Other risk factors that are less well substantiated than GERD and BE include obesity, smoking, alcohol use, use of acid-suppressing medications, and infection with Helicobacter pylori. Of these, obesity has been the best studied but has not been established as a definitive risk factor. For example, one study found that adenocarcinoma was 7 times more likely to develop in individuals with a body mass index (calculated as weight in kilograms divided by the square of height in meters) in the highest quartile (men >23.7, women >22.1) than in those with a body mass index in the lowest quartile (men <20.7, women <19.3).14 However, it was unclear whether the observed effect of obesity in this study was direct, or indirect by exacerbating GERD. Thus, the major risk factors predisposing to the development of EAC are BE and long-standing symptomatic GERD. However, adenocarcinoma may develop in the absence of either. In the case-control study described above, which found a correlation between the risk of adenocarcinoma and the frequency, severity, and duration of reflux symptoms, 40% of patients diagnosed with adenocarcinoma did not have a history of reflux symptoms. Furthermore, 38% of patients with adenocarcinoma did not have BE.10 These findings were supported by a population-based registry study which found that only 19% of patients who were diagnosed with EAC over a 5-year period had BE at subsequent endoscopic examination, surgery, or autopsy.15 Similarly, a recent systematic review found that only 24% to 64% of patients undergoing surgery for EAC had BE.16 It has been suggested that cancer may overgrow the Barrett segment from which it arises, thus causing to underestimate the prevalence of BE in patients with adenocarcinoma.17 Nevertheless, taken together, these results suggest the possibility that EAC may develop in the absence of long-standing symptomatic GERD or BE.