CSF biomarkers of neurotoxicity in childhood cancer survivors after cranial radiotherapy or surgery.

Objective: Treatment of pediatric brain tumors is associated with potential long-term cognitive sequelae. Patients treated with craniospinal irradiation for posterior fossa tumors are at high risk. New biomarkers that could help to differentiate treatment effects from other causes of cognitive dysfunction would be valuable in tailoring optimal survivorship care.

Supratentorial CNS-PNETs in children; a Swedish population-based study with molecular re-evaluation and long-term follow-up.

Background: Molecular analyses have shown that tumours diagnosed as supratentorial primitive neuro-ectodermal tumours of the central nervous system (CNS-PNETs) in the past represent a heterogenous group of rare childhood tumours including high-grade gliomas (HGG), ependymomas, atypical teratoid/rhabdoid tumours (AT/RT), CNS neuroblastoma with forkhead box R2 (FOXR2) activation and embryonal tumour with multi-layered rosettes (ETMR). All these tumour types are rare and long-term clinical follow-up data are sparse. We retrospectively re-evaluated all children (0-18 years old) diagnosed with a CNS-PNET in Sweden during 1984-2015 and collected clinical data.

Cancer in children born after frozen-thawed embryo transfer: A cohort study.

Background: The aim was to investigate whether children born after assisted reproduction technology (ART), particularly after frozen-thawed embryo transfer (FET), are at higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception.

Methods And Findings: We performed a registry-based cohort study using data from the 4 Nordic countries: Denmark, Finland, Norway, and Sweden. The study included 7,944,248 children, out of whom 171,774 children were born after use of ART (2.

DNA methylation profiling improves routine diagnosis of paediatric central nervous system tumours: A prospective population-based study.

Aims: Paediatric brain tumours are rare, and establishing a precise diagnosis can be challenging. Analysis of DNA methylation profiles has been shown to be a reliable method to classify central nervous system (CNS) tumours with high accuracy. We aimed to prospectively analyse CNS tumours diagnosed in Sweden, to assess the clinical impact of adding DNA methylation-based classification to standard paediatric brain tumour diagnostics in an unselected cohort.

Neuropsychological functioning in childhood cancer survivors following cranial radiotherapy - results from a long-term follow-up clinic.

Treatment of malignant childhood posterior fossa tumors (CPFT) often includes surgical resection and craniospinal radiotherapy (CSI). Nasopharyngeal tumors in childhood (CNPHT) are often treated with surgery and radiotherapy (RT), leading to incidental brain irradiation. RT to the developing brain is associated with risks for cognitive impairments.

Droplet digital PCR-based detection of circulating tumor DNA from pediatric high grade and diffuse midline glioma patients.

Background: The use of liquid biopsy is of potential high importance for children with high grade (HGG) and diffuse midline gliomas (DMG), particularly where surgical procedures are limited, and invasive biopsy sampling not without risk. To date, however, the evidence that detection of cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA) could provide useful information for these patients has been limited, or contradictory.

Methods: We optimized droplet digital PCR (ddPCR) assays for the detection of common somatic mutations observed in pediatric HGG/DMG, and applied them to liquid biopsies from plasma, serum, cerebrospinal fluid (CSF), and cystic fluid collected from 32 patients.

The reliability of the health related quality of life questionnaire PedsQL 3.0 cancer module in a sample of Swedish children.

Background: The Pediatric Quality of Life Inventory (PedsQL) is a modular instrument, designed to integrate generic and disease specific measures, and includes both self- and proxy-reports. The aim of the study was to assess the reliability and limited validity of the Swedish version of the disease specific Pediatric Quality of Life Inventory 3.0 Cancer Module Scales (PedsQL 3.

Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma.

Effects of the growth pattern of medulloblastoma on short-term neurological impairments after surgery: results from the prospective multicenter HIT-SIOP PNET 4 study.

Objective: Extensive resection of a tumor in the posterior fossa in children is associated with the risk of neurological deficits. The objective of this study was to prospectively evaluate the short-term neurological morbidity in children after medulloblastoma surgery and relate this to the tumor's growth pattern and to the extent of resection.

Methods: In 160 patients taking part in the HIT-SIOP PNET 4 (Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma) trial, neurosurgeons prospectively responded to questions concerning the growth pattern of the tumor they had resected.

A Weighted Genetic Risk Score of Adult Glioma Susceptibility Loci Associated with Pediatric Brain Tumor Risk.

Genetic risk score (GRS) is used to demonstrate the genetic variants contributing to the polygenic architecture of complex diseases. By using a GRS, we have investigated the additive impact of the known adult glioma susceptibility loci on the pediatric brain tumor (PBT) risk and assessed the proportion of PBT heritability attributable to these susceptibility loci. A GRS was generated for PBTs based on the alleles and associated effect sizes derived from a previously published genome-wide association study on adult glioma.

Central nervous system tumor registration in the Swedish Cancer Register and Inpatient Register between 1990 and 2014.

Background: The Swedish Cancer Register (SCR) is characterized by excellent quality and completeness overall, but the quality of the reporting may vary according to tumor site and age, and may change over time. The aim of the current study was to investigate the completeness of the reporting of central nervous system (CNS) tumor cases to the SCR.

Materials And Methods: Individuals hospitalized for a CNS tumor between 1990 and 2014 were identified using the Inpatient Register; the proportion of identified cases that did not have any cancer diagnosis reported to the SCR was subsequently assessed.

Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial.

Background: Most children with medulloblastoma fall within the standard-risk clinical disease group defined by absence of high-risk features (metastatic disease, large-cell/anaplastic histology, and MYC amplification), which includes 50-60% of patients and has a 5-year event-free survival of 75-85%. Within standard-risk medulloblastoma, patients in the WNT subgroup are established as having a favourable prognosis; however, outcome prediction for the remaining majority of patients is imprecise. We sought to identify novel prognostic biomarkers to enable improved risk-adapted therapies.

Parental age and risk of genetic syndromes predisposing to nervous system tumors: nested case-control study.

Purpose: Phacomatoses are genetic syndromes that are associated with increased risk of developing nervous system tumors. Phacomatoses are usually inherited, but many develop de novo, with unknown etiology. In this population-based study, we investigated the effect of parental age on the risk of phacomatoses in offspring.

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.

Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED).

Information needs of survivors and families after childhood CNS tumor treatment: a population-based study.

Background: This study examines information needs and satisfaction with provided information among childhood central nervous system (CNS) tumor survivors and their parents.

Material And Methods: In a population-based sample of 697 adult survivors in Sweden, 518 survivors and 551 parents provided data. Information needs and satisfaction with information were studied using a multi-dimensional standardized questionnaire addressing information-related issues.

Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures.

Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis.

Correction: A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma.

[This corrects the article DOI: 10.1371/journal.pone.

Quality of survival and cognitive performance in children treated for medulloblastoma in the PNET 4 randomized controlled trial.

Background: The relationship between direct assessments of cognitive performance and questionnaires assessing quality of survival (QoS) is reported to be weak-to-nonexistent. Conversely, the associations between questionnaires evaluating distinct domains of QoS tend to be strong. This pattern remains understudied.

Effects of physically active video gaming on cognition and activities of daily living in childhood brain tumor survivors: a randomized pilot study.

Background: Physical activity can enhance cognitive functions in both animals and humans. We hypothesized that physically active video gaming could: i) improve cognitive functions and ii) improve the execution of activities of daily living among survivors of childhood brain tumors.

Methods: Children 7 to 17 years old who completed treatment, including radiotherapy, for a brain tumor 1 to 5 years earlier were randomized to either intervention or waiting list.

Hypothermia after cranial irradiation protects neural progenitor cells in the subventricular zone but not in the hippocampus.

Purpose: To explore if hypothermia can reduce the harmful effects of ionizing radiation on the neurogenic regions of the brain in young rats.

Materials And Methods: Postnatal day 9 rats were randomized into two treatment groups, hypo- and normothermia, or a control group. Treatment groups were placed in chambers submerged in temperature-controlled water baths (30 °C and 36 °C) for 8 h, after receiving a single fraction of 8 Gy to the left hemisphere.

A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma.

Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g.

Stem cell cultures derived from pediatric brain tumors accurately model the originating tumors.

Brain tumors are the leading cause of cancer-related death in children but high-grade gliomas in children and adolescents have remained a relatively under-investigated disease despite this. A better understanding of the cellular and molecular pathogenesis of the diseases is required in order to improve the outcome for these children. In vitro-cultured primary tumor cells from patients are indispensable tools for this purpose by enabling functional analyses and development of new therapies.

Prenatal and Postnatal Medical Conditions and the Risk of Brain Tumors in Children and Adolescents: An International Multicenter Case-Control Study.

Background: Previous studies have evaluated the effect of medical diagnostic radiation on brain tumors. Recent cohort studies have reported an increased risk associated with exposure to head CT scans.

Methods: Information regarding medical conditions, including prenatal and postnatal exposure to medical diagnostic radiation, was obtained from CEFALO, a multicenter case-control study performed in Denmark, Norway, Sweden, and Switzerland through face-to-face interview.

Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility.

Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk.The study is based on the largest series of PBT cases to date.