A phase II study to determine the ability of gefitinib to reverse fluoropyrimidine resistance in metastatic colorectal cancer (the INFORM study)

There are data suggesting that inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase signalling may reverse resistance to fluoropyrimidine treatment. To investigate this further, the INFORM study was an open-label, non-comparative phase II study of gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE, USA) 250 mg daily in combination with 5-fluorouracil (5-FU administered as an intravenous 400 mg m−2 bolus injection followed by 2800 mg m−2 infusion over 46 h and folinic acid administered as a 350 mg infusion over 2 h) every 2 weeks for up to 12 cycles in 24 patients with metastatic colorectal cancer refractory to previous fluoropyrimidine treatment. There were no objective responses. The stable disease rate was 37.5% (95% CI: 18.80, 59.41), median progression-free survival measured 116 days and overall survival was 226 days. Quality of life was unchanged compared to baseline values, and the commonest toxicities were diarrhoea, rash and fatigue with 7 out of 24 (29%) patients having a grade 3 or 4 toxicity. Gefitinib does not sensitise patients with fluoropyrimidine refractory metastatic colorectal cancer to 5-FU chemotherapy

Measuring the neighbourhood using UK benefits data: a multilevel analysis of mental health status

Background: Evidence from multilevel research investigating whether the places where people live influence their mental health remains inconclusive. The objectives of this study are to derive small area-level, or contextual, measures of the local social environment using benefits data from the Department of Work and Pensions (DWP) and to investigate whether (1) the mental health status of individuals is associated with contextual measures of low income, economic inactivity, and disability, after adjusting for personal risk factors for poor mental health, (2) the associations between mental health and context vary significantly between different population sub-groups, and (3) to compare the effect of the contextual benefits measures with the Townsend area deprivation score. Methods: Data from the Welsh Health Survey 1998 were analysed in Normal response multilevel models of 24,975 individuals aged 17 to 74 years living within 833 wards and 22 unitary authorities in Wales. The mental health outcome measure was the Mental Health Inventory (MHI-5) of the Short Form 36 health status questionnaire. The benefits data available were the means tested Income Support and Income-based Job Seekers Allowance, and the non-means tested Incapacity Benefit, Severe Disablement Allowance, Disability Living Allowance and Attendance Allowance. Indirectly age-standardised census ward ratios were calculated to model as the contextual measures. Results: Each contextual variable was significantly associated with individual mental health after adjusting for individual risk factors, so that living in a ward with high levels of claimants was associated with worse mental health. The non-means tested benefits that were proxy measures of economic inactivity from permanent sickness or disability showed stronger associations with individual mental health than the means tested benefits and the Townsend score. All contextual effects were significantly stronger in people who were economically inactive and unavailable for work. Conclusion: This study provides evidence for substantive contextual effects on mental health, and in particular the importance of small-area levels of economic inactivity and disability. DWP benefits data offer a more specific measure of local neighbourhood than generic deprivation indices and offer a starting point to hypothesise possible causal pathways to individual mental health status

Volunteer Bias in Recruitment, Retention, and Blood Sample Donation in a Randomised Controlled Trial Involving Mothers and Their Children at Six Months and Two Years: A Longitudinal Analysis

BACKGROUND: The vulnerability of clinical trials to volunteer bias is under-reported. Volunteer bias is systematic error due to differences between those who choose to participate in studies and those who do not. METHODS AND RESULTS: This paper extends the applications of the concept of volunteer bias by using data from a trial of probiotic supplementation for childhood atopy in healthy dyads to explore 1) differences between a) trial participants and aggregated data from publicly available databases b) participants and non-participants as the trial progressed 2) impact on trial findings of weighting data according to deprivation (Townsend) fifths in the sample and target populations. 1) a) Recruits (n = 454) were less deprived than the target population, matched for area of residence and delivery dates (n = 6,893) (mean [SD] deprivation scores 0.09[4.21] and 0.79[4.08], t = 3.44, df = 511, p<0.001). b) i) As the trial progressed, representation of the most deprived decreased. These participants and smokers were less likely to be retained at 6 months (n = 430[95%]) (OR 0.29,0.13-0.67 and 0.20,0.09-0.46), and 2 years (n = 380[84%]) (aOR 0.68,0.50-0.93 and 0.55,0.28-1.09), and consent to infant blood sample donation (n = 220[48%]) (aOR 0.72,0.57-0.92 and 0.43,0.22-0.83). ii) Mothers interested in probiotics or research or reporting infants' adverse events or rashes were more likely to attend research clinics and consent to skin-prick testing. Mothers participating to help children were more likely to consent to infant blood sample donation. 2) In one trial outcome, atopic eczema, the intervention had a positive effect only in the over-represented, least deprived group. Here, data weighting attenuated risk reduction from 6.9%(0.9-13.1%) to 4.6%(-1.4-+10.5%), and OR from 0.40(0.18-0.91) to 0.56(0.26-1.21). Other findings were unchanged. CONCLUSIONS: Potential for volunteer bias intensified during the trial, due to non-participation of the most deprived and smokers. However, these were not the only predictors of non-participation. Data weighting quantified volunteer bias and modified one important trial outcome. TRIAL REGISTRATION: This randomised, double blind, parallel group, placebo controlled trial is registered with the International Standard Randomised Controlled Trials Register, Number (ISRCTN) 26287422. Registered title: Probiotics in the prevention of atopy in infants and children