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It was a pleasure to receive a letter from Dr Michael Zinner inviting me to write a perspective on the chapters of Dr Simon Law's group from Hong Kong on the diagnosis and treatment of esophageal cancer, Dr David Sugarbaker's group from Boston on the techniques used to resect the esophagus and reconstruct the foregut, and Dr James Luketich's group from Pittsburgh on minimally invasive esophagectomy. Of truth, I have rarely read such well-written and thoroughly thought-out reviews. While reading, I identified areas where I was motivated to comment on the discussion from my personal experience. These usually took the form of helpful thoughts or alternatives. Occasionally, they raised a note of caution or took a controversial point of view.


The reason for the dramatic rise in adenocarcinoma of the esophagus continues to remain a mystery even though it represents the largest epidemiologic change ever recorded for a solid cancer. The rise is largely confined to the Caucasian population and is widely attributed to gastroesophageal reflux disease and its complication, Barrett's esophagus. Some have also evoked the rise in obesity as the cause. Based on sound logic, I still support the hypothesis that potent acid suppression therapy played a role in the epidemiologic change. The incidence of adenocarcinoma began to rise in 1975; the same time acid suppression with H2 blockers became widely available. Over time the H2 blockers were largely replaced by proton pump inhibitors that had a greater capacity to suppress acid. Although this hypothesis has been difficult to prove short of a large and long prospective randomized study, an unbiased review of the small nonrandomized studies published in the surgical and medical literature to date will convince the practitioner of the truth of this hypothesis. A recent study1 showed that medically treated patients who had relief or mildly persistent reflux symptoms while on proton pump inhibitors have significantly higher odds of developing esophageal adenocarcinoma than medically treated patients who have persistent severe reflux symptoms. My explanation for this observation is that acid suppression therapy decreases reflux symptoms by decreasing the acid content of gastric juice and causing the pH to rise from less than 2 to 4 or greater, that is, in the range of a weak acid. On the stealth side, this increase in pH also increases the solubility of bile acids in the refluxed neutralized gastric juice. Bile acids at the pH of 4–6 have ready access into the Barrett's epithelial cell. When in the cell, bile acids are known stimulants of CDX2, the most powerful genetic stimulus for the development of intestinal metaplasia. They also stimulate the expression of genes involved in the carcinogenesis of intestinalized Barrett's epithelium to adenocarcinoma. In contrast, the persistence of severe reflux symptoms while on medication indicates incomplete acid suppression. The persistent acidic gastric juice causes bile acids to precipitate out of solution. This nullifies their effect, hence less or no intestinal metaplasia or adenocarcinoma.


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