Clinical outcomes in patients with a diagnosis of "indefinite for dysplasia" in Barrett's esophagus: a multicenter cohort study.

BACKGROUND AND STUDY AIM: Data are limited on the natural history of patients with Barrett's esophagus with a diagnosis of "indefinite for dysplasia" (IND). The aims of this study were to: (i) determine rates of progression to high grade dysplasia (HGD) or esophageal adenocarcinoma, and compare these with rates for low grade dysplasia (LGD); and (ii) determine the proportion of patients whose histological IND diagnosis changed on follow-up endoscopy. PATIENTS AND METHODS: Demographic, endoscopic, and histologic information of patients with diagnoses of IND and LGD and at least 12 months of follow-up were extracted from the database of a multicenter Barrett's esophagus study. Rates and times for progression to HGD and esophageal adenocarcinoma and regression to nondysplastic epithelium were calculated. Proportions of diagnoses upgraded to HGD/esophageal adenocarcinoma or downgraded to nondysplastic epithelium at first follow-up endoscopy were evaluated. RESULTS: Amongst 2264 patients, 83 with a diagnosis of IND (mean age 60 years, 95 % men, 95 % white; mean follow-up 5.6 years) and 79 with diagnosis of LGD were identified. In the IND group, annual incidences of esophageal adenocarcinoma and HGD were 0.21 % and 0.64 %, respectively, representing a combined incidence of 0.8 %. Mean time to progression was 4.72 years. Within the IND group 55 % patients showed regression to nondysplastic epithelium at first follow-up endoscopy and the overall regression rate was 80 %. Corresponding rates in LGD patients were similar. CONCLUSIONS: Lesions diagnosed as IND and LGD show similar biological behavior and can be treated as a single category with respect to surveillance and follow-up.

Barrett's oesophagus length is established at the time of initial endoscopy and does not change over time: results from a large multicentre cohort.

OBJECTIVE: It is unclear whether Barrett's oesophagus (BO) length changes over time or whether the full length of the segment is established at the onset of disease recognition. The objectives of this study were to evaluate the association of age and BO length and to evaluate the changes in BO length over time. DESIGN: This is a prospective, multicentre cohort study involving patients with BO from five centres. Patients were divided into groups based on the decade of initial diagnosis of BO. The mean BO length and the mean change in BO length were calculated for each age decade. The mean change in BO length was also calculated between the index endoscopy and the last surveillance endoscopy. RESULTS: 3635 patients with BO were included in the study: 87.8% men, 92.8% Caucasians, mean age 60.9 years and mean BO length 3.5 cm. The mean change in BO length was 0.9 cm. The mean BO length did not significantly change for each age category: <30 years (4.6 cm), 30-39.9 years (3.2 cm), 40-49.9 years (3.1 cm), 50-59.9 years (3.1 cm), 60-69.9 years (3.6 cm), 70-79.7 (4.0 cm) and >80 years (4.5 cm), p=0.47. On subgroup analysis of patients with non-dysplastic BO who had at least 1 year of endoscopic follow up, there was a significant decrease in mean change in BO length across age categories ranging from +1.7 to -0.8 cm, p=0.03. CONCLUSIONS: There was no significant difference in BO length by age category in decades. In addition, the change in BO length from index to follow-up endoscopy was similar among patients >30 years. These findings suggest that a patient's BO segment length attains its full extent by the time of the initial endoscopic examination.

Association between length of Barrett's esophagus and risk of high-grade dysplasia or adenocarcinoma in patients without dysplasia.

BACKGROUND & AIMS: It is not clear whether length of Barrett's esophagus (BE) is a risk factor for high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in patients with nondysplastic BE. We studied the risk of progression to HGD or EAC in patients with nondysplastic BE, based on segment length. METHODS: We analyzed data from a large cohort of patients participating in the BE Study-a multicenter outcomes project comprising 5 US tertiary care referral centers. Histologic changes were graded as low-grade dysplasia, HGD, or EAC. The study included patients with BE of documented length without dysplasia and at least 1 year of follow-up evaluation (n = 1175; 88% male), and excluded patients who developed HGD or EAC within 1 year of their BE diagnosis. The mean follow-up period was 5.5 y (6463 patient-years). The annual risk of HGD and EAC was plotted in 3-cm increments (≤3 cm, 4-6 cm, 7-9 cm, 10-12 cm, and ≥13 cm). We calculated the association between time to progression and length of BE. RESULTS: The mean BE length was 3.6 cm; 44 patients developed HGD or EAC, with an annual incidence rate of 0.67%/y. Compared with nonprogressors, patients who developed HGD or EAC had longer BE segments (6.1 vs 3.5 cm; P < .001). Logistic regression analysis showed a 28% increase in risk of HGD or EAC for every 1-cm increase in BE length (P = .01). Patients with BE segment lengths of 3 cm or shorter took longer to develop HGD or EAC than those with lengths longer than 4 cm (6 vs 4 y; P = nonsignificant). CONCLUSIONS: In patients with BE without dysplasia, length of BE was associated with progression to HGD or EAC. The results support the development of a risk stratification scheme for these patients based on length of BE segment.

Persistence of nondysplastic Barrett's esophagus identifies patients at lower risk for esophageal adenocarcinoma: results from a large multicenter cohort.

BACKGROUND & AIMS: Recent population-based studies have shown a low risk of esophageal adenocarcinoma (EAC) in patients with nondysplastic Barrett's esophagus (NDBE). We evaluated whether persistence of NDBE over multiple consecutive surveillance endoscopic examinations could be used in risk stratification of patients with Barrett's esophagus (BE). METHODS: We performed a multicenter outcomes study of a large cohort of patients with BE. Based on the number of consecutive surveillance endoscopies showing NDBE, we identified 5 groups of patients. Patients in group 1 were found to have NDBE at their first esophagogastroduodenoscopy (EGD). Patients in group 2 were found to have NDBE on their first 2 consecutive EGDs. Similarly, patients in groups 3, 4, and 5 were found to have NDBE on 3, 4, and 5 consecutive surveillance EGDs. A logistic regression model was built to determine whether persistence of NDBE independently protected against development of cancer. RESULTS: Of a total of 3515 patients with BE, 1401 patients met the inclusion criteria (93.3% white; 87.5% men; median age, 60 ±17 years). The median follow-up period was 5 ± 3.9 years (7846 patient-years). The annual risk of EAC in groups 1 to 5 was 0.32%, 0.27%, 0.16%, 0.2%, and 0.11%, respectively (P for trend = .03). After adjusting for age, sex, and length of BE, persistence of NDBE, based on multiple surveillance endoscopies, was associated with a gradually lower likelihood of progression to EAC. CONCLUSIONS: Persistence of NDBE over several endoscopic examinations identifies patients who are at low risk for development of EAC. These findings support lengthening surveillance intervals or discontinuing surveillance of patients with persistent NDBE.

Overutilization of endoscopic surveillance in nondysplastic Barrett's esophagus: a multicenter study.

BACKGROUND: Guidelines suggest that patients with nondysplastic Barrett's esophagus (BE) undergo endoscopic surveillance every 3 to 5 years, but actual use of surveillance endoscopy and the determinants of variation in surveillance intervals are not known. OBJECTIVE: To measure use of surveillance endoscopy and its variation in patients with nondysplastic BE. DESIGN: Multicenter, cross-sectional study. SETTING: Three sites in Arizona, Minnesota, and North Carolina. PATIENTS: This study involved patients who had prevalent BE without a history of high-grade dysplasia or esophageal adenocarcinoma. INTERVENTION: Participants were given validated measures of quality of life, numeracy, and cancer risk perception, and the total number of prior endoscopic surveillance examinations was measured. MAIN OUTCOME MEASUREMENTS: Oversurveillance was defined as >1 surveillance examination per 3-year period. RESULTS: Among 235 patients with nondysplastic BE, 76% were male and 94% were white. The average (± standard deviation [SD]) duration of BE was 6.5 ± 5.9 years. The mean (± SD) number of endoscopies per 3-year period was 2.7 ± 2.6. Oversurveillance was present in 65% of participants, resulting in a mean of 2.3 excess endoscopies per patient. Neither numeracy skills nor patient perception of cancer risk were associated with oversurveillance. LIMITATIONS: Endoscopies were measured by patient report, which is subject to error. Results may be generalizable only to patients seen in academic centers. CONCLUSION: Most patients with nondysplastic BE had more surveillance endoscopic examinations than is recommended by published guidelines. Patient factors did not predict oversurveillance, indicating that other factors may influence decisions about the interval and frequency of surveillance examinations.

Risk factors for progression of low-grade dysplasia in patients with Barrett's esophagus.

BACKGROUND & AIMS: Data vary on the progression of low-grade dysplasia (LGD) in patients with Barrett's esophagus (BE); in patients with LGD, we investigated the incidence of high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) and compared progression in patients with different forms of LGD (prevalent vs incident and multifocal vs unifocal). We assessed the effects of consensus diagnosis of LGD on progression rates to HGD and EAC among expert pathologists. METHODS: In a multicenter outcomes project, 210 patients with BE and LGD (classified as incident, prevalent, or persistent) were included. Patients were followed up for an average of 6.2 years (959.6 patient-years). Persistent LGD was defined as detection of LGD on ≥2 consecutive occasions during the follow-up period and extent as either unifocal (LGD at one level of BE segment) or multifocal (>1 level). Histology specimens were reviewed by 2 blinded pathologists. RESULTS: Six patients developed EAC (incidence of 0.44%/year), and 21 developed HGD (incidence of 1.6%/year). The incidence of the combination of HGD and EAC was 1.83%/year. There were no associations between presence of prevalent, incident, or persistent LGD and the extent of LGD with progression rates. Based on consensus diagnosis of 88 reviewed specimens, there was no difference in the progression of LGD to either EAC (the incidence based on analyses by the local pathologist was 0.18%/year, the incidence when there was agreement between the local and one central pathologist was 0.21%/year, and the incidence when all 3 pathologists were in agreement was 0.39%/year) or combined HGD and EAC (0.94%/year, 0.87%/year, and 0.84%/year, respectively). CONCLUSIONS: Overall, patients with BE and LGD have a low annual incidence of EAC, similar to nondysplastic BE. There are no risk factors for progression and there is significant interobserver variation in diagnosis, even among expert pathologists.

Durability of radiofrequency ablation in Barrett's esophagus with dysplasia.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett's esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. METHODS: We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. RESULTS: After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). CONCLUSIONS: In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.

Patients with nondysplastic Barrett's esophagus have low risks for developing dysplasia or esophageal adenocarcinoma.

BACKGROUND & AIMS: The risks of dysplasia and esophageal adenocarcinoma (EAC) are not clear for patients with nondysplastic Barrett's esophagus (NDBE); the rate of progression has been overestimated in previous studies. We studied the incidences of dysplasia and EAC and investigated factors associated with progression of BE. METHODS: The BE study is a multicenter outcomes project of a large cohort of patients with BE. Neoplasia was graded as low-grade dysplasia, high-grade dysplasia (HGD), or EAC. Patients followed up for at least 1 year after the index endoscopy examination were included, whereas those diagnosed with dysplasia and EAC within 1 year of diagnosis with BE (prevalent cases) were excluded. Of 3334 patients with BE, 1204 met the inclusion criteria (93.7% Caucasian; 88% male; mean age, 59.3 y) and were followed up for a mean of 5.52 years (6644.5 patient-years). RESULTS: Eighteen patients developed EAC (incidence, 0.27%/y; 95% confidence interval [CI], 0.17-0.43) and 32 developed HGD (incidence, 0.48%/y; 95% CI, 0.34-0.68). The incidence of HGD and EAC was 0.63%/y (95% CI, 0.47-0.86). There were 217 cases of low-grade dysplasia (incidence, 3.6%/y; 95% CI, 3.2-4.1). Five and 10 years after diagnosis, 98.6% (n = 540) and 97.1% (n = 155) of patients with NDBE were cancer free, respectively. The length of the BE was associated significantly with progression (EAC <6 cm, 0.09%/y vs EAC ≥ 6 cm, 0.65%/y; P = 0.001). CONCLUSIONS: There is a lower incidence of dysplasia and EAC among patients with NDBE than previously reported. Because most patients are cancer free after a long-term follow-up period, surveillance intervals might be lengthened, especially for patients with shorter segments of BE.

Medication usage and the risk of neoplasia in patients with Barrett's esophagus.

BACKGROUND & AIMS: Experimental evidence indicates that proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs)/aspirin, and statins can protect patients with Barrett's esophagus (BE) from developing neoplasias. However, only limited data are available on chemoprevention in patients with BE. METHODS: A retrospective observational study was performed using data from patients with documented BE. Prescription information was collected from pharmacy records. Cox regression analyses were performed to examine the association between prescriptions for PPIs, NSAIDs/aspirin, or statins and the risk of developing esophageal dysplasia or adenocarcinoma during follow-up (from 1982 to 2005). RESULTS: We examined 344 patients diagnosed with BE (mean age 61 years, 90.4% Caucasian, 94.2% male). After BE diagnosis, 67.2% of the patients were prescribed PPIs for a mean duration of 5.1 years; 49.1% were prescribed NSAIDs for a mean duration of 3.6 years, and 25.3% were prescribed statins for a mean duration of 2.8 years. During 2620 patient-years, high grade dysplasia or esophageal adenocarcinoma developed in 33 patients. PPI treatment after BE diagnosis was associated with a reduced risk of high grade dysplasia or cancer; this association persisted after adjustment for gender, age, and the length of BE. NSAID and/or aspirin therapy were associated with a nonsignificant trend toward lower incidence of high grade dysplasia or esophageal cancer. CONCLUSIONS: PPI therapy reduces the risk of neoplasms in patients with BE. NSAIDs/aspirin appear to reduce cancer risk whereas statin use is not significantly associated with the risk of neoplasia in patients with BE.

Medical treatment of Barrett's esophagus: can it prevent cancer?

The challenge of the title of this article is attention getting. How can medical therapy prevent cancer if anti-reflux surgery cannot prevent the neoplastic progression of Barrett's esophagus? Can anything short of esophagectomy prevent cancer? In the face of the increasing incidence of adenocarcinoma of the esophagus into the twenty-first century, the medical therapy of Barrett's esophagus and its potential role in preventing cancer are explored.

Radiofrequency ablation in Barrett's esophagus with dysplasia.

BACKGROUND: Barrett's esophagus, a condition of intestinal metaplasia of the esophagus, is associated with an increased risk of esophageal adenocarcinoma. We assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barrett's esophagus and decrease the rate of neoplastic progression. METHODS: In a multicenter, sham-controlled trial, we randomly assigned 127 patients with dysplastic Barrett's esophagus in a 2:1 ratio to receive either radiofrequency ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of Barrett's esophagus. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. RESULTS: In the intention-to-treat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5% of those in the ablation group, as compared with 22.7% of those in the control group (P<0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0% of those in the ablation group, as compared with 19.0% of those in the control group (P<0.001). Overall, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3% of those in the control group (P<0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P=0.03) and fewer cancers (1.2% vs. 9.3%, P=0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, one patient had upper gastrointestinal hemorrhage, and five patients (6.0%) had esophageal stricture. CONCLUSIONS: In patients with dysplastic Barrett's esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression. (ClinicalTrials.gov number, NCT00282672.)

A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus.

Esophageal adenocarcinoma risk in Barrett's esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than nonprogressors (70.6 versus 62.5 years; P < 0.001). We evaluated a linear combination of the eight markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; P < 0.001, <0.001, and <0.001, respectively). In addition, even after rigorous overfitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Delta-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models. A methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia.

Endoscopic therapy for Barrett's esophagus.

Recent retrospective cohort data and a prospective randomized sham controlled trial have clearly documented the impact of endoscopic ablation therapy on dysplasia and Barrett's esophagus (BE). The clinical indications for ablation of BE includes high-grade dysplasia and intramucosal adenocarcinoma. The techniques of resection of mucosal irregularities and of ablation are reviewed, primarily thermal and photodynamic ablation. Ablation of BE with neoplasia has appropriately entered the clinical arena.

Expression of bile acid transporting proteins in Barrett's esophagus and esophageal adenocarcinoma.

OBJECTIVES: Barrett's esophagus (BE) is a metaplastic lesion characterized by replacement of the normal squamous epithelium by columnar intestinal epithelium containing goblet cells. It is speculated that this process is an adaptation to protect cells from components of refluxate, such as gastric acid and bile acids. In contrast to the normal squamous epithelium, enterocytes of the distal ileum are adapted to transport bile acids from the intestinal lumen. Several bile acid transporters are utilized for effective removal of bile acids, including the apical sodium-dependent bile acid transporter (ASBT), the ileal bile acid-binding protein (IBABP), and the multidrug-resistant protein 3 (MRP3). We hypothesized that one of the possible functions of newly arising metaplastic epithelium, in the esophagus, is to transport bile acids. Our major goal was to evaluate the expression of bile acid transporters in normal squamous epithelium, BE with different grades of dysplasia, and esophageal adenocarcinoma (EAC). METHODS: A total of 101 patients were included in this study. Immunohistochemistry (IHC) and reverse transcriptase (RT)-PCR were used to detect the expression of these transporters at the mRNA and protein levels. RESULTS: Our immunohistochemical studies showed that all three bile acid transporters are expressed in BE glands, but not in squamous epithelium. ASBT was found in the apical border in BE biopsies. The highest frequency of ASBT expression was in patients with nondysplastic BE (9 of 15, 60%), and a progressive loss of ASBT was observed through the stages of dysplasia. ASBT was not detected in EAC (0 of 15). IBABP staining was observed in the cytoplasm of BE epithelial surface cells. Expression of IBABP was found in 100% of nondysplastic BE (14 of 14), in 93% of low-grade dysplasia (LGD, 15 of 16), in 73% of high-grade dysplasia (HGD, 10 of 14), and in 33% of EAC (5 of 15). MRP3 was expressed in the basolateral membrane in 93% of nondysplastic BE (13 of 14), in 60% of LGD (10 of 16), and in 86% of HGD (11 of 13). Only weak MRP3 staining was detected in EAC biopsies (5 of 15, 33%). In addition, RT-PCR studies showed increased expression of mRNA coding for ASBT (6.1x), IBABP (9.1x), and MRP3 (2.4x) in BE (N=13) compared with normal squamous epithelium (N=15). Significantly increased mRNA levels of IBABP (10.1x) and MRP3 (2.5x) were also detected in EAC (N=21) compared with normal squamous epithelium. CONCLUSIONS: We found that bile acid transporters expression is increased in BE tissue at the mRNA and protein levels and that expression of bile acid transporter proteins decreased with progression to cancer.