Summary Accurate pathological diagnosis is crucial for optimal management of cancer patients. For the ~100 known central nervous system (CNS) tumour entities, standardization of the diagnostic process has been shown to be particularly challenging - with substantial inter-observer variability in the histopathological diagnosis of many tumour types. We herein present the development of a comprehensive approach for DNA methylation-based CNS tumour classification across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that availability of this method may have substantial impact on diagnostic precision compared with standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility we have designed a free online classifier tool (www.molecularneuropathology.org) requiring no additional onsite data processing. Our results provide a blueprint for the generation of machine learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Gene expression profiles and chromosome 3 copy number divide uveal melanomas into two distinct classes correlating with prognosis1–3. Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize. Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%). Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis2. Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 (7; 54%) or EIF1AX (1; 8%). All EIF1AX mutations caused in-frame changes affecting the N terminus of the protein, whereas 17 of 19 SF3B1 mutations encoded an alteration of Arg625. Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors, none of which targeted Arg625.

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.

SummaryThe functional differentiation of immune cells at early age plays a central role in immune physiology, e.g. for the sufficient eradication of pathogens. However, imbalances in effector cell responses may also have an impact in the pathophysiology of childhood diseases such as atopy and autoimmune disorders. As information on immune cell responses in infancy and early childhood is scarce, we conducted an observational, cross-sectional study in healthy newborns ( n = = = = 18), infants and young children ( n = = = = 54) aged 1-96 months and adult controls ( n = = = = 19) to assess cytokine mRNA and protein expression upon phorbol 12-myristate 13-actate/ionomycin stimulation and LPSinduced IL-12 expression in monocytes. The intracellular expression of interferon (IFN)-γ γ γ γ , tumour necrosis factor (TNF)-α α α α ( R = = = = 0·748, P < < < < 0·0001; R = = = = 0·784, P < < < < 0·0001, respectively) and interleukin (IL)-2 protein expression ( R = = = = 0·384, P = = = = 0·008) was demonstrated to increase progressively with age. While a correlation between IL-4 protein expression and age was noted ( R = = = = 0·342, P = = = = 0·007), the levels of IL-5 and IL-10 protein expression tended to be regulated on an individual basis during infancy and early childhood. An age correlation was also observed for intracellular IL-12 expression ( R = = = = 0·331, P = = = = 0·009) in monocytes. These findings are valuable for further assessment of normal variations and maturation processes in immune cell responses and for the clinical-therapeutic monitoring of immunological status in various childhood diseases.

There is growing evidence that sepsis-related complications in neonates are crucially mediated by the action of proinflammatory cytokines. It has previously been demonstrated that elevated IL-6 and IL-8 levels can predict brain damage and chronic lung disease in preterm infants. However, it is the current view that neonates have a reduced capability to produce proinflammatory cytokines. To clarify this issue, we analyzed the inflammatory response in term and preterm infants directly at the single cell level by flow cytometry. Endotoxin challenge was performed under defined conditions on monocytes obtained from 50 healthy adults and 119 neonates, which consist of 45 term infants, 63 preterm infants (26.1-36.7 wk of gestational age), and 11 preterm infants with proven infection (24.6 -29.9 wk). Our results challenge the existing view of an immature inflammatory response by demonstrating that term infants and preterm infants display a higher percentage of IL-6 -and IL-8 -positive cells than adults. After preincubation with dexamethasone the number of cytokine-positive cells decreased in all groups, but the number of IL-8 -positive cells remained higher in term and preterm infants Ͼ32 wk compared with adults. These observations demonstrate not only a well-developed but also an enhanced inflammatory response in term and preterm infants. Under consideration of several detrimental effects of IL-6 and IL-8, our data may have major implications on the pathophysiology of inflammatorytriggered neonatal diseases. Neonatal bacterial sepsis remains a critical determinant of outcome in infants of very low birth weight despite the availability of antibiotics (1-3). The immaturity of the neonatal immune system, especially a reduced cytokine-producing capacity, was assumed to be responsible for the high susceptibility to infections (4 -11). Particularly, the high prevalence of complications secondary to infections represents a major determinant of neonatal mortality and morbidity (3). Although older children and adults are usually able to restrict bacterial infections, neonates often develop a severe systemic inflammatory response with detrimental effects. There is growing evidence that this process is crucially mediated by the action of distinct inflammatory cytokines (12, 13). It has previously been demonstrated that elevated IL-6 and IL-8 levels in cord blood and lung lavage can predict neonatal brain damage and chronic lung disease in preterm infants (14 -16). Furthermore, proinflammatory cytokines could be demonstrated in high amounts in brain white matter lesions of preterm infants (17). These observations strongly suggest a key role of proinflammatory cytokines in the pathogenesis of several neonatal diseases. Although a variety of studies have been performed on inflammatory mediators in neonates during infection, these data can be misleading because of the evolving immunoparalysis occurring in progressing sepsis (18,19). To better characterize the inflammatory response in neonates we performed an ex vivo model of sepsis, ...