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Abstract Medulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically heterogenous. The application of omics technologies—mainly studying nucleic acids—has significantly improved MB classification and stratification, but treatment options are still unsatisfactory. The proteome and their N-glycans hold the potential to discover clinically relevant phenotypes and targetable pathways. We compile a harmonized proteome dataset of 167 MBs and integrate findings with DNA methylome, transcriptome and N-glycome data. We show six proteome MB subtypes, that can be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pG3myc), and synapses/immunological processes (pSHHs, pG3 and pG4). Multiomic analysis reveals different conservation levels of proteome features across MB subtypes at the DNA methylome level. Aggressive pGroup3myc MBs and favorable pWNT MBs are most similar in cluster hierarchies concerning overall proteome patterns but show different protein abundances of the vincristine resistance-associated multiprotein complex TriC/CCT and of N-glycan turnover-associated factors. The N-glycome reflects proteome subtypes and complex-bisecting N-glycans characterize pGroup3myc tumors. Our results shed light on targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures.

Inequalities in research and innovations affect childhood cancer survival across Europe. Vilnius University Hospital Santaros Klinikos (VULSK, the coordinator) and eight research-intensive institutions from seven European countries implemented the TREL project (Twinning in Research and Education to improve survival in childhood solid tumours in Lithuania) supported by the Horizon 2020 Widening programme. TREL aimed to enhance translational, clinical, and survivorship research in paediatric CNS, neuroblastoma, and renal tumours to improve future treatment outcomes in Lithuania. From January 2021 to December 2023, 49 VULSK professionals and 55 peers from partner institutions collaborated in this twinning program. Achievements after three years were: nine educational events, the initiation of basic and clinical research on fertility preservation, ten VULSK researchers joining international research groups, six signed agreements to participate in international academic clinical trials and the implementation of the European Survivorship Passport. Thirty patients received individual treatment recommendations following multidisciplinary discussions with experts from partner institutions. Twenty-five rare genetic variants were classified by the twinning bioinformatician teams with direct consequences on patient management. In conclusion, coordination of the Horizon 2020 project enhanced VULKS’s research capacities, networking channels and attractiveness for industry and academia-initiated innovative actions that will improve survival rates in the long run.

Tumours of the central nervous system (CNS) represent the most common group of solid tumours in children and adolescents up to the age of 18 years. They comprise several biological entities, subgroups, and subtypes. These subtypes and additional factors, including age at diagnosis, location, stage, or genetic characteristics of the tumours result in a very heterogeneous spectrum of treatment-relevant strata for risk-adapted multimodal treatment recommendations, clinical courses, and long-term outcomes. Multidisciplinary teams with highly experienced members are needed to treat these children and adolescents to achieve the best possible outcome in the short and long-term. This is particularly important for the new CNS tumour entities with no established standard of care. On behalf of the Brain Tumour Group of the European Society for Paediatric Oncology, we summarize the key statements of the involved disciplines that need to cooperate in the diagnosis and risk-adapted treatment of children with CNS tumours: neuroradiology, neurosurgery, neuropathology, radiotherapy, endocrinology, neuro-ophthalmology, and quality of survival professionals, covering what should be considered standard clinical practice for diagnostic assessments, treatment modalities, and follow-up of children with CNS-tumours.

Abstract Pediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and biological as well as clinical characteristics have not been addressed specifically. To gain insights into tumorigenesis and molecular profiles of these tumors, and to ultimately suggest alternative treatment options, we generated a genetically engineered mouse model by breeding hGFAP-cre::Trp53 Fl/Fl ::lsl-MYCN mice. All mice developed aggressive forebrain tumors early in their lifetime that mimic human HGG-MYCN regarding histology, DNA methylation, and gene expression. Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from.

Abstract Purpose In Germany, children diagnosed with cancer survive their initial disease in more than 80%, and the majority will become long‐term survivors. Around the age of 18, survivors are transferred to adult healthcare. The transition can be a critical period in the process of care at which many childhood cancer survivors discontinue to participate in regular follow‐up care. Hence, the objective of the paper was to explore (a) survivors' attitudes towards pediatric follow‐up care and (b) their concerns regarding the transition process to draw conclusions for optimizing pediatric care and transition processes. Methods We conducted semi‐structured interviews with 21 adolescent childhood cancer survivors between the ages of 14 and 20. The survivors were recruited via a pediatric oncology department of a university hospital in Germany. Based on the principles of qualitative content analysis, a deductive‐inductive method according to Kuckartz was applied. Results Based on the interview guide and derived from the exploratory research questions, two key categories were generated: (a) Survivors' attitudes towards pediatric follow‐up care, which encompasses all formal and emotional aspects of survivors regarding follow‐up care, and (b) their concerns regarding transition from pediatric to adult healthcare, where hindering and facilitating factors for a successful transition occur. Our results show high satisfaction among survivors with follow‐up care. Nevertheless, they wish to be more integrated into processes and the organization of their follow‐up care. Most adolescent survivors do not feel ready for transition. Conclusion The integration of survivors into the organization processes and routines, and the promotion of emotional detachment from pediatric health care professionals (HCPs) are important to reduce concerns and uncertainties of adolescent survivors regarding the transition process and to promote subjective readiness for transition. To gain confidence in the adult healthcare, it is crucial to provide tailored education depending on individual requirements and needs and to build trusting relationships between survivors and adult HCPs.

ObjectiveTo describe the situation of childhood cancer survivors and their parents before and one year after a family-oriented rehabilitation program (FOR) and to identify factors influencing reintegration.MethodsWe included parents of children diagnosed with leukemia or central nervous system tumor. We assessed parental functioning using the functioning subscale of the Ulm Quality of Life Inventory for Parents (ULQIE) and children's school/kindergarten related quality of life (parental assessment, subscale KINDL-R). Descriptive analyses, group comparisons and multiple regression analyses on data of 285 parents of 174 children diagnosed with leukemia or central nervous system tumor.ResultsParents reported changes in their work situation (e.g., reduction of working hours) due to their child's diagnosis. Parental functioning increased significantly over time. Children's leukemia diagnosis and shorter time since the end of treatment were associated with higher functioning in parents one year after FOR. Parents reported difficulties in the child's work pace, concentration, stress resilience and empathy. The school/kindergarten-related quality of life (QoL) of the children was lower than in the general population. One year after FOR, most children reintegrated fully in school/kindergarten, partly with support (e.g., integration assistant). No significant predictors for children's reintegration were identified.DiscussionParents and children experience major changes in their work/school/kindergarten life. One year after FOR most parents reported a reintegration of their children, however the children's school/kindergarten-related QoL remained below average compared to norm values. Even after rehabilitation families of childhood cancer survivors might benefit from psychosocial and practical support offers to support families with the reintegration into work/school/kindergarten.

Abstract To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups—WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient’s mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations’ impact on carcinogenesis and cancer treatment.

Abstract Background Cancer metabolism influences multiple aspects of tumorigenesis and causes diversity across malignancies. Although comprehensive research has extended our knowledge of molecular subgroups in medulloblastoma (MB), discrete analysis of metabolic heterogeneity is currently lacking. This study seeks to improve our understanding of metabolic phenotypes in MB and their impact on patients’ outcomes. Methods Data from four independent MB cohorts encompassing 1,288 patients were analysed. We explored metabolic characteristics of 902 patients (ICGC and MAGIC cohorts) on bulk RNA level. Moreover, data from 491 patients (ICGC cohort) were searched for DNA alterations in genes regulating cell metabolism. To determine the role of intratumoral metabolic differences, we examined single-cell RNA-sequencing (scRNA-seq) data from 34 additional patients. Findings on metabolic heterogeneity were correlated to clinical data. Results Established MB groups exhibit substantial differences in metabolic gene expression. By employing unsupervised analyses, we identified three clusters of group 3 and 4 samples with distinct metabolic features in ICGC and MAGIC cohorts. Analysis of scRNA-seq data confirmed our results of intertumoral heterogeneity underlying the according differences in metabolic gene expression. On DNA level, we discovered clear associations between altered regulatory genes involved in MB development and lipid metabolism. Additionally, we determined the prognostic value of metabolic gene expression in MB and showed that expression of genes involved in metabolism of inositol phosphates and nucleotides correlates with patient survival. Conclusion Our research underlines the biological and clinical relevance of metabolic alterations in MB. Thus, distinct metabolic signatures presented here might be the first step towards future metabolism-targeted therapeutic options. Graphical Abstract

Abstract Background This study examined care needs and utilisation of psychosocial support services among parents of children who had received specialist paediatric palliative care, as well as the relationship between need fulfilment and grief. Possible differences between parents of children who died of cancer versus a non-cancer disease were explored. Methods This exploratory study, conducted in two specialist paediatric palliative care facilities, included parents who had lost a child within a period of 0.5 to 8 years before this investigation. From the bereavement perspective, parents reported their needs during paediatric palliative care using the Family Inventory of Needs – Peadiatric II (FIN-PED II). Utilisation of psychosocial support services during paediatric palliative care and after the child’s death, as well as potential barriers to accessing services were assessed. Grief symptoms were measured using the Inventory of Complicated Grief - German Version (ICG-D). Results Overall, 56 of 157 approached parents participated in the study. Mean time interval after the child’s death was 3.2 years. Of the 17 FIN-PED II needs, 13 needs were reported to be very/extremely important to more than 75% of the parents each. Highest ranked needs related to asking questions at any time (100%), sincere care for the child (100%), and information about changes in the child’s condition (98%). The highest ranked unmet needs related to hope (61%), interactions with siblings (41–42%), and trust in the health care system (39%). Comparisons showed no significant differences between parents whose child died of cancer (n = 18) versus a non-cancer disease (n = 38). During paediatric palliative care, 61% of the parents had accessed at least one psychosocial support service and 84% had done so after the child’s death. The most prominent barriers for accessing services were sufficient informal support (38%), no subjective need (23%), and lack of time (20%). Overall, 52% of the parents showed noticeable symptoms for complicated grief (ICG-D > 25). A higher level of grief symptoms significantly correlated with a lower fulfilment of the need to say goodbye to the child (p = .042) with a medium correlational effect. Conclusions Our findings may help to guide health care professionals in their assessment of parental needs and provision of support to parents during paediatric palliative care.

Sarcomas are morphologically heterogeneous tumours rendering their classification challenging. Here the authors developed a classifier using DNA methylation data from several soft tissue and bone sarcoma subtypes, which has the potential to improve classification for research and clinical purposes.

Introduction Patients and families affected by paediatric cancer experience psychosocial burden not only during active treatment but also during follow-up care. Use of health services during follow-up treatment should be organised according to patients’ and family members’ needs with regard to their physical and mental situation. This study aims (1) at analysing healthcare use (medical and psychosocial) and associated factors in follow-up care of paediatric cancer patients and (2) at investigating the psychosocial situation and support needs of children and their families during follow-up care. Based on the results, recommendations for healthcare planning and for the development of new and the optimisation of existing support offers will be derived.Methods and analysis We will conduct a prospective observational study using a naturalistic explorative design with quantitative and qualitative methods. Paediatric cancer patients in follow-up care, their parents and siblings will be invited to fill out a questionnaire at three measurement points (baseline, 6 months follow-up, 12 months follow-up; target n=252 complete data sets over all measurement points). Additionally, parents will be interviewed using a semistructured interview guideline (target n=15–20) at baseline. Quantitative data will be analysed using descriptive statistics, linear mixed models and regression models. Moreover, explorative analyses will be conducted. Qualitative data will be analysed using qualitative content analyses.Ethics and dissemination The study was approved by the Local Psychological Ethics Committee (LPEK-0281). Our findings will be published in scientific, peer-reviewed journals and presented to clinicians and researchers on conferences. To assure that results will be available to affected patients and families, a lay summary will be written and disseminated using several ways (upload on the homepage of the research group, upload on the homepage of the psychosocial working group in the Society for Paediatric Oncology/Haematology in Germany, sending to relevant patient organisations).Trial registration number DRKS00025289.

Gorlin syndrome is a genetic condition associated with the occurrence of SHH activated medulloblastoma, basal cell carcinoma, macrocephaly and other congenital anomalies. It is caused by heterozygous pathogenic variants in PTCH1 or SUFU. In this study we included 16 patients from the HIT2000, HIT2000interim, I-HIT-MED, observation registry and older registries such as HIT-SKK87, HIT-SKK92 (1987 – 2020) with genetically confirmed Gorlin syndrome, harboring 10 PTCH1 and 6 SUFU mutations. Nine patients presented with desmoplastic medulloblastomas (DMB), 6 with medulloblastomas with extensive nodularity (MBEN) and one patient with classic medulloblastoma (CMB); all tumors affected the cerebellum, vermis or the fourth ventricle. SHH activation was present in all investigated tumors (14/16); DNA methylation analysis (when available) classified 3 tumors as iSHH-I and 4 tumors as iSHH-II. Age at diagnosis ranged from 0.65 to 3.41 years. All but one patient received chemotherapy according to the HIT-SKK protocol. Ten patients were in complete remission after completion of primary therapy; four subsequently presented with PD. No patient received radiotherapy during initial treatment. Five patients acquired additional neoplasms, namely basal cell carcinomas, odontogenic tumors, ovarian fibromas and meningioma. Developmental delay was documented in 5/16 patients. Overall survival (OS) and progression-free survival (PFS) between patients with PTCH1 or SUFU mutations did not differ statistically (10y-OS 90% vs. 100%, p=0.414; 5y-PFS 88.9% ± 10.5% vs. 41.7% ± 22.2%, p=0.139). Comparing the Gorlin patients to all young, SHH activated MBs in the registries (10y-OS 93.3% ± 6.4% vs. 92.5% ± 3.3%, p=0.738; 10y-PFS 64.9%+-16.7% vs. 83.8%+-4.5%, p=0.228) as well as comparing Gorlin M0 SKK-treated patients to all young, SHH activated, M0, SKK-treated MBs in the HIT-MED database did not reveal significantly different clinical outcomes (10y-OS 88.9% ± 10.5% vs. 88% ± 4%, p=0.812; 5y-PFS 87.5% ± 11.7% vs. 77.7% ± 5.1%, p=0.746). Gorlin syndrome should be considered in young children with SHH activated medulloblastoma, especially DMB and MBEN but cannot be ruled out for CMB. Survival did not differ to patients with SHH-activated medulloblastoma with unknown germline status or between PTCH1 and SUFU mutated patients. Additional neoplasms, especially basal cell carcinomas, need to be expected and screened for. Genetic counselling should be provided for families with young medulloblastoma patients with SHH activation.

Abstract Introduction Risk stratification of children with ependymomas of the posterior fossa in current therapeutic protocols is mainly based on clinical criteria. We aimed to identify independent outcome predictors for this disease entity by a systematic integrated analysis of clinical, histological and genetic information in a defined cohort of patients treated according to the German HIT protocols. Methods Tumor samples of 134 patients aged 0.2–15.9 years treated between 1999 and 2010 according to HIT protocols were analyzed for histological features including mitotic activity, necrosis and vascular proliferation and genomic alterations by SNP and molecular inversion probe analysis. Survival analysis was performed by Kaplan-Meier method with log rank test and multivariate Cox regression analysis. Results Residual tumor after surgery, chromosome 1q gain and structural genomic alterations were identified as predictors of significantly shorter event-free (EFS) and overall survival (OS). Furthermore, specific histological features including vascular proliferation, necrosis and high mitotic activity were predictive for shorter OS. Multivariate Cox regression revealed residual tumor, chromosome 1q gain and mitotic activity as independent predictors of both EFS and OS. Using these independent predictors of outcome, we were able to build a 3-tiered risk stratification model that separates patients with standard, intermediate and high risk, and which outperforms current stratification procedures. Conclusion The integration of defined clinical, histological and genetic parameters led to an improved risk-stratification model for posterior fossa ependymoma of childhood. After validation in independent cohorts this model may provide the basis for risk-adapted treatment of children with ependymomas of the posterior fossa.

Objectives To investigate experiences of parents of paediatric cancer survivors in cancer-related changes in the parents’ daily life (work life, family life, partner relationship and social life) during and after intensive cancer treatment and to examine the reintegration process with its impeding and facilitating factors.Design The design of this cross-sectional study involves a qualitative content analysis of semistructured interviews.Setting Participants were consecutively recruited in clinical settings throughout Germany.Participants Forty-nine parents (59% female) of 31 cancer survivors (aged 0–17 at diagnosis of leukaemia or central nervous system tumour) were interviewed approximately 16–24 months after the end of intensive cancer treatment (eg, chemotherapy).Results During treatment, more than 70% of parents reported difficulties reconciling paid work, household and family responsibilities and caring for the ill child. Couples spent little time with each other and approximately 25% reported dispute and burden. Many parents did not have enough energy for pursuing any hobbies during treatment. However, over the long term, being faced with the child’s disease also led to strengthened relationships, new priorities, improved communication, increased mutual trust and greater appreciation for daily life. Supportive social networks (family/friends/employers), a strong partner relationship prior to the diagnosis and the use of psychosocial services (eg, family-oriented rehabilitation) had a positive impact. At the time of the interview, most families had adapted well. However, reintegration took time and some parents lacked the energy required to continue life as they did before the diagnosis.Conclusions Even though most parents successfully readjusted to a new ‘normality’, reintegrating into daily life after paediatric cancer treatment remains difficult. Professional psychosocial support could help families with the reintegration process. Lastly, clinical staff (eg, physicians, psychologists, social workers) should bear in mind that the burden of parents does not automatically end with the end of intensive cancer treatment.

Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping "Speed", and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation [CSI] or local radiotherapy [LRT]). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes.

Our objective was to further the understanding of the process of reintegration of childhood cancer patients after treatment and to identify factors influencing that process. Using a qualitative approach, we conducted 49 interviews with parents (n = 29 mothers, n = 20 fathers) from 31 families with a child (

Our objective was to further the understanding of the process of reintegration of childhood cancer patients after treatment and to identify factors influencing that process. Using a qualitative approach, we conducted 49 interviews with parents (n = 29 mothers, n = 20 fathers) from 31 families with a child (

Knowledge on immune and stromal cells in medulloblastoma microenvironment is still limited as previous work was frequently restricted by low sample size and the lack of molecular subgroup information. We characterized 10 microenvironment cell populations as well as PD-L1 from gene expression in 1422 brain tumors and 763 medulloblastomas. All in all, medulloblastomas showed low expression of immune markers. Still, there were substantial differences with a clustering of medulloblastoma subgroups according to their microenvironment profile. Specifically, SHH medulloblastomas displayed strong signatures of fibroblasts, T cells and macrophages, while markers of cytotoxic lymphocytes were enriched in Group 4 tumors. PD-L1 gene expression appeared to be relatively high in single SHH and WNT cases but was undetectable by immunohistochemistry. In addition, two diverse immuno-stromal patterns were identified, indicating distinct types of local tumor immunosuppression, which were primarily controlled by either macrophage and regulatory T cell-mediated mechanisms or immunosuppressive cytokines and checkpoints, respectively. None of the immune cell signatures had an independent prognostic value in the present dataset after multiple testing correction. These results suggest a mild, but subgroup-specific infiltration of immune cells in medulloblastoma.

Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths.This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed.Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group.Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.