The primary objective of this career development award application is to provide me with the proper mentored environment to progress and develop into a successful independent researcher in risk factors for progression in esophageal neoplasia. The incidence of esophageal cancer, particularly adenocarcinoma, is rising rapidly in western countries, and the large majority of esophageal cancer patients die from complications of metastatic disease. However, factors that affect site-specific metastasis have not been well described. Our preliminary research indicates that, in patients with esophageal cancer, smoking may increase the risk of lung metastasis, while alcohol significantly reduces the risk of liver metastasis.
The specific aims of the research proposal are to: (1) determine whether smoking increases the risk of lung metastasis from esophageal cancer;(2) determine whether alcohol decreases the risk of liver metastasis from esophageal cancer;and (3) determine whether smoking and alcohol impact site-specific metastatic risk via effects on the primary tumor (the """"""""seed""""""""), the site of metastasis (the """"""""soil""""""""), or both. In order to accomplish Aims 1 and 2, I propose to conduct a nested case-control study from a cohort of esophageal cancer patients to confirm the site-specific effects of smoking and alcohol on patterns of metastasis. Cases will be defined as esophageal cancer patients with lung or liver metastases, and controls as those patients without lung or liver metastases. In order to accomplish Aim 3, exploratory analyses will be performed of the primary tumor and of sites of metastasis. Primary tumor tissue will be analyzed for expression of high mobility group proteins Al and A2, potential markers of metastatic behavior. Lung damage will be quantified by forced expiratory volume (one second) and by the major urinary prostaglandin-E2 metabolite, an experimental measure of tobacco-induced lung injury. Liver fibrosis will be estimated using an algorithm comprised of three serum markers (hyaluronic acid, procollagen III, and TIMP-1). The identification of lifestyle risk factors for site-specific metastasis and their site of action (""""""""seed"""""""" or """"""""soil"""""""") will: improve predictive modeling of patients at risk for spread of esophageal cancer;identify novel targets for future chemopreventive and therapeutic agents;and serve as a model to study risk factors for site-specific metastasis.
|Araujo, James L; Altorki, Nasser K; Sonett, Joshua R et al. (2016) Prediagnosis aspirin use and outcomes in a prospective cohort of esophageal cancer patients. Therap Adv Gastroenterol 9:806-814|
|Freedberg, Daniel E; Salmasian, Hojjat; Abrams, Julian A et al. (2015) Orders for intravenous proton pump inhibitors after implementation of an electronic alert. JAMA Intern Med 175:452-4|
|Sharaiha, Reem Z; Freedberg, Daniel E; Abrams, Julian A et al. (2014) Cost-effectiveness of chemoprevention with proton pump inhibitors in Barrett's esophagus. Dig Dis Sci 59:1222-30|
|Fudman, David I; Lightdale, Charles J; Poneros, John M et al. (2014) Positive correlation between endoscopist radiofrequency ablation volume and response rates in Barrett's esophagus. Gastrointest Endosc 80:71-7|
|Gupta, Milli; Iyer, Prasad G; Lutzke, Lori et al. (2013) Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett's esophagus: results from a US Multicenter Consortium. Gastroenterology 145:79-86.e1|
|Wani, Sachin; Abrams, Julian; Edmundowicz, Steven A et al. (2013) Endoscopic mucosal resection results in change of histologic diagnosis in Barrett's esophagus patients with visible and flat neoplasia: a multicenter cohort study. Dig Dis Sci 58:1703-9|
|Freedberg, Daniel E; Salmasian, Hojjat; Friedman, Carol et al. (2013) Proton pump inhibitors and risk for recurrent Clostridium difficile infection among inpatients. Am J Gastroenterol 108:1794-801|
|Abrams, Julian A; Gonsalves, Lou; Neugut, Alfred I (2013) Diverging trends in the incidence of reflux-related and Helicobacter pylori-related gastric cardia cancer. J Clin Gastroenterol 47:322-7|
|Gonda, Tamas A; Kim, Young-In; Salas, Martha C et al. (2012) Folic acid increases global DNA methylation and reduces inflammation to prevent Helicobacter-associated gastric cancer in mice. Gastroenterology 142:824-833.e7|
|Quante, Michael; Bhagat, Govind; Abrams, Julian A et al. (2012) Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 21:36-51|
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