Differential molecular changes in patients with asymptomatic long-segment Barrett's esophagus treated by antireflux surgery or medical therapy



      The Barrett's to adenocarcinoma sequence is characterized by molecular changes including activation of nuclear factor-κB (NF-κB) and related cytokines. In this observational nonrandomized study this molecular environment was compared in matched asymptomatic cohorts who had undergone either fundoplication or therapy with proton pump inhibitors (PPIs).


      Asymptomatic patients with long-segment Barrett's esophagus had endoscopic biopsy specimens taken from 2 cm below the squamocolumnar junction for measurement of activated NF-κB and a panel of cytokines and growth factors.


      Thirty-seven patients were recruited (surgical: n = 18, medical: n = 19). The mean patient age was 51 years, and the mean follow-up period was 5.6 years. There were no differences in the length of Barrett's segment and endoscopic and histopathologic features in both groups. Mean activated NF-κB p50 and p65 subunits, interleukin (IL)-1α, IL-1β, and interleukin-8 levels, were significantly (P < .05) lower in the surgically treated group.


      This study provides proxy support to the thesis that antireflux surgery may provide an environment that is less inflammatory and tumorigenic than that observed in medically treated patients.


      To read this article in full you will need to make a payment


        • Cameron A.J.
        Barrett's esophagus: does the incidence of adenocarcinoma matter?.
        Am J Gastroenterol. 1997; 92: 193-194
        • Pera M.
        • Cameron A.J.
        • Trastek V.F.
        • et al.
        Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction.
        Gastroenterology. 1993; 104: 510-513
        • Provenzale D.
        • Kemp J.A.
        • Arora S.
        • et al.
        A guide for surveillance of patients with Barrett's oesophagua.
        Am J Gastroenterol. 1994; 89: 670-801
        • Balkwill F.
        • Coussens L.M.
        Cancer: an inflammatory link.
        Nature. 2004; 431: 405-406
        • Maeda S.
        • Omata M.
        Inflammation and cancer: role of nuclear factor-kappaB activation.
        Cancer Sci. 2008; 99: 836-842
        • Barnes P.J.
        • Karin M.
        Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases.
        N Engl J Med. 1997; 336: 1066-1071
        • O'Riordan J.M.
        • Abdel-Latif M.M.
        • Ravi N.
        • et al.
        Proinflammatory cytokine and nuclear factor kappa-B expression along the inflammation-metaplasia-dysplasia-adenocarcinoma sequence in the esophagus.
        Am J Gastroenterol. 2005; 100: 1257-1264
        • Duggan S.P.
        • Gallagher W.M.
        • Fox E.J.
        • et al.
        Low pH induces co-ordinate regulation of gene expression in oesophageal cells.
        Carcinogenesis. 2006; 27: 319-327
        • Murphy J.O.
        • Ravi N.
        • Byrne P.J.
        • et al.
        Neither antioxidants nor COX-2 inhibition against esophageal inflammation protect against esophageal inflammation in an experimental model of severe reflux.
        J Surg Res. 2008; 142: 20-27
        • Abdel-Latif M.M.
        • O'Riordan J.M.
        • Ravi N.
        • et al.
        Activated nuclear factor kappa-B and cytokine profiles in the esophagus parallel tumor regression following neo-adjuvant chemoradiotherapy.
        Dis Esophagus. 2005; 18: 246-252
        • O'Riordan J.M.
        • Byrne P.J.
        • Ravi N.
        • et al.
        Long-term clinical and pathologic response of Barrett's esophagus after anti-reflux surgery.
        Am J Surg. 2004; 188: 27-33
        • Hofstetter W.L.
        • Peters J.H.
        • De Meester T.R.
        • et al.
        Long-term outcomes of anti-reflux surgery in patients with Barrett's esophagus.
        Ann Surg. 2001; 234: 532-538
        • Rantanen T.K.
        • Rasanen J.V.
        • Sihvo E.I.T.
        • et al.
        The impact of anti-reflux surgery on oxidative stress of esophageal mucosa caused by gastroesophageal reflux disease: 4-yr follow-up study.
        Am J Gastroenterol. 2006; 101: 222-228
        • Wetscher G.J.
        • Hinder R.A.
        • Bagchi D.
        • et al.
        Reflux esophagitis in humans is mediated by oxygen-derived free radicals.
        Am J Surg. 1995; 170: 552-557
        • Johnson L.F.
        • DeMeester T.R.
        Twenty-four hour pH monitoring of the distal esophagus.
        Am J Gastroenterol. 1974; 62: 325-332
        • Rossetti M.E.
        • Libermann-Heffert D.
        • Brauner R.B.
        The “Rossetti” modification of the Nissen fundoplication: technique and results.
        Dis Esophagus. 1996; 9: 258-262
        • Comstock G.W.
        • Norkus E.P.
        • Hoffman S.C.
        • et al.
        Stability of ascorbic acid, carotenoids, retinol, and tocopherols in plasma stored at -70 degrees C for 4 years.
        Cancer Epidemiol Biomarkers Prev. 1995; 4: 505-507
        • Kallner A.
        • Hartmann D.
        • Hornig D.
        Steady-state turnover and body pool of ascorbic acid in man.
        Am J Clin Nutr. 1979; 32: 530-539
        • Levine M.
        • Conry-Cantilena C.
        • Wang Y.
        • et al.
        Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance.
        Proc Natl Acad Sci U S A. 1996; 93: 3704-3709
        • Madrigal L.
        • Lynch S.
        • Feighery C.
        • et al.
        Flow cytometric analysis of surface major histocompatibility complex class II expression on human epithelial cells prepared from small intestinal biopsies.
        J Immunol Methods. 1993; 158: 207-214
        • Basu K.K.
        • Bale R.
        • West K.P.
        • et al.
        Persistent acid reflux and symptoms in patients with Barrett's oesophagus on proton-pump inhibitor therapy.
        Eur J Gastroenterol Hepatol. 2002; 14: 1187-1192
        • Theisen J.
        • Peters J.H.
        • Fein M.
        • et al.
        The mutagenic potential of duodenoesophageal reflux.
        Ann Surg. 2005; 241: 63-68
        • Chang E.Y.
        • Morris C.D.
        • Seltman A.K.
        • et al.
        The effect of anti-reflux surgery on esophageal carcinogenesis in patients with Barrett's esophagus: a systematic review.
        Ann Surg. 2007; 246: 11-21
        • Pikarsky E.
        • Porat R.M.
        • Stein I.
        • et al.
        NF-kappaB functions as a tumour promoter in inflammation-associated cancer.
        Nature. 2004; 431: 461-466
        • Abdel-Latif M.M.
        • O'Riordan J.
        • Windle H.J.
        • et al.
        NF-kappaB activation in esophageal adenocarcinoma: relationship to Barrett's metaplasia, survival, and response to neoadjuvant chemoradiotherapy.
        Ann Surg. 2004; 239: 491-500
        • Oh D.S.
        • DeMeester S.R.
        • Vallbohmer D.
        • et al.
        Reduction of interleukin 8 gene expression in reflux esophagitis and Barrett's esophagus with antireflux surgery.
        Arch Surg. 2007; 142: 554-560
        • Lin S.C.
        • Liu C.J.
        • Yeh W.I.
        • et al.
        Functional polymorphism in NFKB1 promoter is related to the risks of oral squamous cell carcinoma occurring on older male areca (betel) chewers.
        Cancer Lett. 2006; 243: 45-47
        • Kim L.H.
        • Shin H.D.
        • Park B.L.
        • et al.
        Identification of variants in NFKBIA and association analysis with hepatocellular carcinoma risk among chronic HBV patients.
        Hum Mutat. 2003; 21: 652-653
        • Karban A.S.
        • Okazaki T.
        • Panhuysen C.I.
        • et al.
        Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis.
        Hum Mol Genet. 2004; 13: 35-45
        • Curran J.E.
        • Weinstein S.R.
        • Griffiths L.R.
        Polymorphic variants of NFKB1 and its inhibitory protein NFKBIA, and their involvement in sporadic breast cancer.
        Cancer Lett. 2002; 188: 103-107
        • Huajie B.U.
        • Inger R.
        • Xiao-Feng S.
        • et al.
        Importance of polymorphisms in NF-κB1 and NF-κBIα genes for melanoma risk, clinicopathological features and tumor progression in Swedish melanoma patients.
        J Cancer Res Clin Oncol. 2007; 133: 859-866
        • Jaiswal K.
        • Lopez-Guzman C.
        • Souza R.F.
        • et al.
        Bile salt exposure increases proliferation through p38 and ERK MAPK pathways in a non-neoplastic Barrett's cell line.
        Am J Physiol Gastrointest Liver Physiol. 2006; 290: G335-G342
        • Mariette C.
        • Piessen G.
        • Leteurtre E.
        • et al.
        Activation of MUC1 mucin expression by bile acids in human esophageal adenocarcinomatous cells and tissues is mediated by the phosphatidylinositol 3-kinase.
        Surgery. 2008; 143: 58-71
        • Burnat G.
        • Rau T.
        • Elshimi E.
        • et al.
        Bile acids induce overexpression of homeobox gene CDX-2 and vascular endothelial growth factor (VEGF) in human Barrett's esophageal mucosa and adenocarcinoma cell line.
        Scand J Gastroenterol. 2007; 42: 1460-1465
        • Kaur B.S.
        • Triadafilopoulos G.
        Acid- and bile-induced PGE(2) release and hyperproliferation in Barrett's esophagus are COX-2 and PKC-epsilon dependent.
        Am J Physiol Gastrointest Liver Physiol. 2002; 283: G327-G334
        • Song S.
        • Guha S.
        • Liu K.
        • et al.
        COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett's oesophagus and oesophageal adenocarcinoma.
        Gut. 2007; 56: 1512-1521
        • Sarela A.I.
        • Hick D.G.
        • Verbeke C.S.
        • et al.
        Persistent acid and bile reflux in asymptomatic patients with Barrett's esophagus receiving proton pump inhibitor therapy.
        Arch Surg. 2004; 139: 547-551
        • Zhang F.
        • Altorki N.K.
        • Wu Y.C.
        • et al.
        Duodenal reflux induces cyclooxygenase-2 in the esophageal mucosa of rats: evidence for involvement of bile acids.
        Gastroenterology. 2001; 121: 1391-1399
        • Spechler S.J.
        • Lee E.
        • Ahnen D.
        • et al.
        Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial.
        JAMA. 2001; 285: 2331-2338
        • Wetscher G.J.
        • Gadenstaetter M.
        • Klingler P.J.
        • et al.
        Efficacy of medical therapy and antireflux surgery to prevent Barrett's metaplasia in patients with gastroesophageal reflux disease.
        Ann Surg. 2001; 234: 627-632
        • Lundell L.
        • Miettinen P.
        • Myrvold H.E.
        • et al.
        Continued (5-year) followup of a randomized clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease.
        J Am Coll Surg. 2001; 192: 172-181
        • Lundell L.
        • Miettinen P.
        • Myrvold H.E.
        • et al.
        Long-term management of gastro-oesophageal reflux disease with omeprazole or open antireflux surgery: results of a prospective, randomized clinical trial. The Nordic GORD Study Group.
        Eur J Gastroenterol Hepatol. 2000; 12: 879-887
        • Isolauri J.
        • Luostarinen M.
        • Viljakka M.
        • et al.
        Long-term comparison of antireflux surgery versus conservative therapy for reflux esophagitis.
        Ann Surg. 1997; 225: 295-299
        • Parrilla P.
        • Martinez de Haro L.F.
        • Ortiz A.
        • et al.
        Long-term results of a randomized prospective study comparing medical and surgical treatment of Barrett's esophagus.
        Ann Surg. 2003; 237: 291-298
        • Rantanen T.K.
        • Sihvo E.I.
        • Rasanen J.V.
        • et al.
        Gastroesophageal reflux disease as a cause of death is increasing: analysis of fatal cases after medical and surgical treatment.
        Am J Gastroenterol. 2007; 102: 246-253
        • DeMeester T.R.
        Surgical therapy for Barrett's esophagus: prevention, protection and excision.
        Dis Esophagus. 2002; 15: 109-116