Yvonne Romero

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Asymptomatic Neoplastic Pancreatic Cysts

This article has an accompanying continuing medical education activity on page e12. Learning Objective: At the conclusion of this exercise, the learner will understand the approach to counseling patients regarding the optimal method and frequency of radiologic imaging, indications for invasive tests like endoscopic ultrasonography (EUS) and surgery, select patients for follow-up after surgery, decide the duration of such follow-up, and decide when to stop surveillance for those with and without surgery.

Secular trends in the epidemiology and outcome of Barrett's oesophagus in Olmsted County, Minnesota

BACKGROUND The incidence of oesophageal adenocarcinoma has increased greatly. Barretts oesophagus is a known risk factor. AIMS To identify changes in the incidence, prevalence, and outcome of Barretts oesophagus in a defined population. SUBJECTS Residents of Olmsted County, Minnesota, with clinically diagnosed Barretts oesophagus, or oesophageal or oesophagogastric junction adenocarcinoma. METHODS Cases were identified using the Rochester Epidemiology Project medical records linkage system. Records were reviewed with follow up to 1 January 1998. RESULTS The incidence of clinically diagnosed Barretts oesophagus (>3 cm) increased 28-fold from 0.37/100 000 person years in 1965–69 to 10.5/100 000 in 1995–97. Of note, gastroscopic examinations increased 22-fold in this same time period. The prevalence of diagnosed Barretts oesophagus increased from 22.6 (95% confidence interval (CI) 11.7–33.6) per 100 000 in 1987 to 82.6/100 000 in 1998. The prevalence of short segment Barretts oesophagus (<3 cm) in 1998 was 33.4/ 100 000. Patients with Barretts oesophagus had shorter than expected survival but only one patient with Barretts oesophagus died from adenocarcinoma. Only four of 64 adenocarcinomas occurred in patients with previously known Barretts oesophagus. CONCLUSIONS The incidence and prevalence of clinically diagnosed Barretts oesophagus have increased in parallel with the increased use of endoscopy. We infer that the true population prevalence of Barretts oesophagus has not changed greatly, although the incidence of oesophageal adenocarcinoma increased 10-fold. Many adenocarcinomas occurred in patients without a previous diagnosis of Barretts oesophagus, suggesting that many people with this condition remain undiagnosed in the community.

Prevalence and Predictive Factors of Eosinophilic Esophagitis in Patients Presenting With Dysphagia: A Prospective Study

OBJECTIVES:Eosinophilic esophagitis (EE) is an increasingly recognized cause of dysphagia. We prospectively assessed the prevalence of EE using midesophageal biopsies in patients presenting with no endoscopically evident cause of dysphagia. We also aimed to determine the clinical and endoscopic factors predictive of EE in outpatients undergoing endoscopy for dysphagia.METHODS:Outpatients (18–60 yr of age) undergoing endoscopy for dysphagia at Mayo Clinic, Rochester between June 2005 and June 2006 were enrolled. Patients completed the validated Mayo Dysphagia Questionnaire (MDQ). Biopsies were obtained from the midesophagus if there was no endoscopically evident cause of dysphagia or there were endoscopic findings suggestive of EE. EE was defined as the presence of >20 eosinophils/high-power field. Logistic regression was performed to identify predictors of EE.RESULTS:Of 376 patients enrolled, 238 (63%) completed the MDQ and 222 (59%) had midesophageal biopsies; 33 (15%, 95% CI 6%–12%) had EE by biopsy. Ten of 102 (9.8%) patients who appeared endoscopically normal had EE by biopsy, while 8 of 21 (38%) patients with endoscopic changes suggestive of EE had EE on biopsy. Predictors of EE were younger age, endoscopic features suggestive of EE, absence of use of proton pump inhibitors, and a history of any food impaction for greater than 5 min.CONCLUSIONS:Midesophageal biopsies from normal-appearing mucosa should be obtained in all patients with unexplained solid food dysphagia; this may diagnose EE in about one in 10 cases.

Swallowed Fluticasone Improves Histologic but Not Symptomatic Response of Adults With Eosinophilic Esophagitis

BACKGROUND & AIMS We evaluated the effect of aerosolized fluticasone therapy on symptomatic dysphagia and histologic eosinophilia in adults with eosinophilic esophagitis (EoE). METHODS We performed a double-blind, randomized, placebo-controlled trial of fluticasone in 42 adult patients with a new diagnosis of EoE (30 men; mean age, 37.5 y). Participants were assigned randomly to groups that swallowed 880 μg of aerosolized fluticasone twice daily (n = 21), or took a placebo inhaler twice daily (n = 15) for 6 weeks. End points of the study were symptomatic and histologic response. RESULTS A complete histologic response (>90% decrease in mean eosinophil count) was observed in 11 of 15 subjects who received 6 weeks of fluticasone (62%), compared with none of the 15 subjects who received placebo (P < .001), based on intention-to-treat analysis; histologic responses were observed in 68% of subjects who received fluticasone (13 of 19) compared with none of those who received placebo (0 of 15) by per-protocol analysis (P < .001). Intracellular staining for eosinophil-derived neurotoxin was reduced in 81% of subjects who received fluticasone (13 of 16) compared with 8% who received placebo (1 of 13) (P < .001). Dysphagia was reduced in 57% of subjects who received fluticasone (12 of 21) compared with 33% who received placebo (7 of 21) (P = .22) by intention-to-treat analysis; dysphagia was reduced in 63% of patients who received fluticasone (12 of 19) and 47% of those who received placebo (7 of 15) (P = .49) based on per-protocol analysis. Esophageal candidiasis developed in 26% of subjects who received fluticasone (5 of 19), but in none of the subjects in the placebo group (P = .05). CONCLUSIONS Aerosolized, swallowed fluticasone leads to a histologic but not a symptomatic response in adults with EoE.

A prospective, randomized, double-blind, placebo-controlled trial of endoscopic steroid injection therapy for recalcitrant esophageal peptic strictures.

BACKGROUND AND AIMS:The aim of the study was to examine whether endoscopic intralesional corticosteroid injection into recalcitrant peptic esophageal strictures reduces the need for repeat stricture dilation.METHODS:Patients with a peptic esophageal stricture and recurrent dysphagia having had at least one dilation in the preceding 18 months were enrolled in a prospective randomized, double-blind study comparing steroid and sham injection. After endoscopic confirmation of recurrent stricture, patients were randomized to receive either 0.5 cc/quadrant triamcinolone (40 mg/cc) or sham injection into the stricture followed by balloon dilation of the stricture. Patients were stratified by the number of dilations required in the preceding 18 months, severity of dysphagia, the presence of esophagitis, stricture severity, and prior therapy with a proton-pump inhibitor. Patients and their physicians were blinded to the type of intervention received. Baseline dysphagia questionnaires were completed. Post-procedurally all patients were placed on a standardized proton-pump inhibitor regimen and standardized telephone follow-up questionnaires were completed at 1 wk and at 1, 3, 6, 9, and 12 months. The original sample-size calculation of 60 patients could not be met in a timely fashion because of a low incidence of recalcitrant peptic stricture patients.RESULTS:A total of 30 patients were enrolled, 15 in the steroid group (10 men, mean age 66 yr) and 15 in the sham group (11 M, mean age 67 yr). Patients were followed for 1 yr, unless they underwent an antireflux operation or died. Two patients, one per group, died of non-esophageal causes at 1 and 12 months. Four patients had fundoplication, two in each group, unrelated to stricture or dysphagia. Two patients in the steroid group (13%) and nine in the sham group (60%) required repeat dilation (p= 0.011).CONCLUSIONS:In patients with recalcitrant peptic esophageal stricture, steroid injection into the stricture combined with acid suppression significantly diminishes both the need for repeat dilation and the average time to repeat dilation compared to sham injection and acid suppression alone.

A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett’s esophagus

Esophageal adenocarcinoma risk in Barretts esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than nonprogressors (70.6 versus 62.5 years; P < 0.001). We evaluated a linear combination of the eight markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; P < 0.001, <0.001, and <0.001, respectively). In addition, even after rigorous overfitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Delta-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models. A methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia.

Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin, and blood leukocytes

Background:The correlation between noninvasive markers with endoscopic activity according to the modified Baron Index in patients with ulcerative colitis (UC) is unknown. We aimed to evaluate the correlation between endoscopic activity and fecal calprotectin (FC), C-reactive protein (CRP), hemoglobin, platelets, blood leukocytes, and the Lichtiger Index (clinical score). Methods:UC patients undergoing complete colonoscopy were prospectively enrolled and scored clinically and endoscopically. Samples from feces and blood were analyzed in UC patients and controls. Results:We enrolled 228 UC patients and 52 healthy controls. Endoscopic disease activity correlated best with FC (Spearmans rank correlation coefficient r = 0.821), followed by the Lichtiger Index (r = 0.682), CRP (r = 0.556), platelets (r = 0.488), blood leukocytes (r = 0.401), and hemoglobin (r = −0.388). FC was the only marker that could discriminate between different grades of endoscopic activity (grade 0, 16 [10–30] &mgr;g/g; grade 1, 35 [25–48] &mgr;g/g; grade 2, 102 [44–159] &mgr;g/g; grade 3, 235 [176–319] &mgr;g/g; grade 4, 611 [406–868] &mgr;g/g; P < 0.001 for discriminating the different grades). FC with a cutoff of 57 &mgr;g/g had a sensitivity of 91% and a specificity of 90% to detect endoscopically active disease (modified Baron Index ≥2). Conclusions:FC correlated better with endoscopic disease activity than clinical activity, CRP, platelets, hemoglobin, and blood leukocytes. The strong correlation with endoscopic disease activity suggests that FC represents a useful biomarker for noninvasive monitoring of disease activity in UC patients.

Aberrant methylation of secreted frizzled-related protein genes in esophageal adenocarcinoma and Barrett's esophagus.

Hypermethylation of secreted frizzled‐related proteins (SFRP) genes frequently occurs with several cancers but has not been studied in esophageal adenocarcinoma or its precursor—Barretts esophagus. To explore the role of SFRP methylation in the neoplastic progression of Barretts esophagus and to evaluate methylated SFRP genes as biomarkers for Barretts esophagus and cancer, methylation of SFRP genes was determined in esophageal adenocarcinomas, Barretts esophagus and normal epithelia using methylation‐specific PCR. Protein expression of SFRP genes was then assessed in these tissues by immunohistochemistry. The mRNA expression of SFRP genes was quantified by real‐time reverse‐transcription PCR in esophageal adenocarcinoma cell lines with and without demethylation by 5‐aza‐2′deoxycytidine and inhibition of deacetylation by trichostatin A treatment. Hypermethylation of SFRP1, 2, 4 and 5 was detected in 93%, 83%, 73% and 85% of 40 cancers; 81%, 89%, 78% and 73% of 37 Barretts epithelia; 25%, 64%, 32% and 21% of 28 adjacent normal epithelia from Barretts patients; and 10%, 67%, 0% and 13% of 30 normal esophagogastric epithelia from healthy individuals, respectively (p < 0.001 for SFRP1, 4 and 5; p < 0.05 for SFRP2). Protein expression of SFRP1, 2 and 4 was downregulated in 87%, 67% and 90% of cancers, and expression correlated inversely with grade and stage of cancers and with grade of dysplasia. Expression of SFRP2 and SFRP4 proteins was lower in cancers with corresponding gene methylation (p < 0.05). Demethylation treatment effectively re‐expressed SFRP mRNA in cancer cell lines. Thus, hypermethylation of SFRP genes is a common early event in the evolution of esophageal adenocarcinoma, and methylation of SFRP1, 4 and 5 might serve as biomarkers for Barretts neoplasia. Aberrant promoter methylation appears to functionally silence SFRP gene expression in esophageal adenocarcinoma.

A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barretts esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barretts esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10−10) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10−9) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10−9) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barretts esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.