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We have recently reported that abnormal acid reflux persists in up to 50% of patients with long segment Barrett’s oesophagus, despite good control of symptoms of gastro-oesophageal reflux disease (GORD) with proton pump inhibitor (PPI) therapy.1 The critical question is whether such persistence of abnormal acid reflux alters the risk of progression to adenocarcinoma. We investigated this issue by studying cellular proliferation and expression of cyclin D1, which is an important marker of neoplastic progression,2,3 in patients with Barrett’s oesophagus on PPI therapy.
A prospective cross-sectional survey of 20 patients with long segment Barrett’s oesophagus (defined as a length ⩾3 cm and presence of specialised intestinal epithelium containing alcian blue staining goblet cells) was conducted. In all cases, GORD symptoms had been well controlled with PPI therapy (omeprazole n = 13 patients, median dose 20 mg (range 10–40); lansoprazole n = 5, 30 mg; or rabeprazole n = 2, 20 mg). Patients had received PPI therapy for a median duration of 30 months (12–66). Oesophageal manometry, 24 hour ambulatory pHmetry, and Bilitec 2000 monitoring were conducted on all patients, without interruption of their usual PPI therapy. Representative endoscopic biopsy specimens of Barrett’s oesophagus from each patient were studied for expression of cyclin D1 protein (primary antibody 1:50 dilution; Novocastra Lab) and Ki-67 protein (primary antibody 1:75; Dako Lab), by standard immunohistochemistry. The histopathologist was blinded to clinical information. A proliferative index was computed for each patient by scoring the percentage of Ki-67 labelled specialised columnar epithelial cells, as previously described.4 Cyclin D1 expression was semi quantitatively assessed. The mean percentage of positive cells in areas of intestinal-type specialised columnar epithelium was assigned to one of three categories: 0, <5%; 1, 5–50%; or 2, >50%. The intensity of cyclin D1 immunostaining was scored as: weak = 1, moderate = 2, or intense = 3. The percentage category of positive cells and staining intensity were multiplied to produce a weighted score for each patient. All cases with weighted scores ⩾1 were designated positive.
Despite PPI therapy and absence of GORD symptoms, pHmetry detected abnormal acid reflux in nine (45%) patients (pH <4 for (median) 19.2% (range 4.6–32.1) of 24 hours; DeMeester score 49.5 (20.2–109.8)). The remaining 11 patients had acid reflux within the normal range (pH <4 for ⩽4.5% of 24 hours). Proliferative indices (mean (SD)) for patients with abnormal acid reflux and those with normal acid reflux were similar (36.5 (8.7) v 37.4 (5.5), respectively; p = 0.3). Cyclin D1 expression was positive in seven (78%) patients with abnormal acid reflux and in seven (64%) patients with normal acid reflux (p = 0.4) (fig 1). The weighted score of cyclin D1 expression was identical (median 2 (range 2–6)) for patients with abnormal acid reflux and those with normal acid reflux.
These data imply that the risk of neoplastic progression was independent of the status of control of acid reflux by PPI therapy. We also examined the association between acid reflux and bile reflux. Absorbance ⩾0.14 for ⩽1.8% of the 24 hour monitoring period was considered the normal range for bile reflux in this study. Despite PPI therapy, abnormal bile reflux was detected in 12 (60%) patients, including six (55%) with normal acid reflux (absorbance ⩾0.14 for 13.0% (2.5–46.5)) and six (66%) with abnormal acid reflux (absorbance ⩾0.14 for 17.4% (3.5–63.7)). Such persistent bile reflux may explain the similarity in expression of Ki-67 or cyclin D1 in the two groups with different control of acid reflux.
In contrast with PPI therapy, antireflux surgery that is successful in controlling acid reflux also controls bile reflux.5 Following successful antireflux surgery, proliferative indices in surface epithelial cells and crypts of Barrett’s oesophagus are significantly lower compared with a failed procedure.6 In the light of the present data, we propose the need for a novel clinical trial of PPI therapy versus antireflux surgery. Patients who are randomised to PPI therapy should undergo serial pH and Bilitec monitoring, with appropriate therapeutic modification to achieve predetermined end points. Patients who are randomised to laparoscopic fundoplication should have additional PPI therapy, as required, to achieve the same end points. Outcomes should be measured by standard serial endoscopic assessment and also by examination of a panel of molecular and cellular markers that is important in the pathogenesis of Barrett’s adenocarcinoma.
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