ORIGINAL ARTICLE: Clinical Endoscopy

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1 ORIGINAL ARTICLE: Clinical Endoscopy Diagnostic yield of methylene blue chromoendoscopy for detecting specialized intestinal metaplasia and dysplasia in Barrett s esophagus: a meta-analysis Saowanee Ngamruengphong, MD, Virender K. Sharma, MD, FACG, FASGE, Ananya Das, MD, FACP, FASGE Scottsdale, Arizona, USA Background: The reported yield of methylene-blue (MB) chromoendoscopy targeted biopsy in detecting specialized intestinal metaplasia (SIM) and, more importantly, dysplasia in patients with Barrett s esophagus (BE) has shown variable results. Objective: To perform a meta-analysis of published studies for assessment of the diagnostic yield of techniques of chromoendoscopy compared with conventional 4-quadrant random biopsy (RB) in detection of SIM and dysplasia in patients with BE. Design: A literature search of the MEDLINE, EMBASE, and the Cochrane Databases was performed, along with a search of PubMed and a manual search of cross-references of eligible articles. Data on yield of both modalities were extracted and analyzed to estimate weighted incremental yield (IY) and 95% CIs of MB over RB using a fixed-effects or random-effects model, as appropriate, based on whether homogeneity or heterogeneity, respectively, was indicated by Cochrane s Q c 2 test. Patients: A total of 450 patients with BE were reported in 9 studies included in the meta-analysis. Results: There was no significant IY with MB over RB for detection of SIM (IY 4%; 95% CI, -7% to 16%; 6 studies, n Z 251), dysplasia (IY 9%; 95% CI, -1% to 20%; 9 studies, n Z 450), and high-grade dysplasia and/or early cancer (IY 5%; 95% CI, -1% to 10%; 8 studies, n Z 405). Limitations: Only data on MB were analyzed because of limited availability of data for other chromoendoscopy dyes, minor variations in inclusion and exclusion criteria, and the small sample size, and because differences in application technique could have led to an underestimation of the diagnostic yield of MB chromoendoscopy. Conclusion: The technique of MB chromoendoscopy has only a comparable yield with RB for the detection of SIM and dysplasia during endoscopic evaluation of patients with BE. (Gastrointest Endosc 2009;69: ) Barrett s esophagus (BE) is a common complication of GERD and affects 10% to 15% of patients with GERD. An estimated 700,000 persons in the United States have BE, and, compared with the general population, they are at 30 to 125 times higher risk of developing esophageal cancer. 1 Abbreviations: BE, Barrett s esophagus; EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia; IY, incremental yield; LGD, low-grade dysplasia; MB, methylene blue; NBI, narrow-band imaging; RB, random biopsy; SIM, specialized intestinal metaplasia. DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. See CME section; p Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy /$36.00 doi: /j.gie BE is characterized by endoscopically distinguishable columnar-lined epithelium, along with the histologic identification of characteristic specialized intestinal metaplasia (SIM). 2 BE is thought to sequentially progress from metaplasia without dysplasia to low-grade dysplasia (LGD) to high-grade dysplasia (HGD) and then to esophageal adenocarcinoma (EAC). 3 The degree of dysplasia on esophageal biopsy in patients with BE is considered the best indicator of risk of progression to EAC. Endoscopic surveillance and random biopsies for the detection of dysplasia and early esophageal cancer is part of standard clinical practice. 4 However, areas of SIM and dysplasia are not easily identifiable by conventional endoscopy, 5-7 and extensive tissue sampling of the endoscopically visible segment of the columnar-lined epithelium during endoscopy is required for surveillance. In Volume 69, No. 6 : 2009 GASTROINTESTINAL ENDOSCOPY 1021

2 patients with nondysplastic and dysplastic BE, 4-quadrant random biopsies (RB) are taken every 1 and 2 cm, respectively, from the columnar-lined esophagus, in addition to targeted biopsies of any macroscopically evident lesion. Despite such intensive biopsy protocol, the yield of detection of dysplasia and early cancer by endoscopic surveillance is suboptimal. 5-7 Methylene blue (MB) based chromoendoscopy has been used for more than a decade in an effort to increase the diagnostic yield for detection of SIM, dysplasia, and EAC. MB is a vital dye that is taken up by actively absorbent intestinal-type epithelium in BE and dysplastic cells but not by squamous or gastric mucosa or gastric-type metaplasia within the distal esophagus. During MB chromoendoscopy, SIM typically stains blue, whereas a lighter intensity and increased heterogeneity in the staining pattern predict HGD and/or EAC. 8 There are a number of controlled studies on the use of MB staining for detection of SIM and dysplasia in patients with BE, but reported performance characteristics of MB chromoendoscopy are surprisingly variable, and controversy exists on the utility of this technique in clinical practice. The aim of the present study was to perform a meta-analysis of the published information to compare the diagnostic yield of MB chromoendoscopy with standard endoscopy with RB in detection of SIM and various grades of dysplasia in patients with BE. MATERIALS AND METHODS By using the MEDLINE, EMBASE, and Cochrane Central Trials databases from January 1980 through October 2007, a thorough literature search for prospective trials that compared MB chromoendoscopy with standard RB for detection of SIM and dysplasia in patients with BE was conducted, along with an additional search of PubMed and a manual search of cited references in selected articles. We used the following text words as search terms: Barrett s esophagus, Barrett s oesophagus, methylene blue chromoendoscopy, random biopsy, white-light endoscopy, four quadrant biopsy, conventional biopsy, intestinal metaplasia, specialized columnar epithelium, dysplasia, esophageal adenocarcinoma, and esophageal cancer. We scanned the bibliographies of all retrieved articles for potentially relevant articles that were not identified by the original search. Our search included articles published in English and non-english languages. An additional manual search of abstracts presented at the proceedings of Digestive Disease Week and the meetings of the American College of Gastroenterology from 2002 to 2007 was performed. If multiple updates of the same data were found, then we used only the most recent version for analysis. For a study to be included in this meta-analysis, predefined criteria had to be met. MB and RB should have been performed on each patient successively in included studies so that the diagnostic yields of the 2 tests were able Capsule Summary What is already known on this topic d The degree of dysplasia on esophageal biopsy in Barrett s esophagus (BE) is an indicator of risk of progression to adenocarcinoma. What this study adds to our knowledge d In a meta-analysis of 450 patients with BE reported in 9 studies, no significant incremental yield was observed with methylene-blue chromoendoscopy compared with conventional random biopsy for detection of specialized intestinal metaplasia, dysplasia, high-grade dysplasia, and/or early cancer. to be compared under comparable conditions. Studies in which lesions were confirmed by histopathologic diagnosis were considered in the analysis. Data were extracted on the yield of findings of SIM and dysplasia. When data were available, yields on detection of patients with LGD and those with HGD and/or EAC were further evaluated. Two reviewers (S.N., A.D.) independently checked each identified trial for fulfillment of predefined inclusion criteria. Because of the small number of trials, we included all articles and an abstract in our analysis. In our judgement, the data reported in the abstract were collected with similar rigor to that in the original articles. Disagreements were resolved by consulting a third reviewer (V.K.S.). If it was not clear whether a trial met the inclusion criteria or if any clarification of data was necessary, we requested further information from the investigators. Statistical analysis Data on the diagnostic yield in MB and RB were extracted, pooled, and analyzed by using the Cochrane Collaboration s software, RevMan version (The Cochrane Collaboration, Oxford, UK). The Cochrane Q c 2 test was used to detect heterogeneity of the effects; P values!.1 were considered significant for heterogeneity, and I 2 statistic was estimated to describe the percentage of the variability attributable to heterogeneity rather than sampling error; a value greater than 50% may indicate substantial heterogeneity. For each yield, the weighted incremental yield (IY) of MB was calculated by subtracting the yield of MB from that of RB, and a 95% CI was calculated. The Mantel- Haenszel method, which assumes a fixed-effects model, was used for analysis when significant heterogeneity was not detected, and the DerSimonian and Laird model, which assumes a random-effects model, was used for analysis when significant heterogeneity was detected. The number needed to test for one additional positive finding with MB and 95% CI was calculated as the inverse of IY. Sensitivity analysis by using only the highest quality trials (defined as trials that were both blinded and published as full 1022 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 6 :

3 Figure 1. Articles search flow diagram for meta-analysis. manuscripts) was conducted for comparisons with 2 or more high-quality trials. Subgroup analyses were also planned to investigate the possible sources of heterogeneity and whether these characteristics have any impact on incremental diagnostic yield in different subgroups. The factors intended to be investigated as possibly having heterogeneous effects in different subgroups included MB concentration, MB contact time, and MB biopsy technique. Meta-regression analysis for investigating the sources of heterogeneity was not performed because there were fewer than 10 trials available for analysis. 9 It is recognized that there was multiple testing of the abstracted outcome data arising from individual studies; however, it is noted that there were no instances in which statistical significance would have been removed by a correction such as Bonferroni inequalities. RESULTS Seventy-four articles were initially identified by using the search strategy described (Fig. 1). Fifty-one articles (clinical reviews [n Z 39], editorials [n Z 8], and brief communications or letters to the editors [n Z 4]) were excluded after preliminary review, which left 23 articles for detailed evaluation. Of these, 8 published articles that met the inclusion criteria were identified One additional abstract was identified by hand search. 18 In total, 9 studies were appropriate for meta-analysis, which involved a total of 450 patients. The characteristics of the studies included in the meta-analysis are summarized in Table 1. All were prospective studies, and MB 0.5% concentration was applied during the MB staining process. In 7 studies, MB contact time was 1 to 2 minutes, 10,12,13-17 whereas data in MB contact time were not available in 2 studies. 11,18 Six studies (n Z 251) 10,11,13,15-17 compared the yield of MB chromoendoscopy with RB for detection of SIM. Nine studies compared the yield of MB chromoendoscopy with RB for detection of dysplasia (n Z 450) Of these, 8 studies (n Z 364) 10-13,15-18 provided the yield of MB and RB for detection of LGD, and 8 studies(n Z 405) 10-12,14-18 provided the yield of MB and RB for detection of HGD and/or EAC. Eight studies were published in the English language. One study was fully published in Portugese Volume 69, No. 6 : 2009 GASTROINTESTINAL ENDOSCOPY 1023

4 TABLE 1. Summary of studies included for meta-analysis Study Country Method No. patients (S, L) MB biopsy technique MB contact time (min) Data on detection (per patient) Canto et al, U.S. Blinded 43 (8, 35) A 2 SIM, LGD, HGD Wo et al, U.S. Blinded 35 (20, 15) A NR SIM, LGD, HGD Ragunath et al, U.K. Blinded 57 (0, 57) A 1 LGD, HGD Saporiti et al, Brazil Unblinded 45 (31, 14) A 2 SIM, LGD Neubrand et al, * Germany NR 56 (40, 16) A NR LGD, HGD Gossner et al, Germany Blinded 86 (22, 64) A 2 HGD Lim et al, U.K. Blinded 30y B 2 SIM, LGD, HGD Horwhat et al, U.S. Blinded 48 (0, 48) A 1 SIM, LGD, HGD Ormeci et al, Turkey Blinded 50 (43, 7) A 2 SIM, LGD, HGD S, Number of patients with short-segment BE; L, number of patients with long-segment BE; A, standard technique (biopsy of both MB-stained and unstained mucosa); NR, not reported; B, modified technique (biopsy at unstained mucosa unstained or heterogeneously stained mucosa, not in homogeneous stained mucosa). *Abstract from a national meeting. ymedian length of BE was 5 cm. Three studies were performed in the United States, 10,11,16 two in Germany, 14,18 two in the United Kingdom, 12,15 and one each in Brazil 13 and Turkey. 17 Additional information was obtained from the investigators for 3 studies. 13,16,17 There was complete agreement among both reviewers regarding decisions on trial inclusion in the analysis. Diagnostic yield: SIM Six studies (n Z 251) 10,11,13,15-17 compared the yield of MB chromoendoscopy with standard RB for detection of SIM (Fig. 2) Study heterogeneity was noted, and, therefore, a random-effects model was applied. The yield of MB was 75% versus 70% for RB, with an IY of 4% with the fixed-effects model and 4% (P Z.44, 95% CI, -7% to 16%) with the random-effects model. Diagnostic yield: dysplasia Nine studies compared the yield of MB chromoendoscopy with standard RB for detection of dysplasia (n Z 450) (Fig. 3). Study heterogeneity was found in the overall analysis, and the random-effects model was applied accordingly. MB had a 43% yield versus 32% for RB, with an IY of 11% with the fixed-effects model but which decreased to 9% (P Z.08; 95% CI, -1% to 20%) with the random-effects model. Diagnostic yield: LGD In a subanalysis of patients for detection of LGD, 8 studies (n Z 364) 10-13,15-18 reported data on the yield of MB chromoendoscopy and standard RB for detection of LGD (Fig. 4A). Study heterogeneity was noted in this subgroup analysis, and, therefore, a random-effects model was applied. The yield for MB was 25% compared with 19% for RB, with an IYof 6% by both the fixed-effects model and the random-effects model (random-effects model, P Z.17; 95% CI, -2% to 14%). Of 8 studies, data in analysis from 4studies 10-12,16 included patients with indefinite dysplasia and patients with LGD. The analysis of these 4 studies was not altered greatly from the main analysis (fixed-effects model, IY Z 7%, P Z.17, 95% CI, -3% to 16%). Diagnostic yield: HGD and early cancer In subanalysis of diagnostic yield in the detection of HGD and/or EAC, 8 studies (n Z 405) 10-12,14-18 provided data on the yield of MB chromoendoscopy and standard RB for detection of HGD and/or EAC (Fig. 4B). Three studies 10,12,14 stated that an obvious neoplastic lesion at endoscopy was one of the exclusion criteria. Study heterogeneity was found, and the random-effects model was applied accordingly. MB had a 26% yield compared with a 19% yield for RB with a fixed-effects model, with an IYof 7% but which decreased to 5% (P Z.11, 95% CI, -1% to 10%) when the random-effects model was applied. Sensitivity analysis In an effort to confirm the findings of the meta-analysis by evaluating only the highest-quality trials, a sensitivity analysis that used only the studies that were blinded and published as full-length original articles was performed. Comparative analyses with 1 study published as a full paper were not evaluated. Five studies (n Z 206) 10,11,15-17 for detection of SIM and 7 studies (n Z 349) 10-12,14-17 for detection of dysplasia were blinded and published as full-length original articles. Six studies (n Z 263) 10-12,15-17 and 7 studies (n Z 349) 10-12,14-17 reported data on detection of LGD and of HGD and/or EAC, respectively. Sensitivity analyses confirmed these main analysis findings, with a nonsignificant IY for 1024 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 6 :

5 Figure 2. IY (%) for individual studies and pooled data for detection of SIM with MB chromoendoscopy compared with standard RB (random-effects model, P Z.44); the test for heterogeneity was c 2 Z (P Z.02, I 2 Z 63.2%). Figure 3. IY (%) for individual studies and pooled data for detection of dysplasia with MB chromoendoscopy compared with standard RB (randomeffects model, P Z.08); the test for heterogeneity was c 2 Z (P!.0001, I 2 Z 75.9%). detection of SIM (random-effects model, IY Z 7%, P Z.23; 95% CI, -5% to 19%), detection of dysplasia (random-effects model, IY Z 10%, P Z.14; 95% CI, -3% to 24%), LGD (random-effects model, IY Z 6%, P Z.30; 95% CI, -6% to 18%); and IY in the detection of HGD and/or EAC (random-effects model, IY Z 5%, P Z.16; 95% CI, -2% to 12%). Subgroup analyses: standard versus modified MB biopsy technique After careful review of the studies included in our analysis, it was realized that the exact technique of obtaining an MB-chromoendoscopy-guided endoscopic biopsy may have led to statistical heterogeneity in our analysis. There were 2 different biopsy techniques applied during MB chromoendoscopy. Almost all studies except one used a standard technique of obtaining biopsy specimens of both stained and unstained areas in the mucosa after application of MB. 19 However, in the study by Lim et al, 15 amodifiedtechnique was used in which biopsies were performed that targeted only the unstained or heterogeneously stained mucosa, but no biopsy specimens were taken from homogeneously stained areas. The modified technique could have led to nonsampling of possible dysplastic area in homogeneously stained epithelium in that particular study, which might explain the much lower yield with MB chromoendoscopy in that particular study compared with the other studies that used the standard technique. Also, in the study by Gossner et al, 14 only those patients with histologically confirmed HGD and/or EAC were included, and this possibly led to a higher diagnostic yield of chromoendoscopy in this study compared with other studies. Thus, we did a subgroup analysis after excluding the studies by Lim et al 15 and Gossner et al 14 (Fig. 5). In this subgroup analyses, 6 studies (n Z 289) 10-12,16-18 provided data on yields for HGD and/or EAC. No study heterogeneity was noted (P Z.41, I 2 Z 1.5%), and a fixed-effects model was applied. The IY of MB over RB in the detection of HGD and/or EAC was not significant at 3% (P Z.10; 95% CI, -1% to 8%) with the fixed-effects model. A funnel plot (Fig. 6) for the analysis of publication bias was performed on the 6 studies and compared the yield of the standard MB biopsy technique with RB for the detection of HGD and/or EAC, and visual inspection of the plot revealed no evidence of publication bias. Volume 69, No. 6 : 2009 GASTROINTESTINAL ENDOSCOPY 1025

6 Figure 4. A, IY (%) for individual studies and pooled data for detection of LGD (random-effects model, P Z.17); the test for heterogeneity was c 2 Z (P Z.02, I 2 Z 56.9%). B, HGD and/or EAC (random-effects model, P Z.11); the test for heterogeneity was c 2 Z (P Z.02, I 2 Z 56.7%), with MB chromoendoscopy compared with standard RB. Figure 5. IY (%) for individual studies and pooled data for detection of HGD and/or EAC with standard biopsy technique during MB chromoendoscopy compared with RB, excluding the study by Gossner et al 14 (fixed-effects model, P Z.10); the test for heterogeneity was c 2 Z 5.07 (P Z.41, I 2 Z 1.5%). DISCUSSION Our meta-analysis found no significant difference in yield of MB chromoendoscopy over RB for detection of SIM, LGD, and, more importantly, for detection of HGD and EAC. Application of the technique of MB chromoendoscopy during endoscopic surveillance of patients with BE is controversial. None of the current practice guidelines recommend routine use of chromoendoscopy during endoscopic surveillance of BE, and some experts point out that MB chromoendoscopy is a tedious, cumbersome technique, with low reproducibility and with potential toxicity related to oxidative DNA damage to MB-stained columnar epithelial cells exposed to white light. The additional effort and time spent in MB 1026 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 6 :

7 Figure 6. Funnel plot for the analysis of publication bias on the studies in detection of HGD and/or EAC with standard biopsy technique during MB chromoendoscopy compared with RB, excluding the study by Gossner et al. 14 may be inappropriate for application in clinical practice given that chromoendoscopy does not have a specific CPT (Current Procedural Terminology [American Medical Association, Chicago, Ill]) code for billing and reimbursement. However, some experts believe that MB-based chromoendoscopy is a valuable tool for improved detection of both SIM and advanced dysplastic changes and the low yield reported in some studies are related to poor technique and a perceived lack of experience of the endoscopists in correctly interpreting chromoendoscopic staining patterns. Chromoendoscopy is not routinely taught in most gastroenterology training programs in the United States. Most endoscopists who use this technique are self taught, and errors in interpretation and suboptimal results may occur in inexperienced hands. Even among experts, there is controversy regarding the most appropriate technique of targeting biopsy during chromoendoscopy and the issue of paucity of objective data in published information on the correlation of intensity of staining with the presence or absence of dysplasia has been recently highlighted (Horwhat et al). 16 This meta-analysis, by pooling and analyzing results from multiple publications with divergent conclusions, provides strong evidence of the futility of the routine use of MB chromoendoscopy in this setting. Even after controlling for differences in technique of targeting biopsy after chromoendoscopy and, also, quality of published articles, our analysis failed to show any advantage of chromoendoscopy over the technique of random biopsy (RB). Since the introduction of chromoendoscopy, several new endoscopic techniques have been developed to improve detection of SIM and associated dysplasia in patients with BE, eg, magnification endoscopy, optical coherence tomography, confocal endomicroscopy, autofluorescence endoscopy, and, interestingly, electronic forms of chromoendoscopy, eg, narrow-band imaging (NBI) and multispectral imaging. Of all these techniques, electronic chromoendoscopy, particularly NBI has received considerable attention, because it shares with conventional chromoendoscopy the advantages of being relatively cheap and widely available; also, it does not require expensive equipment and, at the same time, is not messy and is without any potential toxicity, which are some of the concerns associated with dye-based chromoendoscopy. Advanced dysplastic changes are often accompanied by characteristic changes in the superficial mucosal vasculature, and one of the advantages of electronic chromoendoscopy is that, unlike conventional chromoendoscopy, which highlights only the surface mucosal pattern, electronic chromoendoscopy has the additional advantage of revealing the vascular patterns with a high contrast, which may aid in identification of areas of dysplasia. However, the incremental utility of electronic chromoendoscopy over conventional chromoendoscopy has not yet been established. In addition, NBI endoscopy will require additional training for practicing gastroenterologists, and recent studies suggest poor interobserver and intraobserver agreement, even among expert endoscopists. As with any meta-analysis, there are possible limitations in combining results from separate trials. Besides minor variations in inclusion and exclusion criteria, factors such as relative proportion of patients with short-segment and long-segment BE included in each study, differences in application technique, dye contact time, operator experience, and interpretation of staining certainly have contributed to some of the heterogeneity in our analysis. Sample sizes in the included studies were quite small and potentially subject to selection bias; with pooling of the data from individual small studies, such a bias may have been amplified. It is important to note that technique of chromoendoscopy is operator dependent, and, also, interpretation of chromoendoscopic findings is subject to considerable interobserver variability, 20 partly because of a lack of standardized nomenclature. Also, presently, chromoendoscopy often is combined with magnification endoscopy for the best results, and the studies used in this analysis did not use magnification endoscopy, which may have underestimated the yield of chromoendoscopy. Although small in effect, the results for dysplasia and HGD and/or early cancer were not far from borderline significance. Indeed, a single published study that documented a strong advantage for MB could bring the meta-analytical findings to marginal significance. Because of very limited availability information, in this analysis, we did not include studies that used other staining dyes, such as indigo carmine, crystal violet, and acetic acid. In summary, in this meta-analysis, we found that the technique of targeting biopsies after MB chromoendoscopy was not superior to the technique of RB in detecting SIM and dysplasia of any grade in patients with BE who are undergoing endoscopic surveillance and could not be recommended for routine clinical practice. A large number of published studies on MB chromoendoscopy in Volume 69, No. 6 : 2009 GASTROINTESTINAL ENDOSCOPY 1027

8 patients with BE did not meet the criteria for inclusion in this meta-analysis, and we recommend that all future studies of either conventional or electronic chromoendoscopy should be well designed and randomized, with an appropriate sample size; uncontrolled underpowered studies in this area are unlikely to change current knowledge and should not be undertaken. REFERENCES 1. Provenzale D, Kemp JA, Arora S, et al. A guide for surveillance of patients with Barrett s esophagus. Am J Gastroenterol 1994;89: Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett s esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1998;93: Hameeteman W, Tytgat GN, Houthoff HJ, et al. Barrett s esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96: Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett s esophagus. Am J Gastroenterol 2002;97: Kim SL, Waring JP, Spechler SJ, et al. Diagnostic inconsistencies in Barrett s esophagus. Department of Veterans Affairs Gastroesophageal Reflux Study Group. Gastroenterology 1994;107: Peter JH, Clark GWB, Ireland AP, et al. Outcome of adenocarcinoma arising in Barrett s esophagus in endoscopically surveyed and nonsurveyed patients. J Thorac Cardiovasc Surg 1994;108: Falk GW, Rice TW, Goldblum JR, et al. Jumbo biopsy forceps protocol still misses unsuspected cancer in Barrett s esophagus with high-grade dysplasia. Gastrointest Endosc 1999;49: Canto MI, Setrakian S, Willis JE, et al. Methylene blue staining of dysplastic and nondysplastic Barrett s esophagus: an in vivo and ex vivo study. Endoscopy 2001;33: Deeks JJ, Higgins JPT, Altman DG. Analysing and presenting results. In: Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions [updated September 2006]; Section 8. Available at: htm. Accessed October 18, Canto MI, Setrakian S, Willis J, et al. Methylene blue-directed biopsies improve detection of intestinal metaplasia and dysplasia in Barrett s esophagus. Gastrointest Endosc 2000;51: Wo JM, Ray MB, Mayfield-Stokes S, et al. Comparison of methylene blue-directed biopsies and conventional biopsies in the detection of intestinal metaplasia and dysplasia in Barrett s esophagus: a preliminary study. Gastrointest Endosc 2001;54: Ragunath K, Krasner N, Raman VS, et al. A randomized, prospective cross-over trial comparing methylene blue-directed biopsy and conventional random biopsy for detecting intestinal metaplasia and dysplasia in Barrett s esophagus. Endoscopy 2003;35: Saporiti MR, Almada e Souza RC, Pisani JC, et al. Methylene blue chromoendoscopy for Barrett s esophagus diagnosis. Arq Gastroenterol 2003;40: Gossner L, Pech O, May A, et al. Comparison of methylene blue-directed biopsies and four-quadrant biopsies in the detection of high-grade intraepithelial neoplasia and early cancer in Barrett s oesophagus. Dig Liver Dis 2006;38: Lim CH, Rotimi O, Dexter SP, et al. Randomized crossover study that used methylene blue or random 4-quadrant biopsy for the diagnosis of dysplasia in Barrett s esophagus. Gastrointest Endosc 2006;64: Horwhat JD, Maydonovitch CL, Ramos F, et al. A randomized comparison of methylene blue-directed biopsy versus conventional four-quadrant biopsy for the detection of intestinal metaplasia and dysplasia in patients with long-segment Barrett s esophagus. Am J Gastroenterol 2008;103: Ormeci N, Savas B, Coban S, et al. The usefulness of chromoendoscopy with methylene blue in Barrett s metaplasia and early esophageal carcinoma. Surg Endosc 2008;22: Neubrand M, Reichel C, Fischer H, et al. Does chromoendoscopy with methylene blue improve the detection rate of dysplasia in patients with Barrett s esophagus [abstract]? Gastrointest Endosc 2005; 61:AB Canto MI, Yoshida T, Gossner L. Chromoscopy of intestinal metaplasia in Barrett s esophagus. Endoscopy 2002;34: Meining A, Rösch T, Kiesslich R, et al. Inter- and intra-observer variability of magnification chromoendoscopy for detecting specialized intestinal metaplasia at the gastroesophageal junction. Endoscopy 2004;36: Received April 2, Accepted June 23, Current affiliations: Division of Gastroenterology, Mayo Clinic Arizona, Scottsdale, Arizona, USA. Presented at Digestive Disease Week 2008, May 17-22, 2008, San Diego, California (Gastrointest Endosc 2008;67:AB172). Reprint requests: Ananya Das, MD, Division of Gastroenterology, Mayo Clinic Arizona, E Shea Blvd, Scottsdale, AZ If you want to chat with an author of this article, you may contact him at Das.ananya@mayo.edu GASTROINTESTINAL ENDOSCOPY Volume 69, No. 6 :