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Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort. Supplementary Information The online version contains supplementary material available at 10.1007/s10689-021-00237-1.

INTRODUCTION: Children with suprasellar brain damage are at risk for hypothalamic dysfunction (HD). HD may lead to decreased resting energy expenditure (REE) contributing to the development of hypothalamic obesity. Decreased REE, however, is not present in all children with hypothalamic damage. Our aim was to assess which children suspect for HD have low REE, and if REE outcome can be associated with clinical severity of HD or with radiological posterior hypothalamic damage. METHODS: A retrospective cohort study was performed evaluating all children diagnosed with brain injury at risk for HD in whom REE measurement was performed. Measured REE (mREE) was compared to predicted REE (pREE) using amongst others the Schofield equation. Low REE was defined as mREE

Leptomeningeal malignancy complicates childhood cancers, including leukaemias, brain tumours, and solid tumours. In leukaemia, such malignancy is thought to invade leptomeninges via the vascular route. In brain tumours, dissemination from the primary tumour, before or after surgery, via CSF pathways is assumed; however, evidence exists to support the vascular route of dissemination. Success in treating leptomeningeal malignancy represents a rate-limiting step to cure, which has been successfully overcome in leukaemia with intensified systemic therapy combined with intra-CSF therapy, which replaced cranial radiotherapy for many patients. This de-escalated CNS-directed therapy is still associated with some neurotoxicity. The balanced benefit justifies exploration of ways to further de-escalate CNS-directed therapy. For primary brain tumours, standard therapy is craniospinal radiotherapy, but attendant risk of acute and delayed brain injury and endocrine deficiencies compounds post-radiation impairment of spinal growth. Alternative ways of treating leptomeninges by intensifying drug therapy delivered to CSF are being investigated—preliminary evidence suggests improved outcomes. This Review seeks to describe methods of intra-CSF drug delivery and drugs in use, and consider how the technique could be modified and additional drugs might be selected for this route of administration.

Brain tumors account for over 20% of childhood cancers and are the biggest cancer killer in children and young adults. Several initiatives over the past 40 years have tried to identify more effective drug treatments, but with very limited success. This is largely due to the bloodâ brain barrier, which restricts the entry of many drugs into the brain. In this review, we describe the main techniques that are being developed to enhance brain tumor drug delivery and explore the preclinical brain tumor models that are essential for translational development of these techniques. We also identify existing approved drugs that, if coupled with an efficient delivery method, could have potential as brain tumor treatments. Bringing this information together is part of a funded initiative to highlight drug delivery as a research strategy to overcome the current challenges for children diagnosed with brain tumors., This review was written on behalf of the Children's Brain Tumor Drug Delivery Consortium, which is funded by Children with Cancer UK, grant number 16-244. This review was also supported by Maryland's Cancer Moonshot Initiative in Pediatric Cancer Research, grant number Project 4'.

BACKGROUND: Recent insights highlight how the initiation and growth of gliomas is governed by interactions between glioma stem-like cells and stromal and immune cells in the tumor microenvironment. For pilocytic astrocytomas, the most common pediatric CNS tumor, this relationship is so far less explored. To this end, we used transcriptomic methods to investigate inter-patient heterogeneity, and the stromal and immune microenvironment of pilocytic astrocytomas. MATERIALS AND METHODS: In this study, we collected clinical data and tissue of 90 pre-treatment pilocytic astrocytomas from different CNS compartments: posterior fossa (n=57), supratentorial (n=23), and spinal (n=10). The median age at primary resection was 8 (0-16) years, and 66% (n=59) of our cohort was male. From 10 of these patients, we collected post-treatment samples after re-growth of the tumor as well. We characterized all samples by bulk RNA-sequencing and DNA methylation profiling, and selected a subset (n=10) samples for single-nucleus RNA-sequencing. RESULTS: Principal component analysis and unsupervised clustering of bulk sequencing data revealed gene expression patterns correlating to the CNS location of the tumor, consistent with prior reports. Using differential expression and functional pathway analysis, we found CNS region-associated enrichment of cell-cycle, developmental, and inflammatory-related pathways. With respect to the glioma immune microenvironment, supratentorial tumors were enriched in gene-sets related to T-cell activation and cytotoxicity, while spinal tumors had lowest expression of immune-related genes. Moreover, spinal tumors were enriched in pathways related to cell division, nucleotide synthesis, and neurodevelopment. To resolve cell-type expression programs of glioma and immune cells in the microenvironment, we collected and analyzed snRNA-seq data of 10 pilocytic astrocytomas, as well as harmonized our findings with a pre-existing dataset from Vladoiu, 2019. CONCLUSION: Our integrative transcriptomic analysis of pilocytic astrocytomas highlights CNS region-associated differences in expression programs of the glioma cells and in the immune cell composition of the tumor microenvironment.

Fecal microbiota transplantation (FMT) is a very effective treatment for recurrent Clostridium difficile infection (CDI) in adults. However, there is a paucity of data on FMT in children and associated microbiome changes in this particular group. We describe a child with Down's syndrome and intracranial malignancy, who received FMT for recurrent CDI. Detailed microbiota analysis before and after FMT, and pre- and post-recurrence, linked to microbial communities in the donor feces showed that the patient developed a unique microbiota profile after FMT which was very stable over time despite CDI recurrence and subsequent fidaxomicin therapy. Bacteroidetes were stably acquired from donor feces, while Firmicutes, Actinobacteria, Fusobacteria, Verrucomicrobia, and Proteobacteria were unique to the patient. The diversity of microbiota of the patient increased from a Shannon diversity index of 2.08 pre-FMT to 3.12 post-FMT. Our findings underscore that patients with Down's syndrome may well tolerate and benefit from FMT even in a severely immunocompromised state.

Central nervous system (CNS) tumor with BCOR internal tandem duplication (BCOR-ITD) have recently been introduced in the 5th edition of the WHO classification of CNS tumors, however, their molecular makeup and clinical characteristics remain widely enigmatic. This is further complicated by the recent discovery of tumors characterized by gene fusions involving BCOR or its homologue BCORL1. We identified a cohort of 206 BCOR altered CNS tumors via DNA methylation profiling and conducted in-depth molecular and clinical characterization in an international effort. By performing t-SNE clustering analysis we found that BCOR-fusion tumors form a distinct cluster (n=61), adjacent to BCOR-ITD cases (n=145). The identified fusion partners of BCOR(L1) included EP300 (n=20), CREBBP (n=5), and NUTM2HP (n=1). Notably, three cases within the BCOR-ITD cluster harbored a c-terminal intragenic deletion within BCOR. With respect to clinical characteristics gender ratio was balanced in BCOR-fusion cases (m/f, 1.1), whereas predominance of male patients was observed in the BCOR-ITD group (m/f, 1.5). Moreover, age at diagnosis of BCOR-fusion patients was higher as compared to BCOR-ITD cases (15 vs 4.5 years). Interestingly, BCOR-fusion tumors were exclusively found in the supratentorial region being originally diagnosed as ependymomas or gliomas whereas BCOR-ITD emerged across the entire CNS with diverse original diagnoses. 8% of BCOR-ITD and none of BCOR-fusion cases were disseminated at diagnosis. In line with this observation, 40% of first relapses within the BCOR-ITD group were metastatic which was less frequent in BCOR-fusion tumors. Survival estimates demonstrated no differences, generally showing short median PFS (BCOR-fusion, 2 years, n=15; BCOR-ITD, 1.8 years, n=55) and intermediate OS rates (BCOR-fusion, 6.8 years, n=18; BCOR-ITD 6.3 years, n=60). Further molecular and clinical characterization is ongoing potentially revealing first therapeutic leads for these highly aggressive CNS tumor types.

// Juliette Servante 1 , Jasper Estranero 2 , Lisethe Meijer 2 , Rob Layfield 1 and Richard Grundy 2 1 School of Life Sciences, University of Nottingham, Medical School, Nottingham, NG7 2UH, UK 2 Children’s Brain Tumor Research Centre, Medical School, Queen’s Medical Centre, Nottingham, NG7 2UH, UK Correspondence to: Juliette Servante, email: juliette.servante@nhs.net Keywords: autophagosome; autophagy; childhood brain tumors; chloroquine; mTOR Received: January 20, 2018 Accepted: August 27, 2018 Published: October 16, 2018 ABSTRACT Brain tumors are the leading cause of cancer-related death in children and are the most challenging childhood cancer in relation to diagnosis, treatment, and outcome. One potential novel strategy to improve outcomes in cancer involves the manipulation of autophagy, a fundamental process in all cells. In cancer, autophagy can be thought of as having a “Janus”-like duality. On one face, especially in the early phases of cancer formation, autophagy can act as a cellular housekeeper to eliminate damaged organelles and recycle macromolecules, thus acting as tumor suppressor. On the other face, at later stages of tumor progression, autophagy can function as a pro-survival pathway in response to metabolic stresses such as nutrient depravation, hypoxia and indeed to chemotherapy itself, and can support cell growth by supplying much needed energy. In the context of chemotherapy, autophagy may, in some cases, mediate resistance to treatment. We present an overview of the relevance of autophagy in central nervous system tumors including how its chemical modulation can serve as a useful adjunct to chemotherapy, and use this knowledge to consider how targeting of autophagy may be relevant in pediatric brain tumors.

Summary: The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma. : Using peptide phosphorylation profiling, Zomerman et al. identify two medulloblastoma phosphoprotein-signaling profiles that have prognostic value and are potentially targetable. They find that these profiles extend across transcriptome-based subgroup borders. This suggests that diverse genetic information converges on common protein-signaling pathways and highlights protein-signaling as a unique information layer. Keywords: medulloblastoma, protein-signaling, protein synthesis, MYC, TP53, proteome, phosphoproteome

Approximately 15% of the children with Neurofibromatosis type 1 (NF1) develop a central nervous system (CNS) tumor, predominantly optic pathway glioma. However, other brain tumor types are also frequent, resulting in a heterogenous population regarding tumor type, symptoms and treatment. Even though many tumors are indolent, clinical deterioration or radiological progression requires surveillance and treatment. Pediatric oncology care in the Netherlands has been centralized into the Princess Máxima Center since June 2018, providing care for the majority of Dutch NF1 CNS tumor patients. This retrospective cohort study describes the course of disease in NF1 patients with a CNS tumor diagnosed between 2005–2020, based on data from patient files. The population consisted of 95 patients (48 males), median age at diagnosis 4.3 (range 0.8–17.2) and 12.6 (range 2.9–19.9) years at follow up, 27% familiar NF1, mostly nonsense or frameshift mutations. Neurological and/or visual symptoms were present in 64 (67.4%) patients. 63.6% of the tumors was in the optic pathway, 9.1% in the cerebellum. Biopsy in 19/95 revealed 1 ependymoma and 18 low grade glioma, with rarely additional molecular changes besides NF1. Kaplan Meier median PFS was 24 months (range 3–174.5, n=65) in symptomatic presenting patients, 34 months (range 5–165, n=20) in asymptomatic patients with abnormal ophthalmological and/or neurological exam and 67.3 months (range 7–130, n=10) in asymptomatic patients without abnormalities at exam. Treatment was indicated in 53 (55.8%), predominantly chemotherapy (n=49), with substantial toxicity. Carboplatin allergy was seen in 29/44 (65.9%) patients, peripheral neuropathy in 21/46 (45.7%) patients receiving vincristine, and 5/10 patients receiving irinotecan and bevacizumab ended treatment early due to toxicity. In conclusion: analysis of our extensive cohort of NF1 patients with a CNS tumor indicates the relevance of regular screening of NF1 patients without complaints and critical surveillance and systematical documentation of treatment toxicity.

BACKGROUND: Organohalogen compounds (OHCs), i.e. polychlorinated biphenyls (PCBs, are wide-spread environmental pollutants known to be neurotoxic for the developing brain. The hydroxylated metabolites of PCBs, OH-PCBs, might be even more toxic due to their structure and interference with thyroid hormone metabolism. We found that prenatal exposure to OH-PCBs was associated with thyroid hormone metabolism at toddler age. Little, however, is known about the neurotoxicity of OH-PCBs in humans.OBJECTIVES: To determine whether prenatal background exposure to OHCs has an effect on mental and motor development in children at the age of 18 and 30 months.METHODS: One hundred and eighty-one healthy mother-infant pairs were included in this observational study performed in the Netherlands. We measured maternal pregnancy levels of PCB-153 and three OH-PCBs. In one part of the cohort we measured another nine PCBs and three OH-PCBs and in the other part we measured five brominated diphenyl ethers (BDEs), dichloro-diphenyldichloroethylene (p,p'-DDE), pentachlorophenol (PCP), and hexabromocyclododecane (HBCDD). We used the mental development index (MDI) and the motor development index (PDI) of the Bayley Scales of Infant Development II (BSID-II) to assess children's mental and motor development (mean = 100; delayed score RESULTS: Higher prenatal PCB-153 levels were associated with a delayed MDI score at 18 months. None of the other compounds were associated with a delayed score, but several associations were found between OHC levels and BSID-II scores. The sum of all six OH-PCBs and three individual OH-PCBs, 4-OH-PCB-107, 3-OH-PCB-153, and 4'-OH-PCB-172, correlated positively with MDI at 30 months. The compound 3'-OH-PCB-138 showed a similar trend. A higher 4-OH-PCB-187 was associated with a lower MDI at 18 months. We found a similar trend for higher BDE-99. Higher BDE levels were associated with higher PDI at 18 months. The levels of p,p'-DDE-, PCP, and HBCDD were not associated with BSID-II scores at 18 months.CONCLUSIONS: Higher prenatal levels of PCB-153 were associated with a delayed MDI score at 18 months. None of the other compounds were associated with a delayed score, but several associations were found between OHC levels and BSID-II scores. Prenatal OH-PCBs were positively associated with mental development at 30 months, whereas one OH-PCB was negatively associated at 18 months. BDE levels were positively associated with psychomotor development. Prenatal p,p'-DDE, PCP, and HBCDD levels were not associated with neurodevelopment at 18 months.

Subependymal giant cell astrocytomas (SEGAs) cause serious neurological complications in patients with tuberous sclerosis complex. Using high-throughput sequencing, Bongaarts et al. identify MAPK/ERK activation in SEGAs, potentially via the "Ragulator complex", and propose that the MAPK/ERK pathway could be a novel treatment target., Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1–5 can form a complex, known as the ‘Ragulator’ complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth.

Background: Craniopharyngiomas are frequent hypothalamo-pituitary tumors in children, presenting predominantly as cystic lesions. Morbidity from conventional treatment has focused attention on intracystic drug delivery, hypothesized to cause fewer clinical consequences. However, the efficacy of intracystic therapy remains unclear. We report the retrospective experiences of several global centers using intracystic interferon-alpha.Methods: European Societe Internationale d'Oncologie Pediatrique and International Society for Pediatric Neurosurgery centers were contacted to submit a datasheet capturing pediatric patients with cystic craniopharyngiomas who had received intracystic interferon-alpha. Patient demographics, administration schedules, adverse events, and outcomes were obtained. Progression was clinical or radiological (cyst reaccumulation, novel cysts, or solid growth).Results: Fifty-six children (median age, 6.3 y) from 21 international centers were identified. Median follow-up from diagnosis was 5.1 years (0.3-17.7 y). Lesions were cystic (n = 22; 39%) or cystic/solid (n = 34; 61%). Previous progression was treated in 43 (77%) patients before interferon use. In such cases, further progression was delayed by intracystic interferon compared with the preceding therapy for cystic lesions (P = 0.0005). Few significant attributable side effects were reported. Progression post interferon occurred in 42 patients (median 14 mo; 0-8 y), while the estimated median time to definitive therapy post interferon was 5.8 (1.8-9.7) years.Conclusions: Intracystic interferon-alpha can delay disease progression and potentially offer a protracted time to definitive surgery or radiotherapy in pediatric cystic craniopharyngioma, yet demonstrates a favorable toxicity profile compared with other therapeutic modalities-important factors for this developing age group. A prospective, randomized international clinical trial assessment is warranted.

BACKGROUND AND PURPOSE: Qualitative radiologic MR imaging review affords limited differentiation among types of pediatric posterior fossa brain tumors and cannot detect histologic or molecular subtypes, which could help to stratify treatment. This study aimed to improve current posterior fossa discrimination of histologic tumor type by using support vector machine classifiers on quantitative MR imaging features. MATERIALS AND METHODS: This retrospective study included preoperative MRI in 40 children with posterior fossa tumors (17 medulloblastomas, 16 pilocytic astrocytomas, and 7 ependymomas). Shape, histogram, and textural features were computed from contrast-enhanced T2WI and T1WI and diffusivity (ADC) maps. Combinations of features were used to train tumor-type-specific classifiers for medulloblastoma, pilocytic astrocytoma, and ependymoma types in separation and as a joint posterior fossa classifier. A tumor-subtype classifier was also produced for classic medulloblastoma. The performance of different classifiers was assessed and compared by using randomly selected subsets of training and test data. RESULTS: ADC histogram features (25th and 75th percentiles and skewness) yielded the best classification of tumor type (on average >95.8% of medulloblastomas, >96.9% of pilocytic astrocytomas, and >94.3% of ependymomas by using 8 training samples). The resulting joint posterior fossa classifier correctly assigned >91.4% of the posterior fossa tumors. For subtype classification, 89.4% of classic medulloblastomas were correctly classified on the basis of ADC texture features extracted from the Gray-Level Co-Occurence Matrix. CONCLUSIONS: Support vector machine–based classifiers using ADC histogram features yielded very good discrimination among pediatric posterior fossa tumor types, and ADC textural features show promise for further subtype discrimination. These findings suggest an added diagnostic value of quantitative feature analysis of diffusion MR imaging in pediatric neuro-oncology.

The first Workshop on Drug Delivery in Paediatric Brain Tumours was hosted in London by the charity Children with Cancer UK. The goals of the workshop were to break down the barriers to treating central nervous system (CNS) tumours in children, leading to new collaborations and further innovations in this under-represented and emotive field. These barriers include the physical delivery challenges presented by the blood-brain barrier, the underpinning reasons for the intractability of CNS cancers, and the practical difficulties of delivering cancer treatment to the brains of children. Novel techniques for overcoming these problems were discussed, new models brought forth, and experiences compared: OA gold

The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma.

Organohalogen compounds (OHCs) are toxic environmental pollutants used extensively in pesticides, flame retardants, hydraulic fluids, and in other industrial applications (Mariussen and Fonnum 2006). They are ubiquitously present in the environment, both in neutral and in phenolic form (Law et al. 2003). OHCs are known to bioaccumulate because of their high lipophilicity and resistance to degradation processes (Rahman et al. 2001) and have been detected in human adipose tissue and blood (Jensen 1987). In pregnant women these compounds are transferred across the placenta to the fetus (Lanting et al. 1998; Meijer et al. 2008). During this critical period of fetal growth and development, there is a risk for damage of the central nervous system because OHCs may interfere with developmental processes in the brain. Some compounds have effects on neuronal and glial cell development and are associated with disruption of neurotransmitters. Others interfere with endocrine systems, such as thyroid and sex hormones (Solomon and Schettler 2000; Weisglas-Kuperus 1998). OHCs may also produce their toxic effects through other pathways that are currently not well understood. Previous studies in humans on the effect of prenatal OHC exposure on outcome reported that polychlorinated biphenyls (PCBs) have adverse effects on neurologic performance and cognitive development at 6–11 years of age (Boersma and Lanting 2000; Chen et al. 1992; Jacobson and Jacobson 1996; Stewart et al. 2008; Vreugdenhil et al. 2002). Knowledge of the neurotoxicity of PCBs led to their abandonment in most Western countries in the late 1970s. Despite this, metabolites of PCBs, the hydroxylated PCBs (OH-PCBs), are still present in high concentrations in maternal serum (Guvenius et al. 2003; Meijer et al. 2008). Previous studies postulated that OH-PCBs are even more toxic to brain development than are PCBs (Kimura-Kuroda et al. 2007; Kitamura et al. 2005). The long-term effect of prenatal OH-PCB exposure on human development is unknown. Brominated flame retardants such as polybrominated biphenyls (PBBs) and polybrominated diphenyl ethers (PBDEs) were introduced as the new, allegedly harmless, successors of PCBs. However, the effect of prenatal exposure to brominated flame retardants on neurodevelopmental outcome at school age has never been investigated. The primary aim of this explorative study was to investigate the influence of prenatal OHC exposure, including OH-PCBs and PBDEs, on motor, cognitive, and behavioral outcomes in healthy Dutch children at 5–6 years of age. OHCs are also known to influence fetal thyroid hormone levels (Zoeller 2007). Because thyroid hormones are involved in neurodevelopmental processes, our second aim was to investigate whether thyroid hormone levels at birth were related to outcome in these children.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including cafe-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment. (C) 2016 The Author(s). Published by Elsevier Ireland Ltd.

Polybrominated diphenyl ethers are lipophilic persistent organic pollutants (POPs), which accumulate in the environment, leading to human exposure. The compounds exert a negative impact on human health. Strategies to prevent or diminish their accumulation in humans are required. We investigated in rats whether the disposal rate of C-14-labeled tetrabromodiphenyl ether (BDE-47) could be enhanced by increasing fecal fat excretion through dietary treatment with nonabsorbable fat (sucrose polyester, SPE). As compared to control rats, SPE treatment increased fecal excretion rates of fat (+188%, p

Background Prenatal exposure to endocrine disruptors, like organohalogen compounds (OHCs), might be responsible for the increased aberrations in human male sexual development (hypospadias, cryptorchidism, testicular cancer and fall in sperm count) observed over the past decades. This development is established during fetal life, and reflected in sex hormone levels, testes volume and penile length post-partum. The present study investigates the correlation between prenatal OHC levels and male sexual development outcomes.Methods AND RESULTSLevels of eight neutral [2,2′-bis-(4-chlorophenyl)-1,1′- dichloroethene (4,4′-DDE), 2,2′,4,4′,5,5′- hexachlorobiphenyl, 2,2′,4,4′-tetrabromodiphenyl ether (BDE)-47,-99,-100,-153,-154 and 1,2,5,6,9,10-hexabromocyclododecane, HBCDD] and four phenolic [(pentachlorophenol (PCP), 4OH-CB-107 (4-hydroxy-2,3,3′, 4′,5-pentachlorobiphenyl),-146 and-187)] OHCs were determined in 55 maternal serum samples taken at 35 weeks of pregnancy. Eight sex development-related hormones [testosterone, free testosterone, sex hormone-binding globulin (SHBG); LH, FSH, estradiol (E2), free E2 (FE2) and inhibin B (InhB)] were determined in their sons at 3 months of age, and testes volume and penile length at 3 and 18 months of age. The following prenatal OHC levels correlated significantly with sex hormone levels: PCP with SHBG and InhB (ρ 0.30 and-0.43, respectively), 4OH-CB-107 with testosterone (ρ 0.31) and BDE-154 with FE2, E2 and InhB (ρ 0.49, 0.54 and 0.34, respectively). BDE-154 levels correlated positively with testes volume at 18 months of age (ρ 0.34). Conclusions Prenatal OHC exposure is correlated with aspects of sexual development outcome in boys up to 18 months of age. © 2012 The Author.

INTRODUCTION: Daily intra-cerebrospinal fluid (CSF) etoposide administration regimens are in use, by-passing the blood-brain-barrier and offering higher CSF drug concentrations at 1/30th to 1/340th the dose in conventional systemically administered standard and high dose etoposide regimens, respectively. METHOD: 42 pharmacokinetic samples were obtained from a paediatric (36) and adult patient (6). Etoposide 0.75 mg was administered over 1-2 minutes via the intra-ventricular (IVT) or lumbar route (LR), on 5 consecutive days for 1-3 weeks. CSF sampling at 4h (IVT: 3, LR: 3), 8h (IVT: 3, LR: 2), 18h (IVT: 1, LR: 1), 24h (IVT: 11, LR: 9), and 72h (IVT: 5, LR: 4). Etoposide concentrations were determined by LC/MS analysis, with a detection limit of 0.1 µg/ml. RESULTS: No acute neurotoxicity was observed. Single IVT administration with LR sampling yielded higher concentrations than LR administration with IVT sampling at 4h and 8h (1.73 and 0.93 µg/ml, vs. 1.42 and 0.76 µg/ml, respectively), also observed with simultaneous LR and IVT administration (median LR concentration 5.11 and 1.77 µg/ml at 4h and 8h; median IVT concentration 3.64 and 1.48 µg/ml at 4h and 8h). Concentrations at 24h were

OBJECTIVE: To determine the stability of the scores obtained on tests of motor development from birth until school age in healthy, term singletons and to determine if early motor scores are associated with more complex cognitive functions at school age, such as attention and memory. PATIENTS AND METHODS: This longitudinal, prospective cohort study included 77 infants. The motor development of these infants was assessed during the neonatal period with Prechtl's neurologic examination; in early infancy with Touwen's neurologic examination and general movement assessment; at toddler age with Hempel's neurologic examination and the Psychomotor Developmental Index from the Bayley Scales of Infant Development; and at school age with the Movement Assessment Battery for Children. Cognition was determined at toddler age with the Mental Developmental Index from the Bayley Scales of Infant Development; and at school age with an intelligence test and attention and memory tests. RESULTS: The mean absolute difference in standardized motor scores for all time points was 1.01 SD (95% confidence interval: 0.91–1.11). Only the explained proportions of variance of maternal socioeconomic status and verbal intelligence were significant for sustained attention and verbal memory (r2 = 0.104, P = .030 and r2 = 0.074, P = .027), respectively. The children's scores on early motor tests added little value for their motor and cognitive development at school age. CONCLUSIONS: In healthy children the stability of motor development from birth until school age is low. Maternal socioeconomic status and verbal intelligence rather than the infants' scores on early motor tests signified added value for complex cognitive functions at school age.

As part of a large European Union (EU)-funded comparative toxicology and human epidemiology study, EU-Compare, a selection of organohalogen compounds (OHCs) was analyzed in maternal serum, collected at the 35th week of pregnancy, and in cord serum of a number of their infants to determine maternal concentrations and to investigate the extent of transplacental transfer of these compounds. Eight neutral OHCs were analyzed: one polychlorinated biphenyl (PCB: CB-153),4,4'-DDE, five polybrominated diphenyl ethers (PBDEs: BDE-47, BDE-99, BDE-100, BDE-153, and BDE-154), and hexabromocyclododecane (HBCDD). Five phenolic OHCs were analyzed: three hydroxylated PCBs (40H-CB-107, 40H-CB-146, and 40H-CB-187), one hydroxylated PBDE (60H-BDE-47), and pentachlorophenol (PCP). All OHCs, except 60H-BDE-47, were present in maternal and cord serum. The historically identified OHCs showed the highest concentration: 4,4′'-DDE (median value 89 ng/g lipid in maternal serum and 68 ng/g lipid in cord serum) and PCP (median value 970 pg/g serum in maternal serum and 1500 pg/g serum in cord serum). HBCDD and the PBDEs were present atmuchlowerconcentrations. WeconcludethatOHCs are present in the serum of pregnant women, and all compounds tested are transferred over the placenta. Because transfer is occurring at a critical stage of infant development investigation of the health impact is urgent. © 2008 American Chemical Society.

INTRODUCTION: Continuous intra-CSF etoposide infusion may optimise etoposide pharmacokinetics by bypassing the blood-brain-barrier and compensating for CSF bulk flow removal, at < 1/340th dose of standard regimens. A 3 + 3 phase I study is proposed, escalating target [CSF etoposide] and infusion durations of intra-CSF etoposide in children with LM. We justify target [CSF etoposide] and infusion durations based upon previously reported clinical and our own preclinical studies. METHOD: AUC24 values were calculated from Fleischhack report of 24 patients receiving intra-ventricular etoposide at 0.25 mg/12h, 0.5 mg/24h or 1 mg/24h, for 5 days, q 2-4 wks (n = 119 cycles), no dose limiting toxicity was reported. The AUC24 values derived from these clinical studies were compared to etoposide cytotoxicity data in human tumour and neural stem cell 3D co-cultures. AUC values were selected to derive target [CSF etoposide], levels 1 & 2 for infusion durations of 7, 10 and 14 days: AUC24= [CSF etoposide] x time (h). RESULTS: Based upon 0.25 mg/12h dose level, the AUC24 25 µg x h/ml (level 1) predicted [CSF etoposide] 1 µg/ml over 24 hours and an AUC7day of 175 µg x h/ml. The cytotoxicity assay [etoposide] of 0.8-1.2 µg/ml resulted in 22% neural stem cell and 8% tumour cell viability, illustrating differential toxicity. Level 1[CSF etoposide] was selected as 0.8 µg/ml as equivalent of AUC24 20, for 7 days (AUC7day 140). Level 2 [CSF etoposide] of 1.2 µg/ml was selected, (AUC7day 210, AUC10days 300; AUC14day 420). CONCLUSION: Target [CSF etoposide] will be 0.8 µg/ml (level 1) to 1.2 µg/ml (level 2), with infusion durations of 7, 10 or 14 day.