Giovanni Zaninotto

Abstract: While the phenotypic changes involved in the esophageal oncogenic “cascade” are now well established, the molecular profiling of this pathway remains unreliable. Our understanding of the molecular dysregulations underlying the development/progression of cancer has recently been expanded by the characterization of a new class of small, noncoding RNA gene products, the microRNAs (or miRNAs). These “endogenous silencers” target a large number of genes, functioning as tumor suppressors or tumor promoters, depending on the activity of the targeted genes. In esophageal cancer, miRNA dysregulation plays a significant part in the molecular oncogenic pathway, in cancer prognosis, and in patients’ responsiveness to neo-adjuvant and adjuvant therapies. In addition to these valuable features, miRNAs have been proposed as innovative therapeutics per se and as plausible biological targets in new treatment strategies.

Abstract: While the phenotypic changes involved in the esophageal oncogenic “cascade” are now well established, the molecular profiling of this pathway remains unreliable. Our understanding of the molecular dysregulations underlying the development/progression of cancer has recently been expanded by the characterization of a new class of small, noncoding RNA gene products, the microRNAs (or miRNAs). These “endogenous silencers” target a large number of genes, functioning as tumor suppressors or tumor promoters, depending on the activity of the targeted genes. In esophageal cancer, miRNA dysregulation plays a significant part in the molecular oncogenic pathway, in cancer prognosis, and in patients’ responsiveness to neo-adjuvant and adjuvant therapies. In addition to these valuable features, miRNAs have been proposed as innovative therapeutics per se and as plausible biological targets in new treatment strategies.

Objective: To establish the incidence and risk factors for progression to high-grade intraepithelial neoplasia (HG-IEN) or Barrett's esophageal adenocarcinoma (BAc) in a prospective cohort of patients with esophageal intestinal metaplasia [(BE)]. Background: BE is associated with an increased risk of BAc unless cases are detected early by surveillance. No consistent data are available on the prevalence of BE-related cancer, the ideal surveillance schedule, or the risk factors for cancer. Methods: In 2003, a regional registry of BE patients was created in north-east Italy, establishing the related diagnostic criteria (endoscopic landmarks, biopsy protocol, histological classification) and timing of follow-up (tailored to histology) and recording patient outcomes. Thirteen centers were involved and audited yearly. The probability of progression to HG-IEN/BAc was calculated using the Kaplan-Meier method; the Cox regression model was used to calculate the risk of progression. Results: HG-IEN (10 cases) and EAc (7 cases) detected at the index endoscopy or in the first year of follow-up were considered to be cases of preexisting disease and excluded; 841 patients with at least 2 endoscopies {median, 3 [interquartile range (IQR): 2–4); median follow-up = 44.6 [IQR: 24.7–60.5] months; total 3083 patient-years} formed the study group [male/female = 646/195; median age, 60 (IQR: 51–68) years]. Twenty-two patients progressed to HG-IEN or BAc (incidence: 0.72 per 100 patient-years) after a median of 40.2 (26.9–50.4) months. At multivariate analysis, endoscopic abnormalities, that is, ulceration or nodularity (P = 0.0002; relative risk [RR] = 7.6; 95% confidence interval, 2.63–21.9), LG-IEN (P = 0.02, RR = 3.7; 95% confidence interval, 1.22–11.43), and BE length (P = 0.01; RR = 1.16; 95% confidence interval, 1.03–1.30) were associated with BE progression. Among the LG-IEN patients, the incidence of HG-IEN/EAc was 3.17 patient-years, that is, 6 times higher than in BE patients without LG-IEN. Conclusions: These results suggest that in the absence of intraepithelial neoplastic changes, BE carries a low risk of progression to HG-IEN/BAc, and strict surveillance (or ablative therapy) is advisable in cases with endoscopic abnormalities, LG-IEN or long BE segments.