White-Light or Narrow-Band Imaging Colonoscopy in Surveillance of Ulcerative Colitis: A Prospective Multicenter Study

Transcription

1 Clinical Gastroenterology and Hepatology 2015;13: White-Light or Narrow-Band Imaging Colonoscopy in Surveillance of Ulcerative Colitis: A Prospective Multicenter Study Ludger Leifeld,* Gerhard Rogler, Andreas Stallmach, Carsten Schmidt, Ina Zuber-Jerger, k Franz Hartmann, Mathias Plauth, # Attyla Drabik,** Ferdinand Hofstädter, Hans Peter Dienes, Wolfgang Kruis,* and the Detect Dysplasia Study Group *Department of Internal Medicine, Evangelisches Krankenhaus Kalk, Cologne, Germany; Division of Gastroenterology and Hepatology, Zurich University Hospital, Zurich, Switzerland; Department of Internal Medicine IV, Jena University Hospital, Jena, Germany; k Hospital for Internal Medicine I, Regensburg University Medical Center, Regensburg, Germany; St Marien- Krankenhaus, Frankfurt, Dessau, Germany; # Department of Internal Medicine, Städtisches Klinikum Dessau, Dessau, Germany; **Software Forga, Höhndorf, Germany; Institute of Pathology, University of Regensburg, Regensburg, Germany; Institute of Pathology, Cologne University Hospital, Cologne, Germany BACKGROUND & AIMS: METHODS: RESULTS: CONCLUSIONS: Early detection of neoplastic lesions is essential in patients with long-standing ulcerative colitis but the best technique of colonoscopy still is controversial. We performed a prospective multicenter study in patients with long-standing ulcerative colitis. Two colonoscopies were performed in each patient within 3 weeks to 3 months. In white-light (WL) colonoscopy, stepwise random biopsy specimens (4 biopsy specimens every 10 cm), segmental random biopsies (2 biopsy specimens in 5 segments), and targeted biopsy specimens were taken. In NBI colonoscopy, segmental and targeted biopsy specimens were taken. The sequence of WL and NBI colonoscopy was randomized. In 36 of 159 patients enrolled (22.6%), 54 lesions with intraepithelial neoplasia (IN) were found (51 low-grade, 3 high-grade). In WL colonoscopy we found 11 IN in stepwise biopsy specimens, 4 in segmental biopsy specimens, and 15 in targeted biopsy specimens. In NBI colonoscopy 7 IN were detected in segmental biopsy specimens and 24 IN were detected in targeted biopsy specimens. Almost all IN were found with one technique alone (k value of WL vs NBI, -0.86; P <.001). Statistically equivalent numbers of IN were found in NBI colonoscopy with targeted and segmental biopsy specimens as in WL colonoscopy with targeted and stepwise biopsy specimens, but with fewer biopsy specimens (11.9 vs 38.6 biopsy specimens, respectively; P <.001), and less withdrawal time was necessary (23 vs 13 min, respectively; P <.001). Stepwise biopsy specimens are indispensable in WL colonoscopy. The combination of targeted and segmental biopsy specimens in the NBI technique is as sensitive as targeted together with stepwise biopsy specimens in WL colonoscopy, but requires fewer biopsy specimens and less time. The highest sensitivity should be reached by combining the WL and NBI techniques by switching between the modes. Keywords: Inflammatory Bowel Disease; Ulcerative Colitis; Colonoscopy; Cancer; Dysplasia; Narrow-Band Imaging. Podcast interview: Also available on itunes. See editorial on page The frequency of colorectal neoplasia is increased in ulcerative colitis (UC). Thus, early diagnosis is needed in patients at risk. In patients with UC, colon cancer can develop in masses that appear similar to non colitisrelated sporadic adenomas (adenoma-like) and to those that do not resemble adenomas (non-adenoma-like). 1 However, the endoscopic differentiation between merely inflamed mucosa and dysplastic changes is challenging. Abbreviations used in this paper: IN, intraepithelial neoplasia; NBI, narrow-band imaging; OR, odds ratio; UC, ulcerative colitis; WL, white light. Most current article 2015 by the AGA Institute /$

2 October 2015 WL and NBI Colonoscopy in Ulcerative Colitis 1777 Because of the difficulty in detecting dysplasia, random biopsy specimens are recommended. Four biopsy specimens should be taken from every 10 cm of the colon in addition to biopsy specimens from suspicious areas. 1 3 However, random biopsy specimens are unpopular for many gastroenterologists because of the time requirements and costs. 4 7 Furthermore, some recent studies have shown low detection rates with random biopsy specimens, 8,9 whereas a substantial number of dysplastic areas seem to be visible by the irregular appearance of the colonic mucosa, polypoid lesions, masses, or strictures. 10 Narrow-band imaging (NBI) (Olympus Medical Systems, Tokyo, Japan) may be a tool to enhance the visibility of neoplastic areas by increasing contrast and accenting the capillary pattern. Here, we performed a prospective multicenter study with tandem colonoscopies to evaluate the diagnostic value of random biopsy specimens vs targeted biopsy specimens in white-light (WL) colonoscopy, and the effect of NBI technology for the detection of dysplasia in long-standing UC. The primary end point was the number of intraepithelial neoplasia (IN) detected by stepwise random biopsy specimens vs targeted biopsy specimens. The secondary end point was the number of IN detected by targeted biopsy specimens in NBI mode vs targeted biopsy specimens in conventional WL mode. Patients and Methods The design of the study was a prospective, randomized, investigator-initiated, multicenter study with tandem colonoscopies in patients with long-standing UC. Patients The inclusion criteria were clinically and histologically proven pancolitis for more than 8 years and leftsided UC for more than 15 years, age older than 18 years, last surveillance colonoscopy more than 10 months ago, and clinical remission of UC. The exclusion criteria were contraindications to colonoscopy, history of partial colectomy, and reasonable doubts regarding patient cooperation. Each patient provided written informed consent to participate in the study and clinical trials insurance was obtained. The study was reviewed by the ethics committee of the University of Bonn (109/07) and by the local ethics committees of each participating study center. Study Design All patients underwent 2 colonoscopies: 1 with WL technique, and another with NBI in a randomized sequence. The interval was a minimum of 3 weeks to avoid any visible signs of the prior biopsies and a maximum of 3 months to avoid the development of new neoplasia in the meantime. Each center was equipped with an Evis Exera II Video system and a CV H180 videocolonoscope (Olympus Medical Systems, Tokyo, Japan). The colonoscopic procedure including bowel cleansing and sedation was performed according to the standards of each study center. Targeted biopsy specimens were taken at locations suspicious for possible dysplasia, whereas random biopsy specimens were taken at predefined displacements independent from endoscopic appearance. Colonoscopy in WL mode included stepwise random biopsy specimens in each quadrant every 10 cm. Furthermore, 2 segmental random biopsy specimens were taken in 5 segments of the colon each (ascending, transverse, descending, sigmoid, and rectum). In 16 patients no segmental biopsy specimens were taken using WL colonoscopy. In addition, targeted biopsy specimens were taken and were photodocumented and described individually. In NBI colonoscopy segmental and targeted biopsy specimens were taken. We categorized lesions into flat (invisible, visible within the mucosa, or slightly raised areas of mucosa) or raised lesions. The endoscopist was blinded regarding the histopathologic findings of the first examination (with the exception of possible cancer to avoid surgery being performed too late). Each histopathologic examination was performed by 2 different pathologists in 2 pathology institutes (University of Cologne and University of Regensburg). Pathologists were blinded regarding the endoscopic procedure chosen and the other pathologist s histopathologic diagnosis. In case of differences a third pathologist was consulted and consensus was reached between all pathologists. The duration of the colonoscopy was documented in 178 colonoscopies. Statistical Analysis Sample size. The sample size calculation was performed by statisticians (Dr M. Elze and R. Eisebitt, Clin- Research GmbH, Cologne, Germany). When setting the probability of failure as a ¼.025 (1-sided) and the probability of IN as 10%, a statistical power of 90% was reached for noninferiority when 150 patients were enrolled in the study (nquery Advisor version 5.0; Statistical Solutions, Saugus, MA). Part of the statistical analysis was advised by W. Lehmacher (Institute of Medical Statistics, University of Cologne). Analysis of the results was performed using an SPSS software package by A. Drabik (Stanford, CA). Data are shown as means SD. Differences between the groups were calculated using the McNemar test. Correlations between groups were calculated using the Spearman correlation index.

3 1778 Leifeld et al Clinical Gastroenterology and Hepatology Vol. 13, No. 10 Table 1. Baseline Characteristics and Basic Endoscopic Findings Age, mean, y (SD) 48/11.3 Male sex, n (%) 101 (64) Duration of UC, mean, y (SD) 18/8 Actual number of stools per day, mean (SD) 2.4/1.3 Actual number of bloody stools per day, mean (SD) 0.17/0.7 Number of flares within the past year, mean (SD) 1.1/0.63 Number of flares in lifetime, mean (SD) 7.5/11 Number of hospitalizations in lifetime, mean (SD) 1.9/2.9 History of primary sclerosing cholangitis, n (%) 11 (6.9) First colonoscopy, NBI/WL 57%/43% Colon length, mean, cm (SD) 91/12 Extent of colitis Backwash: 2 Pancolitis: 99 Subtotal: 6 Left-sided: 52 Results The study was conducted between September 2007 and July A total of 186 patients were randomized into the study. Twenty-seven patients were excluded: 22 did not undergo the second colonoscopy for personal reasons or because of a UC flare between colonoscopies. Other reasons for exclusion were histologically severe inflammation, change of diagnosis to Crohn s disease, or various violations of the study protocol. A total of 159 patients were accounted for in the analyses. The baseline characteristics and basic endoscopic findings are shown in Table 1. A total of 9448 biopsy specimens were taken (WL random biopsy specimens, 5904 stepwise, 1426 segmental, and 235 targeted biopsies; NBI, 1580 segmental and 303 targeted biopsy specimens). Dysplastic lesions: histologic type, appearance, and position. A total of 22.6% (n ¼ 36) of all enrolled patients had at least 1 to at most 4 dysplastic lesions. A total of 54 dysplastic lesions were found, 30 non adenoma-like and 24 adenoma-like lesions (counting lesions in 1 segment that were found in both colonoscopies as 1) (Figure 1). Fifty-one of 54 lesions showed low-grade IN and 3 showed high-grade IN. One highgrade IN later was unmasked as carcinoma when it was removed by endoscopic submucosal dissection (R1) and afterward surgically. Most non adenoma-like lesions were flat (flat, 24; raised, 6; P <.001), whereas adenoma-like lesions more often were raised (flat, 4; raised, 20; P <.001). Although significantly more non adenoma-like IN were found in the left-sided colon than in the right-sided colon (20 vs 10; P <.001), the distribution of adenoma-like IN was identical between both sides (12 vs 12). In endoscopically left-sided colitis, 6 IN were found in the right colon proximal to the inflamed segments (non adenoma-like, 2; adenoma-like, 4). One lesion was found in random biopsy specimens using NBI technology, the others were found in targeted biopsy specimens (3 WL, 2 NBI). Numbers of detected intraepithelial neoplasia in whitelight and narrow-band imaging colonoscopy. We report the per-lesion analysis. The results of the per-patient analysis were similar and are shown in the Supplementary Results section. White-light colonoscopy. In WL colonoscopy 30 IN were detected (non adenoma-like, 21; adenoma-like, 9). Half of the IN were found in targeted biopsy specimens (15 IN), 37% (11 IN) were found in stepwise random biopsy specimens (target vs stepwise biopsies: P ¼.557), and 13% (4 IN) were found by adding 10 more segmental random biopsy specimens (Figure 1). Although targeted biopsy specimens detected non adenoma-like and adenoma-like IN in similar frequencies (7 vs 8; P ¼.121), random biopsy specimens detected almost only non adenoma-like IN (14 vs 1; P ¼.004). Figure 1. The total numbers of lesions with IN found using WL colonoscopy in stepwise, segmental, and targeted biopsy specimens or using NBI colonoscopy in segmental or targeted biopsy specimens, differentiated by non adenomalike and adenoma-like lesions or the sum of both (total). Furthermore, the sum of dysplastic lesions in stepwise and targeted biopsy specimens in WL colonoscopy and of targeted and segmental biopsy specimens in NBI colonoscopy is shown.

4 October 2015 WL and NBI Colonoscopy in Ulcerative Colitis 1779 The detection rate of stepwise random biopsy specimens together with targeted biopsy specimens by WL was 48%. Although in WL colonoscopy 537 stepwise random biopsy specimens were necessary to detect 1 IN, targeted biopsy specimens took, on average, only 16 specimens for 1 IN (P <.001; odds ratio [OR], 36.5). Narrow-band imaging colonoscopy. By using NBI colonoscopy 31 IN were detected (non adenoma-like, 15; adenoma-like, 16). Seven IN were detected with segmental random biopsy specimens (non adenomalike, 6; adenoma-like, 1) and 24 IN were detected in targeted biopsy specimens (non adenoma-like, 10; adenoma-like, 14) (Figure 1). With the NBI technique, targeted biopsy specimens detected significantly more IN than segmental biopsy specimens (P ¼.001). The detection rate of targeted biopsy specimens together with segmental random biopsy specimens was 57%. A total of 226 segmental random biopsy specimens were necessary to detect 1 IN whereas 13 targeted biopsy specimens were needed to detect 1 IN (P <.001; OR, 19.3). White-light versus narrow-band imaging colonoscopy. Withdrawal time was 23 8 minutes in WL colonoscopy and 13 5 minutes in NBI colonoscopy (P <.001). In targeted biopsy specimens 1.6 times more IN were detected by NBI than by WL (24 vs 15 IN; P ¼.175) (Figure 1). NBI colonoscopy with segmental and targeted biopsy specimens found similar numbers of IN as WL colonoscopy with targeted biopsy specimens and stepwise biopsy specimens (NBI, 31 IN; WL, 26 IN; P ¼.888) (Supplementary Figure 1). Significantly lower numbers of biopsy specimens per patient were taken during NBI than during WL colonoscopy (38.6 vs 11.9 biopsy specimens; P <.001). In addition, much fewer biopsy specimens were necessary to detect 1 IN using NBI colonoscopy than using WL colonoscopy (WL, 361 biopsy specimens to detect 1 IN; NBI, 118 biopsies to detect 1 IN; P <.001; OR, 3.9). Missed intraepithelial neoplasia. Similar miss rates were found using WL and NBI colonoscopy. Twenty-six IN were detected only during WL colonoscopy but not in NBI. Each of these 26 lesions was detected in only 1 of the 3 modalities of WL colonoscopy (stepwise, segmental, or target). Twenty-four IN were detected using the NBI technique but not using WL colonoscopy. One of them was detected during NBI colonoscopy in both segmental and targeted biopsy specimens. The other 23 IN were detected in only one of both modalities. Four IN were detected in WL and in NBI colonoscopy. When focusing on the high-grade IN only, 2 high-grade IN were found in WL random biopsy specimens and 1 high-grade IN was detected in WL and NBI targeted biopsy specimens and in NBI random biopsy specimens. The k value of WL vs NBI is (P <.001). Complications. In 1 patient a biopsy caused a submucosal hematoma, which was monitored on an inpatient basis without further consequences. Discussion In our study we found a high rate of dysplastic lesions (22.6%) that were detected by WL and/or NBI colonoscopy. The standard to take random biopsy specimens is ignored by many endoscopists, 4 7 which limits the sensitivity of those colonoscopies because we show that WL colonoscopy random biopsy specimens detect 37% of the IN. The sensitivity of stepwise random biopsy specimens could be increased further by adding 10 more segmental random biopsy specimens, which uncovered an additional 13% of lesions. Fourteen of 15 lesions were non adenoma-like, indicating that random biopsy specimens were most important, especially for the detection of non adenoma-like lesions. Most non adenoma-like lesions were flat and only rarely could be found in targeted biopsy specimens. A further 50% of the findings were detected by targeted biopsy specimens with equal proportions of non adenoma-like lesions and adenomalike lesions. Other studies found lower sensitivities of random biopsy specimens. 8,10,11 In 1 retrospective analysis, dysplasia was detected in 10.7% of 525 patients. Although 77% of these dysplastic areas were visible, 23% were detected by random biopsy specimens in macroscopically normal mucosa. 9 However, in this study, only 8 to 12 random biopsy specimens were taken. In another retrospective analysis of 466 surveillance colonoscopies, random biopsy specimens accounted for only 5.7% of the detected neoplastic lesions. 11 This study shows a (statistically not significant) trend toward a 1.6 times higher detection rate of targeted biopsy specimens with the NBI technique in patients with UC. In 2 earlier small studies no advantage was found. A pilot study using the first-generation prototype of the Exera system with 42 patients found no difference in the detection rate between WL and NBI. 12 The second small study by the same group 13 used the Lucera system (Olympus, Tokyo, Japan) in 48 patients and again no differences were found. A third study was performed with only 1 colonoscopy for each patient, using either WL or NBI (Lucera) technology. 14 This study stopped after 4 years of recruitment with 112 patients instead of the planned 220 because of the noneffectiveness of NBI. 14 In addition, a comparison between parallel groups did not match the statistical quality of a paired design with 2 colonoscopies in each patient, in which each patient served as his own control. The quality and sensitivity of the colonoscopies in our study are reflected further by the high number of 23% of patients with detected neoplastic lesions, even though most of them were low grade. It generally is accepted that chromoendoscopy enhances the sensitivity 2- to 3-fold. 8,10,15 18 However, chromoendoscopy is unpopular for many endoscopists because it is time consuming and methylene blue has

5 1780 Leifeld et al Clinical Gastroenterology and Hepatology Vol. 13, No. 10 been shown to induce DNA damage in the mucosa when it was illuminated during endoscopy. 19,20 To date, there has been 1 study with 60 patients that compared NBI with chromoendoscopy. Both NBI and chromoendoscopy found similar numbers of lesions (12 vs 10 lesions; P ¼.644), but withdrawal time was longer in chromoendoscopy (27 vs 16 min). However, NBI had a trend toward a higher miss rate than chromoendoscopy (31.8% vs 13.6%; P ¼.2). 21 Our study allowed 2 different clinical consequences. An attractive approach is to combine targeted biopsy specimens using NBI technology with only 10 segmental random biopsy specimens. Such segmental biopsy specimens are taken by many endoscopists anyway for histologic characterization of inflammatory changes. This strategy led to a detection rate of 57% and was statistically equipotent to WL colonoscopy with targeted and stepwise random biopsy specimens that detected 48% of all IN, but needed significantly longer procedure times and more biopsy specimens. Our data further allow us to assume that even higher sensitivity should be reached by visualizing each segment by switching between both techniques. All techniques including random and targeted biopsy specimens with WL or NBI overlook a considerable number of lesions. This indicates limited accuracy of current colonoscopic techniques for surveillance in patients with UC. The high miss rates between WL and NBI and a negative k value also indicate that both techniques might visualize different manifestations of dysplastic lesions and therefore should be combined to detect as much as possible. Similar to other investigators, we found enhanced numbers of neoplastic lesions in the left-sided colon. 22,23 Therefore, it may be advisable to pay particular attention to the number and localization of biopsy specimens in the left-sided colon. In summary, our study shows the high yield of stepwise random biopsy specimens in long-standing colitis. When the WL technique is used, stepwise biopsy specimens are indispensable. Combining targeted biopsy specimens using NBI technology with 10 segmental biopsy specimens is an equipotent alternative to targeted biopsy specimens using WL in addition to 4 biopsy specimens every 10 cm. However, this approach significantly saves time and numbers of biopsy specimens, which should have positive effects on feasibility, costs, and endoscopist compliance. The highest sensitivity may be achieved by combining both methods in 1 colonoscopy. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at and at References 1. Van Assche G, Dignass A, Bokemeyer B, et al. Second European evidence-based consensus on the diagnosis and management of LID. J Crohns Colitis 2013;7: Dignass A, Preiss JC, Aust DE, et al. [Updated German guideline on diagnosis and treatment of ulcerative colitis]. Z Gastroenterol 2011;49: Rubin Ce, Haggitt RC, Burmer GC, et al. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology 1992;103: Kaltz B, Bokemeyer B, Hoffmann J, et al. [Surveillance colonoscopy in ulcerative colitis patients in Germany]. Z Gastroenterol 2007;45: van Rijn AF, Fockens P, Siersema PD, et al. Adherence to surveillance guidelines for dysplasia and colorectal carcinoma in. World J Gastroenterol 2009;15: Eaden JA, Ward BA, Mayberry JF. How gastroenterologists screen for colonic cancer in ulcerative colitis: an analysis of performance. Gastrointest Endosc 2000;51: Gearry RB, Wakeman CJ, Barclay ML, et al. Surveillance for dysplasia in patients with inflammatory bowel disease: a national survey of colonic practice in New Zealand. Dis Colon Rectum 2004;47: Kiesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial. Gastroenterology 2003;124: Rutter MD, Saunders BP, Wilkinson KH, et al. Most dysplasia in ulcerative colitis is visible at colonoscopy. Gastrointest Endosc 2004;60: Rutter MD, Saunders BP, Wilkinson KH, et al. Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances. Gut 2004;53: van den Broek FJ, Stokkers PC, Reitsma JB, et al. Random biopsies taken during colonoscopic surveillance of patients with longstanding ulcerative colitis: low yield and absence of clinical consequences. Am J Gastroenterol 2014;109: Dekker E, van den Broek FJ, Reitsma JB, et al. Narrow-band imaging compared with conventional colonoscopy for the detection of. Endoscopy 2007;39: van den Broek FJ, Fockens P, van Eeden S, et al. Narrow-band imaging versus high-definition endoscopy for the diagnosis of neoplasia in ulcerative colitis. Endoscopy 2011;43: Ignjatovic A, East JE, Subramanian V, et al. Narrow band imaging for detection of dysplasia in colitis: a randomized controlled trial. Am J Gastroenterol 2012;107: Kiesslich R, Goetz M, Lammersdorf K, et al. Chromoscopyguided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis. Gastroenterology 2007;132: Hurlstone DP, McAlindon ME, Sanders DS, et al. Further validation of high-magnification chromoscopic-colonoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2004;126: Sada M, Igarashi M, Yoshizawa S, et al. Dye spraying and magnifying endoscopy for dysplasia and cancer surveillance in. Dis Colon Rectum 2004;47: Hurlstone DP, Sanders DS, Lobo AJ, et al. Indigo carmineassisted high-magnification chromoscopic colonoscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis: a prospective evaluation. Endoscopy 2005; 37:

6 October 2015 WL and NBI Colonoscopy in Ulcerative Colitis Davies J, Burke D, Olliver JR, et al. Methylene blue but not indigo carmine causes DNA damage to colonocytes in vitro. Gut 2007;56: Olliver JR, Wild CP, Sahay P, et al. Chromoendoscopy with methylene blue and associated DNA damage in Barrett s. Lancet 2003;362: Pellise M, Lopez-Ceron M, Rodriguez de Miguel C, et al. Narrow-band imaging as an alternative to chromoendoscopy for the detection of dysplasia in long-standing inflammatory bowel disease: a prospective, randomized, crossover study. Gastrointest Endosc 2011;74: Goldstone R, Itzkowitz S, Harpaz N, et al. Progression of lowgrade dysplasia in ulcerative colitis: effect of colonic. Gastrointest Endosc 2011;74: Goldstone R, Itzkowitz S, Harpaz N, et al. Dysplasia is more common in the distal than proximal colon in ulcerative colitis. Inflamm Bowel Dis 2012;18: Reprint requests Address requests for reprints to: Ludger Leifeld, MD, St Bernward Krankenhaus Hildesheim, Treibestrasse 9, Hildesheim, Germany. l.leifeld@ bernward-khs.de; fax: Acknowledgments The authors thank M. Elze, R. Eisebitt, and W. Lehmacher for supporting the statistical analysis. The Detect Dysplasia study group comprised the following members: Reinhard Büttner, Heike Löser, and Uta Drebber (Institute of Pathology, Cologne University Hospital, Cologne, Germany); Axel Dignass (Agaplesion Frankfurter Diakonie Kliniken, Frankfurt, Germany); Birgit Terjung (St Josef Hospital, Bonn, Germany); Tilman Sauerbruch (Department of Internal Medicine, University of Bonn, Germany); Stefan Schreiber (Department of Internal Medicine I, Schleswig-Holstein University Hospital, Kiel, Germany); Barbara Lanyi, Roland Pfuetzer, and Julia Morgenstern (Department of Internal Medicine, Evangelisches Krankenhaus Kalk, Cologne, Germany); Stephan Böhm (Department of Medicine, University Hospital, Bruderholz, Switzerland), Ulrich Böcker (Vivantes Klinikum Berlin, Germany), Ann-Kathrin Rupf (Department of Internal Medicine, Klinikum Friedrichshafen, Friedrichshafen, Germany), Beate Appenroth (Department of Medicine II, Saarland University Medical Center, Homburg, Germany), Erwin Biecker (Department of Gastroenterology and Hepatology, HELIOS Klinikum Siegburg, Germany), and Jens Walldorf (Universitätsklinikum Halle, Halle, Germany). Conflicts of interest The authors disclose no conflicts. Funding Supported by a grant from the Deutsche Morbus Crohn/Colitis Ulcerosa Vereinigung, the Working Group for Endoscopic Research of the DGVS, and by the Kurscheid Foundation (Cologne, Germany), and Olympus Medical borrowed 2 EXERA II systems for 2 study centers and funded part of the clinical trial insurance.

7 1781.e1 Leifeld et al Clinical Gastroenterology and Hepatology Vol. 13, No. 10 Supplementary Results Per-Patient Analysis White-light colonoscopy. By using WL colonoscopy 24 patients with IN were detected. Thirteen patients were found by targeted biopsy specimens, 10 by stepwise random biopsy specimens (target vs stepwise: P ¼.66), and 4 by segmental random biopsy specimens (Supplementary Figure 1). Narrow-band imaging colonoscopy. In NBI colonoscopy, 22 patients with IN were detected. Twenty-one patients were found by targeted biopsy specimens, 7 patients were found by segmental random biopsy specimens (target vs segmental: P ¼.001) (Supplementary Figure 1). White-light versus narrow-band imaging colonoscopy. Targeted biopsy specimens during WL colonoscopy found 13 patients with IN whereas targeted biopsy specimens during NBI colonoscopy found 1.6 times more patients with IN (13 vs 21 IN; P ¼.134) (Figure 1). NBI colonoscopy with segmental and targeted biopsy specimens found an identical number of patients with IN as WL colonoscopy with targeted biopsy specimens and stepwise biopsy specimens (NBI, 22 patients with IN; WL, 22 patients with IN; P ¼ 1.0) (Supplementary Figure 1). Supplementary Figure 1. Per-patient analysis. The total number of patients with intraepithelial neoplasia found in WL colonoscopy in stepwise, segmental, and targeted biopsy specimens or in NBI colonoscopy in segmental or targeted biopsy specimens.