AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer

Purpose: Despite the use of 5-fluorouracil (5-FU)–based adjuvant treatments, a large proportion of patients with high-risk stage II/III colorectal cancer will relapse. Thus, novel therapeutic strategies are needed for early-stage colorectal cancer. Residual micrometastatic disease from the primary tumor is a major cause of patient relapse.

Experimental Design: To model colorectal cancer tumor cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53-null) colorectal cancer cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins that underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumors from patients with early-stage colorectal cancer (N = 336) were examined for AXL expression.

Results: Invasive colorectal cancer cell subpopulations showed a transition from an epithelial-to-mesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability, and an attenuation of EGF receptor (EGFR)/HER2 autocrine signaling. RTK arrays showed significant increases in AXL levels in all invasive sublines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion, and targeting AXL using pharmacologic inhibition or RNA interference (RNAi) approaches suppressed basal and 5-FU–induced migration and invasion. Significantly, high AXL mRNA and protein expression were found to be associated with poor overall survival in early-stage colorectal cancer tissues.

Conclusions: We have identified AXL as a poor prognostic marker and important mediator of cell migration/invasiveness in colorectal cancer. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in colorectal cancer, in particular in the adjuvant disease in which EGFR/VEGF–targeted therapies have failed.

Treatment of a cochlear implant biofilm infection: a potential role for alternative antimicrobial agents

OBJECTIVE:
This study aimed to investigate antimicrobial treatment of an infected cochlear implant, undertaken in an attempt to salvage the infected device.

METHODS:
We used the broth microdilution method to assess the susceptibility of meticillin-sensitive Staphylococcus aureus isolate, cultured from an infected cochlear implant, to common antimicrobial agents as well as to novel agents such as tea tree oil. To better simulate in vivo conditions, where bacteria grow as microcolonies encased in glycocalyx, the bactericidal activity of selected antimicrobial agents against the isolate growing in biofilm were also compared.

RESULTS:
When grown planktonically, the S aureus isolate was susceptible to 17 of the 18 antimicrobials tested. However, when grown in biofilm, it was resistant to all conventional antimicrobials. In contrast, 5 per cent tea tree oil completely eradicated the biofilm following exposure for 1 hour.

CONCLUSION:
Treatment of infected cochlear implants with novel agents such as tea tree oil could significantly improve salvage outcome.

Variation of clinical outcomes used in glaucoma randomised controlled trials:a systematic review

Purpose: In randomised clinical trials (RCTs) the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. The purpose of this review is to identify different clinical outcomes reported in glaucoma trials.

Methods We conducted a systematic review of glaucoma RCTs. A sample or selection of glaucoma trials were included bounded by a time frame (between 2006 and March 2012). Only studies in English language were considered. All clinical measured and reported outcomes were included. The possible variations of clinical outcomes were defined prior to data analysis. Information on reported clinical outcomes was tabulated and analysed using descriptive statistics. Other data recorded included type of intervention and glaucoma, duration of the study, defined primary outcomes, and outcomes used for sample size calculation, if nominated.

Results The search strategy identified 4323 potentially relevant abstracts. There were 315 publications retrieved, of which 233 RCTs were included. A total of 967 clinical measures were reported. There were large variations in the definitions used to describe different outcomes and their measures. Intraocular pressure was the most commonly reported outcome (used in 201 RCTs, 86%) with a total of 422 measures (44%). Safety outcomes were commonly reported in 145 RCTs (62%) whereas visual field outcomes were used in 38 RCTs (16%).

Conclusions There is a large variation in the reporting of clinical outcomes in glaucoma RCTs. This lack of standardisation may impair the ability to evaluate the evidence of glaucoma interventions.

Changes in management and outcome of patients with rectal cancer in northern ireland:1996-2006

Aim This study aimed to document developments in rectal cancer services in a UK population and evaluate changes in outcome over a 10-year period.

Method Patients diagnosed with primary rectal carcinoma in 1996, 2001 and 2006 were identified by the Northern Ireland Cancer Registry. Data were retrospectively collected on presentation, investigation, treatment and staging. Differences over the period were analysed using the chi-squared test; Kaplan–Meier and Cox regression tests were used for survival analysis.

Results After exclusions there were 636 patients, including 187 presenting in 1996, 203 in 2001 and 246 in 2006. The use of preoperative MRI of the rectum, endorectal ultrasound and abdominal CT increased during the study period. For patients treated by surgery, total mesorectal excision (TME) increased from 19% in 1996 to 64% in 2006 (P < 0.001). The use of radiotherapy (27% in 1996, 47% in 2006) and chemotherapy (21% in 1996, 32% in 2006) increased. The overall 5-year survival improved significantly between 1996 and 2006 from 34% in 1996 to 45% in 2006 (P = 0.02). Among patients having surgery, 5-year survival increased from 43% in 1996 to 63% in 2006 (P < 0.001). Multivariate analysis showed that the improvement in survival was associated with TME and chemotherapy, while radiotherapy was not.

Conclusion Survival of patients with rectal cancer in Northern Ireland has improved significantly over the last decade, probably due to the increased use of TME and chemotherapy.

Keywords Surgery, rectum, oncology

What does this paper add to the literature?
This population-based study demonstrates a significant improvement in survival over recent years of rectal cancer patients in Northern Ireland. It concludes that surgical resection with TME and chemotherapy have had a significant impact on survival and that the improvement was not due to a stage-migration effect.

Optimal Front Page Advertising

We consider a model of an on-line software market, where an intermediary distributes products from sellers to buyers. When products of sellers are vertically differentiated, an intermediary, earning a proportion of sales, has an incentive to hide the worse product on the second page, and only keep the better product on the front page: that weakens the competition, allowing the seller with the better product to charge a higher price. With heterogeneous visiting costs to the second page, the platform's revenue might improve, but the outcome will become socially suboptimal.

PET-CT as a predictor of outcome in resectable colorectal liver metastases

Introduction
PET-computed tomography (PET-CT) is a useful staging imaging modality in colorectal liver metastases (CRLM). This study aimed to determine whether PET-CT parameters, standardized uptake value (SUV) and reconstructed tumour volume (RTV), are predictors of prognosis and survival.

Methods
A study of all resectable CRLM patients in the regional HPB unit from 2007–2009 was performed. Preoperative PET-CT scans were retrospectively reviewed; SUV, diameter and RTV for each lesion was recorded. Correlation analysis was performed with other pathological and biochemical parameters, by Pearson’s correlation analysis. Survival analysis was performed using Cox regression hazard model. A P value of less than 0.05 was considered statistically significant.

Results
A total of 79 patients were included. SUV moderately correlated with tumour diameter, both PET-CT (r=0.4927; P<0.0001) and histology (r=0.4513; P=0.0003); RTV (r=0.4489; P<0.001), preoperative carcinoembryonic antigen (CEA) (r=0.4977; P=0.0001), and postoperative CEA (r=0.3727; P=0.004). Multivariate analysis found that an independent predictor of SUVmax was preoperative CEA (P=0.03). RTV strongly correlated with preoperative CEA (r=0.9389; P<0.0001). SUV and RTV had a negative effect on survival.

Conclusion
PET-CT, in the setting of CRLM, may have a prognostic role in assessing survival. Although no definite conclusions can be drawn regarding the prognostic role of SUV and RTV, it acts to reinforce the need for further prospective studies to validate these findings.

Do Children Who Experience Regret Make Better Decisions? A Developmental Study of the Behavioral Consequences of Regret

Although regret is assumed to facilitate good decision making, there is little research directly addressing this assumption. Four experiments (N = 326) examined the relation between children's ability to experience regret and the quality of their subsequent decision making. In Experiment 1 regret and adaptive decision making showed the same developmental profile, with both first appearing at about 7 years. In Experiments 2a and 2b, children aged 6–7 who experienced regret decided adaptively more often than children who did not experience regret, and this held even when controlling for age and verbal ability. Experiment 3 ruled out a memory-based interpretation of these findings. These findings suggest that the experience of regret facilitates children's ability to learn rapidly from bad outcomes.

Knowledge of UK physical activity guidelines:Implications for better targeted health promotion

Objective. The aim of this study is to investigate the correlates of knowledge of the UK physical activity (PA) guidelines.

Method. A Northern Ireland-wide population survey (2010/2011) of 4653 adults provided cross-sectional data on PA, knowledge of guidelines and socio demographic characteristics. Multinomial logistic regression was used to investigate the associations between knowledge and socio-demographic characteristics (Model 1); and modifiable health behaviours (Model 2).

Results. Results showed that 47% of respondents were unaware of PA guidelines. Males who had a lower level of education (OR 5.91; 95% CI 1.67, 20.94), lived in more deprived areas (OR 4.80; 95% CI 1.87, 12.30), low income (OR 2.36; 95% CI 1.63, 3.41) and did no PA (OR 2.74; 95% CI 1.31, 5.76) were more likely to be unaware of the guidelines. Females who were younger (OR 1.03; 95% CI 1.02, 1.05) and reported poor health (OR 2.71; 95% CI 1.61, 4.58) were more likely to be unaware of the guidelines.

Conclusion. There is a lack of awareness about the levels of PA needed to promote health. An understanding of the characteristics of those who are unaware of the guidelines has important implications for the design of targeted, effective health promotion.