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.

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 Barrett's 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 (RR(a)) 5.6; 95% CI 3.1 to 10.3), but the risk was even higher with loss of p53 expression (RR(a) 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.

Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett's esophagus.

BACKGROUND & AIMS: Acid exposure contributes to the development of Barrett's 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.

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

AIM: To investigate the value of α-methylacyl-CoA racemase (AMACR) immunohistochemistry for predicting neoplastic progression in Barrett's oesophagus (BO). METHODS AND RESULTS: We conducted a case-control study within a prospective cohort of 720 BO patients. Patients who developed high-grade dysplasia or oesophageal adenocarcinoma were classified as cases, and patients without neoplastic progression as controls. AMACR expression was determined by immunohistochemistry in 12 127 biopsies from 635 patients, and was scored independently by two expert pathologists. Relative risks adjusted for age, gender, BO length and oesophagitis (RR(a)) were calculated in log-linear models. During a median follow-up of 6.6 years, 49 patients (8%) developed high-grade dysplasia or oesophageal adenocarcinoma. Although mild AMACR expression was associated with a trend towards an increased risk of neoplastic progression (RR(a) 1.6, 95% CI 0.9-3.1), the risk was especially elevated with strong AMACR expression (RR(a) 4.8, 95% CI 1.9-12.6). The positive predictive value of strong AMACR expression was slightly higher than that of low-grade dysplasia (22% versus 15%); the negative predictive value was slightly lower (91% versus 93%). CONCLUSIONS: Strong AMACR expression is associated with an increased risk of neoplastic progression in BO. However, AMACR expression appears to be a less powerful predictor for neoplastic progression than low-grade dysplasia.

Nonsteroidal anti-inflammatory drugs and statins have chemopreventative effects in patients with Barrett's esophagus.

BACKGROUND & AIMS: The incidence of Barrett's esophagus and esophageal adenocarcinoma has increased despite surveillance of patients with Barrett's 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 Barrett's esophagus. METHODS: We performed a prospective study of 570 patients with Barrett's 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 Barrett's 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 Barrett's esophagus. Use of a combination of NSAIDs and statins appears to have an additive protective effect.

Head-and-neck paragangliomas are associated with sleep-related complaints, especially in the presence of carotid body tumors.

OBJECTIVES: The carotid body functions as a chemoreceptor. We hypothesized that head-and-neck paragangliomas (HNP) may disturb the function of these peripheral chemoreceptors and play a role in sleep-disordered breathing. DESIGN: This is a case-control study. SETTING: This study was conducted in a tertiary referral center. PARTICIPANTS AND MAIN OUTCOME MEASURES: We assessed fatigue, sleep, and exercise capacity in 74 HNP patients using three questionnaires (Epworth Sleepiness Scale, St. George Respiratory Questionnaire, and a standard clinical sleep assessment questionnaire). Outcomes were compared to those of age- and sex-matched controls. RESULTS AND CONCLUSIONS: Activity, disturbance of psychosocial function, and total score were worse compared to controls (15.4 ± 18.5 vs. 7.2 ± 9.9, P = 0.007; 5.3 ± 10.5 vs. 1.2 ± 2.6, P = 0.008; and 10.4 ± 12.9 vs. 5.0 ± 4.8, P = 0.006, respectively). Patients reported more daytime fatigue, concentration difficulties, and depression (51% vs. 24%, P = 0.006; 31% vs. 10%, P = 0.010; and 19% vs. 2%, P = 0.012). Waking up was reported to be less refreshing in HNP patients (53% vs. 73%, P = 0.038). Dysphonia was a predictor of symptoms, activity, disturbance of psychosocial function, and total scores. Remarkably, the presence of a carotid body tumor was an independent predictor of increased daytime sleepiness (ß = 0.287, P = 0.029). In conclusion, patients with HNP have remarkable sleep-related complaints. Especially the presence of carotid body tumors appears to be associated with increased daytime somnolence.

Value of cyclin A immunohistochemistry for cancer risk stratification in Barrett esophagus surveillance: A multicenter case-control study.

The value of endoscopic Barrett esophagus (BE) surveillance based on 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 of cyclin A expression and to combine these results with our previously reported immunohistochemical p53, AMACR, and SOX2 data, to identify a panel of biomarkers predicting neoplastic progression in BE.We conducted a case-control study within a prospective cohort of 720 BE patients. BE patients who progressed to high-grade dysplasia (HGD, n = 37) or esophageal adenocarcinoma (EAC, n = 13), defined as neoplastic progression, were classified as cases and patients without neoplastic progression were classified as controls (n = 575). Cyclin A expression was determined by immunohistochemistry in all 625 patients; these results were combined with the histological diagnosis and our previous p53, AMACR, and SOX2 data in loglinear regression models. Differences in discriminatory ability were quantified as changes in area under the ROC curve (AUC) for predicting neoplastic progression.Cyclin A surface positivity significantly increased throughout the metaplasia-dysplasia-carcinoma sequences and was seen in 10% (107/1050) of biopsy series without dysplasia, 33% (109/335) in LGD, and 69% (34/50) in HGD/EAC. Positive cyclin A expression was associated with an increased risk of neoplastic progression (adjusted relative risk (RR) 2.4; 95% CI: 1.7-3.4). Increases in AUC were substantial for P53 (+0.05), smaller for SOX2 (+0.014), minor for cyclin A (+0.003), and none for AMARC (0.00).Cyclin A immunopositivity was associated with an increased progression risk in BE patients. However, compared to p53 and SOX2, the incremental value of cyclin A was limited. The use of biomarkers has the potential to significantly improve risk stratification in BE.

[Surveillance for Barrett's oesophagus: worthwhile?]. / Surveillance voor Barrett-slokdarm de moeite waard?

Patients with Barrett's oesophagus have an increased risk of developing oesophageal adenocarcinoma; surveillance is therefore recommended for these patients. However, it has never been proven that Barrett surveillance is actually effective. A recent article in The American Journal of Gastroenterology shows that patients with Barrett's oesophagus with high-grade dysplasia had a lower risk of developing oesophageal adenocarcinoma when they had previous surveillance or endoscopic therapy. These results suggest that surveillance may improve survival of patients with Barrett's oesophagus. However, there is no convincing evidence that surveillance has an effect on mortality due to oesophageal adenocarcinoma. Although the absolute overall risk of developing oesophageal adenocarcinoma in Barrett's oesophagus is low, surveillance is important in the small group of patients with a high risk of neoplastic progression.