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Background & Aims Radiofrequency ablation (RFA) is safe and effective treatment for flat dysplasia associated with Barrett's esophagus (BE). However, there are limited data on the safety of RFA in patients who had prior endoscopic mucosal resection (EMR), which might increase the risk of complications. We compared complications and histologic outcomes between patients who had EMR before RFA and those who received only RFA. Methods We performed a retrospective analysis of data collected from patients treated for BE, associated with dysplasia or intramucosal cancer, at the Mayo Clinic in Rochester, Minnesota, from 1998–2009. Patients were divided into groups that had RFA after EMR (group 1, n=44) or only RFA (group 2, n=46). We compared the incidence of complications (strictures, bleeding, and esophageal perforation) and histologic features (complete resolution of dysplasia and complete resolution of intestinal metaplasia [CR-IM]) between groups. Logistic regression analysis was performed to assess predictors of stricture formation. Results Stricture rates were 14% in group 1 and 9% in group 2 (odds ratio, 1.53; 95% confidence interval [CI], 0.26–9.74). The rates of CR-IM were 43% in group 1 and 74% in group 2 (odds ratio, 0.33; 95% CI, 0.14–0.78). The rates of complete resolution of dysplasia were 76% in group 1 and 71% in group 2 (odds ratio, 1.28; 95% CI, 0.39–4.17). The adjusted odds ratio for CR-IM in group 1 (adjusting for age, segment length, and grade of dysplasia) was 0.50 (95% CI, 0.15–1.66). Conclusions Stricture rates among patients who receive only RFA are comparable to those of patients who had prior EMR. EMR appears safe to perform prior to RFA.

Barrett esophagus (BE) predisposes patients to esophageal adenocarcinoma, a cancer with one of the fastest rising incidence rates over the past decade and a highly lethal malignancy once it is symptomatic.1,2 It is believed that esophageal adenocarcinoma arises as the final step of a postulated sequential change in the metaplastic epithelium, progressing from low-grade dysplasia (LGD), to high-grade dysplasia (HGD), and finally carcinoma. HGD on histologic samples has been used as the most reliable clinical biomarker of potential carcinogenesis, with studies reporting variable rates of progression to esophageal carcinoma (range, 16%–59%).3–5 Interruption of the metaplasia-dysplasia-carcinoma sequence by ablating or resecting this at-risk mucosa has been proposed as a strategy to reduce the incidence of esophageal adenocarcinoma and has served as the rationale for the recommendation of esophagectomy for patients with HGD. Over the past few years, endoscopic therapy has emerged as an alternative to esophagectomy because of the significant mortality and morbidity associated with esophagectomy.6,7 Multiple modalities, including photodynamic therapy (PDT),8 argon plasma coagulation,9 and multipolar electrocoagulation10 in isolation and in combination with endoscopic mucosal resection (EMR),11,12 have been reported in the treatment of HGD. Variable success rates have been reported (range, 75%–90%). A randomized multicenter trial compared PDT with surveillance and treatment with omeprazole in patients with HGD. After a 24-month follow-up, complete ablation of HGD was noted in 77% of patients versus 39% in the omeprazole group. Thirteen percent of patients who received PDT plus omeprazole progressed to cancer compared with 28% of patients in the omeprazole group.13 This led to U.S. Food and Drug Administration approval for the use of PDT for the treatment of HGD in BE. We recently reported that long-term outcomes (overall mortality and cancer-free survival) were comparable between patients who underwent esophagectomy and patients who received PDT.14 Several genetic alterations have been described in BE. These include loss of cell cycle checkpoint genes, such as p16 and p53. Loss of these genes by allelic loss (deletions or loss of heterozygosity [LOH]), point mutations, or promoter hypermethylation (for p16) have been observed in a substantial number of patients with BE.15,16 Several other genetic alterations that involve gains/amplifications of proto-oncogenes (and growth factors/growth factor receptors) as well as changes in DNA content (as assessed by flow cytometry and image cytometry) also have been described.17,18 Currently, histology is used as the endpoint to define success with ablative therapy in HGD. However, recurrences and/or progression to cancer despite ‘successful’ ablation/resection are common. To our knowledge, predictors of recurrent dysplasia have not been defined. Few studies have assessed genetic alterations after ablation of BE19–21: those studies primarily assessed patients with predominantly nondysplastic BE (a category for which ablation currently is not recommended) rather than HGD (in which endoscopic ablation is gaining acceptance as an alternative to esophagectomy) by using techniques that lack long-term data on successful ablation. Studies also have raised concern about the appearance of cancer-associated biomarkers after ablation (in patients with nondysplastic BE)20: however, data are lacking on the clinical implication of this phenomenon in terms of the recurrence or progression of dysplasia. The role of biomarkers in defining response to PDT remains unclear. The correlation between histologic response and ‘biomarker response’ also is unknown. We hypothesized that patients who remain positive for genetic alterations despite achieving a histologic response to PDT would be at risk for recurrence of dysplasia. In this study, we used fluorescence in situ hybridization (FISH) to characterize genetic alterations that were present in patients with HGD and mucosal cancer before treatment with PDT and compared them with the alterations observed after PDT. In addition, we assessed the recurrence of dysplasia after initial histologic response and correlated those findings with post-PDT genetic alterations assessed by FISH.

Background & Aims Superficial (T1) esophageal adenocarcinoma (EAC) commonly is treated by endoscopic resection, yet little is known about factors that predict outcomes of this approach. We assessed clinical and histologic variables associated with the overall survival times of patients with T1 EAC who received therapy. Methods In a retrospective analysis, we collected data from patients who underwent endoscopic mucosal resection (EMR) for T1 EAC (194 patients with T1a and 75 patients with T1b) at the Mayo Clinic, from 1995 through 2011. EMR specimens were reviewed systematically for depth of invasion, presence of lymphovascular invasion, grade of differentiation, and status of resection margins. Kaplan–Meier curves and proportional hazards regression models were used in statistical analyses. Results Demographic characteristics were similar between patients with T1a and T1b EAC. Overall survival at 5 years after EMR was 74.4% for patients with T1a (95% confidence interval [CI], 67.6%−81.8%) and 53.2% for patients with T1b EAC (95% CI, 40.3%–70.1%). Of surviving patients with T1a EAC, 94.1% remained free of cancer (95% CI, 89.8%–98.5%), and 94.7% of surviving patients with T1b EAC remained free of cancer (95% CI, 85.2%−100%). A multivariable model associated older age (per 10-year increment), evidence of lymphovascular invasion, and deep margin involvement with reduced overall survival in patients with T1 EAC. Conclusions Systematic assessment of EMR specimens can help predict mortality and potentially guide treatment options for patients with T1 EAC.

Objective. Guidelines on antiplatelet medication use during endoscopy are based on limited evidence. We investigate the risk of bleeding and ischemic events in patients undergoing endoscopic mucosal resection (EMR) of esophageal lesions in the setting of scheduled cessation and prompt resumption of clopidogrel. Design. Single centre retrospective review. Patients. Patients undergoing EMR of esophageal lesions. Interventions. Use of clopidogrel before EMR and resumption after EMR. Patients cease antiplatelets and anticoagulants 7 days before EMR and resume clopidogrel 2 days after EMR in average risk patients. Main Outcomes. Gastrointestinal bleeding (GIB) and ischemic events (IE) within 30 days of EMR. Results. 798 patients underwent 1716 EMR. 776 EMR were performed on patients on at least 1 antiplatelet/anticoagulant (APAC). 17 EMR were performed following clopidogrel cessation. There were 14 GIB and 2 IE. GIB risk in the setting of recent clopidogrel alone (0%) was comparable to those not on APAC (1.1%) (P=1.0). IE risk on clopidogrel (6.3%) was higher than those not on APAC (0.1%) (P=0.03). Limitations. Retrospective study. Conclusions. Temporary cessation of clopidogrel before EMR and prompt resumption is not associated with an increased risk of gastrointestinal bleeding but may be associated with increased ischemic events.

Background & Aims Endoscopic therapy is emerging as an alternative to surgical therapy in patients with mucosal (T1a) esophageal adenocarcinoma (EAC) given the low likelihood of lymph node metastases. Long-term outcomes of patients treated endoscopically and surgically for mucosal EAC are unknown. We compared long-term outcomes of patients with mucosal EAC treated endoscopically and surgically. Methods Patients treated for mucosal EAC between 1998 and 2007 were included. Patients were divided into an endoscopically treated group (ENDO group) and a surgically treated group (SURG group). Vital status information was queried using an institutionally approved internet research and location service. Statistical analysis was performed using Kaplan–Meier curves and Cox proportional hazard ratios. Results A total of 178 patients were included, of whom 132 (74%) were in the ENDO group and 46 (26%) were in the SURG group. The mean follow-up period was 64 months (standard error of the mean, 4.8 mo) in the SURG group and 43 months (standard error of the mean, 2.8 mo) in the ENDO group. Cumulative mortality in the ENDO group (17%) was comparable with the SURG group (20%) ( P = .75). Overall survival also was comparable using the Kaplan–Meier method. Treatment modality was not a significant predictor of survival on multivariable analysis. Recurrent carcinoma was detected in 12% of patients in the ENDO group, all successfully re-treated without impact on overall survival. Conclusions Overall survival in patients with mucosal EAC when treated endoscopically appears to be comparable with that of patients treated surgically. Recurrent carcinoma occurs in a limited proportion of patients, but can be managed endoscopically.

Background: 2-NBDG is a fluorescent glucose analog with preferential uptake in rapidly metabolizing cells. The use of 2-NBDG in ex-vivo Barrett's esophagus endoscopic mucosal resection specimens has been shown to enhance detection of dysplasia. Topical esophageal delivery of this agent may have a role in in-vivo detection of dysplasia. This is the first invivo feasibility study on topical esophageal delivery of 2-NBDG. Aim: To study the feasibility of topical esophageal delivery of 2-NBDG using wild type and a surgical mouse model of esophagitis. Methods: Eight week old male mice underwent esophago-jejunostomy using neodymium magnets to induce bile acid reflux as a model of esophagitis. On post-operative day 7, 2-NBDG was delivered mixed in aqueous gel at a concentration of 1mM to the proximal esophagus. The mice were euthanized 20 minutes after 2-NBDG ingestion followed by esophageal resection. Esophageal specimens were cut longitudinally to expose the esophageal lumen for wide field fluorescence intensity imaging. Non-operated wild type mice that ingested 2-NBDG served as a comparison group. A control group of mice did not receive 2-NBDG. Fluorescence intensity measurements were performed using NIH Image J. Results: Esophageal delivery of 2-NBDG was performed in 8 wild type mice: 4 underwent esophagojejunostomy as a model for esophagitis and 4 did not undergo surgery. An additional 4 wild type mice did not receive 2-NBDG and served as a control group. Wide field esophageal fluorescence intensity measurements were obtained for mice in each group. The mean esophageal fluorescence intensity of the control group (background fluorescence) was subtracted from the remaining groups. There was a significant difference inmean (SD) esophageal fluorescence intensity between the non-operated group and mice that underwent esophagojejunostomy, 19.2(0.8) au compared to 164.2(61.3) au, p=0.03. (figure 1) No side-effects of 2-NBDG delivery were noted. Conclusion: Topical esophageal delivery of 2-NBDG is feasible in mice and shows increased fluorescence intensity in a mouse model of esophagitis compared to wild type mice. The successful use of this agent to detect inflammatory change is promising for further human application.

therapies with endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) are gaining momentum and acceptance as alternatives in the management of EM. Aims: Compare changes in treatment trends and evaluate disease eradication from 2000-2010. Methods: Treatment strategies for Barrett’s-associated EM lesions were collected from a prospectively maintained database. Decisions for treatment were based on standard histological Barrett’s sampling, staging EMRs of visible lesions and EUS in all patients, and/or CT or PET/CT. Barrett’s segment from surgical and endoscopic therapies were analyzed for: complete eradication of EM, residual dysplasia, treatment complications and disease status at follow-up. Results: Eighty one patients were included (median age of 65 yrs [29-83]; male ratio of 3.8). Forty eight patients had surgical resection; 6 patients were upgraded to surgery following staging EMRs for visible lesions (with no residual invasive component in 5 of these). Pre-surgical histological grades of EM were: HGD (n 4), IMC (n 25) and T1 mucosal carcinoma (n 19). The morbidity for esophagectomy was 29% with one in-hospital death (2%). Anastomotic stricture requiring dilatation occurred in 4 (8%) patients. The followup time for surgical patients ranged from 9 days to 8 yrs; all patients were cured of EM.Endoscopic treatment with curative intent was performed in 27 patients (80% requiring EMR followed by RFA). The pre-treatment EM grades for the endoscopy group included: HGD (n 13), IMC (n 11) and T1 mucosal carcinoma (n 3). Overall, follow-up for this cohort ranged from 11 days to 3 yrs. All patients were treated as day cases. A median of 2.4 RFA sessions were required. The rate of complete resolution for EM was 100% in the endoscopic group; 69% had complete eradication of Barrett’s. Six high risk surgical candidates, unsuitable for 1st-line endoscopy with curative intent, had endoscopic salvage treatment for EM lesions; followup available was from 0.2 to 1.8 yrs, with 4 patients still alive & undergoing treatment. Complications of endoscopy were a single arterial bleed (2%) following an EMR which was controlled by clipping; the patient required a blood transfusion. Conclusions: The addition of minimally-invasive endoscopic approaches to staging & therapy for Barrett’s-related EM has represented a safe & accurate means of triaging patients to appropriate therapies. Use of EMR & RFA is an effective & safe alternative to surgery in selected patients. However, close interdisciplinary collaboration of specialists in gastroenterology, surgery, & pathology is mandatory for optimum outcomes.

Detection of High-Grade Dysplasia and Esophageal Adenocarcinoma Using Endoscopic Mucosal Resection in Combination with Fluorescence in Situ Hybridization Wytske Westra, Ganapathy A. Prasad, Kevin C. Halling, Shannon M. Brankley, Emily Barr Fritcher, Trynda N. Oberg, Jesse S. Voss, Michael B. Campion, Navtej Buttar, LouisMichel Wong Kee Song, Lori S. Lutzke, Kelly T. Dunagan, Lynn S. Borkenhagen, Agnieszka M. Rygiel, Kausilia K. Krishnadath, Kenneth K. Wang