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Background: Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe. Methods: This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list. Findings: The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included two new medicines (everolimus and vinorelbine) following applications we made as a result of this project. Interpretation: Medicines that were defined as essential within this project should be available for the treatment of childhood and adolescent cancer continuously and across Europe. This list can be used to support and guide stakeholders and policy makers in negotiations on a national and European level regarding shortages, accessibility, and affordability of these medicines. Funding: None.

Background The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using fresh frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit. Methods Analysis of patients aged 0 to 21 years, enrolled in Germany between April 2019 and February 2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing, and RNA-Seq were performed. Results FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n = 71), BRAF V600E-mutation (n = 12), and alterations in FGFR1 (n = 14) as the most frequent alterations, among other common molecular drivers (n = 12). N = 16 cases (13%) presented rare gene fusions (eg, TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n = 27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 internal tandem duplications (n = 6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols. Conclusions The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

BACKGROUND & AIMS: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood.METHODS: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls.RESULTS: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor.CONCLUSIONS: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.

Background: The peak incidence of central nervous system (CNS) tumors in childhood indicates that intrauterine or neonatal characteristics are potential risk factors or symptoms of early onset of disease.Methods: We conducted a registry-based case-control study nested in the childhood populations of Denmark, Finland, Sweden, and Norway on the association between indicators of fetal growth and neonatal stress and childhood CNS tumor risk diagnosed during the period 1985-2006. Each of the 3,443 cases was matched individually on date of birth, sex, and country to five controls sampled randomly from population registries. Information on birth characteristics was obtained from national birth registries. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) by conditional logistic regression analyses.Results: We observed a U-shaped relation between risk for CNS tumors and birthweight, at >4.5 kg (OR, 1.27; 95% CI, 1.03-1.55) and 38 cm (1.80; 95% CI, 1.18-2.74), 5-minute Apgar score Conclusions: This study supports intrauterine or neonatal onset of childhood CNS tumors. The findings provide insight into the natural history of childhood CNS tumors indicating an early onset or, alternatively, potentially harmful exposures in the neonatal period that might be preventable. Cancer Epidemiol Biomarkers Prev; 19(4); 1042–52. ©2010 AACR.

Supplementary Appendix from Fetal Growth, Preterm Birth, Neonatal Stress and Risk for CNS Tumors in Children: A Nordic Population- and Register-Based Case-Control Study

BACKGROUND: Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder, predisposing development of benign and malignant tumours. Given the oncogenic potential, long-term surveillance is important in patients with NF1. Proposals for NF1 care and its specific manifestations have been developed, but lack integration within routine care. This guideline aims to assimilate available information on NF1 associated tumours (based on evidence and/or expert opinion) to assist healthcare professionals in undertaking tumour surveillance of NF1 individuals. METHODS: By comprehensive literature review, performed March 18th 2020, guidelines were developed by a NF1 expert group and patient representatives, conversant with clinical care of the wide NF1 disease spectrum. We used a modified Delphi procedure to overcome issues of variability in recommendations for specific (national) health care settings, and to deal with recommendations based on indirect (scarce) evidence. FINDINGS: We defined proposals for personalised and targeted tumour management in NF1, ensuring appropriate care for those in need, whilst reducing unnecessary intervention. We also incorporated the tumour-related psychosocial and quality of life impact of NF1. INTERPRETATION: The guideline reflects the current care for NF1 in Europe. They are not meant to be prescriptive and may be adjusted to local available resources at the treating centre, both within and outside EU countries. FUNDING: This guideline has been supported by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). ERN GENTURIS is funded by the European Union. DGE is supported by the Manchester NIHRBiomedical Research Centre (IS-BRC-1215-20007). ispartof: ECLINICALMEDICINE vol:56 ispartof: location:England status: published

Influence of radiotherapy technique on incidental dose to the whole ventricular system in focal irradiation of nongerminomatous germcell tumours

Aim: To evaluate survival distributions, long-term socioeconomic consequences, and health care costs in patients with childhood and adolescent onset of brain tumours in a Danish nationwide prospective cohort study. Method: A search of national registries identified 2283 patients (1198 males, 1085 females; mean age 9 years 6 months [SD 5 years 7 months]) diagnosed with a brain tumour between 1980 and 2015 and aged no older than 18 years at diagnosis. These were compared with sex-, age-, and residency-matched comparison individuals. Patients with malignant tumours were compared with those with benign tumours. Survival distributions were estimated by the Kaplan–Meier method and hazard ratio by the Cox proportional hazard model. Socioeconomic data at age 20 and 30 years were assessed. Results: The probability of mortality was highest during the first year after tumour diagnosis. In young adulthood, the patients were generally less likely to be married, had lower grade-point averages, educational levels, and income, were less likely to be in employment, and had higher health care costs than comparison individuals. Patients with malignant tumours had worse outcomes with respect to education, employment, and health care costs than those with benign tumours. Interpretation: A diagnosis of brain tumour in childhood and adolescence adversely affects survival and has negative long-term socioeconomic consequences, especially in patients with malignant tumours. These patients require continuous social support.

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors—distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.

Heterozygous POLE or POLD1 germline pathogenic variants (PVs) cause polymerase proofreading associated polyposis (PPAP), a constitutional polymerase proofreading deficiency that typically presents with colorectal adenomas and carcinomas in adulthood. Constitutional mismatch-repair deficiency (CMMRD), caused by germline bi-allelic PVs affecting one of four MMR genes, results in a high propensity for hematological, brain, intestinal tract, and other malignancies in childhood. Non-malignant clinical features, such as skin pigmentation alterations, are found in nearly all CMMRD patients and are important diagnostic markers. Here, we excluded CMMRD in three cancer patients with highly suspect clinical phenotypes, but identified in each a constitutional heterozygous POLE PV. These, and two additional POLE PVs identified in published CMMRD-like patients, have not previously been reported as germline PVs despite all being well-known somatic mutations in hyper-mutated tumors. Together, these five cases show that specific POLE PVs may have a stronger "mutator" effect than known PPAP-associated POLE PVs and may cause a CMMRD-like phenotype distinct from PPAP. The common underlying mechanism, i.e. a constitutional replication error repair defect, and a similar tumor spectrum provide a good rationale for monitoring these patients with a severe constitutional polymerase proofreading deficiency according to protocols proposed for CMMRD. This article is protected by copyright. All rights reserved.

Medulloblastoma (MB) recurrence is usually incurable despite intensive therapy including high-dose chemotherapy. An evolving alternative approach to conventional chemotherapy aims at interfering with tumor angiogenesis at different levels. We report on a novel combinatorial metronomic antiangiogenic approach. The study is a retrospective observational study of 29 consecutive patients with first or multiple recurrences prospectively treated according to the MEMMAT strategy (“MEMMAT-like”) before the formal protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) started. The study period was 11/2006 to 06/2016. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by IV bevacizumab and intraventricular therapy consisting of alternating etoposide and liposomal cytarabine. Median overall survival (OS) after recurrence for the whole group was 29.5 months, OS was 48.3 ± 9.3% at three years and 34.5 ± 8.8% at five years, and progression-free survival was 42.0 ± 9.5% at three years and 29.4 ± 9% at five years. As of 07/2022, 9/29 patients are alive 86 to 164 months after the recurrence that prompted the “MEMMAT-like” therapy. Treatment was primarily out-patient and generally well-tolerated. Toxicities did occur but were manageable. In conclusion, antiangiogenic therapy according to the MEMMAT strategy increased median OS of patients with recurrent MB and may lead to long-term survival. Adherence to the protocol, including intraventricular therapy, appears important.

Background Central nervous system (CNS) tumors cause the highest death rates among childhood cancers, and survivors frequently have severe late effects. Magnetic resonance imaging (MRI) is the imaging modality of choice, but its specificity can be challenged by treatment-induced signal changes. In adults, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET can assist in interpreting MRI findings. We assessed the clinical impact and diagnostic accuracy of adding [18F]FET PET to MRI in children with CNS tumors. Methods A total of 169 [18F]FET PET scans were performed in 97 prospectively and consecutively included patients with known or suspected childhood CNS tumors. Scans were performed at primary diagnosis, before or after treatment, or at relapse. Results Adding [18F]FET PET to MRI impacted clinical management in 8% [95% confidence interval (CI): 4%-13%] of all scans (n = 151) and in 33% [CI: 17%-53%] of scans deemed clinically indicated due to difficult decision making on MRI alone (n = 30). Using pathology or follow-up as reference standard, the addition of [18F]FET PET increased specificity (1.00 [0.82-1.00] vs 0.48 [0.30-0.70], P = .0001) and accuracy (0.91 [CI: 0.87-0.96] vs 0.81 [CI: 0.75-0.89], P = .04) in 83 treated lesions and accuracy in 58 untreated lesions (0.96 [CI: 0.91-1.00] vs 0.90 [CI: 0.82-0.92], P < .001). Further, in a subset of patients (n = 15) [18F]FET uptake correlated positively with genomic proliferation index. Conclusions The addition of [18F]FET PET to MRI helped discriminate tumor from non-tumor lesions in the largest consecutive cohort of pediatric CNS tumor patients presented to date.

BACKGROUND Genomic alterations and dysregulation of RAF are the main oncogenic driver in almost all pediatric low-grade gliomas (pLGGs). About 50%‒60% of pLGGs harbor KIAA1549-BRAF fusion and 5%‒15% BRAF V600E mutation. No targeted therapy has received regulatory approval for either relapsed or newly diagnosed pLGG to date. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II panRAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study with tovorafenib in pediatric patients with recurrent/progressive LGG is currently ongoing. METHODS LOGGIC/FIREFLY-2 (EudraCT 2022-001363-27) is a registrational, randomized, multicenter, global (~100 sites across Australia, Canada, Egypt, Europe, New Zealand, Singapore, South Korea, Taiwan, and USA), phase 3 trial evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients < 25 years old with LGG harboring a RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m2 ( ≤ 600 mg) weekly (tablet or liquid suspension for 26, 28-day cycles), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C (81 weeks) regimen, or single-agent vinblastine (70 weeks). After completing 26 cycles tovorafenib, patients may continue tovorafenib or opt to enter a drug holiday at any point. Patients who progress in the SoC arm may receive tovorafenib. Patients who progress after stopping tovorafenib may be re-challenged. Primary endpoint is ORR based on RANO criteria, as determined by an independent radiology committee. Key secondary endpoints are progression-free survival and duration of response per RANO criteria, and ORR per RAPNO criteria. Other secondary endpoints include changes in neurological and visual function, and safety and tolerability. Exploratory objectives include quality of life and health utilization measures, molecular biomarker evaluation for treatment response and resistance, efficacy of tovorafenib after progression on chemotherapy and retreatment upon progression during drug holiday.

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT–TYR, ATRT–MYC and ATRT–SHH. ATRT–SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT–SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT–SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT–SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT–SHH has prognostic relevance and might aid to stratify patients within future clinical trials.

BackgroundThe underlying cause of central nervous system (CNS) tumors in children is largely unknown. In this nationwide, prospective population-based study we investigate rare germline variants across known and putative CPS genes and genes exhibiting evolutionary intolerance of inactivating alterations in children with CNS tumors.MethodsOne hundred and twenty-eight children with CNS tumors underwent whole-genome sequencing of germline DNA. Single nucleotide and structural variants in 315 cancer related genes and 2,986 highly evolutionarily constrained genes were assessed. A systematic pedigree analysis covering 3,543 close relatives was performed.ResultsThirteen patients harbored rare pathogenic variants in nine known CPS genes. The likelihood of carrying pathogenic variants in CPS genes was higher for patients with medulloblastoma than children with other tumors (OR 5.9, CI 1.6-21.2). Metasynchronous CNS tumors were observed exclusively in children harboring pathogenic CPS gene variants (n=2, p=0.01).In general, known pCPS genes were shown to be significantly more constrained than both genes associated with risk of adult-onset malignancies (p=5e−4) and all other genes (p=5e−17). Forty-seven patients carried 66 loss-of-functions variants in 60 constrained genes, including eight variants in six known pCPS genes. A deletion in the extremely constrained EHMT1 gene, formerly somatically linked with sonic hedgehog medulloblastoma, was found in a patient with this tumor.Conclusions∽10% of pediatric CNS tumors can be attributed to rare variants in known CPS genes. Analysis of evolutionarily constrained genes may increase our understanding of pediatric cancer susceptibility.3 key points∽10% of children with CNS tumors carry a pathogenic variant in a known cancer predisposition geneKnown pediatric-onset cancer predisposition genes show high evolutionary constraintLoss-of-function variants in evolutionarily constrained genes may explain additional riskImportance of this studyAlthough CNS tumors constitute the most common form of solid neoplasms in childhood, our understanding of their underlying causes remains sparse. Predisposition studies often suffer from selection bias, lack of family and clinical data or from being limited to SNVs in established cancer predisposition genes. We report the findings of a prospective, population-based investigation of genetic predisposition to pediatric CNS tumors. Our findings illustrate that 10% of children with CNS tumors harbor a damaging alteration in a known cancer gene, of which the majority (9/13) are loss-of-function alterations. Moreover, we illustrate how recently developed knowledge on evolutionarily loss-of-function intolerant genes may be used to investigate additional pediatric cancer risk and present EHMT1 as a putative novel predisposition gene for SHH medulloblastoma. Previously undescribed links between variants in known cancer predisposition genes and specific brain tumors are presented and the importance of assessing both SV and SNV is illustrated.

Background The aim of the project was to identify risk factors associated with visual progression and treatment indications in pediatric patients with neurofibromatosis type 1 associated optic pathway glioma (NF1-OPG). Methods A multidisciplinary expert group consisting of ophthalmologists, pediatric neuro-oncologists, neurofibromatosis specialists, and neuro-radiologists involved in therapy trials assembled a cohort of children with NF1-OPG from 6 European countries with complete clinical, imaging, and visual outcome datasets. Using methods developed during a consensus workshop, visual and imaging data were reviewed by the expert team and analyzed to identify associations between factors at diagnosis with visual and imaging outcomes. Results Eighty-three patients (37 males, 46 females, mean age 5.1 ± 2.6 y; 1–13.1 y) registered in the European treatment trial SIOP LGG-2004 (recruited 2004–2012) were included. They were either observed or treated (at diagnosis/after follow-up). In multivariable analysis, factors present at diagnosis associated with adverse visual outcomes included: multiple visual signs and symptoms (adjusted odds ratio [adjOR]: 8.33; 95% CI: 1.9–36.45), abnormal visual behavior (adjOR: 4.15; 95% CI: 1.20–14.34), new onset of visual symptoms (adjOR: 4.04; 95% CI: 1.26–12.95), and optic atrophy (adjOR: 3.73; 95% CI: 1.13–12.53). Squint, posterior visual pathway tumor involvement, and bilateral pathway tumor involvement showed borderline significance. Treatment appeared to reduce tumor size but improved vision in only 10/45 treated patients. Children with visual deterioration after primary observation are more likely to improve with treatment than children treated at diagnosis. Conclusions The analysis identified the importance of symptomatology, optic atrophy, and history of vision loss as predictive factors for poor visual outcomes in children with NF1-OPG.

Background Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated in the management of hematologic malignancies in adults, safety in children has also been demonstrated repeatedly. Materials and methods A retrospective series of patients who received decitabine upon relapse or progression following therapy according to the EU‐RHAB regimen is presented. Due to the retrospective nature of analyses, response was defined as measurable regression of at least one lesion on imaging. 850k methylation profiling was done whenever tumor tissue was available. Results A total of 22 patients with RT of any anatomical localization were included. Most patients (19/22) presented with metastases. All received low‐dose decitabine with or preceding conventional chemotherapy. Patients received a median of two (1‐6) courses of decitabine; 27.3% (6/22) demonstrated a radiological response. Molecular analyses revealed increased methylation levels in tumors from responders. No excessive toxicity was observed. Clinical benefits for responders included eligibility for early phase trials or local therapy. Responders showed prolonged time to progression and overall survival. Due to small sample size, statistical correction for survivorship bias demonstrated no significant effect on survival for responders. Conclusions Patients with RT demonstrate promising signs of antitumor activity after multiagent relapse therapy including decitabine. Analyses of methylation data suggest a specific effect on an epigenetic level. We propose to consider decitabine and other epigenetic drugs as candidates for further clinical investigations in RT., publishedVersion

BACKGROUND: Brain tumours are the most common solid tumours in childhood. Half of these tumours occur in the posterior fossa, where surgical removal is complicated by the risk of cerebellar mutism syndrome, of which postoperative speech impairment (POSI) is a cardinal symptom, in up to 25% of patients. The surgical approach to midline tumours, mostly undertaken by transvermian or telovelar routes, has been proposed to influence the risk of POSI. We aimed to investigate the risk of developing POSI, the time course of its resolution, and its association with surgical approach and other clinical factors. METHODS: In this observational prospective multicentre cohort study, we included children (aged

Background and objectives: Sleep disturbances are frequently reported in children with brain tumours. The objective of our cross-sectional study was to systematically examine sleep in these children. We hypothesised that children with tumours involving the sleep-wake-regulatory areas have an altered sleep-wake-regulation. Methods: Sixty-one patients aged 0–18 years and with a diagnosis of a primary brain or cervical medullary tumour were included. They were categorised based upon tumour location into two groups – those affecting the sleep-wake regulatory regions, i.e. brain stem, basal forebrain, hypothalamus, thalamus, and posterior fossa compressing the brain stem and those that did not. Sleep history, questionnaire surveys, polysomnography, and multiple sleep latency test were used, as indicated clinically. Surveys included Pediatric Daytime Sleepiness Scale, Children's Sleep Habits Questionnaire, Strengths and Difficulties Questionnaire, and Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale. Results: Patients with tumours involving the sleep-wake regulatory areas were sleepier/more fatigued (p = 0.03). Sleep apnoea was observed in 86% of all the patients and comorbid narcolepsy in 8%, without group differences (p ≥ 0.12). Patients with tumours involving the sleep-wake-regulatory areas had more emotional problems (p = 0.04), were more affected by mental health problems (p < 0.001), and had poorer quality of life (p ≤ 0.03). Conclusions: Many children with brain tumours suffer from disturbed sleep, poor mental health, and low quality of life. We recommend that systematic sleep evaluation is included in their routine care along with psychological and social support.

Hospitalized children and adolescents are at risk of short sleep and subsequent adverse health effects, but little is known about actual sleep duration, the factors that cause sleep disturbances in an inpatient pediatric setting, and what has been done to promote sleep in this population. The aim of this review was to systematically identify, categorize, and synthesize the literature on sleep in children and adolescents in an inpatient setting. We searched five electronic databases (PubMed, CENTRAL, CINAHL, PsycINFO, and Scopus) and of the 3770 references identified, 28 were eligible for inclusion. From studies reporting age-specific sleep durations, we found that four out of nineteen fell within the National Sleep Foundations recommendations for age-specific sleep durations. Reported causes of sleep disturbances were primarily related to modifiable, external factors, e.g., nursing care activities and noise from equipment and other patients. Sleep-promoting interventions seemed acceptable to patients, parents, and healthcare professionals. However, the literature in this area is heterogeneous regarding methodology, reporting, and population characteristics. Our findings underline the importance of prioritizing and optimizing sleep in hospitalized pediatric patients and highlight the need for standardization in the planning and reporting of studies within this field.

Background: Brain tumours are the most common childhood tumours. Half of them are in the posterior fossa, where surgical removal is complicated by postoperative speech impairment (POSI) in up to 25% of patients. POSI manifests within days of surgery, while improvement takes weeks or months. The surgical approach to midline tumours, mostly undertaken by transvermian or telovelar routes, has been proposed to influence the risk of POSI. We investigated the risk of developing POSI, the time course of its resolution and its association with surgical approach and other clinical factors. Methods: 426 children aged 0–17·9 years undergoing primary surgery for a posterior fossa tumour at 26 centres in nine European countries were prospectively included. Speech was classified as either mutism, reduced or habitual at two weeks, two months, and one year after surgery. Findings: POSI developed in 30% of patients: Mutism in 15% (56/378) a median 1 day after surgery (IQR, 0–2; max 10) and reduced speech in 15% (58/378). In multivariate analysis, POSI was associated with using a telovelar approach (odds ratio (OR), 1·7; 95% CI, 1·03–2·9, p

Background Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as “CNS-primitive neuroectodermal tumors” (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. Methods Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. Results DNA methylation profiling of “CNS-PNET” classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. Conclusion The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.

Germline pathogenic variants in CDKN2A predispose to various cancers, including melanoma, pancreatic cancer, and neural system tumors, whereas CDKN2B variants are associated with renal cell carcinoma. A few case reports have described heterozygous germline deletions spanning both CDKN2A and CDKN2B associated with a cancer predisposition syndrome (CPS) that constitutes a risk of cancer beyond those associated with haploinsufficiency of each gene individually, indicating an additive effect or a contiguous gene deletion syndrome. We report a young woman with a de novo germline 9p21 microdeletion involving the CDKN2A/CDKN2B genes, who developed six primary cancers since childhood, including a very rare extraskeletal osteosarcoma (eOS) at the age of 8. To our knowledge this is the first report of eOS in a patient with CDKN2A/CDKN2B deletion.

Pediatric brain tumors frequently develop in the cerebellum, where ependymoma, medulloblastoma and pilocytic astrocytoma are the most prevalent subtypes. These tumors are currently treated using non-specific therapies, in part because few somatically mutated driver genes are present, and the underlying pathobiology is poorly described. Circular RNAs (circRNAs) have recently emerged as a large class of primarily non-coding RNAs with important roles in tumorigenesis, but so far they have not been described in pediatric brain tumors. To advance our understanding of these tumors, we performed high-throughput sequencing of ribosomal RNA-depleted total RNA from 10 primary ependymoma and 3 control samples. CircRNA expression patterns were determined using two independent bioinformatics algorithms, and correlated to disease stage, outcome, age, and gender. We found a profound global downregulation of circRNAs in ependymoma relative to control samples. Many differentially expressed circRNAs were discovered and circSMARCA5 and circ-FBXW7, which are described as tumor suppressors in glioma and glioblastomas in adults, were among the most downregulated. Moreover, patients with a dismal outcome clustered separately from patients with a good prognosis in unsupervised hierarchical cluster analyses. Next, we performed NanoString nCounter experiments using a custom-designed panel including 66 selected circRNA targets and analyzed formalin-fixed paraffin-embedded (FFPE) samples from a larger cohort of ependymoma patients as well as patients diagnosed with medulloblastoma or pilocytic astrocytoma. These experiments were used to validate our findings and, in addition, indicated that circRNA expression profiles are different among distinct pediatric brain tumor subtypes. In particular, circRMST and a circRNA derived from the LRBA gene were specifically upregulated in ependymomas. In conclusion, circRNAs have profoundly different expression profiles in ependymomas relative to controls and other pediatric brain tumor subtypes.

Meningiomas are rare in children. They are highly complex, harboring unique clinical and pathological characteristics, and many occur in patients with neurofibromatosis type 2. Hereby, we present a case of a two-year-old boy presented with a diagnostically challenging intraventricular tumor. It was incompletely resected 6 times over 14 months but kept progressing and was ultimately deemed unresectable. Histologically, the tumor was initially classified as schwannoma, but extensive international review concluded it was most likely an atypical meningioma, WHO grade II. Comprehensive genomic profiling revealed a TFG-ROS1 fusion, suggesting that ROS1-signaling pathway alterations were driving the tumor growth. In light of this new information, the possibility of a diagnosis of inflammatory myofibroblastic tumor was considered; however the histopathological results were not conclusive. This specific molecular finding allowed the potential use of precision medicine and the patient was enrolled in the AcSé phase 2 trial with crizotinib (NCT02034981), leading to a prolonged partial tumor response which is persisting since 14 months. This case highlights the value of precision cancer medicine in children.

Chemotherapy is the mainstay of non-surgical treatment in pLGG but many patients progress again after the end of the first treatment. Apart from the standard carboplatin-vincristine, new regimens with less toxicity are therefore desirable. Single agent vinblastine is an established regimen. PDGFRA TKI inhibitors have shown efficacy in refractory pLGG as well. The VINILO phase I showed the feasibility of the combination of vinblastine with nilotinib at the expense of a 50% decrease of the dose of vinblastine. The phase II trial therefore compared vinblastine 6 mg/m2 weekly (standard arm) to vinblastine 3mg/m2 weekly plus nilotinib 230mg/m2/day. The primary endpoint was the PFS, analysed on the intention-to-treat population. The target sample size was 120 patients. Accrual was stopped after recruitment of 109 patients (53 and 56 in the vinblastine-arm and the vinblastine+nilotinib arm, respectively) between July 2016 and April 2019. Fifty-four patients had an optic pathway glioma and 45 had NF1 (these patients were allowed to enter the trial as initial therapy). Half of the patients were treated after more than one line of therapy. The planned interim analysis showed that the vinblastine+nilotinib arm was associated with a worse PFS as compared to the standard arm (HR=2.37; 95%CI, 1.26–4.46; p=0.007; with 2-year PFS of 28% versus 49%). Overall, 156 biological adverse events (AE) of grade ≥ 3 have been reported after randomization (94 in vinblastine alone arm, 62 in vinblastine+nilotinib arm) and 84 non-biological adverse events of grade ≥ 3 (50 in vinblastine alone arm, 34 in vinblastine+nilotinib arm). We conclude that the combination of vinblastine plus nilotinib was less effective than vinblastine alone, possibly because of a lower dose intensity of vinblastine in the experimental arm. Vinblastine can serve as a backbone for combinations but lowering its dose may jeopardize the efficacy.

Complete resection is the treatment of choice for most pediatric brain tumors, but early postoperative MRI for detection of residual tumor may be misleading because of MRI signal changes caused by the operation. PET imaging with amino acid tracers in adults increases the diagnostic accuracy for brain tumors, but the literature in pediatric neurooncology is limited. A hybrid PET/MRI system is highly beneficial in children, reducing the number of scanning procedures, and this is to our knowledge the first larger study using PET/MRI in pediatric neurooncology. We evaluated if additional postoperative 18F-fluoro-ethyl-tyrosine ( 18F-FET) PET in children and adolescents would improve diagnostic accuracy for the detection of residual tumor as compared with MRI alone and would assist clinical management. Methods: Twenty-two patients (7 male; mean age, 9.5 y; range, 0–19 y) were included prospectively and consecutively in the study and had 27 early postoperative 18F-FET PET exams performed preferentially in a hybrid PET/MRI system (NCT03402425). Results: Using follow-up (93%) or reoperation (7%) as the reference standard, PET combined with MRI discriminated tumor from treatment effects with a lesion-based sensitivity/ specificity/accuracy (95% confidence intervals) of 0.73 (0.50–1.00)/ 1.00 (0.74–1.00)/0.87 (0.73–1.00) compared with MRI alone: 0.80 (0.57–1.00)/0.75 (0.53–0.94)/0.77 (0.65–0.90); that is, the specificity for PET/MRI was 1.00 as compared with 0.75 for MRI alone (P 5 0.13). In 11 of 27 cases (41%), results from the 18F-FET PET scans added relevant clinical information, including one scan that directly influenced clinical management because an additional residual tumor site was identified. 18F-FET uptake in reactive changes was frequent (52%), but correct interpretation was possible in all cases. Conclusion: The high specificity for detecting residual tumor suggests that supplementary 18F-FET PET is relevant in cases where reoperation for residual tumor is considered.

Background Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European “Care for CMMRD” (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment. Methods Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017. Results Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1–40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19–45) and 22% (95% CI: 12–37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families). Conclusions Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches.

INTRODUCTION Patients with recurrent medulloblastoma have a poor prognosis with only around 8% of patients surviving at 5 years irrespective of salvage therapy used. We report on 29 patients from four institutions treated with a “MEMMAT” based antiangiogenic combination therapy. PATIENTS AND METHODS From 11/2006 to 06/2016, 29 patients were diagnosed with a recurrent medulloblastoma (19 first, 10 multiple recurrences). Median age at start of antiangiogenic therapy was 10 years (range 1–27). Subgroup of medulloblastoma was available in 18 patients and was group 3 or 4 in all except two (one WNT, one SHH-infant). For their current relapse patients received an antiangiogenic combination therapy consisting of bevacizumab, thalidomide, celecoxib, fenofibrate, and etoposide, alternating with cyclophosphamide and augmented with intraventricular therapy (etoposide and liposomal cytarabine). RESULTS As of 01/2020, 8/29 patients are alive at a median of 44 months after recurrence. 6/8 surviving patients are currently in CCR between 66 and 134 months after recurrence that prompted MEMMAT therapy. Two patients are again in remission after intercurrent relapses 105 and 102 months after first starting MEMMAT therapy. Five patients died of another cause (accident, leukemia, septicemia). OS (median 44 months) was 44±10% at 5 years and 39±10% at 10 years, PFS was 33±10% at 5 years and 28 ±9% at 10 years. Therapy was well tolerated and toxicities were manageable. CONCLUSION Our results suggest that antiangiogenic metronomic chemotherapy has clinical activity in recurrent medulloblastoma. Further investigation with an international phase II study is ongoing (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290).

OBJECTIVE Cerebellar mutism syndrome (CMS) is a severe neurological complication of tumour surgery in the posterior fossa in childhood. The incidence is reported between 8 and 39%, where CMS sets in within days of surgery and resolves within months, yet long-term sequelae are seen in most patients. This prospective cohort study investigates the course of CMS and the surgical cause of the syndrome. POPULATION AND METHODS We included 500 children with a tumour in the posterior fossa with planned surgery or open biopsy. Enrolment was conducted between 2014 and 2020 in 26 centres in ten European countries. Speech, neurological symptoms and surgical procedure were registered in predefined standardized forms pre-operatively and at three post-operative follow-ups within one year. PRELIMINARY RESULTS A total of 426 children underwent primary surgery and were eligible for analyses. CMS occurred in 56 patients (13.1%) one day (median; IQR: 0–2 days) after surgery and resolved within 38 days (median; IQR: 4–52 days). Another 58 patients (13.6%) had less severe speech impairment. Mutism was associated with lower age (OR: 0.91 [95%CI: 0.85;0.98, p=0.014]), medulloblastoma (OR: 2.5 [95%CI: 1.4;4.7, p=0.0036]) and ATRT (OR: 12.9 [95%CI: 3.4;51.9, p=0.00018]) and tumour location in the fourth ventricle (OR: 4.0 [95%CI: 2.3;7.2, p CONCLUSION CMS is a common complication predominantly seen in younger children after tumour surgery for a medulloblastoma or ATRT in the fourth ventricle. The incidence is not related to the surgical access in this study population.

Complete resection is the treatment of choice for most pediatric brain tumors, but early postoperative MRI for detection of residual tumor may be misleading because of MRI signal changes caused by the operation. PET imaging with amino acid tracers in adults increases the diagnostic accuracy for brain tumors, but the literature in pediatric neurooncology is limited. A hybrid PET/MRI system is highly beneficial in children, reducing the number of scanning procedures, and this is to our knowledge the first larger study using PET/MRI in pediatric neurooncology. We evaluated if additional postoperative

BACKGROUND: Intracranial germinoma (WHO grade IV) has a good prognosis as over 90% can be cured with chemo- and radiotherapy, while intracranial nongerminomatous germ cell tumors (NGGCT) also have a good although somewhat less favorable outcome. We evaluated the use of (18)F-fluoro-ethyltyrosine ((18)F-FET) positron emission tomography (PET) for response assessment in intracranial germinoma and NGGCT. METHODS: Six patients (5 males, age 13-17 years) diagnosed with intracranial germinoma (n=4) or NGGCT (elevated alpha-fetoprotein (AFP)) (n=2) were included and (18)F-FET PET scans were performed at baseline and after 9-12 weeks of chemotherapy (treated according to SIOP CNS GCT 2). One germinoma patient declined follow-up (18)F-FET PET. RESULTS: All germinoma and one NGGCT patients had partial or complete response on MRI and were subsequently treated with proton radiation therapy, and are in clinical complete response (cCR). The second NGGCT patient had normalisation of AFP but progression on MRI; he was subsequently operated where histology showed only residual teratoma. He received further chemo- and radiotherapy and is in cCR. All patients with follow-up PET showed marked decrease of (18)F-FET activity uptake after chemotherapy. Maximal tumor-to-background ratio decreased from 2.2 ± 0.4 before chemotherapy to 1.4 ± 0.3, p=0.001 (paired t-test). CONCLUSIONS: In five patients treated successfully for intracranial germ cell tumors, (18)F-FET PET showed a marked decrease in activity uptake in response to chemotherapy. The results are promising for further studies of the use of (18)F-FET PET in response assessment in this disease, possibly to assist radiation therapy dosing with the aim to reduce late effects.

Histiocytosis is a heterogeneous group of disease entities, comprised by two main categories, namely Langerhans and non-Langerhans cell histiocytoses. Central nervous system involvement in histiocytosis is considered very rare and is often secondary to affection of anatomically related bone structures and/or multi-organ disease. We present a never-before described case of rare childhood histiocytosis with hybrid features of Langerhans cell histiocytosis and juvenile xanthogranuloma confined to the central nervous system in a 2- and a half-year-old boy with distinct treatment response to clofarabine. The case also emphasizes the diagnostic significance of stereotactic brain biopsy.

Purpose: Pediatric cancers are often difficult to classify and can be complex to treat. To ensure precise diagnostics and identify relevant treatment targets, we implemented comprehensive molecular profiling of consecutive pediatric patients with cancer relapse. We evaluated the clinical impact of extensive molecular profiling by assessing the frequency of identified biological onco-drivers, altered diagnosis, and/or identification of new relevant targeted therapies. Patients and Methods: Forty-six tumor samples (44 fresh-frozen; two formalin-fixed paraffin embedded), two bone marrow aspirates, three cerebrospinal fluid samples, and one archived DNA were obtained from 48 children (0-17 years; median 9.5) with relapsed or refractory cancer, where the disease was rapidly progressing in spite of their current treatment or they had exhausted all treatment options. The samples were analyzed by whole-exome sequencing (WES), RNA sequencing (RNAseq), transcriptome arrays, and SNP arrays. Final reports were available within 3-4 weeks after patient inclusion and included mutation status, a description of copy number alterations, differentially expressed genes, and gene fusions, as well as suggestions for targeted treatment. Results: Of the 48 patients, 33 had actionable findings. The most efficient method for the identification of actionable findings was WES (39%), followed by SNP array (37%). Of note, gene fusions were identified by RNAseq in 21% of the samples. Eleven findings led to clinical intervention, i.e., oncogenetic counseling, targeted treatment, and treatment based on changed diagnosis. Four patients received compassionate use targeted therapy. Six patients experienced direct benefits in the form of stable disease or response. Conclusion: The application of comprehensive genetic diagnostics in children with recurrent cancers allowed for discovery and implementation of effective targeted therapies and hereby improvement of outcome in some patients.

Medulloblastoma is the most common malignant brain tumor in childhood. Radical surgery in the non-metastatic stage is an important factor with respect to overall survival. In this case, 5-aminolevulinic acid (5-ALA) was used at second-look surgery in order to improve surgical results. The child was pretreated with 3 × 4 mg dexamethasone for 4 days prior to the second surgery. At 5 a.m. on the day of surgery, a freshly prepared solution of 5-ALA (20 mg/kg body weight; Medac, Germany) was given orally. At surgery, through the original opening, the vague red fluorescence of the tumor was clearly distinctive from the cerebellum with no tumor infiltration. All fluorescent tissue was removed. Postoperative MRI gave suspicion of yet at small tumor residue, but this structure is less than 1.5 ml in calculated volume, and consequently the recommended adjuvant therapy of the child changed from the high-risk medulloblastoma regimen to the standard-risk regimen. In this particular difficult case of non-contrast-enhancing tumor, 5-ALA was of vital importance to improve rate of resection and change the aggressiveness needed in postsurgery radiation therapy.

Medulloblastomas are the most common, and often fatal, paediatric brain tumours that feature high genomic instability, frequent infection by human cytomegalovirus (HCMV) and resistance to radiation and chemotherapy. The causes of the pronounced chromosomal instability and its potential links with HCMV infection and/or resistance to genotoxic therapies remain largely unknown. To address these issues, here we have combined immunohistochemical analysis of a series of 25 paediatric medulloblastomas, complemented by medulloblastoma cell culture models including experimental HCMV infection. Using eight established immunohistochemical markers to assess the status of the DDR machinery, we found pronounced endogenous DNA damage signalling (γH2AX marker) and robust constitutive activation of both the ATM-Chk2 and ATR-Chk1 DNA damage checkpoint kinase cascades, yet unexpectedly modest p53 tumour suppressor activation, across our medulloblastoma cohort. Most tumours showed high proliferation (Ki67 marker), variable oxidative DNA damage (8-oxoguanine lesions) and formation of 53BP1 nuclear 'bodies', the latter indicating (along with ATR-Chk1 signalling) endogenous replication stress. The bulk of the clinical specimens also showed expression of HCMV immediate early and late proteins, in comparative analyses using three immunohistochemical protocols. Cell culture experiments validated the chronic endogenous replication stress in medulloblastoma cell lines and showed sharply differential, intriguing responses of normal cells and medulloblastoma cells to HCMV infection, including differential subcellular mislocalization and enhancement of replication stress-related 53BP1 body formation, the latter in cell-non-autonomous manner. Overall, our results strongly indicate that in human medulloblastomas, the DDR checkpoint barrier is widely activated, at least in part due to replication stress. Furthermore, we propose that unorthodox p53 defects other than mutations may allow high proliferation despite the ongoing checkpoint signalling and that the highly prevalent HCMV may impact the medulloblastoma host cell replication stress and DNA repair. Collectively, the scenario we report here likely fuels genomic instability and evolution of medulloblastoma resistance to standard-of-care genotoxic treatments.

AimGerm cell tumours (GCTs) are a rare heterogeneous tumour group derived from primordial germ cells, which can be benign or malignant and occur in the gonads or extragonadally. This study mapped the paediatric GCTs in Denmark from 1984 to 2013 to study the incidence and outcome.MethodsWe identified paediatric GCTs from the Danish Childhood Cancer and National Pathology Registries and reviewed the case records for patient characteristics, tumour characteristics and clinical outcome.ResultsWe identified 403 (71% female) paediatric GCTs and the crude incidence was 1.43 per 100 000. Of these, 79 (20%) were malignant, 39 (10%) were potentially malignant and 285 (70%) were benign. Extragonadal GCTs (39%) were mainly observed in early childhood and were predominately sacrococcygeal teratomas. Gonadal GCTs (61%) in late childhood were most frequently mature teratomas in the ovaries. Nearly all patients underwent surgery. Of the malignant tumours, 62% were treated with chemotherapy. Radiotherapy was only administered to intracranial GCTs. In the cohort, 12 patients died (3%).ConclusionPaediatric GCTs in Denmark were mainly benign and mortality was low, even for malignant tumours. We identified a peak of extragonadal GCTs in early childhood and a peak of gonadal GCTs in late childhood, which was comparable to previous reports.

Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1–4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition. Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.

Background Despite major treatment attempts, the prognosis for pediatric diffuse intrinsic pontine gliomas (DIPGs) remains dismal. Gliomas are highly vascularized tumors, suggesting that the prevention of vessel formation by anti-angiogenic treatment might be effective. Procedure Forty-one pediatric patients with DIPG were treated according to the Angiocomb protocol, starting with radiotherapy combined with topotecan and followed by anti-angiogenic triple medication consisting of thalidomide, etoposide, and celecoxib. Overall survival, radiological response, quality of life, requirement of corticosteroids, and adverse effects were monitored. Eight patients treated with only radiotherapy were used as controls. Results For study patients, the 12 and 24 months overall survival was 61% and 17%, respectively. The median overall survival was 12 months (range 4–60 months). Four radiological complete responses were seen, of which two were transient. Radiologically, 56% of the tumors reduced in size and 78% in signal intensity. Study patients were able to visit school or daycare and walk for a significantly longer time compared to controls (Log Rank 0.036 and 0.008, respectively). Adverse effects were generally minor. Conclusions The Angiocomb protocol created a noticeable share of long-term survivors and was well tolerated, suggesting that anti-angiogenic therapy for patients with DIPG should be studied more in the future. Pediatr Blood Cancer 2014;61:1603–1609. © 2014 Wiley Periodicals, Inc.

In 2016, the WHO classification of diffuse astrocytoma began to include isocitrate dehydrogenase (IDH) mutation in addition to histology. We here demonstrate a case where a 14-year-old boy presented with a parietal tumor with no histological evidence of neoplasia but with an IDH1 mutation. Due to the IDH1 R132H mutation, the patient was diagnosed with diffuse astrocytoma WHO grade II and underwent successful gross total resection of this near-eloquently located tumor. This case exemplifies how inclusion of immunohistochemistry in tumor classification alters surgical strategy and might improve accuracy and time to diagnosis.