Ana E. Bennett

Radiofrequency Ablation in Barrett's Esophagus with Dysplasia

BACKGROUND Barretts esophagus, a condition of intestinal metaplasia of the esophagus, is associated with an increased risk of esophageal adenocarcinoma. We assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barretts esophagus and decrease the rate of neoplastic progression. METHODS In a multicenter, sham-controlled trial, we randomly assigned 127 patients with dysplastic Barretts esophagus in a 2:1 ratio to receive either radiofrequency ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of Barretts esophagus. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. RESULTS In the intention-to-treat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5% of those in the ablation group, as compared with 22.7% of those in the control group (P<0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0% of those in the ablation group, as compared with 19.0% of those in the control group (P<0.001). Overall, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3% of those in the control group (P<0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P=0.03) and fewer cancers (1.2% vs. 9.3%, P=0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, one patient had upper gastrointestinal hemorrhage, and five patients (6.0%) had esophageal stricture. CONCLUSIONS In patients with dysplastic Barretts esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression. (ClinicalTrials.gov number, NCT00282672.)

Durability of Radiofrequency Ablation in Barrett's Esophagus With Dysplasia

BACKGROUND & AIMS Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barretts esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. METHODS We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. RESULTS After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). CONCLUSIONS In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.

Fundic gland polyp dysplasia is common in familial adenomatous polyposis.

BACKGROUND & AIMS Fundic gland polyps (FGPs) are common in familial adenomatous polyposis (FAP) but have been considered nonneoplastic. Gastric carcinoma arises from FGPs in FAP presumably from a dysplasia-carcinoma pathway. Our study examined the prevalence of FGPs and FGP dysplasia in FAP and identified endoscopic or demographic features associated with FGPs and dysplasia. METHODS Demographic and endoscopic information were obtained prospectively from 75 consecutive subjects undergoing upper-endoscopic surveillance for FAP. Systematic biopsy specimens of FGPs, normal-appearing fundic mucosa, and antral mucosa for Helicobacter pylori were obtained. Multivariable analysis assessed the association of demographic or endoscopic factors with the presence of FGP or FGP dysplasia. RESULTS FGPs were detected in 88% of subjects and were dysplastic in 41% (38% low grade, 3% high grade). H pylori infection was rare in subjects with vs without FGPs (1.5% vs 33.3%, P = .005). In the multivariable analysis larger FGP size (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.1-14.4), higher stage of duodenal polyposis (OR, 2.3; 95% CI, 1.2-4.5), and antral gastritis (OR, 11.2; 95% CI, 1.2-103.9) were associated with FGP dysplasia. Exposure to acid-suppressive medications was associated with a marked decrease in dysplastic FGPs (OR, 0.14; 95% CI, 0.03-0.64). CONCLUSIONS The majority of FAP patients have FGPs and nearly half will have dysplastic FGPs. There is an inverse relationship between H pylori and FGPs. FGP dysplasia is associated with larger polyp size, increased severity of duodenal polyposis, and antral gastritis. Acid-suppressive therapy use appears protective against dysplasia in FGPs.

Maintenance therapy with a probiotic in antibiotic‐dependent pouchitis: experience in clinical practice

Background : Management of antibiotic‐dependent pouchitis is often challenging. Oral bacteriotherapy with probiotics (such as VSL #3) as maintenance treatment has been shown to be effective in relapsing pouchitis in European trials. However, this agent has not been studied in the US, and its applicability in routine clinical practice has not been evaluated.

Poor Interobserver Agreement in the Distinction of High-Grade Dysplasia and Adenocarcinoma in Pretreatment Barrett's Esophagus Biopsies

OBJECTIVE:Grading Barretts dysplasia at the lower end of the metaplasia-dysplasia spectrum (negative, indefinite, and low-grade dysplasia) suffers from poor interobserver agreement, even among gastrointestinal pathologists. Data evaluating interobserver agreement in Barretts mucosal biopsies with changes at the upper end of the dysplasia spectrum (high-grade dysplasia, intramucosal, and submucosal adenocarcinoma) have not been published. The accurate categorization of pretreatment biopsies drives therapeutic decision making, but if the diagnostic distinction between cancer and high-grade dysplasia in Barretts biopsies is inconsistent, then the use of these diagnoses to make management decisions is suspect. To this end, our aim was to assess interobserver reproducibility among a group of gastrointestinal pathologists in the interpretation of preresection biopsies.METHODS:All study pathologists agreed upon the histologic criteria distinguishing four diagnostic categories, including high-grade dysplasia; high-grade dysplasia with marked distortion of glandular architecture, cannot exclude intramucosal adenocarcinoma; intramucosal adenocarcinoma; and submucosally invasive adenocarcinoma. The histologic criteria were used to independently review preresection biopsies from 163 consecutive Barretts esophagus patients with at least high-grade dysplasia who ultimately underwent esophagectomy. Reviewers recorded the specific histologic criteria used to categorize each case and Kappa statistics were calculated to assess interobserver agreement.RESULTS:Using kappa statistics, the overall agreement was only fair (κ= 0.30). Agreement for high-grade dysplasia was moderate (κ= 0.47), while agreement for high-grade dysplasia with marked architectural distortion, cannot exclude intramucosal adenocarcinoma and intramucosal adenocarcinoma were only fair (κ= 0.21 and 0.30, respectively) and agreement for submucosal adenocarcinoma was poor (κ= 0.14).CONCLUSIONS:The overall poor interobserver reproducibility among gastrointestinal pathologists who see a high volume of Barretts cases calls into question treatment regimens based on the assumption that high-grade dysplasia, intramucosal adenocarcinoma, and submucosal adenocarcinoma can reliably be distinguished in biopsy specimens.

Treatment of Rectal Cuff Inflammation (Cuffitis) in Patients with Ulcerative Colitis Following Restorative Proctocolectomy and Ileal Pouch-Anal Anastomosis

BACKGROUND:Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the treatment of choice in the majority of patients with ulcerative colitis (UC) who require surgery. To ease the construction of the IPAA and improve functional outcome by minimizing sphincter related stretch injury, a stapling technique is being commonly used in the pouch-anal anastomosis. Despite its advantages, the procedure normally leaves a 1–2 cm of anal transitional zone or rectal cuff, which is susceptible to recurrence of residual UC or cuffitis. Cuffitis can cause symptoms mimicking pouchitis.AIM:To conduct an open-labeled trial of topical mesalamine in patients with cuffitis.METHODS:We treated 14 consecutive patients with cuffitis by giving mesalamine suppositories 500 mg b.i.d. (mean 3.2 months, range 1–9 months). The Cuffitis Activity Index (adapted from the Pouchitis Disease Activity Index) scores and improvement in symptoms of bloody bowel movements and arthralgias were measured as primary and secondary outcomes.RESULTS:All patients had surgery for medically refractory UC. There were significant reductions in the total Cuffitis Activity Index scores after the therapy (11.93 ± 3.17 vs 6.21 ± 3.19, p < 0.001). Symptom (3.24 ± 1.28 vs 1.79 ± 1.31), endoscopy (3.14 ± 1.29 vs 1.00 ± 1.52), and histology (4.93 ± 1.77 vs 3.57 ± 1.39) scores each were significantly reduced (p < 0.05). Ninety-two percent of patients with bloody bowel movements and 70% of patients with arthralgias improved after the therapy. No systemic or topical adverse effects were reported.CONCLUSION:Topical mesalamine appears well tolerated and effective in treating patients with cuffitis, with improvement in symptom as well as endoscopic and histologic inflammation.

Preoperative colorectal neoplasia increases risk for pouch neoplasia in patients with restorative proctocolectomy.

BACKGROUND & AIMS Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has substantially reduced the risk for ulcerative colitis (UC)-associated dysplasia or cancer (neoplasia). We characterized features, risk factors, and outcomes of pouch neoplasia in patients with inflammatory bowel disease in a historical cohort study. METHODS A total of 3203 patients with a preoperative diagnosis of inflammatory bowel disease underwent restorative proctocolectomy with IPAA from 1984 to 2009 at the Cleveland Clinic. Demographic, clinical, and endoscopic data were reviewed and samples were examined by histological analyses. Univariable and Cox regression analyses were performed. RESULTS Cumulative incidences for pouch neoplasia at 5, 10, 15, 20, and 25 years were 0.9%, 1.3%, 1.9%, 4.2%, and 5.1%, respectively. Thirty-eight patients (1.19%) had pouch neoplasia, including 11 (0.36%) with adenocarcinoma of the pouch and/or the anal-transitional zone (ATZ), 1 (0.03%) with pouch lymphoma, 3 with squamous cell cancer of the ATZ, and 23 with dysplasia (0.72%). In the Cox model, the risk factor associated with pouch neoplasia was a preoperative diagnosis of UC-associated cancer or dysplasia, with adjusted hazard ratios of 13.43 (95% confidence interval: 3.96-45.53; P < .001) and 3.62 (95% confidence interval: 1.59-8.23; P = .002), respectively. Mucosectomy did not protect against pouch neoplasia. CONCLUSIONS Risk for neoplasia in patients with UC and IPAA is small and not eliminated by colectomy or mucosectomy. A preoperative diagnosis of dysplasia or cancer of colon or rectum is a risk factor for pouch dysplasia or adenocarcinoma.

Clostridium difficile infection in patients with ileal pouch-anal anastomosis.

BACKGROUND & AIMS There has been an increase in the incidence and severity of Clostridium difficile-associated diarrhea in the U.S. The importance of C difficile infection in patients with ileal pouch-anal anastomosis (IPAA) is unknown. This study was designed to determine risk of acquiring C difficile infection in pouch disorders. METHODS Consecutive ulcerative colitis patients (n = 115) with IPAA undergoing pouch endoscopy were enrolled from May 2005-March 2006. Fecal specimens of pouch aspirate were collected during pouch endoscopy and analyzed for C difficile toxin A and B by enzyme-linked immunosorbent assay. Nineteen clinical, endoscopic, and histologic variables were assessed with stepwise selection methods. Two multivariate logistic regression models were constructed. RESULTS Twenty-one patients (18.3%) were positive for C difficile infection. Adjusting for other factors in the model, men were 5.12 (95% confidence interval, 1.38-20.46) times more likely to have C difficile infection than women. Compared with patients with pancolitis, those with preoperative left-sided colitis were 8.4 (95% confidence interval, 1.25-56.4) times more likely to have C difficile infection. Six of 6 patients with C difficile infection (3 with refractory pouchitis, 2 with Crohns disease, and 1 with irritable pouch syndrome) with repeat clinical, endoscopic, and laboratory evaluation after anti-C difficile therapy experienced clinical remission and disappearance of C difficile toxin from stools, with 4 showing decreased mucosal inflammation. CONCLUSIONS C difficile infection involving IPAA is common, characteristically occurring with or without previous receipt of antibiotics. Treatment of C difficile infection in patients with IPAA might improve the clinical outcome.

Risk Factors for Clinical Phenotypes of Crohn's Disease of the Ileal Pouch

BACKGROUND:Crohns disease (CD) of the pouch can occur in patients with colectomy and ileal pouch-anal anastomosis (IPAA) originally performed for a preoperative diagnosis of ulcerative colitis. The clinical presentations of CD of the pouch are inflammatory, fibrostenotic, and fistulizing. Risk factors for clinical phenotypes of CD of the pouch have not been characterized.METHODS:A total of 78 eligible patients with CD of the pouch together with 294 nonselected non-CD patients with IPAA seen in the Pouchitis Clinic were enrolled, including 28 with inflammatory CD, 18 with fibrostenotic CD, and 32 with fistulizing CD. The clinical phenotypes of CD were diagnosed based on a combined assessment of clinical, endoscopic, radiographic, and histologic features. Three separate analyses were performed, and for each analysis, the outcome of interest was having one of the phenotypes versus not having it. A stepwise selection multivariable logistic regression analysis was used.RESULTS:In the multivariable analysis, the risk factor for inflammatory CD was higher afferent-limb endoscopy scores (hazard ratio [HR] 1.87 95% confidence interval [CI] 1.54–2.27); the risk factors for fibrostenotic CD were higher afferent-limb (95% CI 1.81–3.48, HR 2.51) and higher cuff (95% CI 1.01–1.84, HR 1.36) endoscopy scores; and for fistulizing CD the risk factors were younger age (95% CI 0.93–0.99, HR 0.96), female gender (95% CI 1.35–6.97, HR 3.07), a preoperative diagnosis of indeterminate colitis (95% CI 1.72–9.34, HR 4.00), and no use of nonsteroidal antiinflammatory drugs (95% CI 1.31–8.25, HR 3.28).CONCLUSIONS:Each of the three phenotypes of CD of the pouch was associated with certain risk factors, suggesting that each of these diseases has a different etiology and disease process. The identification and management of some of the modifiable risk factors may reduce CD-related morbidity.

Detection of Dysplasia in Barrett's Esophagus With In Vivo Depth-Resolved Nuclear Morphology Measurements

BACKGROUND & AIMS Patients with Barretts esophagus (BE) show increased risk of developing esophageal adenocarcinoma and are routinely examined using upper endoscopy with biopsy to detect neoplastic changes. Angle-resolved low coherence interferometry (a/LCI) uses in vivo depth-resolved nuclear morphology measurements to detect dysplasia. We assessed the clinical utility of a/LCI in the endoscopic surveillance of patients with BE. METHODS Consecutive patients undergoing routine surveillance upper endoscopy for BE were recruited at 2 endoscopy centers. A novel, endoscope-compatible a/LCI system measured the mean diameter and refractive index of cell nuclei in esophageal epithelium at 172 biopsy sites in 46 patients. At each site, an a/LCI measurement was correlated with a concurrent endoscopic biopsy specimen. Each biopsy specimen was assessed histologically and classified as normal, nondysplastic BE, indeterminate for dysplasia, low-grade dysplasia (LGD), or high-grade dysplasia (HGD). The a/LCI data from multiple depths were analyzed to evaluate its ability to differentiate dysplastic from nondysplastic tissue. RESULTS Pathology characterized 5 of the scanned sites as HGD, 8 as LGD, 75 as nondysplastic BE, 70 as normal tissue types, and 14 as indeterminate for dysplasia. The a/LCI nuclear size measurements separated dysplastic from nondysplastic tissue at a statistically significant (P < .001) level for the tissue segment 200 to 300 μm beneath the surface with an accuracy of 86% (147/172). A receiver operator characteristic analysis indicated an area under the curve of 0.91, and an optimized decision point gave 100% (13/13) sensitivity and 84% (134/159) specificity. CONCLUSIONS These preliminary data suggest a/LCI is accurate in detecting dysplasia in vivo in patients with BE.