Background: Esophageal adenocarcinoma (EA) arises from Barrett's epithelium (BE), and chronic gastroesophageal reflux disease is considered the strongest risk factor for disease progression. All BE patients undergo acid suppressive therapy, surveillance, and BE removal by surgery or endoscopic ablation, yet the incidence of EAC continues to increase. Despite the known side effects and mortality, the one-size-fits-all approach is the standard clinical management as there are no reliable methods for risk stratification. Methods: Paired-end Illumina NextSeq500 RNA sequencing was performed on total RNA extracted from 20-week intervals (0, 20, 40, and 60 W) of an in vitro BE carcinogenesis (BEC) model to construct time series global gene expression patterns (GEPs). The cells from two strategic time points (20 and 40 W) based on the GEPs were grown for another 20 weeks, with and without further acid and bile salt (ABS) stimulation, and the recurrent neoplastic cell phenotypes were evaluated. Results: Hierarchical clustering of 866 genes with ≥ twofold change in transcript levels across the four time points revealed maximum variation between the BEC20W and BEC40W cells. Enrichment analysis confirmed that the genes altered ≥ twofold during this window period associated with carcinogenesis and malignancy. Intriguingly, the BEC20W cells required further ABS exposure to gain neoplastic changes, but the BEC40W cells progressed to malignant transformation after 20 weeks even in the absence of additional ABS. Discussion: The transcriptomic gene expression patterns in the BEC model demonstrate evidence of a clear threshold in the progression of BE to malignancy. Catastrophic transcriptomic changes during a window period culminate in the commitment of the BE cells to a "point of no return," and removal of ABS is not effective in preventing their malignant transformation. Discerning this "point of no return" during BE surveillance by tracking the GEPs has the potential to evaluate risk of BE progression and enable personalized clinical management.

Gastro-oesophageal reflux disease is a common medical problem in developed countries, and is a risk factor for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Both proton pump inhibitor therapy and antireflux surgery are effective at controlling endoscopic signs and symptoms of gastro-oesophageal reflux in patients with Barrett's oesophagus, but often fail to eliminate pathological oesophageal acid exposure. The current available studies strongly suggest that acid suppressive therapy, both pharmacological as well as surgical acid suppression, can reduce the risk the development and progression in patients with Barrett's oesophagus, but are not capable of complete prevention. No significant differences have been found between pharmacological and surgical therapy. For clinical practice, patients should be prescribed a proton pump inhibitor once daily as maintenance therapy, with the dose guided by symptoms. Antireflux surgery can be a good alternative to proton pump inhibitor therapy, but should be primarily offered to patients with symptomatic reflux, and not to asymptomatic patients with the rationale to protect against cancer.

Barrett's esophagus (BE) is the most predictive risk factor for development of esophageal adenocarcinoma (EAC), a malignancy with the fastest increasing incidence in the US. The aim of this study was to investigate differences in exposures, demographics, and comorbidities between regressing and non-regressing patients.

We retrospectively collected and analyzed data from a cohort of BE patients participating in a single-center study comprised of all patients diagnosed with BE over a 10-year period. We collected information from the patient's electronic medical records regarding demographic data, endoscopic findings, histological findings, exposures, and history of antireflux surgery.

This study included 1,342 BE patients, 505 (37.6%) of which experienced regression. The regressed group was 52.3% male, while the non-regressing group was 68.3% male (p < 0.001). Mean age was 65.2 ± 12.8 and 62.0 ± 13.1 years for non-regressing and regressing patients, respectively (p < 0.001). No difference was seen in BMI between regressing and non-regressing groups (27.5 ± 5.7 vs. 27.7 ± 5.4, p = 0.52). No difference was seen between groups with respect to PPI use (93.5% non-regressing vs. 94.1% regressed patients, p = 0.70), but regressed patients were more likely to take vitamin D than non-regressing patients (34.1 vs. 42.1%, p = 0.003). Regressed patients had an average segment length of 1.48 cm (±1.58 cm), in contrast to those not regressing (3.58 ± 3.09 cm (p < 0.001)). Interestingly, one patient in the regression group progressed to dysplasia, while 101 of the non-regressing patients progressed to dysplasia/EAC, a result found to be independent of segment length on multivariate analysis (p < 0.001).

Currently, several studies have shown risk factors that can predict progression of non-dysplastic BE, but few investigate predictors for regression. Our study reports several factors that can be used to predict patients who will regress from BE and those who likely will not, tools that will be useful in tailoring therapeutic and surveillance strategies.

Esophageal adenocarcinoma (EAC) is the eighth most common cancer worldwide, and approximately 15% of patients survive 5years. Reflux disease (GERD) and Barrett's esophagus (BE) are major risk factors for the development of EAC, and epidemiologic studies highlight a strong association with obesity. The immune, inflammatory and intracellular signaling changes resulting from chronic inflammation of the esophageal squamous epithelium are increasingly well characterized. In GERD and Barrett's, an essential role for T-cells in the initiation of inflammation in the esophagus has been identified, and a balance between T-cell responses and phenotype may play an important role in disease progression. Obesity is a chronic low-grade inflammatory state, fueled by adipose tissue derived- inflammatory mediators such as IL-6, TNF-α and leptin, representing a novel area for targeted research. Additionally, reactive oxygen species (ROS) and receptor tyrosine kinase (RTK) activation may drive progression from esophagitis to EAC, and downstream signaling pathways employed by these molecules may be important. This review will explain the diverse range of mechanisms potentially driving and maintaining inflammation within the esophagus and explore both existing and future therapeutic strategies targeting the process.

Better criteria are needed to identify patients who should be screened for Barrett's esophagus (BE) to reduce overtesting and improve the cost effectiveness. There is evidence that chemopreventive agents such as nonsteroidal anti-inflammatory drugs, particularly aspirin, reduce the risk of esophageal adenocarcinoma (EAC), but little is known about their effects on BE. We analyzed characteristics of patients with BE for factors that might be used in screening and management.

In this case-controlled study, we identified 434 patients with BE diagnosed at the first endoscopy (incident cases) at a single institution (1997-2010). BE cases were matched with controls on the basis of indication for endoscopy, year of endoscopy, and endoscopist. Risk factors analyzed included age, sex, body mass index, medical and social history, and medications. We performed a multivariate logistic regression analysis to identify clinical risk factors for BE.

In a multivariate regression model, men had a greater risk for developing BE (odds ratio, 3.2; 95% confidence interval, 2.3-4.4), whereas current aspirin users had a lower risk than nonusers (odds ratio, 0.56; 95% confidence interval, 0.39-0.80). A subset analysis, limited to patients who had endoscopies for symptoms of gastroesophageal reflux disease, yielded similar findings. No interactions were found between aspirin use and smoking or use of acid-suppressive medications.

In a case-controlled study of 434 patients with BE, current aspirin use appeared to reduce the risk of BE; previous studies associated aspirin use with a reduced risk of EAC. Although efforts were made to minimize biases in our analysis, the possibility of residual confounding remains.

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.

Barrett's oesophagus normally affects the distal oesophagus when metaplastic columnar lined epithelium replaces stratified squamous epithelium which predisposes to cancer development. This develops as a consequence of chronic gastroesophageal reflux (GORD). Those with Barrett's have a 40 fold increased risk of oesophageal adenocarcinoma [1]. There are is still a lack of understanding of the natural history of the cell of origin. This does hamper research into this area. We accept that there is a limitation in testing of the pathogenesis of Barrett's oesophagus due to a lack of a universally accepted animal model. The major questions surrounding Barrett's oesophagus include validity of surveillance strategies, the optimal treatment and more importantly an agent that can prevent progression to cancer without unacceptable side effects. The main chemopreventative agents that show promise are aspirin and proton pump inhibitors (PPIs). There are other agents such as green tea, berries and antioxidants and diet that have been suggested; we discuss the evidence available for these strategies. We hope for continued improvement in the clinical trial infrastructure to facilitate testing of new pharmacological and endoscopic interventions for Barrett's oesophagus.

Barrett's esophagus is a well-known acquired condition resulting from gastroesophageal reflux disease (GERD). However, it is still unknown whether Barrett's esophagus develops gradually over time in patients with GERD. To address this issue, we investigated the change in the prevalence and length of short-segment Barrett's esophagus (SSBE) over time.

From January 2005 to March 2007, we enrolled 5338 patients who received upper gastrointestinal endoscopy. Prevalence and length of endoscopically identified SSBE were evaluated within groups divided on the basis of 10-year age intervals. The factors possibly influencing SSBE length such as symptoms, antacid use, and endoscopic findings were also evaluated. Additionally, the length change in 236 patients with histologically confirmed Barrett's esophagus was evaluated over a 2-year follow-up.

Of the 5338 enrolled patients, 1997 had SSBE. The prevalence of endoscopically identified SSBE was significantly higher and its length was significantly longer in elderly patients. Multiple regression analysis showed that age, presence of reflux esophagitis, reflux symptoms, and hiatal hernia were positively correlated with SSBE length. Analysis of the 2-year follow-up study of histologically confirmed SSBE revealed significant extension of Barrett's length in 28.0% of 236 patients. Presence of reflux symptoms and hiatal hernia were identified as positive predictors and proton pump inhibitor administration as a negative predictor of SSBE elongation.

Positive predictors for the extension of SSBE were presence of hiatal hernia and reflux symptoms, but not age.

In animal models, mixed acid and bile reflux into lower esophagus induces histological changes comparable to Barrett's metaplasia (BM) and neoplasia. The aim of this study was to compare the effects of Roux-en-Y (REY) surgery and medical therapy on BM in animals before the development of neoplasia. Vagus preserving esophagojejunostomy operation was performed on Sprague-Dawley rats to achieve gastroduodenal reflux (GDR) into the esophagus in 30 animals. After 3 months, changes were reversed in 10 animals (Group REY) by REY operation, 10 animals (Group proton pump inhibitor [PPI]) were given PPI during the postoperative period, and 10 animals (Group GDR) did not have further intervention. At 4 months, histological examination of the lower esophagus was performed by an experienced pathologist. Physiological parameters were also analyzed in all animals preoperatively and at 4 months postoperatively. The length of columnar mucosa, degree of acute inflammation, degree of metaplasia, and composite BM score were significantly reduced by REY surgery compared with medical therapy and with control (columnar mucosa in cm [mean +/- standard error of the mean] Group REY 0.44 +/- 0.06, Group PPI 0.92 +/- 0.08, P < 0.001/Group GDR 1.17 +/- 0.31, P < 0.03). There was no neoplasia seen in any specimen. At 4 months, postoperatively controls Group REY surgery showed significantly more normalization of physiological parameters to preoperative levels than Group PPI (P < 0.05). REY surgery is potentially more beneficial than medical therapy in reversing the histological and biochemical changes of Barrett's esophagus due to GDR.

Oesophageal adenocarcinoma is an increasingly common cancer with a poor prognosis. It develops in a stepwise progression from Barrett's metaplasia to dysplasia, and then adenocarcinoma followed by metastasis.

To outline the key molecular changes in oesophageal adenocarcinoma and to summarize the chemopreventative and therapeutic strategies proposed.

A literature search was performed to identify appropriate research papers in the field. Search terms included: Barrett's (o)esophagus, intestinal metaplasia, (o)esophageal adenocarcinoma, molecular changes, genetic changes, pathogenesis, chemoprevention, therapeutic strategies and treatment. The search was restricted to English language articles.

A large number of molecular changes have been identified in the progression from Barrett's oesophagus to oesophageal adenocarcinoma although there does not appear to be an obligate order of events. Potential chemoprevention strategies include acid suppression, anti-inflammatory agents and antioxidants. In established adenocarcinoma, targeted treatments under evaluation include receptor tyrosine kinase inhibitors of EGFR and cyclin-dependent kinase inhibitors, which may benefit a subgroup of patients.

Advances in molecular methodology have led to a greater understanding of the oesophageal adenocarcinoma pathways, which provides opportunities for chemoprevention and therapeutic strategies with a mechanistic basis. More work is required to assess both the safety and efficacy of these new treatments.

Acid suppressive therapy has been reported to regress Barrett's esophagus. However, it is still controversial as to whether all Barrett's esophagus patients respond to this therapy. The factors that might facilitate newly developed squamous re-epithelialization after biopsy excision of Barrett's mucosa were evaluated to identity individuals who may favorably respond to the regression therapy.

Two hundred and forty-seven biopsy sites from 185 patients with Barrett's esophagus were examined by endoscopy to investigate possible squamous re-epithelialization of Barrett's mucosa after endoscopic biopsy. Before endoscopic examination, all participants were requested to answer questionnaires concerning sociodemographic characteristics, lifestyle habits and drugs usage. The mucin phenotype, Cdx2 expression, cyclooxygenase-2 expression, cellular proliferation and apoptosis of Barrett's mucosa were immunohistochemically investigated in the biopsy samples taken from Barrett's esophagus. The influence of these factors on the newly developed squamous re-epithelialization of Barrett's mucosa after endoscopic biopsy excision was evaluated.

By multivariate analysis, the independent factors that favored squamous re-epithelialization were the gastric mucin predominant phenotype of Barrett's mucosa and the absence of Cdx2 protein expression. In Barrett's mucosa with the gastric predominant mucin phenotype, proton pump inhibitor administration, the absence of reflux esophagitis and a low proliferating cell nuclear antigen index were found to be independent predictors for squamous re-epithelialization.

The absence of the intestinal predominant mucin phenotype was a positive predictor for newly developed squamous re-epithelialization at the site of biopsy of Barrett's mucosa. Only Barrett's esophagus with the gastric predominant mucin phenotype may predict a favorable response to acid suppressive therapy.

Attention has focused on whether normalization, regression, and development of dysplasia and cancer in specialized intestinal metaplasia (SIM) differ among long-segment Barrett's esophagus (LSBE), short-segment BE (SSBE), and esophagogastric junction SIM (EGJSIM). We prospectively followed a cohort of SIM patients receiving long-term antisecretory medications to determine: (a) histologic normalization (no evidence of SIM on biopsy), (b) change in SIM length, (c) incidence of dysplasia and cancer, and (d) factors associated with normalization.

One hundred forty-eight patients with SIM were identified in our original cohort. Of these, 60.5% (23/38) LSBE, 69.8% (44/63) SSBE, and 72.3% (34/47) EGJSIM patients underwent repeat surveillance over a mean 44.4 +/- 9.7 months. Demographic, clinical, and endoscopic data were obtained.

(a) With long-term, antisecretory therapy, normalization occurred in 0/23 LSBE, 30% (13/44) of SSBE, and 68% (23/34) of EGJSIM (P < 0.001). (b) Normalization was more likely with EGJSIM (odds ratio [OR] 6.7, CI 2.3-19.3, P= 0.005), female gender (OR 7.3, CI 2.3-23.1, P= 0.001), or absence of hiatal hernia (OR 2.9, CI 1.02-8.06, P= 0.002). (c) A significant decrease in mean SIM length was noted for the entire population (2.5 +/- 0.3 to 2.13 +/- 0.3 cm, P= 0.004). (d) Follow-up incidence of dysplasia and cancer was 26.1% (3 indefinite, 2 low-grade dysplasia [LGD], 1 cancer) for LSBE, 6.8% (2 indefinite, 1 LGD) for SSBE, and none for EGJSIM (P < 0.004).

(a) Normalization of SIM occurs most frequently in EGJSIM>SSBE>LSBE. (b) Factors associated with normalization favor less severe GER and shorter segments of SIM. (c) Surveillance of LSBE results in the greatest yield for identifying dysplasia and cancer.

Oesophageal dysmotility contributes to the pathogenesis of Barrett's epithelium (BE) allowing prolonged mucosal contact with injurious refluxate. Argon plasma coagulation (APC) is effective for BE ablation, but it is unknown whether the procedure affects oesophageal motility.

To assess the effect of low power (30 W) APC therapy on oesophageal motility in patients with BE.

Thirty-three patients with at least 4 cm of BE underwent oesophageal manometry before and after APC ablation. All were on proton pump inhibitors. Oesophageal body peristaltic wave duration and amplitude, and lower oesophageal sphincter (LOS) pressure and length were compared before and after treatment.

In a total of 28 men and five women, with a mean age of 63.4 years (range 39-79) and mean BE length 6.5 cm (range 4-19), macroscopic clearance was achieved in 28 patients. A small statistically significant (P<0.05) increase in peristaltic wave amplitude was seen after APC [mean (SD) mmHg before versus after: 30.4 (15.2) versus 36.2 (20.1) at 13.5 cm, 47.6 (27.1) versus 54.5 (26.8) at 8.5 cm, and 51.2 (35.3) versus 58 (34.4) at 3.5 cm above the LOS]. No changes in either peristaltic wave duration or LOS parameters [mean (SD) pressure 10.6 (5.6) versus 10.3 (4.3) mmHg; length 2.8 (1.3) versus 2.8 (1.0) cm] were observed.

APC ablation of BE at a power setting of 30 W does not impair oesophageal motility.

There is little evidence that treatment of patients with Barrett's oesophagus with proton pump inhibitors over periods up to 6 years results in major regression of Barrett's oesophagus.

To determine if longer periods of treatment with proton pump inhibitors lead to significant regression of Barrett's oesophagus, and to determine the incidence of oesophageal adenocarcinoma in the proton pump inhibitor-treated patients.

We analysed prospectively-collected data on Barrett's oesophagus patients treated with proton pump inhibitors for 1-13 years.

188 patients with Barrett's oesophagus and intestinal metaplasia, were treated for 1-13 years with a proton pump inhibitor (966 years of treatment; mean 5.1 years). No change in length was seen during treatment but 48% of patients developed squamous islands (25% after 1-3 years; 100% at 12-13 years). Squamous islands correlated with treatment duration and male sex but not with proton pump inhibitor dose or patient age. Six patients developed dysplasia and three males developed adenocarcinoma during treatment (cancer incidence 0.31%).

Proton-pump inhibitor treatment over 1-13 years does not shorten the Barrett's oesophagus segment but squamous islands appear in many patients. The incidence of oesophageal adenocarcinoma was low in these proton pump inhibitor-treated patients compared with published series.

Barrett's oesophagus is the consequence of excessive and prolonged gastro-oesophageal reflux. The therapeutic objectives in Barrett's oesophagus include the reduction of gastro-oesophageal reflux in order to relieve symptoms and the prevention of the biologic progression to adenocarcinoma. The first objective may be achieved with standard proton pump inhibitor (PPI) therapy, which is the base of the medical therapy in this type of patients, but this therapy has been found not to be associated with normalization of the intraluminal pH of the oesophagus in many patients with Barrett's oesophagus. This condition seems to be necessary in order to reduce mucosal cell proliferation in some studies. Therefore, it has been proposed that patients with Barrett's oesophagus need profound acid inhibition with high-dose PPI. This therapeutic approach provides symptom relief, but there is no direct evidence that it is associated with Barrett's oesophagus regression or progression to adenocarcinoma. Nevertheless, recent and preliminary data suggest that long-term PPI therapy may reduce the risk of developing disease progression. Profound acid inhibition is also combined with endoscopy ablative or resection therapy in patients with Barrett's oesophagus. This therapeutic approach should be still regarded as experimental and more data are needed before its therapeutic role in patients with Barrett's oesophagus is established.

The incidence of oesophageal adenocarcinoma is increasing in the UK faster than any other malignancy. Despite its relatively poor prognosis and the limited success of existing treatments, there is enthusiasm that chemopreventive agents might be able to stem the transition from normal squamous epithelium to adenocarcinoma. We discuss gastro-oesophageal reflux as the main risk factor for the development of Barrett's metaplasia, the only known precursor of oesophageal adenocarcinoma. Treatment options for reflux disease are considered with regard to their effects on cancer risk. Recent advances in the molecular and cell biology of Barrett's are outlined, and potential targets for chemoprevention examined. Available treatments for reflux disease have not convincingly altered the likelihood of cancer development. Epidemiological and animal studies support the use of non-steroidal anti-inflammatory drugs as potential chemopreventive agents. Dietary agents, however, have a more favourable side-effect profile and may prove to be an attractive alternative, although more work is needed to fully explore this prospect.

The causal relationship between GERD and esophageal adenocarcinoma, although unclear just a few decades ago, now is established fairly well. The physiologic changes and the biocellular alterations of the damaged esophageal mucosa are documented better. Despite this knowledge, the dramatic increase in the incidence of esophageal cancer cannot be explained. The absolute risk of esophageal adenocarcinoma arising from GERD is low, and, at present, does not justify population-screening programs. Still, with the notion that adenocarcinoma of the esophagus is an aggressive cancer once documented, important questions still are in need of answers for patients suffering from reflux symptoms. Patients who have reflux disease are not necessarily symptomatic. It remains unclear if patients experiencing reflux symptoms should undergo mandatory endoscopy with biopsies at the esophagogastric junction. Furthermore, metaplasia of the lower esophagus often is not readily recognizable at endoscopy, and only biopsies can document abnormal histology. A severe and prolonged history of reflux always should orient to the possibility of a reflux-related columnar-lined esophagus. Once documented, Barrett's esophagus needs to be seen as a premalignant condition not necessarily leading to adenocarcinoma formation; despite their increased risk of tumor formation, most patients who have Barrett's esophagus die of other causes. During regular endoscopic follow-up, multilevel circumferential biopsies should document the evolution of the histologic changes in the lower esophagus and at the gastroesophageal junction of these patients. It is the only method available to document the appearance of dysplasia. It still is unclear if medicine or surgery provides the best quality of life and the best protection against the development of dysplasia and the possible progression toward adenocarcinoma formation when intestinal metaplasia is present in the esophagus.

Chronic proton pump inhibitor (PPI) therapy may lead to partial regression of Barrett's esophagus (BE), resulting in the development of reepithelialized islands of squamous mucosa that may cover the underlying BE. The purpose of this study was to evaluate the clinical, histologic, and biologic characteristics of BE that is situated underneath squamous islands (BUSI). A total of 97 mucosal biopsies from 44 BE patients with BUSI were evaluated for a variety of histologic features (eg, type of epithelium, anatomic relationship of the underlying glands to the luminal surface, presence of adjacent mucosal glands or ducts, and the presence and degree of dysplasia), and immunostained for Ki-67, cyclin D1, and p53. BUSI was compared with adjacent areas of BE for all parameters. A clinical control group consisting of 50 BE patients without microscopic evidence of BUSI was selected for comparison of clinical and endoscopic features. The study group (34 males, 10 females; mean age, 67 years; mean length of BE, 5.5 cm) consisted of 27 (61%) and 12 (27%) patients on low- and high-dose PPI, respectively. On endoscopy, visible islands of squamous mucosa were noted in only 43% of study group patients (despite the presence of BUSI microscopically in all cases); one island was noted in 2%, multiple islands in 27%, and extensive islands in 14% of patients. The extent of squamous islands was unrelated to PPI dose. The study group was significantly more likely to have endoscopic evidence of extensive squamous islands compared with the control group (P = 0.009). Histologically, 89% of biopsies with BUSI showed intestinal-type, and 11% showed cardia-type, epithelium. Low- and high-grade dysplasia was noted in 4 (4%) and 5 (5%) biopsies, respectively. All patients with dysplasia in BUSI also showed dysplasia in other areas of the esophagus as well. Interestingly, BUSI reached the mucosal surface either by penetrating directly through, or by wrapping around, islands of squamous epithelium, in 68% of biopsies. Twenty-one percent of biopsies showed BUSI adjacent to submucosal glands or ducts. BUSI showed a significantly lower Ki-67 proliferation rate (29% vs. 49%, P < 0.001), and a lower, albeit nonsignificant, degree of cyclin D1 (16% vs. 29%) and p53 (4% vs. 17%) positivity in comparison to adjacent areas of BE. Furthermore, significantly lower proliferation rates were observed in BUSI that did not reveal an opening to the mucosal surface in comparison to foci that did. BUSI is phenotypically similar to typical surface BE but shows less severe proliferative abnormalities, particularly in buried glands that have no detectable connection to the esophageal lumen. Reduced proliferation may be due either to decreased exposure to luminal contents or to disruption of sloughing of surface epithelial cells into the crypt lumen. Prospective studies of large numbers of patients with BUSI will be required to determine the magnitude of its risk of progression to cancer.

To value whether omeprazole could induce the healing of DIS and regression of symptoms in patients with DGER.

We enrolled 15 symptomatic patients with a pathological esophageal 24-h pH-metry and bilimetry. Patients underwent endoscopy and biopsies were taken from the distal esophagus. Specimens were analyzed at histology and transmission electron microscopy (TEM). Patients were treated with omeprazole 40 mg/d for 3 mo and then endoscopy with biopsies was repeated. Patients with persistent heartburn and/or with an incomplete recovery of DIS were treated for 3 more months and endoscopy with biopsies was performed.

Nine patients had a non-erosive reflux disease at endoscopy (NERD) while 6 had erosive esophagitis (ERD). At histology, of the 6 patients with erosive esophagitis, 5 had mild esophagitis and 1 moderate esophagitis. No patients with NERD showed histological signs of esophagitis. After 3 mo of therapy, 13/15 patients (86.7%, P<0.01) showed a complete recovery of DIS and disappearance of heartburn. Of the 2 patients treated for 3 more months, complete recovery of DIS and heartburn were achieved in one.

Three or 6 mo of omeprazole therapy led to a complete regression of the ultrastructural esophageal damage in 86.7% and in 93% of patients with DGER, NERD and ERD respectively. The ultrastructural recovery of the epithelium was accompanied by regression of heartburn in all cases.

Guidelines for the diagnosis and treatment of gastroesophageal reflux disease (GERD) were published in 1995 and updated in 1999. These and other guidelines undergo periodic review. Advances continue to be made in the area of GERD, leading us to review and revise previous guideline statements. GERD is defined as symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus. These guidelines were developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee, and approved by the Board of Trustees. Diagnostic guidelines address empiric therapy and the use of endoscopy, ambulatory reflux monitoring, and esophageal manometry in GERD. Treatment guidelines address the role of lifestyle changes, patient directed (OTC) therapy, acid suppression, promotility therapy, maintenance therapy, antireflux surgery, and endoscopic therapy in GERD. Finally, there is a discussion of the rare patient with refractory GERD and a list of areas in need of additional study.

We present the preliminary results obtained by our research group utilizing Nd:YAG and diode lasers to treat Barrett's esophagus (BE). A total of 15 patients with BE (mean age 58 years) underwent endoscopic laser therapy: 11 with intestinal metaplasia, 2 with low-grade dysplasia, and 2 with high-grade dysplasia. The mean length of BE was 4 cm (range 1-12 cm). Six of these patients also underwent antireflux surgery, and nine were prescribed acid-suppressive medication. Endoscopic Nd:YAG laser treatment was carried out from 1997 to 1999; thereafter, diode laser was employed. The mean follow-up of these patients after the first laser session was 28 months. Patients underwent a mean of 6.5 laser sessions (range 3-17 sessions), with no apparent complications. The mean energy per session was 1705 JJ. Only six of these patients (40%) showed complete endoscopic and histologic remission, but a mean of 77% (SD 23.8%) of the total metaplastic tissue in all these patients was ablated. The percentage of healed mucosa was higher in patients with short-segment BE (92%) ( p < 0.05) and in subjects treated by two or more laser sessions per centimeter of BE length (89%) ( p < 0.05). All four patients with dysplasia showed histologic regression to nondysplastic BE or to squamous epithelium, without recurrence during a mean follow-up of 30 months. The patients who underwent antireflux surgery and those prescribed pharmacologic treatment had similar results. Nd:YAG and diode laser treatment of BE is a safe, effective procedure; it required two sessions per centimeter of metaplasia; and it achieved complete regression of the dysplasia. Further studies are necessary to quantify its effect on cancer incidence.

Accurate measurements of Barrett's esophagus length are important in clinical follow-up as well as in studies of therapeutic intervention in Barrett's esophagus. Our aim was to evaluate both the inter- and intraobserver reliability in measuring Barrett's length during two consecutive endoscopies by either the same or different experienced endoscopists. The relationship between Barrett's mucosa length and the absolute change in Barrett's length measurements on a follow-up endoscopy was also evaluated.

A total of 96 Barrett's patients underwent two consecutive endoscopies. The diagnosis of Barrett's esophagus was confirmed by the presence of intestinal metaplasia on biopsy. The Barrett's esophagus length was carefully measured and recorded during the two endoscopies. Procedures were performed by only two experienced endoscopists, who were not aware of previous endoscopic measurements. Only patients with long-segment (> or =3 cm) Barrett's esophagus were included in this study.

The 55 patients who had their consecutive endoscopies performed by the same endoscopist had a mean 1.6-cm difference between the two measurements as compared to 1.4 cm in the 41 patients who had their endoscopies performed by different endoscopists (p = 0.3). The agreement between the two Barrett's length measurements was high in both groups, although it was slightly higher for endoscopies performed by the same endoscopist (r = 0.79 vs r = 0.67). Linear regression analysis of the absolute change in Barrett's length between the two endoscopic measurements and Barrett's mucosa length demonstrated a significant relationship (r = 0.28, p = 0.005). For every 1-cm increase in the mean length of Barrett's mucosa, a 0.15-cm increase in the absolute difference between two consecutive endoscopic measurements of Barrett's length was observed.

Consecutive measurements of Barrett's length performed by different experienced endoscopists or by the same experienced endoscopist demonstrated a high degree of agreement. A range of variability in Barrett's length measurement was determined (+/-1.4-1.6 cm). True regression or progression of Barrett's mucosa should be considered only if the change is greater than the range of variability. In addition, endoscopists should be well aware that the longer the Barrett's mucosa the greater the absolute difference in Barrett's length measurement on follow-up endoscopy.

With the common use of proton pump inhibitors (PPIs), the medical treatment of gastroesophageal reflux disease (GERD) and its complications is now successful in relieving symptoms, healing esophagitis, and preventing complications. Physiologic factors that may contribute to a poor response to these drugs include the considerable variation in the bioavailability of PPIs, the need to take PPIs with meals, the influence of Helicobacter pylori-associated gastritis, and genetic variation in enzyme capacity, resulting in rapid and slow metabolizers of PPIs. Subsets of reflux patients, such as the elderly, pregnant women, and those with supraesophageal symptoms or Barrett esophagus, may have special treatment requirements. Medical treatment of GERD with PPIs has been demonstrated to equal the success of antireflux surgery in short- and long-term follow-up with reasonably few side effects. Furthermore, a good response to PPI therapy predicts a successful outcome with antireflux surgery.

Despite the availability of many clinical trials, there is no evidence that APC has any role in the management of Barrett's esophagus. Ablation therapy is not indicated for nondysplastic Barrett's esophagus (and this is true, whatever the technique used), and it should not be performed outside of a carefully designed and approved clinical trial. Indeed, these patients have a low risk of cancer, and there is no evidence that Barrett's esophagus ablation will be of any benefit for these patients. In some cases, APC could be of some help, especially for treating short segments of dysplastic Barrett's esophagus. In this field, however, it competes with the growing indication of mucosectomy, which clearly offers advantages in terms of treatment's quality control assessment.

Barrett's metaplasia of some extent is found commonly in patients with GERD. Detection is possible only by endoscopy and biopsy of the columnar appearing mucosa; no symptoms or signs distinguish patients with Barrett's metaplasia from those without. The management goals in patients with Barrett's are to alleviate reflux symptoms and to control the risk of adenocarcinoma. Symptom control is achieved primarily with PPIs. Acid inhibition does not, however, cause regression of Barrett's metaplasia and has not been shown to reduce the risk of esophageal adenocarcinoma. The risk of adenocarcinoma is managed by surveillance with endoscopy and biopsy searching for dysplastic change. LGD merits more intense surveillance. The optimal management of HGD, however, remains controversial, as evidenced by the multitude of ablation therapies that have been introduced recently. These techniques will be discussed in depth in subsequent articles in this volume.

The two main aspects relevant to the role of surgery in the management of patients with Barrett's esophagus are to define the role of surgery in controlling reflux and associated symptoms and to define the surgical options in case of dysplasia or early neoplasia. This article also will address the issue of whether complete reflux control in patients with Barrett's esophagus can prevent the metaplastic mucosa from further progression to dysplasia and adenocarcinoma.

This article explores issues related to the diagnosis of Barrett's esophagus (BE) in endoscopic biopsies and dysplasia in Barrett's epithelium. The definitions of BE, including long- and short-segment BE, are reviewed, with an emphasis on the significance of intestinal metaplasia (IM). IM of the gastroesophageal junction and cardia is reviewed and problems in its distinction from short-segment BE are discussed. In addition, the article reviews the classification of dysplasia in Barrett's mucosa, with reference to problematic areas, such as sampling error and interobserver variability. Biomarkers and their role in the diagnosis of dysplasia and stratification of risk are summarized.

Barrett's oesophagus is usually the result of severe reflux disease. Relief of reflux symptoms is the primary aim of treatment in patients with Barrett's oesophagus who do not have high-grade dysplasia. Some studies with medium-term (2-5 years) follow up show that antireflux surgery can provide good or excellent symptom control, with normal oesophageal acid exposure, in more than 90% of patients with Barrett's oesophagus. Antireflux surgery, but not medical therapy, can also reduce duodenal nonacid reflux to normal levels. There is no conclusive evidence that antireflux surgery can prevent the development of dysplasia or cancer, or that it can reliably induce regression of dysplasia, and patients with Barrett's oesophagus should therefore remain in a surveillance programme after operation. Some data suggest that antireflux surgery can prevent the development of intestinal metaplasia (IM) in patients with reflux disease but no IM. The combination of antireflux surgery plus an endoscopic ablation procedure is a promising treatment for patients with Barrett's oesophagus with low-grade dysplasia.

The effect of antireflux operation on the natural history of columnar-lined esophagus (CLE) is not fully understood. The aim of this study was to assess a single center's experience and review the literature on the impact of antireflux operation on CLE without high-grade dysplasia.

The medical records of 26 patients with CLE but without high-grade dysplasia who underwent antireflux operation in our unit were retrospectively analyzed at longterm followup with detailed endoscopic investigation. Thirteen patients presented with intestinal metaplasia (6 had short segments, and 1 had preoperative laser ablation) and 13 without intestinal metaplasia. For the group of 13 patients presenting with intestinal metaplasia, the mean endoscopic followup was 74.7 months (median 46 months). Three of six with short-segment lesion and two of seven with circumferential involvement had complete regression of intestinal metaplasia (one after laser therapy). None had progression to dysplasia or carcinoma.

For the group of 13 patients without intestinal metaplasia, mean endoscopic followup was 43.9 months (median 28 months). One had complete regression of CLE, and none developed intestinal metaplasia during surveillance.

Our study suggests that antireflux operation can alter the natural history of CLE, allowing disease stabilization in a substantial proportion of patients. After antireflux operation, total regression of CLE is possible, but in an unpredictable manner.

Barrett's esophagus, or columnar-lined esophagus (CLE), is a premalignant disorder in which the stratified squamous epithelium is replaced by metaplastic epithelium. To gain more insight into the process of carcinogenesis in CLE, we studied several factors involved in the apoptotic pathway in biopsies with gastric metaplasia (GM), intestinal metaplasia (IM), dysplasia, and/or adenocarcinoma. Immunohistochemistry was performed for Fas, Bcl-2, Bax, Bcl-xl, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2). Fas staining was positive in the epithelium of all biopsies from patients with CLE but negative in normal gastric mucosa. Fas staining was positive in all tumor cells of the 8 cases containing adenocarcinoma. Bcl-2 was positive in lamina propria immune cells of all specimens. Bax staining was positive in the epithelium of all biopsies, including tumor cells. Bcl-xl was positive in dysplasia and tumor cells, but negative in 8 of 17 biopsies containing IM. iNOS was positive in 20 of 21 biopsies with IM and in 4 of 8 dysplasia biopsies. COX-2 was positive in 7 of 8 adenocarcinomas. We conclude that the apoptotic balance in the transformation from IM to adenocarcinoma switches to an antiapoptotic phenotype because of increased Bcl-xl expression and decreased Bax expression. Fas can be used as a marker for the differentiation of gastric mucosa and metaplasia in the esophagus. iNOS is highly positive in CLE-associated intestinal metaplasia. COX-2 is negative in nonmalignant CLE. Therefore, pharmacologic inhibition of COX-2 activity is unlikely to be effective in the preventing CLE-associated adenocarcinoma. There was no clear correlation between iNOS expression and activation of proapoptotic and antiapoptotic genes.

Barrett's esophagus is an acquired condition resulting from severe esophageal mucosal injury. It still remains unclear why some patients with gastroesophageal reflux disease develop Barrett's esophagus whereas others do not. The diagnosis of Barrett's esophagus is established if the squamocolumnar junction is displaced proximal to the gastroesophageal junction and if intestinal metaplasia is detected by biopsy. Despite this seemingly simple definition, diagnostic inconsistencies remain a problem, especially in distinguishing short segment Barrett's esophagus from intestinal metaplasia of the gastric cardia. Barrett's esophagus would be of little importance were it not for its well-recognized association with adenocarcinoma of the esophagus. The incidence of esophageal adenocarcinoma continues to increase and the 5-year survival rate for this cancer remains dismal. However, cancer risk for a given patient with Barrett's esophagus is lower than previously estimated. Current strategies for improved survival in patients with esophageal adenocarcinoma focus on cancer detection at an early and potentially curable stage. This can be accomplished either by screening more patients for Barrett's esophagus or with endoscopic surveillance of patients with known Barrett's esophagus. Current screening and surveillance strategies are inherently expensive and inefficient. New techniques to improve the efficiency of cancer surveillance are evolving rapidly and hold the promise to change clinical practice in the future. Treatment options include aggressive acid suppression, antireflux surgery, chemoprevention, and ablation therapy, but there is still no clear consensus on the optimal treatment for these patients.

Endoscopic management options for BE with high-grade dysplasia consist of either surveillance methods or endoscopic mucosal ablative therapies. Intensive surveillance once a person is diagnosed with high-grade dysplasia may avoid an unneeded esophagectomy because it appears that most patients with high-grade dysplasia may not progress to esophageal adenocarcinoma. Only a single study has been presented that demonstrates that this approach does not lead to missed opportunities for intervention before progression to advanced stage disease [20]. This study excluded patients with cancer detected within 1 year of diagnosis of high-grade dysplasia; thus, patients who wish to proceed with an observation approach should be aware that the rate of missed esophageal adenocarcinomas ranges from 38% to 73%. The ability to observe a patient with high-grade dysplasia, however, does have appeal because a number of these patients appear to lose the high-grade dysplasia over time. The other endoscopic management option for Barrett's esophagus with high-grade dysplasia is endoscopic mucosal ablative therapies. These include the KTP:YAG laser, the Nd:YAG laser, photodynamic therapy, and endoscopic mucosal resection. All ablative therapies are used in combination with control of gastroesophageal reflux. This allows the esophageal tissue to heal in an environment that is conducive to squamous mucosa. Although most are relatively small series with short durations of observation, they all have shown some promise in treating BE with high-grade dysplasia. These approaches have the advantage of eliminating the problem. The patient who is being observed must live with the thought of developing cancer. Patients who undergo successful ablation are returned to a normal life. The combination of therapies such as EMR with PDT may be the most promising approach to BE with high-grade dysplasia; however, the long-term effects of ablative therapy are not known and continued surveillance is still advised for this group of patients. The choice of a nonsurgical approach for the management of BE with high-grade dysplasia is ultimately up to the individual patient. All patients must be carefully informed of the treatment effects, possible outcomes, and the surgical alternative. Most patients who select nonsurgical approaches are either elderly or are not good surgical candidates. The choice is often affected by local expertise, as surgical procedures should be performed in centers with surgeons expert in esophagectomy. Nonsurgical approaches should also be performed by physicians who are familiar with their application. Future advances in nonsurgical techniques such as new photosensitizers in PDT and improvements in diagnostic techniques may allow patients a greater opportunity to preserve their esophagus.

With the high prevalence of gastroesophageal reflux-like symptoms in the United States and the association between GERD symptoms and the premalignant condition of BE, there is more and more demand for new and efficacious techniques to treat BE. A wide variety of endoscopic mucosal ablative techniques have been developed with promising initial results. Long-term control of neoplastic risk, however, has not been demonstrated, and most studies demonstrate that there is still potentially some intestinal mucosa present underneath squamous mucosa. Currently, more study is needed to determine which patient groups require therapy of any kind and to determine which therapies would be the most efficacious. Genetic markers may aid in identification of subgroups that are at risk for cancer and help to identify those who would respond to mucosal therapy. Even in patients who have HGD, subgroups of patients who have focal HGD have been found to have better prognosis than those who have more widespread HGD. Currently, there is sufficient information to consider mucosal ablative techniques in patients who are not good surgical candidates. Photodynamic therapy, APC, KTP, Nd:YAG and argon lasers, MPEC, and EMR may provide good alternatives, depending on the degree of dysplasia, the extent of disease, and the age of the patient. Photodynamic therapy and Nd:YAG laser therapy have been applied to more neoplastic lesions, whereas KTP:YAG, APC, and multipolar coagulation have been successful in nondysplastic Barrett's mucosa. In the future, there will be more information to justify the application of mucosal ablative therapy in selected patients.

To assess proliferation in the columnar-lined esophageal mucosa before and after antireflux surgery.

Intestinal metaplasia persists in Barrett's mucosa after reflux control. It remains at risk for uncontrolled cellular proliferation and adenocarcinoma formation.

Forty-five patients with Barrett's esophagus had a mean follow-up of 4 years after a Collis-Nissen gastroplasty. Proliferative activity was assayed immunohistochemically for Ki-67 expression in 73 preoperative and 176 postoperative biopsies. Correlation with manometric and 24-hour pH results was obtained.

The Collis-Nissen gastroplasty restored the median lower esophageal sphincter gradient from 5.5 mmHg before surgery to 14.5 mmHg at 24 months and 12.9 mmHg at 48 months after surgery. The median esophageal acid exposure was reduced from 8% to 1% and 1% of recording time, respectively. The median Ki-67 labeling index increased from 28.5% before surgery to 36.1% at 12 to 23 months. It returned to preoperative level (26.9%) at 24 to 47 months. After surgery, abnormal intraesophageal acid exposure was documented in 12 patients but could not be correlated with sphincter pressure. After surgery, the pattern of proliferation in patients with acid exposure less than 4% in their esophagus showed significant differences when compared with the proliferation pattern of patients where abnormal intraesophageal acid exposure was recorded. New present dysplasia was observed only in patients with abnormal acid exposure.

In Barrett's mucosa, from preoperative values, proliferation peaked early after surgery and then decreased to preoperative levels. Despite sphincter restoration and global reflux control, abnormal esophageal acid exposure persisted in 12 patients. Patients with abnormal esophageal acid exposure displayed more proliferation and more dysplasia.

Barrett's esophagus is a metaplastic change in the esophageal lining with an increased risk for adenocarcinoma. Multiple endoscopic techniques have been applied in an effort to reverse Barrett's. This is a multicenter trial defining the efficacy and safety of multipolar electrocoagulation combined with high-dose acid inhibition.

Patients with a 2- to 6-cm segment of Barrett's esophagus without dysplasia were enrolled at 3 centers. They were treated with omeprazole 40 mg twice daily and then with up to 6 sessions with electrocoagulation aimed at eliminating all the endoscopically apparent Barrett's. Four quadrant large-capacity biopsies every 2 cm were centrally assessed for residual intestinal metaplasia.

Fifty-eight patients reached the endpoint of failure of visual reversal of Barrett's after 6 treatment sessions or a 6-month follow-up after the last session. Eighty-five percent had visual reversal and 78% both visual and histologic reversal. Four patients had histologic evidence of residual intestinal metaplasia. Transient esophageal symptoms were common. One patient developed a stricture requiring dilation and one required overnight hospitalization for chest pain.

The majority of patients with 2 to 6 cm of nondysplastic Barrett's esophagus can be safely reversed with this combination therapy. Long-term follow-up will be necessary to document the durability of the new squamous epithelium.

There has been a dramatic increase in recent years in the incidence of Barrett's oesophagus and the oesophageal adenocarcinoma associated with it. Adequate monitoring strategies and improved diagnostic procedures are therefore essential. Alongside conventional video-endoscopy with four-quadrant biopsies, many additional diagnostic procedures are now available to improve monitoring. These allow the early diagnosis of dysplastic areas and early carcinomas. Both thermal procedures (argon plasma coagulation, multipolar electrocoagulation and KTP laser and Nd&ratio;YAG laser treatment) and non-thermal ablation procedures (photodynamic therapy) are used for the endoscopic ablation of Barrett's mucosa without dysplasia, being employed in addition to acid suppression treatment. On the basis of the data currently available, it is, however, not yet possible to offer a general recommendation in favour of endoscopic ablation. Alongside surgical treatment for high-grade dysplasia and early carcinoma, endoscopic treatment procedures, which have a much lower complication and mortality rate, will probably play an important role in the future. Endoscopic mucosal resection and photodynamic therapy are particularly promising. Long-term results with these procedures are, however, still awaited.

Barrett esophagus has malignant potential and seems to be an acquired abnormality. It is associated with chronic gastroesophageal reflux disease and represents its severest form. The literature comparing medical treatment with antireflux surgery was reviewed. Questions regarding the advantages of surgery, who should undergo surgery, whether surgery can change the course of Barrett esophagus, the change in cancer risk, who needs surveillance, and cost-effectiveness were addressed. The incidence of developing Barrett cancer was 1 in 145 patient-years in reviewing 2032 patient-years of medical therapy compared with 1 in 294 patient-years in reviewing 4122 patient-years after surgery. Median follow-up time in the 2 groups was 2.7 years in the medically treated patients and 4.0 years in the surgically treated patients. Surveillance of Barrett esophagus is required irrespective of treatment. Laparoscopic antireflux surgery was found to be cost-effective after 7 years. Although these data do not prove that surgery is superior to medical treatment in the prevention of cancer related to Barrett esophagus, we found a tendency for surgery to be better than medical therapy to prevent the development and progression of Barrett carcinoma.

Barrett's oesophagus, a significant complication of gastro-oesophageal reflux disease (GERD), is the single most important risk factor for oesophageal adenocarcinoma. The strong association between Barrett's oesophagus and chronic GERD suggests that abnormal oesophageal acid exposure plays an important role in this condition. The progression of Barrett's oesophagus from specialized intestinal metaplasia to dysplasia and finally invasive carcinoma is incompletely understood, but increased and disordered proliferation is a key cellular event. In ex vivo organ culture experiments, cell proliferation is increased after exposure to short pulses of acid, whilst proliferation is reduced in Barrett's oesophagus specimens taken from patients with oesophageal acid exposure normalized by antisecretory therapy. In long-term clinical studies, consistent and profound intra-oesophageal acid suppression with proton pump inhibitors decreases cell proliferation and increases differentiation in Barrett's oesophagus, but the clinical importance of such favourable effects on these surrogate markers is not clear. In clinical practice, proton pump inhibitors relieve symptoms and induce partial regression to squamous epithelium, but abnormal oesophageal acid exposure and the risk for dysplasia or adenocarcinoma persist in many patients. The ability of proton pump inhibitors to suppress acid profoundly and consistently may be critical in the long-term management of Barrett's oesophagus.

Gastro-oesophageal reflux disease and its sequela, Barrett's oesophagus, are the major recognized risk factors for oesophageal adenocarcinoma, a tumour whose frequency has increased dramatically in Western countries over the past few decades. Barrett's oesophagus develops through the process of metaplasia in which one adult cell type replaces another. The metaplastic, intestinal-type cells of Barrett's oesophagus are predisposed to develop genetic changes that eventuate in cancer. This report reviews the recent controversy regarding diagnostic criteria for Barrett's oesophagus, and provides practical guidelines for identifying the condition. The risks and benefits of the proposed medical, surgical and endoscopic therapies for Barrett's oesophagus are discussed in detail, and the approach to management recently endorsed by the American College of Gastroenterology is summarized.

Gastro-oesophageal reflux disease (GERD) is the most common peptic acid disease in the western world and is the commonest indication for acid suppression therapy. Major advances have been made over the past 30 years in the understanding of lower oesophageal sphincter function and the mechanism of acid secretion. Developments in surgical and pharmacological therapy have paralleled these advances. Pharmacotherapy for GERD has evolved from antacids to H2-receptor antagonists (H2RAs) to prokinetics to proton pump inhibitors (PPIs). The H2RAs, while modestly effective in symptom relief and healing of GERD, are limited by pharmacological tolerance. The prokinetics (metoclopramide and cisapride) are limited by low efficacy, pharmacological tolerance and toxicity. The PPIs have emerged as the most effective therapy for symptom relief, healing and long-term maintenance. They have also proved to be remarkably safe and cost-effective in long-term therapy. This review evaluates the pharmacology, efficacy, tolerability, safety and cost-effectiveness of the four currently available PPIs, lansoprazole, omeprazole, pantoprazole and rabeprazole, in the treatment of GERD.

The term Barrett's esophagus refers to a premalignant condition that is characterized by the replacement of the esophageal squamous mucosa by a columnar-lined one. Preliminary studies have demonstrated reversal of Barrett's mucosa after endoscopic coagulation with different techniques associated with acid inhibition. However, most of these studies have shown that residual Barrett's glands are found underneath the new squamous epithelium in up to 40% of patients. The goal of our study is to verify whether complete restoration of Barrett's mucosa can be achieved by the combination of high power setting argon plasma coagulation and omeprazole.

A total of 33 patients (mean age: 55.2 yr, range: 21-84 yr; 21 men and 12 women) with histologically demonstrated Barrett's esophagus (mean length: 4.05 cm, range: 0.5-7 cm) were treated. Fourteen cases presented with low-grade dysplasia and one with high-grade dysplasia. All of the extent, or until a maximum of 4 cm, of the Barrett's mucosa was cauterized in each session using argon beam coagulation at a power setting of 65-70 W. All patients received 60 mg omeprazole during the treatment period.

Complete restoration of squamous mucosa was obtained in all 33 cases after a mean of 1.96 sessions (range, 1-4). Endoscopic results were histologically confirmed. Nineteen (57.5%) patients experienced moderate to severe chest pain and odyno-dysphagia lasting for 3-10 days after the procedure. Five of these cases experienced high fever and a small volume of pleural effusion, and three patients developed esophageal strictures that needed to be dilated. Another patient developed pneumomediastinum and subcutaneous emphysema without evidences of perforation. After a mean follow-up of 10.6 months there was one endoscopic, as well as histological, recurrence of Barrett's mucosa in a patient with an ineffective laparoscopic fundoplication.

High power setting argon plasma coagulation combined with intensive acid suppression is an effective treatment for the total endoscopic ablation of Barrett's esophagus, at least in the short term. Long-term follow-up of treated patients in whom gastroesophageal reflux is surgically or medically alleviated seems mandatory before drawing definitive conclusions about this therapy.

Barrett's esophagus (BE) results from acid and bile reflux and predisposes to cancer. We investigated the effect of bile salts, with or without acid, on cell proliferation in BE and assessed mechanism(s) involved. To mimic physiological conditions, biopsies of esophagus, BE, and duodenum were exposed to a bile salt mixture, either continuously or as a 1-h pulse, and were compared with control media without bile salts (pH 7.4) for < or =24 h. Similar experiments were also performed with acidified media (pH 3.5) combined with the bile salt mixture as a 1-h pulse. Cell proliferation was assessed by a [(3)H]thymidine incorporation assay with or without bisindolylmaleimide (BIM), a selective protein kinase C inhibitor. Bile salt pulses enhanced cell proliferation in BE without affecting cell proliferation in esophageal or duodenal epithelia. In the presence of BIM, there was complete obliteration of the bile salt-induced BE hyperproliferation. In contrast, 1-h pulses of bile salts in combination with acid significantly inhibited proliferation in BE but had no effect on esophagus or duodenum. We conclude that in BE explants, brief exposure to bile salts, in the absence of acid, increases proliferation, whereas exposure to a combination of bile salts and acid together inhibits proliferation.

Demographic, endoscopic, and histological features of Barrett's esophagus at initial diagnosis were examined for their ability to predict complete endoscopic and histological regression of Barrett's during long-term follow-up.

Barrett's patients who have been followed up for a minimum of 2 yr and who have had at least two follow-up surveillance examinations were included in the analysis. Complete regression of Barrett's was defined as total disappearance of all tongues and patches of Barrett's epithelium at endoscopy (confirmed with Lugol's iodine) in conjunction with only squamous epithelium on biopsy. Chi2 and stepwise logistic regression analyses were performed on the following clinical, endoscopic, and histological variables with regards to their ability to predict complete Barrett's regression: patient age in years (<65 or > or =65), length in cm of Barrett's (< or =2, >2<6, and > or =6), presence of a hiatal hernia (yes or no), presence of dysplasia at diagnosis (yes or no), and type of long-term medical treatment (histamine antagonists, proton pump inhibitor [PPI], or PPI and cisapride).

Ninety-nine patients, all men with a mean age +/- SD in years of 61.6+/-13.1 have been followed prospectively for 24-106 months (mean +/- SD, 48.0+/-19.8). Seven patients have had complete regression of Barrett's. Univariate analysis showed that complete regression of Barrett's was associated only with absence of a hiatal hernia (p = 0.012). Stepwise logistic regression analysis revealed that complete regression was significantly and independently associated again only with absence of a hiatal hernia (p = 0.025). Stepwise logistic regression analysis utilizing only hiatal hernia (yes vs no) and length of Barrett's (<6 cm vs > or =6 cm) as variables revealed that absence of a hiatal hernia (p = 0.0447) and shorter lengths (<6 cm) of Barrett's (p = 0.0418) were significantly and independently predictive of complete Barrett's regression.

The absence of a hiatal hernia was noted to be the most important factor associated with Barrett's regression. Complete regression of Barrett's esophagus occurs in a minority of patients, primarily in those with no hiatal hernia and shorter lengths of Barrett's epithelium.

The aim of this study was to report the results of a retrospective series of 26 patients with Barrett's esophagus treated by antireflux surgery.

From 1979 to 1998, 21 men and five women (mean age: 53 years) with histologically proven Barrett's esophagus underwent an antireflux procedure. The mean length of Barrett's epithelium was 5.9 cm for 19 patients (73.1%). Six patients (23.1%) had tongue lesions of Barrett's epithelium, and one (3.8%) had ectopic gastric mucosa. None of the patients had a preoperative esophageal biopsy that revealed high-grade dysplasia or carcinoma. Laparotomy was performed in 17 cases and laparoscopy in nine cases. Preoperative endoscopic local treatment with argon coagulation was performed in one patient.

Clinical mean follow-up was 78 months and endoscopic mean follow-up was 59.3 months. No increase in the length of the Barrett's epithelium was observed. Seven patients (27%) had complete or partial regression (among them three patients with tongue lesions and one patient preoperatively treated by argon). No patients developed high-grade dysplasia or carcinoma.

Regression of Barrett's esophagus is possible but not frequent and unpredictable after antireflux procedure. However, endoscopic and histological surveillance should be continued postoperatively.

Thermoablation is being used to eliminate the metaplastic epithelium of Barrett's esophagus and allow its reversal into squamous epithelium in an acid-controlled environment. This study assessed the efficacy and safety of a new thermoablation technique, argon plasma coagulation.

Patients with circumferential Barrett's esophagus 2 to 5 cm long were enrolled. Acid suppression was accomplished with lansoprazole. One-half the circumference of Barrett's mucosa was treated with argon plasma coagulation, and the other half served as an internal control. After macroscopic squamous re-epithelialization occurred, biopsy specimens were obtained from both areas systematically.

Nine patients, all men with a mean age of 51.1 years, completed the study. During 24-hour esophageal pH monitoring a pH less than 4 occurred on average 2.8% of the time with a mean dose of lansoprazole of 70 mg/day. Squamous re-epithelialization developed in treated areas in all 9 patients. Biopsy showed that 7 of 9 patients (77.8%) had squamous re-epithelialization without intestinal metaplasia. Biopsy showed that 2 of 9 patients (22.2%) had squamous re-epithelialization with evidence of underlying intestinal metaplasia. There were no serious complications.

Argon plasma coagulation in an acid-controlled environment was both efficacious and safe in the treatment of Barrett's esophagus. However, the reappearance of squamous epithelium after therapy did not exclude the presence of underlying intestinal metaplasia.

The aim of this study was to review the need for regular endoscopic biopsy of Barrett's esophagus in children.

This was a retrospective case-notes review of 38 children with Barrett's esophagus treated between January 1982 and August 1997. The mean age at diagnosis was 6.3 years (range, 1 to 15 years). All had gastroesophageal reflux at diagnosis. Two patients were treated medically, and 36 underwent antireflux surgery (32 Nissen fundoplication, four Thal procedures). At follow-up, for a mean of 43 months (range, 0 to 13 years), 25 underwent repeated endoscopy and biopsies, two underwent further surgery and biopsies, and four underwent endoscopy only. Seven have had follow-up at their referring hospital.

In the 27 patients who underwent rebiopsy, there was continued evidence of Barrett's esophagus in 15. There was reversion to normal tissue in 10 patients, and mild esophagitis was present in two. There was no evidence of any dysplastic or malignant change in any patient. All cases that reverted to normal esophagus or mild esophagitis had previously undergone a Nissen fundoplication.

Dysplastic degeneration and malignant change did not occur in any of the authors' patients. In addition, 12 patients with Barrett's esophagus reverted to normal. The authors therefore question whether regular endoscopic surveillance is necessary in children under 16 years of age.