Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract.

The Runx1 transcription factor plays an important role in tissue homeostasis through its effects on stem/progenitor cell populations and differentiation. The effect of Runx1 on epithelial differentiation of the secretory cell lineage of the colon was recently demonstrated. This study aimed to examine the role of Runx1 in tumor development in epithelial cells of the gastrointestinal tract. Conditional knockout mice that lacked Runx1 expression in epithelial cells of the GI tract were generated. These mice were crossed onto the Apc(Min) background, killed and their intestinal tumor phenotypes were compared with Apc(Min) Runx1 wild-type control mice. Apc-wild-type Runx1-mutant mice were also examined for tumor development. Colons from Runx1 knockout and wild-type mice were used for genome-wide mRNA expression analyses followed by gene-specific quantitative RT-PCR of whole colon and colon epithelium to identify Runx1 target genes. Runx1 deficiency in intestinal epithelial cells significantly enhanced tumorigenesis in Apc(Min) mice. Notably, epithelial Runx1 deficiency in Apc-wild-type mice was sufficient to cause tumor development. Absence of Runx1 was associated with global changes in the expression of genes involved in inflammation and intestinal metabolism, and with gene sets indicative of a metastatic phenotype and poor prognosis. Gene-specific analysis of Runx1-deficient colon epithelium revealed increased expression of genes linked to an expansion of the stem/progenitor cell population. These results identify Runx1 as a novel tumor suppressor gene for gastrointestinal tumors and support a role for Runx1 in maintaining the balance between the intestinal stem/progenitor cell population and epithelial differentiation of the GI tract.

Development, calibration, and validation of a U.S. white male population-based simulation model of esophageal adenocarcinoma.

BACKGROUND: The incidence of esophageal adenocarcinoma (EAC) has risen rapidly in the U.S. and western world. The aim of the study was to begin the investigation of this rapid rise by developing, calibrating, and validating a mathematical disease simulation model of EAC using available epidemiologic data. METHODS: The model represents the natural history of EAC, including the essential biologic health states from normal mucosa to detected cancer. Progression rates between health states were estimated via calibration, which identified distinct parameter sets producing model outputs that fit epidemiologic data; specifically, the prevalence of pre-cancerous lesions and EAC cancer incidence from the published literature and Surveillance, Epidemiology, and End Results (SEER) data. As an illustrative example of a clinical and policy application, the calibrated and validated model retrospectively analyzed the potential benefit of an aspirin chemoprevention program. RESULTS: Model outcomes approximated calibration targets; results of the model's fit and validation are presented. Approximately 7,000 cases of EAC could have been prevented over a 30-year period if all white males started aspirin chemoprevention at age 40 in 1965. CONCLUSIONS: The model serves as the foundation for future analyses to determine a cost-effective screening and management strategy to prevent EAC morbidity and mortality.

Patient preferences for the chemoprevention of colorectal cancer.

Although evidence suggests that aspirin and celecoxib may reduce the risk of colorectal cancer (CRC), these drugs can also cause harmful side effects. The aim of this study was to characterize patient preferences for celecoxib and aspirin. Participants completed a computer-based patient decision-making questionnaire that included an educational component outlining the benefits and harms of celecoxib and aspirin. Under the base conditions 7.4% would take celecoxib and 43.6% would take aspirin; males were more willing than females to take aspirin. Patients identified the increased risk of myocardial infarction and gastrointestinal events as the primary reasons for their unwillingness to take celecoxib and aspirin, respectively. A majority of subjects would not take either drug, after considering their benefits and harms, although participants were almost six times more likely to take aspirin than celecoxib. These data serve to inform physicians and researchers regarding the variability and factors that affect patient preferences for CRC chemoprevention.

Treatment of Barrett's esophagus with high-grade dysplasia or cancer: predictors of surgical versus endoscopic therapy.

BACKGROUND & AIMS: Patients with Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma are at risk of progression to invasive carcinoma. Both esophagectomy and endoscopic ablation are treatment options. The aim of this study was to identify predictors of surgical versus endoscopic therapy at a tertiary center. METHODS: An institutional database identified patients with Barrett's esophagus between 2003 and 2007. Demographic data and International Classification of Diseases-9th revision codes for esophagectomy, endoscopic ablation, as well as selected medical comorbidities were retrieved. Individual endoscopy, surgical, and pathology reports were reviewed. RESULTS: Among 2107 individuals with Barrett's esophagus, 79 underwent esophagectomy and 80 underwent endoscopic ablation. The mean age was 63.1 +/- 10.6 years in the surgical group and 69.7 +/- 9.4 years in the ablation group (P < .0001). Among high-grade dysplasia/intramucosal carcinoma patients, 9 of 76 (12%) first seen by a gastroenterologist underwent esophagectomy, whereas 18 of 21 (86%) first seen by a surgeon underwent esophagectomy. In a logistic regression model, factors associated independently with esophagectomy were as follows: patient age of 60 or younger (odds ratio [OR], 4.95; 95% confidence interval [CI], 1.65-14.9), cancer stage T1sm or greater (OR, 16.0; 95% CI, 5.60-45.6), and initial consultation performed by a surgeon (vs gastroenterologist) (OR, 35.1; 95% CI, 9.58-129). CONCLUSIONS: Patient age and cancer stage predict treatment modality for Barrett's esophagus with neoplasia. Treatment choice is influenced further by whether the initial evaluation is performed by a gastroenterologist or a surgeon.