A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Linkage analysis in a large family with nonspecific X-linked mental retardation.

We report on a large 5-generation family with "nonspecific" X-linked mental retardation. Nine living affected males have an IQ between 50 and 70 but have normal stature, facial appearance, and testicular volumes and no other abnormalities. Two obligate carrier females had borderline intellectual abilities and visual-psychomotor difficulties similar to those seen in affected males. Results of chromosome studies, including fragile X, were normal in males and females. Linkage analysis was undertaken, with 19 X-specific chromosomal restriction fragment length polymorphisms (RFLPs), giving a maximal LOD score of 1.60 at a 0.10 recombination fraction for F9, suggesting a localization to distal Xq for the mutant gene in this family.

An evaluation of the presence of pathogens on broilers raised on poultry litter treatment-treated litter.

Two trials were conducted to evaluate the presence of salmonella, campylobacter, and generic Escherichia coli on broilers raised on Poultry Litter Treatment (PLT)-enhanced litter in comparison with those raised on untreated litter. Two Company A farms included three houses on each farm as the treated group and three houses per farm as controls. Two complete growouts were evaluated on each farm. The Company B study included 10 farms with two paired houses per farm, one house as the treated group and one house as the control. One growout was evaluated per farm. The pathogen sampling consisted of litter sampling and whole bird rinses on the farm and in the processing plant. Litter pH, ammonia concentration, total litter bacteria, temperatures, and humidity were also recorded. The study with Company A resulted in lower mean levels of pH, ammonia concentration, total litter bacteria, litter E. coli, and bird rinse counts for salmonella and E. coli in houses treated with PLT. The results for Company B closely resembled those for Company A, but also included campylobacter data, which showed no difference between treated and control groups. The data indicate that PLT may be a beneficial component for on-farm pathogen reduction.