A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer.

PURPOSE: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery. PATIENTS AND METHODS: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety. RESULTS: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, P = 0.97; Ki-67: -75.4%, P = 0.98). No new safety findings were identified. CONCLUSIONS: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Phase I study of orally administered 14Carbon-isotope labelled-vistusertib (AZD2014), a dual TORC1/2 kinase inhibitor, to assess the absorption, metabolism, excretion, and pharmacokinetics in patients with advanced solid malignancies.

PURPOSE: Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy settings. The pharmacokinetic, metabolic and excretion profiles of 14Carbon-isotope (14C)-labelled vistusertib were characterised in this open-label phase I patient study. METHODS: Four patients with advanced solid malignancies received a single oral solution dose of 14C-labelled vistusertib. Blood, urine, faeces, and saliva samples were collected at various time points during the 8-day in-patient period of the study. Safety and preliminary efficacy were also assessed. RESULTS: 14C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (Tmax) < 1.2 h in all subjects). Overall, > 90% of radioactivity was recovered with the majority recovered as metabolites in faeces (on average 80% vs. 12% recovered in urine). The majority of circulating radioactivity (~ 78%) is unchanged vistusertib. Various morpholine-ring oxidation metabolites and an N-methylamide circulate at low concentrations [each < 10% area under the concentration-time curve from zero to infinity (AUC0-∞)]. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis. CONCLUSIONS: The pharmacokinetic (PK) profile of vistusertib is similar to previous studies using the same dosing regimen in solid malignancy patients. The majority of vistusertib elimination occurred via hepatic metabolic routes.

The advocacy for pedestrian safety study: cluster randomised trial evaluating a political advocacy approach to reduce pedestrian injuries in deprived communities.

OBJECTIVE: To determine whether advocacy targeted at local politicians leads to action to reduce the risk of pedestrian injury in deprived areas. DESIGN: Cluster randomised controlled trial. SETTING: 239 electoral wards in 57 local authorities in England and Wales. PARTICIPANTS: 617 elected local politicians. INTERVENTIONS: Intervention group politicians were provided with tailored information packs, including maps of casualty sites, numbers injured and a synopsis of effective interventions. MAIN OUTCOME MEASURES: 25-30 months post intervention, primary outcomes included: electoral ward level: percentage of road traffic calmed; proportion with new interventions; school level: percentage with 20 mph zones, Safe Routes to School, pedestrian training or road safety education; politician level: percentage lobbying for safety measures. Secondary outcomes included politicians' interest and involvement in injury prevention, and facilitators and barriers to implementation. RESULTS: PRIMARY OUTCOMES DID NOT SIGNIFICANTLY DIFFER: % difference in traffic calming (0.07, 95%CI: -0.07 to 0.20); proportion of schools with 20 mph zones (RR 1.47, 95%CI: 0.93 to 2.32), Safe Routes to School (RR 1.34, 95%CI: 0.83 to 2.17), pedestrian training (RR 1.23, 95%CI: 0.95 to 1.61) or other safety education (RR 1.16, 95%CI: 0.97 to 1.39). Intervention group politicians reported greater interest in child injury prevention (RR 1.09, 95%CI 1.03 to 1.16), belief in potential to help prevent injuries (RR 1.36, 95%CI 1.16 to 1.61), particularly pedestrian safety (RR 1.55, 95%CI 1.19 to 2.03). 63% of intervention politicians reported supporting new pedestrian safety schemes. The majority found the advocacy information surprising, interesting, effectively presented, and could identify suitable local interventions. CONCLUSIONS: This study demonstrates the feasibility of an innovative approach to translational public health by targeting local politicians in a randomised controlled trial. The intervention package was positively viewed and raised interest but changes in interventions were not statistically significance. Longer term supported advocacy may be needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN91381117.

Risk factors for ciprofloxacin-resistant Campylobacter infection in Wales.

OBJECTIVES: To identify risk factors for ciprofloxacin resistance in both travel-related and domestically acquired Campylobacter infection. METHODS: Case-comparison study of patients with ciprofloxacin-resistant and ciprofloxacin-susceptible Campylobacter infection conducted in Wales during 2003 and 2004. RESULTS: Foreign travel was the major risk factor for ciprofloxacin-resistant infection [adjusted odds ratio (adjOR) 24.0, 95% confidence interval (95% CI) 12.6-45.9]. Among travellers, case patients were five times more likely to drink still bottled water (adjOR 4.7, 95% CI 1.0-21.7), whilst among non-travellers, case patients were three times more likely to drink sparkling bottled water (adjOR 3.3, 95% CI 1.5-7.4). There was no increased risk associated with eating poultry or prior quinolone use. CONCLUSIONS: Foreign travel remains the most important risk factor for ciprofloxacin-resistant Campylobacter infection. The possible association of both domestic- and travel-related ciprofloxacin-resistant Campylobacter infection with bottled water needs to be further explored.

Short-term and medium-term clinical outcomes of quinolone-resistant Campylobacter infection.

BACKGROUND: Campylobacter species is a leading cause of bacterial gastroenteritis worldwide. Quinolone resistance has emerged as an increasing problem among persons with Campylobacter infection over the past decade, but the clinical consequences are unclear. METHODS: A case-comparison study of patients infected with ciprofloxacin-resistant or ciprofloxacin-susceptible Campylobacter species was conducted in Wales during the period 2003-2004. Campylobacter isolates were classified as resistant or susceptible to ciprofloxacin on the basis of standardized disk diffusion methods. Participants were interviewed by telephone at the time of illness, 3 months later, and 6 months later to compare disease severity, duration of illness, and medium-term clinical outcomes. RESULTS: There was no difference between 145 persons with ciprofloxacin-resistant infection and 411 with ciprofloxacin-susceptible infection with regard to the severity or duration of acute illness. Mean duration of diarrhea was similar in patients with ciprofloxacin-resistant versus ciprofloxacin-susceptible infection (8.2 vs. 8.6 days; P = .57) and did not alter significantly after adjustment for potential covariates, including age, underlying disease, foreign travel, use of antidiarrheal medication, and use of antimicrobials in a multiple linear regression model. There was no difference between case patients and comparison patients in the frequency of reported symptoms or in general practitioner consultation rates at either the 3-month or the 6-month follow-up interview. CONCLUSIONS: In this study, there was no evidence of more-severe or prolonged illness in participants with quinolone-resistant Campylobacter infection, nor was there evidence of any adverse medium-term consequences. This suggests that the clinical significance of quinolone resistance in Campylobacter infection may have been overestimated.

Sentinel surveillance for travellers' diarrhoea in primary care.

BACKGROUND: Travellers' diarrhoea is the most common health problem among international travellers and much of the burden falls on general practitioners. We assessed whether sentinel surveillance based in primary care could be used to monitor changes in the epidemiology of travellers' diarrhoea. METHODS: A sentinel surveillance scheme of 30 volunteer general practices distributed throughout Wales provides weekly reports of consultations for eight infectious diseases to the national Communicable Disease Surveillance Centre. Travellers' diarrhoea was introduced as a new reportable infection in July 2002. RESULTS: Between 1 July 2002 and 31 March 2005 there were 90 reports of travellers' diarrhoea. The mean annual consultation rate was 15.2 per 100,000 population (95% confidence interval: 12.2-18.7), with the highest rates in summer, in people aged 15-24 years, and in travellers to Southern Europe. A higher proportion of travellers than expected had visited destinations outside Europe and North America when compared to the proportion of all United Kingdom travellers visiting these destinations (38% vs. 11%; Chi2 = 53.3, p < 0.0001). CONCLUSION: Sentinel surveillance has the potential to monitor secular trends in travellers' diarrhoea and to help characterise population groups or travel destinations associated with higher risk.

Effects of probiotics on the composition of the intestinal microbiota following antibiotic therapy.

The effects of probiotic supplementation on the intestinal re-growth microbiota following antibiotic therapy were studied in a double-blind placebo-controlled study. In the placebo group, numbers of facultative anaerobes and enterobacteria increased significantly, and at day 35 the numbers were significantly higher in the placebo group than in the active group; in the active group, the numbers of bacteroides increased significantly. Although the numbers of enterococci in both groups did not change, in the placebo group the number of patients harbouring antibiotic-resistant enterococci post therapy increased significantly. There was no change in the incidence rate of antibiotic resistance among the patients in the probiotic group.