Medulloblastoma in adults: evaluation of the Dutch society for neuro-oncology treatment protocol.

PURPOSE: Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients. METHODS: Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed. RESULTS: Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn't statistically significant. CONCLUSION: Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.

Electroencephalographic (EEG) density spectral array monitoring in children during sevoflurane anaesthesia: a prospective observational study.

Electroencephalographic density spectral array monitoring has been developed to facilitate the interpretation of unprocessed electroencephalogram signals. The primary aim of this prospective observational study, performed in a tertiary children's hospital, was to identify the clinical applicability and validity of density spectral array monitoring in infants and children during sevoflurane anaesthesia. We included 104 children, aged < 6 years, undergoing elective surgery during sevoflurane anaesthesia. We investigated the correlation between non-steady state end-tidal sevoflurane and the expression of the four electroencephalogram frequency bands ß, α, θ and δ, representing density spectral array. Patients were divided into three age groups (< 6 months, 6-12 months, > 12 months). There was a significant correlation between end-tidal sevoflurane and density spectral array in the age groups 6-12 months (p < 0.05) and 1-6 years (p < 0.0001). In infants < 6 months of age, the relative percentages of density spectral array did not correlate with end-tidal sevoflurane. The main finding was that different end-tidal concentrations of sevoflurane produce age-dependent changes in the density spectral array power spectrum. In infants younger than 6 months-old, α and ß coherence are absent, whereas θ and δ oscillations have already emerged. In cases where anaesthesia was too deep, this presented as burst suppression on the electroencephalogram, θ disappeared, leaving the electroencephalographic activity in the δ range. Future research should address this issue, aiming to clarify whether the emergence of θ oscillations in infants helps to prevent sevoflurane overdosing.

Intelligence quotient scores at the age of 6 years in children anaesthetised before the age of 5 years.

We analysed the association of independent variables with non-verbal cognition at 6 years in children with complete data (3441 from a cohort of 9901), of whom 415 were anaesthetised before the age of 5 years. Using multivariable regression, cognition was reduced by a mean (95% CI) score for children: anaesthetised before the age of 5 years, 2.1 (0.7-3.5), p = 0.004; born prematurely, 9.8 (4.1-15.4), p = 0.001; whose mothers smoked while pregnant, 2.3 (0.8-3.8), p = 0.004; whose mothers had lower IQ scores, 0.3 (0.2-0.3) for each unit reduction in maternal IQ, p < 0.0001. The association of child IQ with exposure to anaesthetic drugs was sensitive to missing data.

Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis.

Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the fibroblast growth factor receptor type 3 gene (FGFR3). This frequently occurs as a new mutation, manifesting one of the highest documented rates for any transversion in the human genome. To understand the biology of this mutation, we have investigated its parental origin, and the ages of the parents, in 19 families with de novo c.749C>G mutations. All ten informative cases originated from the paternal allele (95% confidence interval 74-100% paternal); the average paternal age at birth overall was 34.7 years. An exclusive paternal origin of mutations, and increased paternal age, were previously described for a different mutation (c.1138G>A) of the FGFR3 gene causing achondroplasia, as well as for mutations of the related FGFR2 gene causing Apert, Crouzon and Pfeiffer syndromes. We conclude that similar biological processes are likely to shape the occurrence of this c.749C>G mutation as for other mutations of FGFR3 as well as FGFR2.

Deletion of the TWIST gene in a large five-generation family.

In this article, we describe a large five-generation family with characteristics of the Saethre-Chotzen syndrome as well as of the blepharophimosis ptosis epicanthus inversus syndrome. Segregating with their phenotype is a deletion of the chromosome 7p21 TWIST gene locus. The TWIST gene indeed is involved in Saethre-Chotzen syndrome, a craniosynostosis syndrome further characterized by specific facial and limb abnormalities. However, only two members of our family exhibited craniosynostosis. This report demonstrates that the genetics of craniofacial anomalies are less straightforward than they sometimes appear to be. Not only craniosynostosis, but also subtle facial deformities could be indicative of an abnormality of the TWIST gene. In conclusion, the clinical spectrum of genetic abnormalities of the TWIST gene is highly variable. We therefore recommend that genetic analysis of the TWIST gene locus, including fluorescence in situ hybridization, should be considered in familial cases of facial and eyelid abnormalities without the presence of craniosynostosis.