Florine Kastelein

Predictors for neoplastic progression in patients with Barrett's Esophagus: a prospective cohort study

OBJECTIVES:Patients with Barretts esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors.METHODS:We included 713 patients with BE (≥2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance.RESULTS:After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3–7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01–1.2), esophagitis (RR 3.5; 95% CI 1.3–9.5), and LGD (RR 9.7; 95% CI 4.4–21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18–40%).CONCLUSIONS:In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Proton Pump Inhibitors Reduce the Risk of Neoplastic Progression in Patients With Barrett's Esophagus

BACKGROUND & AIMS Acid exposure contributes to the development of Barretts esophagus (BE) and its progression toward esophageal adenocarcinoma. Patients with BE are frequently treated with acid suppressants, but it is unclear whether these prevent the development of BE-related cancer. We investigated whether acid suppression reduces the risk of neoplastic progression in patients with BE. METHODS We performed a multicenter prospective cohort study of 540 patients with BE. We collected information on medication use at each surveillance visit, which was cross-checked with pharmacy records. Patients also completed a questionnaire about their use of over-the-counter medication. Incident cases of high-grade dysplasia and esophageal adenocarcinoma were identified during a median follow-up period of 5.2 years. Time-dependent Cox regression models were used to investigate the effect of acid suppression on the risk of neoplastic progression. RESULTS Forty patients (7%) developed high-grade dysplasia or esophageal adenocarcinoma during the follow-up period. Use of histamine-2 receptor antagonists did not affect the incidence of neoplastic progression. However, use of proton pump inhibitors (PPIs) at inclusion in the study or during the follow-up period reduced the risk of neoplastic progression (hazard ratio, 0.41; 95% confidence interval, 0.18-0.93 and hazard ratio, 0.21; 95% confidence interval, 0.07-0.66). Prolonged use of PPIs and good adherence were associated with an additional protective effect. The prevalence of esophagitis decreased during PPI use, but length of BE was not affected. CONCLUSIONS In a multicenter prospective cohort study, PPI use was associated with a reduced risk of neoplastic progression in patients with BE.

Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with Barrett's oesophagus

Objective The value of surveillance for patients with Barretts oesophagus (BO) is under discussion given the overall low incidence of neoplastic progression and lack of discriminative tests for risk stratification. Histological diagnosis of low-grade dysplasia (LGD) is the only accepted predictor for progression to date, but has a low predictive value. The aim of this study was therefore to evaluate the value of p53 immunohistochemistry for predicting neoplastic progression in patients with BO. Design We conducted a case–control study within a prospective cohort of 720 patients with BO. Patients who developed high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC) were classified as cases and patients without neoplastic progression were classified as controls. P53 protein expression was determined by immunohistochemistry in more than 12 000 biopsies from 635 patients and was scored independently by two expert pathologists who were blinded to long-term outcome. Results During follow-up, 49 (8%) patients developed HGD or OAC. P53 overexpression was associated with an increased risk of neoplastic progression in patients with BO after adjusting for age, gender, Barrett length and oesophagitis (adjusted relative risks (RRa) 5.6; 95% CI 3.1 to 10.3), but the risk was even higher with loss of p53 expression (RRa 14.0; 95% CI 5.3 to 37.2). The positive predictive value for neoplastic progression increased from 15% with histological diagnosis of LGD to 33% with LGD and concurrent aberrant p53 expression. Conclusions Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with BO and appears to be a more powerful predictor of neoplastic progression than histological diagnosis of LGD.

Nonsteroidal Anti-Inflammatory Drugs and Statins Have Chemopreventative Effects in Patients With Barrett's Esophagus

BACKGROUND & AIMS The incidence of Barretts esophagus and esophageal adenocarcinoma has increased despite surveillance of patients with Barretts esophagus. Limited data indicate that nonsteroidal anti-inflammatory drug (NSAID) and statin use reduce the risk for esophageal adenocarcinoma. We investigated whether NSAID or statin use reduces the risk of neoplastic progression from Barretts esophagus. METHODS We performed a prospective study of 570 patients with Barretts esophagus at 3 academic and 12 regional Dutch hospitals. Information on medication use was collected in patient interviews at each surveillance visit and cross-checked with pharmacy records. Patients completed a questionnaire about use of over-the-counter medication. Incident cases of high-grade dysplasia and adenocarcinoma were identified during the follow-up period. RESULTS During a median follow-up period of 4.5 years, 38 patients (7%) developed high-grade dysplasia or adenocarcinoma. After Barretts esophagus had been diagnosed, 318 patients (56%) used NSAIDs for a median duration of 2 months, 161 (28%) used aspirin for a median duration of 5 years, 209 (37%) used statins for a median duration of 5 years, and 107 (19%) used NSAIDs and statins. NSAID and statin use were each associated with a reduced risk of neoplastic progression (hazard ratio [HR], 0.47; P = .030 and HR, 0.46; P = .048, respectively). Use of a combination of NSAIDs and statins increased the protective effect (HR, 0.22; P = .028). CONCLUSIONS NSAID and statin use reduce the risk of neoplastic progression in patients with Barretts esophagus. Use of a combination of NSAIDs and statins appears to have an additive protective effect.

Cyclooxygenase inhibitors use is associated with reduced risk of esophageal adenocarcinoma in patients with Barrett’s esophagus: a meta-analysis

Background:Esophageal adenocarcinoma (EAC) has high mortality and is increasing in incidence. Barrett’s esophagus (BE) increases the risk for EAC. Studies have reported inconsistent findings on the association between use of cyclooxygenase (COX) inhibitors and the risk of neoplastic progression in BE patients. Therefore, we performed a meta-analysis to investigate this association.Methods:A meta-analysis was undertaken among a total of 9 observational studies using fixed- and random-effects models, comprising 5446 participants; 605 had EAC or high-grade dysplasia (HGD).Results:Overall, COX inhibitors use was associated with a reduced risk of EAC/HGD among BE patients (relative risk (RR)=0.64, 95% confidence interval (CI)=0.53–0.77). Aspirin use also reduced the risk of EAC/HGD (RR=0.63, 95% CI=0.43–0.94), as well as non-aspirin COX inhibitors (RR=0.50, 95% CI=0.32–0.78). The chemopreventive effect seemed to be independent of duration response.Conclusions:Cyclooxygenase inhibitors use is associated with a reduced risk of developing EAC in patients with BE. Both low-dose aspirin and non-aspirin COX inhibitors are associated with a reduced risk of neoplasia. More well-designed randomised controlled trials are needed to increase our understanding of the chemopreventive effect of COX inhibitors.

Surveillance in patients with long-segment Barrett's oesophagus: a cost-effectiveness analysis

Objective Surveillance is recommended for Barretts oesophagus (BO) to detect early oesophageal adenocarcinoma (OAC). The aim of this study was to evaluate the cost-effectiveness of surveillance. Design We included 714 patients with long-segment BO in a multicentre prospective cohort study and used a multistate Markov model to calculate progression rates from no dysplasia (ND) to low-grade dysplasia (LGD), high-grade dysplasia (HGD) and OAC. Progression rates were incorporated in a decision-analytic model, including costs and quality of life data. We evaluated different surveillance intervals for ND and LGD, endoscopic mucosal resection (EMR), radiofrequency ablation (RFA) and oesophagectomy for HGD or early OAC and oesophagectomy for advanced OAC. The incremental cost-effectiveness ratio (ICER) was calculated in costs per quality-adjusted life-year (QALY). Results The annual progression rate was 2% for ND to LGD, 4% for LGD to HGD or early OAC and 25% for HGD or early OAC to advanced OAC. Surveillance every 5 or 4 years with RFA for HGD or early OAC and oesophagectomy for advanced OAC had ICERs of €5.283 and €62.619 per QALY for ND. Surveillance every five to one year had ICERs of €4.922, €30.067, €32.531, €41.499 and €75.601 per QALY for LGD. EMR prior to RFA was slightly more expensive, but important for tumour staging. Conclusions Based on a Dutch healthcare perspective and assuming a willingness-to-pay threshold of €35.000 per QALY, surveillance with EMR and RFA for HGD or early OAC, and oesophagectomy for advanced OAC is cost-effective every 5 years for ND and every 3 years for LGD.

Impact of surveillance for Barrett's oesophagus on tumour stage and survival of patients with neoplastic progression

Objective Endoscopic surveillance for Barretts oesophagus (BO) is under discussion given the overall low incidence of neoplastic progression and lack of evidence that it prevents advanced oesophageal adenocarcinoma (OAC). The aim of this study was to evaluate the impact of endoscopic BO surveillance on tumour stage and survival of patients with neoplastic progression. Design 783 patients with BO of at least 2 cm were included in a multicentre prospective cohort and followed during surveillance according to the American College of Gastroenterology guidelines. Cases of high-grade dysplasia and OAC were identified during follow-up. OAC staging was performed according to the 7th UICC-AJCC classification. Survival data were collected and crosschecked using death and municipal registries. Data from patients with OAC in the general population were obtained from the Dutch cancer registry. We compared survival of patients with BO with neoplastic progression during surveillance with those of patients without neoplastic progression and patients with OAC in the general population. Results 53 patients with BO developed high-grade dysplasia or OAC during surveillance. Thirty-five (66%) were classified as stage 0, 14 (26%) as stage 1 and 4 (8%) as stage 2. OAC was diagnosed at an earlier stage during BO surveillance than in the general population (p<0.001). Survival of patients with BO with neoplastic progression was not significantly worse than those of patients without neoplastic progression and similar to survival of patients with stage 0 or stage 1 OAC in the general population. Conclusions OAC is detected at an earlier stage during BO surveillance than in the general population with good survival rates.

Value of α‐methylacyl‐CoA racemase immunochemistry for predicting neoplastic progression in Barrett's oesophagus

To investigate the value of α‐methylacyl‐CoA racemase (AMACR) immunohistochemistry for predicting neoplastic progression in Barretts oesophagus (BO).

Role of acid suppression in the development and progression of dysplasia in patients with Barrett's esophagus.

Barrett’s esophagus (BE) usually develops in patients with gastroesophageal reflux disease and therefore it has been suggested that esophageal acid exposure plays an import role in the initiation of BE and its progression towards esophageal adenocarcinoma (EAC). The mechanisms whereby acid exposure causes BE are not completely revealed and the potential role of esophageal acid exposure in carcinogenesis is unclear as well. Since acid exposure is thought to play an important role in the progression of BE, therapies aimed at preventing the development of EAC have primarily focused on pharmacological and surgical acid suppression. In clinical practice, acid suppression is effective in relieving reflux symptoms and decreases esophageal acid exposure in most patients. However, in some individuals, pathological acid exposure persists and these patients continue to be at risk for developing dysplasia or EAC. To date, published trials suggest that acid suppression is able to prevent the development and progression of dysplasia in patients with BE, but definite and compelling proof is still lacking. This article reviews the mechanisms of acid-induced carcinogenesis in BE and the role of acid suppression in the prevention of neoplastic progression.

SOX2 as a novel marker to predict neoplastic progression in Barrett's esophagus

OBJECTIVES:The value of Barrett’s esophagus (BE) surveillance based on the histological diagnosis of low-grade dysplasia (LGD) remains debated given the lack of adequate risk stratification. The aim of this study was to evaluate the predictive value (PV) of SOX2 expression for neoplastic progression in BE patients.METHODS:We conducted a case–control study within a prospective cohort of 720 BE patients. Patients with neoplastic progression, defined as the development of high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), were classified as cases and patients without neoplastic progression were classified as controls. SOX2 expression was determined by immunohistochemistry in more than 12,000 biopsies from 635 patients; these results were combined with our previous p53 immunohistochemical data.RESULTS:Nondysplastic BE showed homogeneous nuclear staining for SOX2, whereas SOX2 was progressively lost in dysplastic BE. Loss of SOX2 was seen in only 2% of biopsy series without dysplasia, in contrast to 28% in LGD and 67% in HGD/EAC. Loss of SOX2 expression was associated with an increased risk of neoplastic progression in BE patients after adjusting for gender, age, BE length, and esophagitis (adjusted relative risk 4.8; 95% CI 3.2–7.0). The positive PV for neoplastic progression increased from 16% with LGD alone to 56% with concurrent loss of SOX2 and aberrant p53 expression.CONCLUSIONS:SOX2 expression is lost during transition from nondysplastic BE to HGD/EAC, and it is associated with an increased risk of neoplastic progression. The highest PV is achieved by concurrent loss of SOX2 and aberrant p53 expression in BE patients with LGD. The use of these markers has the potential to significantly improve risk stratification of Barrett surveillance.