Funding information Fulcrum Therapeutics (industry)Aims: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD). Methods: This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C: FSHD subjects received open-label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging-normal appearing (Part B) and affected muscle identified by abnormal short-tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol-stimulated blood. Results: PK profiles were similar between healthy volunteers and FSHD subjects, with mean C max and AUC 0-12 for 15 mg in FSHD subjects (Part B) of 85.0 ± 16.7 ng*h/mL and 410 ± 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose-dependent concentrations in muscle (42.1 ± 10.5 ng/g [7.5 mg]to 97.2 ± 22.4 ng/g [15 mg]) were observed, with plasma-to-muscle ratio from $0.67 to $1 at estimated t max of 3.5 hours postdose. TE was observed in blood and muscle.Adverse events (AEs) were mild and self-limited. Conclusion:Losmapimod was well tolerated, with no serious AEs. Dose-dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD.

Background The quantification of human papilloma virus (HPV)‐induced skin lesions is essential for the clinical assessment of the course of disease and the response to treatment. However, clinical assessments that measure dimensions of lesions using a caliper do not provide complete insight into three‐dimensional (3D) lesions, and its inter‐rater variability is often poor. Objective The aim of this study was to validate a stereophotogrammetric 3D camera system for the quantification of HPV‐induced lesions. Methods The camera system was validated for accuracy, precision and interoperator and inter‐rater variability. Subsequently, 3D photographs were quantified and compared to caliper measurements for clinical validation by Bland–Altman modelling, based on data from 80 patients with cutaneous warts (CW), 24 with anogenital warts (AGW) patients and 12 with high‐grade squamous intraepithelial lesions of the vulva (vulvar HSIL) with a total lesion count of 220 CW, 74 AGW and 31 vulvar HSIL. Results Technical validation showed excellent accuracy [coefficients of variation (CV) ≤ 0.68%] and reproducibility (CVs ≤ 2%), a good to excellent agreement between operators (CVs ≤ 8.7%) and a good to excellent agreement between different raters for all three lesion types (ICCs ≥ 0.86). When comparing 3D with caliper measurements, excellent biases were found for diameter of AGW (long diameter 5%), good biases were found for diameter of AGW (short diameter 10%) and height of CW (8%), and acceptable biases were found for the diameter of CW (11%) and vulvar HSIL (short diameter 14%, long diameter 16%). An unfavourable difference between these methods (bias 25%) was found for the assessment of height of AGWs. Conclusion Stereophotogrammetric 3D imaging is an accurate and reliable method for the clinical visualization and quantification of HPV‐induced skin lesions.

Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2–3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5–4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients.Electronic supplementary materialThe online version of this article (10.1007/s10689-017-0061-3) contains supplementary material, which is available to authorized users.

The link between cancer and the microbiome is a fast-moving field in research. There is little knowledge on the microbiome in ((pre)malignant) conditions of the vulvar skin. This systematic review aims to provide an overview of the literature regarding the microbiome composition of the healthy vulvar skin and in (pre)malignant vulvar disease. This study was performed according to the PRISMA guidelines. A comprehensive, electronic search strategy was used to identify original research articles (updated September 2021). The inclusion criteria were articles using culture-independent methods for microbiome profiling of the vulvar region. Ten articles were included. The bacterial composition of the vulva consists of several genera including Lactobacillus, Corynebacterium, Staphylococcus and Prevotella, suggesting that the vulvar microbiome composition shows similarities with the corresponding vaginal milieu. However, the vulvar microbiome generally displayed higher diversity with commensals of cutaneous and fecal origin. This is the first systematic review that investigates the relationship between microbiome and vulvar (pre)malignant disease. There are limited data and the level of evidence is low with limitations in study size, population diversity and methodology. Nevertheless, the vulvar microbiome represents a promising field for exploring potential links for disease etiology and targets for therapy.