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BackgroundGermline pathogenic variants in DICER1cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (Global developmental delay, Lung cysts, Overgrowth, Wilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.MethodsWhole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with DICER1RNase III domain mutations were performed.ResultsA de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of DICER1was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome.ConclusionThe phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to DICER1hotspot mutations in the RNase IIIb domain. We show that an individual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome (‘DICER1 syndrome plus’), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.

A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored1–5. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns. Multiregional analysis in 54 childhood cancers highlights four evolutionary patterns of intratumoral variation. Multiple patterns are often found in the same tumor, suggesting that tumors follow different evolutionary strategies concurrently.

The efficacy of oral acyclovir, a purine nucleoside analogue with activity against human herpes viruses, is limited as a result of its low bioavailability. Valacyclovir, the L-valyl ester of acyclovir, has been developed as a pro-drug to improve the bioavailability. The aim of the present study was to compare the pharmacokinetics of acyclovir after intravenous administration and after oral administration of vala cyclovir. The pharmacokinetics of acyclovir were studied in 18 children aged 1.4–18.1 years (median: 6.9 years; 9 females) after intravenous infusion (1 hr; median dose: 10.5 mg/kg). In 10 of the children the pharmacokinetics of acyclovir were also studied after oral administration of valacyclovir (median dose: 34.1 mg/kg). Quantification of acyclovir in serum was performed by reversed-phase liquid chromatography with fluorometric detection. The pharmacokinetic analysis was performed by pharmacokinetic modelling. The serum concentration versus time curves of acyclovir were described by the two compartment model after intravenous administration and by the one compartment model with a zero- or first-order absorption phase after oral administration of valacyclovir. The bioavailability of acyclovir after oral administration of valacyclovir was 45% (median value; 95% CI: 37–55%). It is possible to substitute intravenous acyclovir therapy by oral valacyclovir therapy in children with leukopenia and mucositis after chemotherapy. This finding can at present not be fully implemented in clinical practice, since a commercial pharmaceutical formulation of valacyclovir aimed for children not able to swallow intact tablets is lacking. Crushed valacyclovir tablets have a very unpleasant taste, but can be administered to children through nasogastric tubes. Med. Pediatr. Oncol. 2002;38:240–246. © 2002 Wiley-Liss, Inc.