Barrett’s esophagus in 2016: From pathophysiology to treatment

Esophageal complications caused by gastroesophageal reflux disease (GERD) include reflux esophagitis and Barrett’s esophagus (BE). BE is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). The carcinogenic sequence may progress through several steps, from normal esophageal mucosa through BE to EAC. A recent advent of functional esophageal testing (particularly multichannel intraluminal impedance and pH monitoring) has helped to improve our knowledge about GERD pathophysiology, including its complications. Those findings (when properly confirmed) might help to predict BE neoplastic progression. Over the last few decades, the incidence of EAC has continued to rise in Western populations. However, only a minority of BE patients develop EAC, opening the debate regarding the cost-effectiveness of current screening/surveillance strategies. Thus, major efforts in clinical and research practice are focused on new methods for optimal risk assessment that can stratify BE patients at low or high risk of developing EAC, which should improve the cost effectiveness of screening/surveillance programs and consequently significantly affect health-care costs. Furthermore, the area of BE therapeutic management is rapidly evolving. Endoscopic eradication therapies have been shown to be effective, and new therapeutic options for BE and EAC have emerged. The aim of the present review article is to highlight the status of screening/surveillance programs and the current progress of BE therapy. Moreover, we discuss the recent introduction of novel esophageal pathophysiological exams that have improved the knowledge of the mechanisms linking GERD to BE.     

Clinical significance and management of Barrett's esophagus with epithelial changes indefinite for dysplasia

Barrett's esophagus(BE) is defined as the extension of salmon-colored mucosa into the tubular esophagus ≥1 cm proximal to the gastroesophageal junction with biopsy confirmation of intestinal metaplasia. Patients with BE are at increased risk of esophageal adenocarcinoma(EAC), and undergo endoscopic surveillance biopsies to detect dysplasia or early EAC. Dysplasia in BE is classified as no dysplasia, indefinite for dysplasia(IND), low grade dysplasia(LGD) or high grade dysplasia(HGD). Biopsies are diagnosed as IND when the epithelial abnor-malities are not sufficient to diagnose dysplasia or the nature of the epithelial abnormalities is uncertain due to inflammation or technical issues. Specific diagnostic criteria for IND are not well established and its clinical significance and management has not been well studied. Previous studies have focused on HGD in BE and led to changes and improvement in the management of BE with HGD and early EAC. Only recently, IND and LGD in BE have become focus of intense study. This review summarizes the definition, neoplastic risk and clinical management of BE IND.     

Screening for Barrett's esophagus in colonoscopy patients with and without heartburn

BACKGROUND & AIMS: The population prevalence of Barrett's esophagus (BE) is uncertain. Our aim was to describe the prevalence of BE in a volunteer population. METHODS: Upper endoscopy (EGD) was performed in 961 persons with no prior history of EGD who were scheduled for colonoscopy. Symptom questionnaires were completed prior to endoscopy. Biopsy specimens were taken from the gastric cardia and any columnar mucosa extending > or =5 mm into the tubular esophagus and from the stomach for H. pylori infection in the last 812 patients. RESULTS: The study sample was biased toward persons undergoing colonoscopy, males, and persons with upper GI symptoms. The prevalence of BE was 65 of 961 (6.8%) patients, including 12 (1.2%) with long-segment BE (LSBE). Among 556 subjects who had never had heartburn, the prevalences of BE and LSBE were 5.6% and 0.36%, respectively. Among 384 subjects with a history of any heartburn, the prevalences of BE and LSBE were 8.3% and 2.6%, respectively. In a univariate analysis, LSBE was more common in those with any heartburn vs. those with no heartburn (P = 0.01), but the sample size was insufficient to allow multivariate analysis of predictors of LSBE. In a multivariate analysis, BE was associated with increasing age (P = 0.02), white race (P = 0.03), and negative H. pylori status (P = 0.04). Overall, BE was not associated with heartburn, although heartburn was more common in persons with LSBE or circumferential short segments. CONCLUSIONS: LSBE is very uncommon in patients who have no history of heartburn. SSBE is relatively common in persons age > or =40 years with no prior endoscopy, irrespective of heartburn history.     

Magnifying endoscopy for the diagnosis of specialized intestinal metaplasia in short-segment Barrett’s esophagus

AIM:To determine whether magnified observation of short-segment Barrett’s esophagus(BE)is useful for the detection of specialized intestinal metaplasia(SIM).METHODS:Thirty patients with suspected short-segment BE underwent magnifying endoscopy up to×80.The magnified images were analyzed with respect to their pit-patterns,which were simultaneously classified into five epithelial types[Ⅰ(small round),Ⅱ(straight),Ⅲ(long oval),Ⅳ(tubular),Ⅴ(villous)]by Endo’s classification.Then,a 0.5%solution of methylene blue(MB)was sprayed over columnar mucosa.The patterns of the magnified image and MB staining were analyzed.Biopsies were obtained from the regions previously observed by magnifying endoscopy and MB chromoendoscopy.RESULTS:Three of five patients with a typeⅤ(villous)epithelial pattern had SIM,whereas 21 patients with a non-typeⅤepithelial patterns did not have SIM.The sensitivity,specificity,accuracy,positive predictive value,and negative predictive value of pit-patterns in detecting SIM were 100%,91.3%,92.3%,60%and100%,respectively(P=0.004).Three of the 12 patients with positive MB staining had SIM,whereas 14patients with negative MB staining did not have SIM.The sensitivity,specificity,accuracy,positive predictive value,and negative predictive value of MB staining in detecting SIM were 100%,60.9%,65.4%,25%and100%,respectively(P=0.085).The specificity and accuracy of pit-pattern evaluation were significantly superior compared with MB staining for detecting SIM by comparison with the exact McNemar’s test(P=0.0391).CONCLUSION:The magnified observation of a shortsegment BE according to the mucosal pattern and its classification can be predictive of SIM.     

Risk factors associated with Barrett’s epithelial dysplasia

AIM:To elucidate risk factors associated with dysplasia of short-segment Barrett’s esophagus(BE).METHODS:A total of 151 BE patients who underwent endoscopic examination from 2004 to 2008 in Aoyama Hospital,Tokyo Women’s Medical University,Japan and whose diagnosis was confirmed from biopsy specimens were enrolled in the study.BE was diagnosed based on endoscopic findings of gastric-appearing mucosa or apparent columnar-lined esophagus proximal to the esophagogastric junction.Dysplasia was classified into three grades-mild,moderate and severe-according to the guidelines of the Vienna Classification System for gastrointestinal epithelial neoplasia.Anthropometric and biochemical data were analyzed to identify risk factors for BE dysplasia.The prevalence of Helicobacter pylori(H.pylori)infection and the expression of p53 by immunohistological staining were also investigated.RESULTS:Histological examination classified patients into three types:specialized columnar epithelium(SCE)(n=65);junctional(n=38);and gastric fundic(n =48).The incidence of dysplasia or adenocarcinoma from BE of the SCE type was significantly higher than that of the other two types(P<0.01).The univariate analysis revealed that sex,H.pylori infection,body weight,p53 overexpression,and low diastolic blood pressure(BP)were associated with BE dysplasia.In contrast,body mass index,waist circumference,metabolic syndrome complications,and variables related to glucose or lipid metabolism were not associated with dysplasia.Multivariate logistic analysis showed that overexpression of p53[odds ratio(OR)=13.1,P=0.004],H.pylori infection(OR=0.19,P=0.066),and diastolic BP(OR=0.87,P=0.021)were independent risk factors for epithelial dysplasia in BE patients with the SCE type.CONCLUSION:Overexpression of p53 is a risk factor for dysplasia of BE,however,H.pylori infection and diastolic BP inversely associated with BE dysplasia might be protective.     

Role of chemoprophylaxis with either NSAIDs or statins in patients with Barrett’s esophagus简

The incidence of esophageal adenocarcinoma, a poor prognosis neoplasia, has risen dramatically in recent decades. Barrett’s esophagus represents the best-known risk factor for esophageal adenocarcinoma development. Non-steroidal anti-inflammatory drugs through cyclooxygenase-2 inhibition and prostaglandin metabolism regulation could control cell proliferation, increase cell apoptosis and regulate the expression of growth and angiogenic factors. Statins can achieve equivalent effects through prenylation and subsequently control of cellular signaling cascades. At present, epidemiological studies are small and underpowered. Their data could not justify either medication as a chemo-preventive agent. Population based studies have shown a 43% reduction of the odds of developing an esophageal adenocarcinoma, leaving out or stating a 25% reduction in patients consuming non-aspirin nonsteroidal anti-inflammatory drugs and a 50% reduction in those patients consuming aspirin. They have also stated a 19% reduction of esophageal cancer incidence when statins have been used. Observational studies have shown that non-steroidal anti-inflammatory drugs could reduce the adenocarcinoma incidence in patients with Barrett’s esophagus by 41%, while statins could reduce the risk by 43%. The cancer preventive effect has been enhanced in those patients taking a combination of non-steroidal anti-inflammatory drugs and statins (a 74% decrease). Observational data are equivocal concerning the efficacy of non-steroidal anti-inflammatory drug subclasses. Non-steroidal anti-inflammatory drugs clearly have substantial potential for toxicity, while statins are rather safe drugs. In conclusion, both non-steroidal anti-inflammatory drugs and statins are promising chemopreventive agents and deserve further exploration with interventional studies. In the meanwhile, their use is justified only in patients with cardiovascular disease.     

Molecular markers and imaging tools to identify malignant potential in Barrett's esophagus

Due to its rapidly rising incidence and high mortality, esophageal adenocarcinoma is a major public health concern, particularly in Western countries. The steps involved in the progression from its predisposing condition, gastroesophageal reflux disease, to its premalignant disorder, Barrett's esophagus, and to cancer, are incompletely understood. Current screening and surveillance methods are limited by the lack of population-wide utility, incomplete sampling of standard biopsies, and subjectivity of evaluation. Advances in endoscopic ablation have raised the hope of effective therapy for eradication of high-risk Barrett's lesions, but improvements are needed in determining when to apply this treatment and how to follow patients clinically. Researchers have evaluated numerous potential molecular biomarkers with the goal of detecting dysplasia, with varying degrees of success. The combination of biomarker panels with epidemiologic risk factors to yield clinical risk scoring systems is promising. New approaches to sample tissue may also be combined with these biomarkers for less invasive screening and sur-veillance. The development of novel endoscopic imaging tools in recent years has the potential to markedly improve detection of small foci of dysplasia in vivo. Current and future efforts will aim to determine the combination of markers and imaging modalities that will most effectively improve the rate of early detection of highrisk lesions in Barrett's esophagus.     

Barrett's esophagus: Macroscopic markers and the prediction of dysplasia and adenocarcinoma

BACKGROUND AND AIMS: Surveillance endoscopy has been advocated for patients with Barrett's esophagus but the cost-effectiveness of this has been questioned. The aim of this study is to identify an optimum surveillance protocol by examining if macroscopic markers at diagnosis predict the development of dysplasia. METHODS: The sample was 353 patients with Barrett's esophagus undergoing surveillance by a community-based group of gastroenterologists between 1981 and 2001. At diagnosis the presence of macroscopic and microscopic markers was noted. The presence and pattern of dysplasia and development of adenocarcinoma was documented during subsequent surveillance. RESULTS: Three hundred and fifty-three patients (71% male) underwent regular surveillance over 19 056 patient-months (median 42 months), having a median number of three surveillance endoscopies (range 1-40). Nine patients (seven male) developed adenocarcinoma (1/176 patient years) and four male patients developed high-grade dysplasia (1/397 patient years). Twelve of these 13 patients entered with one or more macroscopic markers: severe esophagitis, nodularity, Barrett's ulcer or stricture. Dysplasia risk was associated with macroscopic markers. Patients who entered with one marker were 6.7 times more likely to develop high-grade dysplasia/adenocarcinoma (HR = 6.7, 95% CI = 1.3, 35). Patients who entered with two or more markers were 14 times more likely to develop high-grade dysplasia/adenocarcinoma (HR = 14.1, 95% CI = 2.02, 102). CONCLUSIONS: The presence of severe esophagitis, Barrett's ulcer, nodularity or stricture at entry indicates a high-risk group for Barrett's esophagus. Cost-effectiveness of surveillance for these patients and those with dysplasia at entry would thus improve.     

Endoscopic options for treatment of dysplasia in Barrett's esophagus

Recent advances in the endoscopic treatment of dysplasia in Barrett's esophagus(BE) have allowed endoscopists to provide effective and durable eradication therapies. This review summarizes the available endoscopic eradication techniques for dysplasia in patients with BE including endoscopic mucosal resection, endoscopic submucosal dissection, photodynamic therapy, argon plasma coagulation, radiofrequency ablation and cryotherapy.     

Photodynamic therapy vs radiofrequency ablation for Barrett’s dysplasia: Efficacy,safety and cost-comparison

AIM:To compare effectiveness,safety,and cost of photodynamic therapy(PDT)and radiofrequency ablation(RFA)in treatment of Barrett’s dysplasia(BD).METHODS:Consecutive case series of patients undergoing either PDT or RFA treatment at single center by a single investigator were compared.Thirty-three patients with high-grade dysplasia(HGD)had treatment with porfimer sodium photosensitzer and 630 nm laser(130 J/cm),with maximum of 3 treatment sessions.Fifty-three patients with BD(47 with low-grade dysplasia-LGD,6 with HGD)had step-wise circumferential and focal ablation using the HALO system with maximum of 4 treatment sessions.Both groups received proton pump inhibitors twice daily.Endoscopic biopsies were acquired at 2 and 12 mo after enrollment,with 4-quadrant biopsies every 1 cm of the original BE extent.A complete histological resolution response of BD(CR-D)was defined as all biopsies at the last endoscopy session negative for BD.Fisher’s exact test was used to assess differences between the two study groups for primary outcomes.For all outcomes,a two-sided P value of less than 0.05 was considered to indicate statistical significance.RESULTS:Thirty(91%)PDT patients and 39(74%)RFA were men(P=0.05).The mean age was 70.7±12.2 and 65.4±12.7(P=0.10)year and mean length of BE was 5.4±3.2 cm and 5.7±3.2 cm(P=0.53)for PDT and RFA patients,respectively.The CR-D was(18/33)54.5%with PDT vs(47/53)88.7%with RFA(P=0.001).One patient with PDT had an esophageal perforation and was managed with non-surgical measures and no perforation was seen with RFA.PDT was five times more costly than RFA at our institution.The two groups were not randomized and had different BD grading are the limitations of the study.CONCLUSION:In our experience,RFA had higher rate of CR-D without any serious adverse events and was less costly than PDT for endoscopic treatment of BD.     

Early experience with radiofrequency energy ablation therapy for Barrett''s esophagus with and without dysplasia

Radiofrequency (RF) ablation using the HALO(360) system combined with proton pump inhibitor (PPI) therapy is a new treatment for Barrett's esophagus (BE). We assessed the safety and effectiveness of this combination therapy at a community-based, BE referral center. After symptom evaluation, endoscopy and histologic assessment, esophageal motility, pH monitoring on PPI, computed tomography, endoscopic ultrasonography and mucosal resection for nodules, we performed HALO(360) ablation followed by twice daily PPI and 3-monthly surveillance for up to 12 months. If metaplasia or dysplasia were present at follow-up, the patients received a second ablation. Thirteen patients (12 male) were treated, three with high-grade dysplasia, four with low-grade and six with non-dysplastic intestinal metaplasia. The mean baseline BE length was 6 cm (range 2-12); nine patients had an hiatal hernia and two had a prior fundoplication. Esophageal pH < 4.0 for < 4% of time was achieved only in 5/13 patients. A mean of 1.4 ablation sessions were performed, without serious adverse events or strictures. Complete eradication of BE was achieved in 6/13 (46%) patients. The mean endoscopic surface regression was 84% (from a mean length of 6 +/- 1 cm to 1.2 +/- 0.5 cm, P < 0.001). Complete elimination of dysplasia was achieved in 5/7 (71%) patients. Ablation efficacy was better in those patients who had maximal pH control (P < 0.05). HALO(360) ablation of BE with or without dysplasia is safe, well-tolerated and effective in the community setting. Follow-up ablation further reverses residual BE or dysplasia.     

Novel biomarkers of fibrosis in Crohn&rsquo;s disease

Fibrosis represents a major challenge in Crohn’s disease (CD), and many CD patients will develop fibrotic strictures requiring treatment throughout their lifetime. There is no drug that can reverse intestinal fibrosis, and so endoscopic balloon dilatation and surgery are the only effective treatments. Since patients may need repeated treatments, it is important to obtain the diagnosis at an early stage before strictures become symptomatic with extensive fibrosis. Several markers of fibrosis have been proposed, but most need further validation. Biomarkers can be measured either in biological samples obtained from the serum or bowel of CD patients, or using imaging tools and tests. The ideal tool should be easily obtained, cost-effective, and reliable. Even more challenging is fibrosis occurring in ulcerative colitis. Despite the important burden of intestinal fibrosis, including its detrimental effect on outcomes and quality of life in CD patients, it has received less attention than fibrosis occurring in other organs. A common mechanism that acts via a specific signaling pathway could underlie both intestinal fibrosis and cancer. A comprehensive overview of recently introduced biomarkers of fibrosis in CD is presented, along with a discussion of the controversial areas remaining in this field.     

Management strategies of Barrett's esophagus

Barrett’s esophagus is a condition resulting from chronic gastro-esophageal reflux disease with a documented risk of esophageal adenocarcinoma. Current strategies for improved survival in patients with Barrett''s adenocarcinoma focus on detection of dysplasia. This can be obtained by screening programs in high-risk cohorts of patients and/or endoscopic biopsy surveillance of patients with known Barrett’s esophagus (BE). Several therapies have been developed in attempts to reverse BE and reduce cancer risk. Aggressive medical management of acid reflux, lifestyle modifications, antireflux surgery, and endoscopic treatments have been recommended for many patients with BE. Whether these interventions are cost-effective or reduce mortality from esophageal cancer remains controversial. Current treatment requires combinations of endoscopic mucosal resection techniques to eliminate visible lesions followed by ablation of residual metaplastic tissue. Esophagectomy is currently indicated in multifocal high-grade neoplasia or mucosal Barrett’s carcinoma which cannot be managed by endoscopic approach.     

Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in Barrett's esophagus

BACKGROUND & AIMS: Photodynamic therapy (PDT) for high-grade dysplasia (HGD) in Barrett's esophagus is a Food and Drug Administration-approved alternative to esophagectomy. Critical information regarding overall survival of patients followed up long-term after these therapies is lacking. Our aim was to compare the long-term survival of patients treated with PDT with patients treated with esophagectomy. METHODS: We reviewed records of patients with HGD seen at our institution between 1994 and 2004. PDT was performed 48 hours following the intravenous administration of a photosensitizer using light at 630 nm. Esophagectomy was performed by either transhiatal or transthoracic approaches by experienced surgeons. We excluded all patients with evidence of cancer on biopsy specimens. Vital status and death date information was queried using an institutionally approved Internet research and location service. Statistical analysis was performed using Kaplan-Meier curves and Cox proportional hazards ratios. RESULTS: A total of 199 patients were identified. A total of 129 patients (65%) were treated with PDT and 70 (35%) with esophagectomy. Overall mortality in the PDT group was 9% (11/129) and in the surgery group was 8.5% (6/70) over a median follow-up period of 59 +/- 2.7 months for the PDT group and 61 +/- 5.8 months for the surgery group. Overall survival was similar between the 2 groups (Wilcoxon test = 0.0924; P = .76). Treatment modality was not a significant predictor of mortality on multivariate analysis. CONCLUSIONS: Overall mortality and long-term survival in patients with HGD treated with PDT appears to be comparable to that of patients treated with esophagectomy.     

Bcl—2基因蛋白在食管异型增生组织和鳞癌中的表达变化及其意义

目的：目前食管癌的主要诊断方法有赖于病理学，至今尚无特异性肿瘤标志物，为此对找辅助食管癌早期诊断的分子标志物进行研究。方法：采用单克隆抗体免疫组化LSAB方法检测了BCl－2基因在EM、EED和SCCE中表达变化及其意义。结果：EM组无异常表达；EED组阳性表达率为65．7％，与EM组相比差异有显著性（P＜0．05），在EED中BCl－2蛋白表达增加主要发生在2和3级EED中（P＜0．05）；在SCCE中阳性表达率为77．1％，与EED组相比差异无显著性（P＞0．05），Bcl－2蛋白过表达主要与高分化的SCCE有关（P＜0.05）。结论：食管癌早期发生阶段存在Bcl－2基因表达异常，早期检测Bcl－2基因表达变化可能有助于食管癌早期发生的评估；Bcl－2基因对食管癌的进展不起重要作用。