Medical and endoscopic management of high-grade dysplasia in Barrett's esophagus.

The management of high-grade dysplasia in Barrett's esophagus has clearly changed over recent years. The risk of cancer development is still substantial, with about one in three patients developing cancer, but a number of patients do not develop cancer. The nature of high-grade dysplasia has also been genetically elucidated with more evidence of chromosomal instability being present at this stage than previously thought. Therapy of the condition has evolved more toward endoscopic therapy, given the good results of radio-frequency ablation and photodynamic therapy in eliminating dysplasia and decreasing cancer development in randomized controlled trial. The best candidates for treatment include compliant patients that have relatively short segments of Barrett's esophagus, an anatomically straight segment, lack of nodularity, and an intact p16. However, even with excellent long-term results similar to surgical resection, the risk of recurrence is present in over 14% of patients, which indicates that there will be a need to continue surveillance endoscopy in these patients.

Photodynamic therapy for Barrett's esophagus: does light still have a role?

Photodynamic therapy was the first treatment to have been shown to significantly decrease high-grade dysplasia and cancer in patients with Barrett's esophagus. However, its use has been limited, primarily because of the side effects, which include esophageal strictures, cutaneous photosensitivity, chest pain, and nausea and vomiting. The tolerability aspects of photodynamic therapy, as well as the dosimetry, though, can be improved with existing technologies to further develop this therapy into truly a widely applicable therapy. Studies have recently been done to help identify patients more likely to suffer stricture after photodynamic therapy. In addition there has been evidence to suggest that the efficacy of photodynamic therapy also can be limited by genetic abnormalities in the mucosa. By combining knowledge of tissue biology, optical properties of the tissue, and dosimetry issues with ablation, photodynamic therapy can still have a potentially bright future.

Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett's esophagus.

BACKGROUND: Endoscopic mucosal resection (EMR) and photodynamic therapy have been proposed as treatments for early stage cancers. EMR is limited by its focal nature whereas photodynamic therapy is dependent on precise staging. The combination of EMR and photodynamic therapy were studied in the treatment of superficial cancer in patients with Barrett's esophagus. METHODS: Seventeen consecutive nonsurgical patients with superficial cancers underwent EMR followed by photodynamic therapy with a porphyrin photosensitizer. Photoradiation was performed at 630 nm for a total dose of 200 J/cm of diffuser. RESULTS: Seventeen patients (15 men; mean age 69 +/- 13 years) underwent EMR. The mean diameter of mucosal resection was 1 cm. The margins were involved by cancer in 3 cases. EMR improved staging in 8 patients (47%). Sixteen (94%) patients remained in remission (median follow-up 13 months). Complications included minor bleeding after EMR in 1 patient (6%), stricture in 5 (30%), cutaneous phototoxicity in 2 (12%), and supraventricular tachycardia in 1 patient (6%). CONCLUSIONS: Combined EMR and photodynamic therapy appears to be an effective and safe therapy for superficial esophageal cancer within Barrett's esophagus. This combination improves cancer staging, removes the superficial cancer, and eliminates remaining mucosa at risk for cancer development.

Contribution of intraoperative enteroscopy in the management of obscure gastrointestinal bleeding.

Obscure gastrointestinal bleeding remains a significant diagnostic challenge. Our aims were (1) to determine the efficacy of intraoperative enteroscopy (IOE) in identifying lesions responsible for obscure gastrointestinal bleeding and (2) to determine the outcome of patients after treatment of these lesions. We retrospectively reviewed all patients who underwent IOE for obscure gastrointestinal bleeding from 1992 to 1998. Patients were divided into those with overt and those with occult gastrointestinal bleeding. Follow-up was complete in 67 patients (96%), with a median of 32 months (range 1 to 91 months). Seventy patients (52 overt and 18 occult) underwent IOE after extensive preoperative evaluation. Median duration of bleeding was 12 months, requiring a median of 14 blood transfusions. Risk factors for bleeding were identified in 46 patients (61%). A lesion was identified and treated in 52 patients (74%)-39 in the overt group and 13 in the occult group. Lesions identified were vascular (54%), ulcerations (31%), tumors (11%), and small bowel diverticula (4%). Overall, 35 patients (52%) were found to have one or more lesions at IOE that were treated surgically and had no further bleeding. IOE, through a mid-small bowel enterotomy, has low morbidity and is effective in that it identified a treatable lesion in 74% of patients, which led to cure of bleeding in 52%.

Extent of high-grade dysplasia in Barrett's esophagus correlates with risk of adenocarcinoma.

BACKGROUND & AIMS: The identification of any high-grade dysplasia (HGD) in Barrett's esophagus has been considered to be an indication for esophagectomy because of the increased risk of cancer. The aim of this study was to determine if a limited extent of HGD has the same potential for cancer as diffuse HGD. METHODS: A retrospective cohort study was performed to assess the risk of developing adenocarcinoma in relationship to the extent of HGD found on endoscopic surveillance. The extent of HGD was defined as focal if cytologic and/or architectural changes of HGD were limited to a single focus of 5 or fewer crypts and diffuse if more than 5 crypts were involved in a single biopsy specimen or if HGD involved more than one biopsy fragment. The relative risk of cancer was assessed using a Cox proportional hazard model, and cancer-free survival was determined using survival curves. RESULTS: Sixty-seven patients with diffuse HGD and 33 with focal HGD satisfied selection criteria. Cancer-free survival rates at 1 and 3 years were 93% and 86% for focal HGD compared with 62% and 44% for diffuse HGD (P < 0.001). On univariate analysis, extent of HGD (relative risk, 5.36; 95% confidence interval, 1.84-15.56), nodularity on endoscopy (relative risk, 3.98; 95% confidence interval, 1.97-8.04), and lack of acid suppression (relative risk, 2.48; 95% confidence interval, 1.16-5.28) were associated with an increased risk of esophageal adenocarcinoma. Diffuse HGD had a 3.7-fold increase in the risk of esophageal cancer compared with focal HGD (P = 0.02) on multivariate analysis. CONCLUSIONS: Patients with focal HGD are less likely to have cancer during the first year after diagnosis or on subsequent follow-up compared with diffuse HGD.

Pathogenesis of gastroesophageal reflux and Barrett esophagus.

Barrett esophagus is a metaplastic condition that affects the lower esophagus and is a complication of gastroesophageal reflux disease (GERD). Under normal circumstances, the reflux of gastric contents into the esophagus is prevented by a complex barrier at the esophagogastric junction. Dysfunction of the lower esophageal sphincter and the presence of a hiatal hernia lead to failure of this barrier. Esophageal mucosal damage results from the chronic exposure of the esophageal mucosa to gastroduodenal contents and the lack of an effective mucosal defense. This article is an overview of the dysfunction of the esophagogastric junction that leads to GERD. The role of the contents of the reflux and that of Helicobacter pylori infection in the pathogenesis of Barrett esophagus are also summarized.

The "aspirin" of the new millennium: cyclooxygenase-2 inhibitors.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis via the cyclooxygenase (COX) enzyme, the key to both therapeutic benefits and toxicity. COX enzyme exists in 2 isoforms, COX-1 and COX-2. COX-1 enzyme is thought to mediate "housekeeping" or homeostatic functions, and COX-2 is considered an inducible enzyme in response to injury or inflammation. COX-2 inhibitors are the "next-generation" NSAIDs that may selectively block the COX-2 isoenzyme without affecting COX-1 function. This may result in control of pain and inflammation with a lower rate of adverse effects compared with older nonselective NSAIDs. Rapidly evolving evidence suggests that COX-2 enzyme has a diverse physiologic and pathologic role. This article addresses the role of COX-2 enzyme in health and disease as well as the potential therapeutic value and safety issues related to COX-2 inhibition.

Persistent genetic abnormalities in Barrett's esophagus after photodynamic therapy.

BACKGROUND & AIMS: Photodynamic therapy (PDT) is a technique for nonsurgical treatment of patients with dysplasia in Barrett's esophagus. The primary endpoint for PDT has been resolution of dysplasia. We studied the effect of PDT at the genetic level. METHODS: Archival material from 3 patients who had initial improvement in dysplasia after PDT but occurrence of high-grade dysplasia during follow-up was used. Biopsy specimens were analyzed for increased proliferation, aneuploidy, p53 protein overexpression, p53 mutations, and p16 promoter hypermethylation. RESULTS: Patients developed high-grade dysplasia 16, 28, and 37 months after PDT. In all cases, one or more genetic markers were positive after PDT treatment, whereas histology was downstaged consistently after therapy. Increasing genetic abnormalities were noted by the end of follow-up. CONCLUSIONS: Genetic abnormalities may persist after PDT despite phenotypical improvement of dysplasia. These patients may progress to high-grade dysplasia or develop adenocarcinoma. Histologic improvement in dysplasia is an inadequate endpoint for PDT in patients with Barrett's esophagus.