Barrett's esophagus

The Barrett's esophagus showing columnar metaplasia upward to the esophagus from the esophago-gastric junction is one of the final appearance of reflux esophagitis and important as a precancerous state of esophageal adenocarcinoma. Especially the Barrett's mucosa with intestinal metaplasia has high potential risk for adenocarcinoma. Although the clinical definition of the esophago-gastric junction is not easy, the criteria of the esophago-gastric junction and the Barrett's mucosa proposed by the Japanese Society for Esophageal Diseases is useful. The gastro-esophageal reflux is important in the development of Barrett's mucosa not only in the classical Barrett's esophagus but also in the short-segment Barrett's.     

Barrett's esophagus

Gastroesophageal reflux disease (GERD) is a condition commonly managed in the primary care setting. Patients with GERD may develop reflux esophagitis as the esophagus repeatedly is exposed to acidic gastric contents. Over time, untreated reflux esophagitis may lead to chronic complications such as esophageal stricture or the development of Barrett's esophagus. Barrett's esophagus is a premalignant metaplastic process that typically involves the distal esophagus. Its presence is suspected by endoscopic evaluation of the esophagus, but the diagnosis is confirmed by histologic analysis of endoscopically biopsied tissue. Risk factors for Barrett's esophagus include GERD, white or Hispanic race, male sex, advancing age, smoking, and obesity. Although Barrett's esophagus rarely progresses to adenocarcinoma, optimal management is a matter of debate. Current treatment guidelines include relieving GERD symptoms with medical or surgical measures (similar to the treatment of GERD that is not associated with Barrett's esophagus) and surveillance endoscopy. Guidelines for surveillance endoscopy have been published; however, no studies have verified that any specific treatment or management strategy has decreased the rate of mortality from adenocarcinoma.     

Barrett's esophagus

Esophageal cancer staging is a widely accepted indication for endoscopic ultrasonography (EUS). The evaluation of Barrett's esophagus (BE) with EUS is indicated only when there is high-grade dysplasia or a concern for malignancy in an endoscopic lesion. Because the options for the management of BE and early adenocarcinoma are diverse, proper selection of patients by accurate staging with EUS is critical, particularly when nonoperative management is considered. For example, patients with BE with high-grade dysplasia may be offered esophagectomy in some medical centers, but nonoperative therapies such as endoscopic ablative therapy or mucosal resection may be the preferred treatment options in other gastroenterology practices. This article discusses the scientific evidence for the use of EUS in BE or early esophageal adenocarcinoma.     

The pathogenesis of Barrett's esophagus

Significant progress has been made in clinicians' understanding of the molecular pathogenesis of BE, and the laboratory findings are beginning to lead to hypothesis-driven clinical studies; however, the following questions remain unanswered: (1) how can clinicians identify the persons most at risk for the development of esophageal adenocarcinoma, (2) what are the environmental gene interactions in esophageal carcinogenesis, and (3) can clinicians prevent the development of esophageal adenocarcinoma in the population at risk? As esophageal adenocarcinoma starts to reach epidemic proportions, further research in these areas is urgently required. With the advent of the genomic era and an explosion in studies in BE, significant progress can be made.     

The definition of Barrett's esophagus

Recently, according to increasing gastroesophageal reflux disease (GERD), the patients with Barrett's esophagus (BE) are increasing. Since Barrett have reported cases of esophageal ulcers surrounding by columnar epithelium, the various criteria of the BE have been proposed. In 1998, practice guidelines for BE were developed under the auspices of the American College of Gastroenterology. They proposed that BE was a chance in the esophageal epithelium of any length that can be recognized at endoscopy, and confirmed to have intestinal metaplasia by biopsy of the tubular esophagus and excludes intestinal metaplasia of the cardia. Endoscopically, BE is determined, when 'gastric-appearing mucosa' or apparent 'columnar lined esophagus' is evident proximal to the esophagogastric junction. Histologically, BE has double muscularis mucosae, and contains a mixture cell types; gastric-fundic type epithelium, junctional type epithelium, and specialized columnar epithelium (SCE). Especially SCE is distinctive features of BE, available for diagnosis. On the other hand, BE is premalignant condition for the adenocarcinoma of the esophagus, therefore the features of the BE are researched to prevent and find out earlier development of adenocarcinoma. In this review, we referred to the definition of BE with some topics.     

The operation of Barrett's esophagus

The purpose of operation in Barrett's esophagus is to protect against esophageal acid exposure. In Western countries antireflux surgery is positive because Barrett's esophagus is recognized as premalignancy. But in Japan many people have SSBE without intestinal metaplasia. Thus if cancer is not detected in Barrett's esophagus, it is difficult to accept surgery. Besides antireflux surgery is not always successful. So the extra-surgical treatment is more recommended than operation in Japan.     

Endoscopic therapy for Barrett's esophagus

There are many foreign reports about the endoscopic ablation therapy for Barrett's esophagus. Endoscopic ablation therapy include thermal therapy (electrocoagulation, laser etc.), photodynamic therapy or endoscopic resection and so on. Ablation of Barrett's esophagus by these therapy in combination with adequate acid suppression lead to mucosal replacement by squamous epithelium. But the true value of these endoscopic therapy has not been fully investigated. Further studies are required.     

Endoluminal therapy for Barrett's esophagus

This article reviews methods to minimize the complications associated with endoscopic therapy for patients with Barrett's esophagus. To place this discussion in context, the natural history of Barrett's esophagus and the risks associated with progression to dysplasia and invasive carcinoma are reviewed. Operative esophageal resection traditionally is recommended for patients with Barrett's high-grade dysplasia and early carcinoma, and these surgical risks also are reviewed. Finally, all currently approved and commercially available methods for endoscopic ablation and resection of Barrett's disease are categorized according to their application methods of ablation: focal ablation, field ablation, and mucosal resection. The clinical experience with these devices is reviewed with their associated adverse events and complications. Caveats, concerns, and recommendations are discussed to help minimize the complications associated with the use of these important technologies that hold the promise of removing or destroying Barrett's disease to prevent the development of invasive carcinoma.     

Endoscopic therapy for Barrett's esophagus

With the increase in the rate of esophageal adenocarcinoma in the United States and the Western world matched with the high morbidity and mortality of esophagectomy, there is an increasing need for new and effective techniques to treat and prevent esophageal adenocarcinoma. A wide variety of endoscopic mucosal ablative techniques have been developed for early esophageal neoplasia. However, long-term control of neoplasic risk has not been demonstrated. Most studies show that specialized intestinal metaplasia may persist underneath neo-squamous mucosa, posing a risk for subsequent neoplastic progression. In this article we review current published literature on endoscopic therapies for the management of Barrett's esophagus.     

Biomarkers in Barrett's esophagus

This article provides a framework for clinicians who are attempting the difficult task of interpreting the Barrett's biomarker literature with the goal of improving care for their patients. Although many articles. including more that 60 proposed biomarkers, have been published on this subject, only a few describe phase 3 and 4 studies that are of interest to the clinical gastroenterologist (Table 1). For year, dysplasia grade has been the sole means of risk stratification for patients with BE, and it likely will continue to be used in the foreseeable future. The current authors believe that dysplasia classification can be valuable using the team management approach and quality controls described previously. Significant problems, however, have emerged in phase 2 through 4 studies of dysplasia that make it imperative for the Barrett's field to incorporate additional biomarkers as they are validated. These problems include poor reproducibility of dysplasia interpretations, poor predictive value for negative, indefinite, and low-grade dysplasia, and inconsistent results for HGD in different centers, all of which makes it virtually impossible to develop national guidelines for surveillance. Some studies have even suggested that endoscopic biopsy surveillance using dysplasia may not be worthwhile. Currently, flow cytometric tetraploidy and aneuploidy have progressed furthest in biomarker validation (see Table 1). With proper handling, endoscopic biopsy specimens can be shipped to reference laboratories that have the instruments, computer analytic methods, and expertise to reproducibly detect tetraploidy and aneuploidy. The results of phase 4 studies indicate that flow cytometry appears to be useful in detecting a subset of patients who do not have HGD and yet have an increased risk of progression to cancer that cannot be identified by dysplasia grade. For many reasons, the authors anticipate that the number of validated biomarkers will increase substantially in the future. Biopsy repositories are now readily available for phase 3 studies that can evaluate and compare biomarkers. There are initiatives for multi-institutional Barrett's Centers of Excellence that could provide rapid progress in biomarker evaluation. In addition to new candidate biomarkers, the human genome project has provided high-throughput methodologies and methods for computer analysis of data, which can provide the volume and quality control required for clinically useful biomarkers. Currently, 17p (p53) LOH has progressed the furthest among molecular biomarkers. The authors do not recommend its routine clinical use at the present time, however. Finally, it is likely that clinicians will want to follow the results of clinical treatment-response studies and epidemiologic studies that evaluate relationship between clinical interventions or environmental risk and protective factors and surrogate endpoints, especially if the endpoints are progessing well along the phases of biomarker validation. These studies are likely to be of clinical interest because they may becoming the basis for randomized clinical trials to prevent cancer in BE.     

Barrett's esophagus: chemoprevention

The clinical applicability of the experimental data discussed previously remains questionable, and results of clinical studies on chemoprevention in Barrett's esophagus are needed. The utility of selectively targeting acid exposure, ODC, and COX-2 is not clear, and elucidation of that role will be facilitated by a better understanding of the contribution of these factors in the development of Barrett's cancers. The insights already gained into the basic mechanisms of acid exposure, ODC, and COX-2 in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma hold promise for the development of future therapies aimed at these molecular targets and their signaling pathways. In preclinical studies, the ability of COX-2 selective NSAIDs and DFMO to inhibit carcinogenesis is encouraging. Results of well-designed, prospective clinical studies, however, are still needed to establish the efficacy of potent acid suppression, COX-2 inhibitors, and DFMO in the prevention of this malignancy.     

Barrett's esophagus in children

Barrett's esophagus (BE) is a condition of esophageal dysplasia in which the tubular esophagus is lined with columnar instead of squamous mucosa--not with just any type of columnar mucosa, but with a specialized type with goblet cells. It is considered to be an acquired phenomenon secondary to acid exposure from gastro-esophageal reflux (GER). This report shows a review of BE of children and our data about BE from the study of 19 handicapped children with GER. 3 had intestinal dysplasia with goblet cells (BE). The % time of pH under 4 on 24-hour pH monitoring was significantly lower in the patients with esophagitis including BE than in them with normal esophagus. BE of our study seemed to be reversible after the surgery and anti-acid therapy. It is suggested that BE is not a rare condition even in children and biopsy specimens should be taken to establish the diagnosis.     

Barrett's esophagus complicating scleroderma

Two patients with scleroderma whose esophageal involvement was associated with longstanding reflux esophagitis were found to also have Barrett's esophagus. Since Barrett's esophagus is a premalignant condition, these patients with scleroderma should be considered at high risk for the development of adenocarcinoma of the esophagus.     

Carcinogenesis of Barrett's esophagus

Barrett's esophagus is a premalignant condition and remains the number one risk factor for developing adenocarcinoma. Gastro-esophageal reflux disease is a strong risk factor for both esophageal adenocarcinoma and the precancerous lesion Barrett's esophagus. Both of these conditions are related to the reflux of acid and bile into the esophagus. This results in inflammation and cell damage which initiates a sequence of events termed the metaplasia-dysplasia sequence in which the squamous epithelium is replaced by columnar epithelium exhibiting increasing degrees of dysplasia and overt malignancy. The underlying disease mechanisms remain unclear, but tumor suppression genes (p53, p16, APC) and, oncogenes (K-ras, cyclin D1, c-erb-2) seem to cause the malignant transformation of Barrett's esophagus, and the genetic or epigenetic alterations of these genes have been reported.     

Cytology in Barrett's esophagus

Brush cytology is complementary to endoscopic biopsy and is recommended by some to be part of the routine endoscopic surveillance of patients with BE. Advantages of cytology include the ability to sample a greater area of involved epithelium, preferential exfoliation of the less cohesive dysplastic cells, simplicity, and lower cost. There are clear cytologic criteria for dysplasia, and biomarker studies can be performed on cytologic specimens. Despite these advantages, cytology is used by only 17% of gastroenterologists in the United States today. Limited data are available on the usefulness of cytology in the diagnosis and surveillance of BE. Cytology has good sensitivity for the detection of adenocarcinoma and HGD and good specificity for the detection of IM without dysplasia. Furthermore, cytology may detect abnormalities missed by biopsy. Cytology has problems in the detection of LGD, however. For cytology to become a useful surveillance option, its sensitivity for low-grade lesions must be improved. One potential way to accomplish this is to add biomarkers to routine cytologic specimens to define patients at increased risk of progression to cancer. If simple prognostic biomarkers could be developed and validated in histology and cytologic specimens, this would provide additional support for the utility of cytologic brushings in the surveillance of BE. Cytology could then conceivably accomplish the goals of improved efficiency, risk stratification, and decreased costs in BE surveillance programs.     

Modeling using baseline characteristics in a small multicenter clinical trial for Barrett's esophagus

ObjectiveUtilizing data obtained during a multicenter investigation, this paper illustrates how the use of covariates and careful modeling techniques can be useful in assessing whether a negative outcome from a small multicenter clinical trial could be due to imbalance in baseline characteristics. The Chemoprevention for Barrett's Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett's esophagus. The primary outcomes for the original study were the proportion of biopsy samples exhibiting dysplasia in the celecoxib and placebo groups. The secondary and tertiary outcomes included histologic change and measurements of biologically relevant markers, including COX-1 and ? 2 mRNA, prostanoid levels, and methylation of tumor suppressor genes p16, APC, and E-cadherin. The original study reported no significant differences in primary, secondary or tertiary outcomes. In this paper, we focus on the results of one of the secondary measures, quantitative endoscopy (QE).DesignThe study utilizes data from 56 patients in the CBET for whom baseline (BL) QE and one-year follow-up QE (F04) studies were performed. Of these, 29 were treated with celecoxib (200 mg twice daily for a minimum of 48 weeks) and 27 received the placebo. These patients are segmented as to the presence or absence of circumferential, tongues or islands of Barrett's.MeasurementsThe response of interest is total affected area at one year (Total F04); affected area at baseline (Total BL) is used as a covariate.ResultsControlling for complexity and clinic, there is a significant treatment effect. In addition, there is significant evidence that the area of Barrett's involvement decreased for patients in the treatment group.ConclusionsThat there was a decrease for the celecoxib over the placebo group adds to the body of evidence that relates COX-2 specific inhibitors and cancer incidence.