Background & Aims Fibroblast growth factor 21 (FGF21) is a hepatic protein that plays a critical role in metabolism, stimulating fatty acid oxidation in liver and glucose uptake in fat. Systemic administration to obese rodents and diabetic monkeys leads to improved glucose homeostasis and weight loss. In rodents, FGF21 increases with fasting and consumption of a ketogenic diet (KD). In humans, FGF21 correlates with body mass index, but studies evaluating other parameters show inconsistent results. We examined FGF21 serum levels in lean and obese individuals and in response to dietary manipulation. We also evaluated FGF21 serum levels and liver mRNA expression in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Methods Serum FGF21 was measured after an overnight fast in individuals with BMI ranging from normal to obese. Volunteers fasted for 16 or 72 hours and then ate a standard meal. Another group consumed KD for 12 days. Serum FGF21 and hepatic mRNA expression were measured in obese individuals with NAFLD or NASH. Results There was a positive correlation between BMI and FGF21. There was no change in FGF21 in response to a short fast or KD. A non-statistically significant fall in FGF21 levels was seen after a 72 hour fast. Hepatic FGF21 mRNA expression was significantly elevated in NAFLD, which correlated with a substantial increase in serum FGF21. In NASH, serum FGF21 but not liver mRNA was increased. Conclusion FGF21 correlates with BMI and may be a novel biomarker for NAFLD but is not nutritionally regulated in humans.

SummaryBackgroundCarboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.MethodsIn this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC–IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).FindingsBetween June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0–26·0] in group 1, 24·9 months [24·0–25·9] in group 2, 25·3 months [23·9–26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6–not reached] in group 1, 20·8 months [11·9–59·0] in group 2, 21·0 months [12·0–54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.InterpretationWeekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly Eur...

Progress in therapeutics for rare disorders like prion disease is impeded by the lack of validated outcome measures and a paucity of natural history data derived from prospective observational studies. The first analysis of the U.K. National Prion Monitoring Cohort involved 1337 scheduled clinical assessments and 479 telephone assessments in 437 participants over 373 patient-years of follow-up. Scale development has included semi-quantitative and qualitative carer interviews, item response modelling (Rasch analysis), inter-rater reliability testing, construct analysis and correlation with several existing scales. The proposed 20-point Medical Research Council prion disease rating scale assesses domains of cognitive function, speech, mobility, personal care/feeding and continence, according to their relative importance documented by carer interviews. It is quick and simple to administer, and has been validated for use by doctors and nurses and for use over the telephone, allowing for frequent assessments that capture the rapid change typical of these diseases. The Medical Research Council Scale correlates highly with widely used cognitive and single item scales, but has substantial advantages over these including minimal floor effects. Three clear patterns of decline were observed using the scale: fast linear decline, slow linear decline (usually inherited prion disease) and in some patients, decline followed by a prolonged preterminal plateau at very low functional levels. Rates of decline and progress through milestones measured using the scale vary between sporadic, acquired and inherited prion diseases following clinical expectations. We have developed and validated a new functionally-oriented outcome measure and propose that future clinical trials in prion disease should collect data compatible with this scale, to allow for combined and comparative analyses. Such approaches may be advantageous in orphan conditions, where single studies of feasible duration will often struggle to achieve statistical power.