A Photo Score for Aesthetic Outcome in Sagittal Synostosis:An ERN CRANIO Collaboration

European Reference Network (ERN) CRANIO is focused on optimizing care for patients with rare or complex craniofacial anomalies, including craniosynostosis and/or rare ear, nose, and throat disorders. The main goal of ERN CRANIO is to collect uniform data on treatment outcomes for multicenter comparison. We aimed to develop a reproducible and reliable suture-specific photo score that can be used for cross-center comparison of phenotypical severity of sagittal synostosis and aesthetic outcome of treatment. We conducted a retrospective study among nonsyndromic sagittal synostosis patients aged &lt;19 years. We included preoperative and postoperative photo sets from 6 ERN CRANIO centers. Photo sets included bird's eye, lateral, and anterior-posterior views. The sagittal synostosis photo score was discussed in the working group, and consensus was obtained on its contents. Interrater agreement was assessed with weighted Fleiss' Kappa and intraclass correlation coefficients.The photo score consisted of frontal bossing, elongated skull, biparietal narrowness, temporal hollowing, vertex line depression, occipital bullet, and overall phenotype. Each item was scored as normal, mild, moderate, or severe. Results from 36 scaphocephaly patients scored by 20 raters showed kappa values ranging from 0.38 [95% bootstrap CI: 0.31, 0.45] for biparietal narrowness to 0.56 [95% bootstrap CI: 0.47, 0.64] for frontal bossing. Agreement was highest for the sum score of individual items [intraclass correlation coefficients agreement 0.69 [95% CI: 0.57, 0.82]. This is the first large-scale multicenter study in which experts investigated a photo score to assess the severity of sagittal synostosis phenotypical characteristics. Agreement on phenotypical characteristics was suboptimal (fair-moderate agreement) and highest for the summed score of individual photo score items (substantial agreement), indicating that although experts interpret phenotypical characteristics differently, there is consensus on overall phenotypical severity.</p

Brain and ventricular volume in patients with syndromic and complex craniosynostosis

textabstractPurpose: Brain abnormalities in patients with syndromic craniosynostosis can either be a direct result of the genetic defect or develop secondary to compression due to craniosynostosis, raised ICP or hydrocephalus. Today it is unknown whether children with syndromic craniosynostosis have normal brain volumes. The purpose of this study was to evaluate brain and ventricular volume measurements in patients with syndromic and complex craniosynostosis. This knowledge will improve our understanding of brain development and the origin of raised intracranial pressure in syndromic craniosynostosis. Methods: Brain and ventricular volumes were calculated from MRI scans of patients with craniosynostosis, 0.3 to 18.3 years of age. Brain volume was compared to age matched controls from the literature. All patient charts were reviewed to look for possible predictors of brain and ventricular volume. Results: Total brain volume in syndromic craniosynostosis equals that of normal controls, in the age range of 1 to 12 years. Brain growth occurred particularly in the first 5 years of age, after which it stabilized. Within the studied population, ventricular volume was significantly larger in Apert syndrome compared to all other syndromes and in patients with a Chiari I malformation. Conclusions: Patients with syndromic craniosynostosis have a normal total brain volume compared to normal controls. Increased ventricular volume is associated with Apert syndrome and Chiari I malformations, which is most commonly found in Crouzon syndrome. We advice screening of all patients with Apert and Crouzon syndrome for the development of enlarged ventricle volume and the presence of a Chiari I malformation

Correction: A european spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics (PLoS ONE (2016) 11:9 (e0162866) DOI: 10.1371/journal.pone.0162866)

The thirty-Third author's name is spelled incorrectly. The correct name is: Jadranka Sertić

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome:phenotype comparison in two related syndromes

Background Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. Methods Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. Results Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. Conclusions Results show significant between and within syndrome variability. DifferentNFIXvariants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit

A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant interpopulation pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective

Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study

Purpose: Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis. Experimental design: In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days. Results: For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration-time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime. Conclusion: Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies

Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial

Background Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. Methods This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 μg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4–12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and