology patients
Authors: IJgosse Irene , Looijenga Leendert , Klijn Aart , Oude-Ophuis Ralph , van den Heuvel Marry , Veening margreet , Bos Annelies , Broer Simone , van Leeuwen Jeanette , van der Steeg Lideke , van de Wetering Marianne 
Published: June 2022

Abstract
INTRODUCTION: In the Netherlands pediatric oncology care is centralized in one hospital since 2018. 600 new patients a year are seen with 100-120 new neuro-oncology (NO) patients. Of the NO patients 20-25% classify as high risk for infertility (HR) such as patients with medulloblastoma, ependymoma, ATRT and germinoma . An onco-fertility program was started navigated by a nurse-practitioner. The program runs with intense collaboration between the different specialties. All new patients are identified according to the international guidelines on fertility care. The fertility-risk is based on the CED score (cyclofosfamide equivalent dose) and radiotherapy dose. Since 2018 awareness was created by teaching sessions among colleagues, nursing staff, and parent association organizations. METHODS: All HR children are informed by the nurse-practitioner and can be referred for counseling to gynaecology for OTC (ovarian tissue cryopreservation) or urology for sperm cryopreservation or testicular biopsy. Monthly the onco-fertility working-group members discuss cases and research in the field. RESULTS: In 2019, 19% NO cases and in 2020 18% of cases were HR for infertility. In both years 36% of these cases had fertility preservation performed. In 2021, 22% cases HR were identified and in 55% preservation was performed. Reasons for not preserving fertility were diverse, varying from poor prognosis, or too ill to be included. CONCLUSION: Awareness of the fertility risk in NO patients who are HR is necessary. These patients need to be informed, and stratified for counseling and offered fertility preservation before start of their treatment. An active onco-fertility program helps to offer the best option for future fertility for these patients
QOL-16. A 6-year longitudinal study of neurocognition in children treated for a brain tumor
Authors: Bullens Kristien , Sleurs Charlotte , Van den Wyngaert Linde , Vandenabeele Karen , Vercruysse Trui , Claeys Laura , Prikken Sofie , Jacobs Sandra , Lemiere Jurgen 
Published: June 2022

Abstract
Long-term neurocognitive difficulties in children treated for a brain tumor are well documented and known to be affected by treatment. However, longitudinal studies of these neurocognitive difficulties are scarce. In the present study, we investigated the impact of radiotherapy (RT) on the evolution of neurocognition between different consecutive time points after diagnosis, and throughout treatment and survivorship. This study included 69 children diagnosed with a brain tumor at the University Hospitals Leuven who completed a comprehensive neuropsychological test battery (intelligence, memory, visuomotor functioning, and QoL) on at least three consecutive time points (2-year interval). Of all patients, 40 completed the test battery at 4 time points. The first assessment was conducted at the earliest possible moment after diagnosis and before the start of any adjuvant therapy. Mean age at diagnosis and first assessment were 7.75 and 7.92 years, respectively. The most common diagnoses were pilocytic astrocytoma (n=33) and medulloblastoma (n=11). 29.0% of the children received local RT and 15.9% received craniospinal RT. A repeated measures analysis with cranial irradiation (no, focal, craniospinal) as between-subjects factor and age at diagnosis as covariate demonstrated a significant interaction effect between time and type of irradiation for both overall intelligence (p=0.007) and QoL (p=0.006) for children with three and four assessments. Children who received craniospinal irradiation demonstrated a significant decline in overall intelligence and a significant worsening of QoL. For the non-irradiated group, an improvement of QoL was observed. For processing speed, a significant time effect was found for children with three and four assessments (p&lt;0.001), with a significant improvement for the overall group. The results of this longitudinal study demonstrated diverse longitudinal trajectories. Children who received craniospinal irradiation are most often confronted with intellectual decline and worsening of QoL.
QOL-25. Neurocognitive assessment of pediatric medulloblastoma treated by MBMET_MEYER trial. Censullo M.L1, Bertoluzzo G2, Fonte C1, Pavone R1, Guidi M1, Enrico G1, Gori C.G1, Martin R2, Teodori C2, Sardi I1 1Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s University Hospital, Florence, Italy2Psychology Unit, Meyer Children’s University Hospital, Florence, Italy
Authors: Censullo Maria Luigia , Bertoluzzo Giulia , Fonte Carla , Pavone Rossana , Guidi Milena , Giorgia Enrico , Gori Carlotta Gemma , Martin Rosanna , Teodori Caterina , Sardi Iacopo 
Published: June 2022

Abstract
The MBMET_MEYER is an interventistic monocentric trial of Meyer Children’s Hospital. The goal of this protocol is to reduce toxicity by use of protontherapy and reducing chemo-induced neurotoxicity by limited use of high dose chemotherapy. To date, a neurocognitive assessment is the standard in medulloblastomas but it is very difficult an assessment at baseline for clinical problems such as age, intracranial hypertension and immediate intervention. 10 neurocognitive assessments were reviewed in patients with medulloblastoma treated by MBMET_MEYER protocol: 3 anaplastic medulloblastoma M0 and 7 classic (2 M0, 1 M1, 1 M2, 3 M3). The median age was 10 years (range 5-18). All the patients were treated with surgery (gross total removal), 2 received chemotherapy and conventional radiotherapy, 8 chemotherapy and protontherapy and only 1 received autologos-hemotopoietic stem cell transplant for progression disease after induction chemotherapy. As for protocol, the neurocognitive assessment was defined by Weschler Intelligence Scales, fonemic and semantic fluency, immediate and deferred memory, tests for working memory, attention and visuo-spatial tests at baseline, after treatment and at the end of follow-up. For 3 patients it was not possible a baseline assessment for bad clinic conditions, 8 are still in treatment. From interviews and assessments emerged that 80% of patients had neurocognitive deficits: at baseline 5 had speed elaboration difficulties, 1 of these also presented verbal deficit, 1 showed problems in recalling verbal material and 1 in working memory; after two years from chemotherapy and radiotherapy 2 presented speed processig and working memory deficit. In conclusion, an assessment at baseline is very difficult for post-surgical problems but necessary to perform as soon. In this way, it is possible to evaluate the impact of the treatment on neurocognitive impairment. Further investigations are necessary to well understand the appropriate schedule of neurocognitive assessment of pediatric medulloblastoma.
QOL-28. Clinico-molecular correlates of quality of survival and neurocognitive outcomes in medulloblastoma; a meta-analysis of the SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 trials
Authors: Chevignard* Mathilde , Bull* Kim S , Holt James , Harrington Bertie , Castle Jemma , Heng Marie-Amelie , Kennedy Colin , Doz Francois , Lannering Birgitta , Rutkowski Stefan , Massimino Maura , Bailey Simon , Oyefiade Adeoye , Mabbott Donald , Clifford† Steven C , Hicks† Debbie 
Published: June 2022

Abstract
Determinants of survivorship outcomes are emerging from limited studies of medulloblastoma (MB) survivors. We undertook an integrated analysis of biological (tumour group, host genetics) and clinico-demographic features in patients treated on the SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 clinical trials with available quality of survival (QoS) data (n=218), to determine key correlates of survivorship, and their clinical potential. Treatment/demographic factors and molecular subgroup (MBWNT, MBSHH, MBGrp3, MBGrp4) were assessed against health status, behavioural functioning, and health-related quality of life (HrQoL). In DNA from HIT-SIOP-PNET4 (n=74), 39 candidate SNPs with known modifying effects on neurocognitive outcomes (e.g., involved in oxidative stress/inflammation) were genotyped and assessed against Wechsler Intelligence Scale (WISC) scores. As expected, MBSHH was associated with improved HrQoL, but subgroup did not associate further with QoS outcomes. SIOP-UKCCSG-PNET3 patients receiving chemotherapy before craniospinal irradiation (CSI) had significantly lower health status (p=0.021) and behavioural functioning (p&lt;0.016) compared to patients treated with CSI alone, and those treated on both arms (maintenance chemotherapy and hyperfractionated (36Gy) or standard (23.4Gy) CSI) of HIT-SIOP-PNET4. SIOP-UKCCSG-PNET3 patients receiving CSI-only had better HrQoL scores than those who received pre-CSI chemotherapy and both HIT-SIOP-PNET4 arms (p=0.004). Females reported worse HrQoL/behavioural functioning across both trials (p&lt;0.04). In HIT-SIOP-PNET4, longer intervals from diagnosis to CSI predicted worse HrQoL/health status (p&lt;0.05). Neither molecular group nor clinico-demographic features tested were associated with neurocognition. In contrast, 6 SNPs significantly associated with ≥1 WISC domain; 4/6 showed multiple associations and were independently prognostic; further associations were apparent at the gene/pathway level. This large, integrated and multi-disciplinary analysis of two independent trials cohorts has revealed multiple factors predictive of medulloblastoma survivorship including treatment (chemotherapy, time to CSI), tumour (molecular group) and host genetic factors. Assessment in further prospective series are required to determine their potential as a basis for modifications to disease management.
QOL-33. Adaptive behaviour of patients treated for malignant brain tumor in the first three years of life
Authors: Giaquinta Simonetta , Tremolada Marta , Rossi Bartolomeo , Biffi Alessandra , Viscardi Elisabetta 
Published: June 2022

Abstract
BACKGROUND: Adaptive behavior is defined as the effectiveness and degree to which an individual meets social/cultural standards of personal independence and social responsibility. Patients treated for brain tumor are at risk of alteration of adaptive behaviour that, with a reduced intellectual function, makes diagnosis of mental retard. OBJECTIVE: The aim of this study was to evaluate the adaptive behaviour of patients treated for malignant brain tumor in the first three years of life and the variables that may correlate with its alteration. PATIENTS AND METHODS: Twelve survivors of brain tumor diagnosed in the first three years of life followed in the Pediatric Hematology and Oncology Department of Padua between January 2000 and December 2020 were enrolled in this study. We defined the level of the adaptive behaviour by evaluation adaptive behavior questionnaire (ABAS II) completed by the parents. RESULTS: None of the patients shows a high level of adaptive behavior. Preliminary evidences suggest that, the level of adaptive behavior may be influenced by the sex, irradiation and time from the end of treatment. In details, females show a higher level of performance than males, patients not treated with radiotherapy performed better than patients irradiated and longer-term survivors have a better level of adaptive behaviour. CONCLUSIONS: This study confirms that patients treated for brain tumor show a lower level of adaptive behaviour than peers. The future objective is to assess adaptive behaviour at many times to recognize the problem early.