Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's esophagus.

BACKGROUND & AIMS: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation. METHODS: Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n = 38) or placebo (n = 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point. RESULTS: The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P = .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P = .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P = .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3). CONCLUSIONS: In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.

A combination of esomeprazole and aspirin reduces tissue concentrations of prostaglandin E(2) in patients with Barrett's esophagus.

UNLABELLED: BACKGROUND& AIMS: Proton pump inhibitors and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barrett's esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled, phase 2 trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin (PG) E(2) in patients with BE with no dysplasia or low-grade dysplasia. METHODS: Participants were recruited through the multicenter Cancer Prevention Network and randomly assigned to groups that were given 40 mg esomeprazole twice daily in combination with an aspirin placebo once daily (arm A; n = 30), with 81 mg aspirin once daily (arm B; n = 47), or with 325 mg aspirin once daily (arm C; n = 45) for 28 days. We collected esophageal biopsy specimens before and after the intervention period to determine the absolute change in mean concentration of PGE(2) (the primary end point). RESULTS: Based on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentration of PGE(2) was reduced by 67.6 ± 229.68 pg/mL in arm A, 123.9 ± 284.0 pg/mL in arm B (P = .10 vs arm A), and 174.9 ± 263.62 pg/mL in arm C (P = .02 vs arm A). CONCLUSIONS: In combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE(2) in patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients. Clinical trial registration number NCT00474903.

Assessment of photobleaching during endoscopic autofluorescence imaging of the lower GI tract.

BACKGROUND AND OBJECTIVES: In autofluorescence endoscopy, the difference in the fluorescence of intrinsic fluorophores is imaged to help visualize pre-malignant lesions, as in the system evaluated here. In this, blue light is used for excitation and the green autofluorescence is normalized by the red diffuse reflectance and presented using a false color scale. The present study was designed to quantify the degree of fluorescence photobleaching induced by the excitation light during use in the colon, since significant photobleaching could lead to false interpretation of the images, particularly false-positive lesions. STUDY DESIGN: Measurements were made ex vivo and in vivo, both using the endoscopic imaging system and a separate fiberoptic spectroscopy probe in externalized rat jejunum and in patients undergoing routine colonoscopy, using exposures typical of autofluorescence endoscopic examination. RESULTS: Photobleaching could be potentially caused at blue light exposure. However, at light intensities and exposure times that are typically used in clinical practice, the average photobleaching (% loss of peak fluorescence intensity) was <1% and <6% in the rat and human tissues, respectively. Nevertheless, the range was large: from -17% to +18% in rats and -33% to +43% in patients, where negative values denote an apparent increase in fluorescence. Both the large positive and negative deviations are believed in part to be due to a measurement artifact caused by uncontrollable tissue motility. SUMMARY AND CONCLUSIONS: It is concluded that, using exposures typically encountered in clinical practice, there is minimal photobleaching during fluorescence endoscopy at exposure such as are used in the Onco-LIFE and comparable systems. The small changes in fluorescence intensity and spectral shift that do occur are not likely to be detectable by eye, and so should not impact significantly on the diagnostic accuracy of the technique.

Clinical characteristics may distinguish patients with esophageal adenocarcinoma arising from long- versus short-segment Barrett's esophagus.

BACKGROUND AND AIMS: Patients with long-segment Barrett's esophagus (LSBE; ≧3 cm) have higher risk of developing esophageal adenocarcinoma (EAC) than those with short-segment Barrett's esophagus (SSBE; <3 cm). However, it is unclear whether patients developing EAC from LSBE or SSBE differ significantly according to baseline clinical characteristics. METHODS: We conducted a retrospective analysis of a prospectively maintained database comprising consecutive patients with early EAC treated by endoscopic mucosal resection at a single, tertiary-referral center. Information regarding baseline clinical characteristics were determined. Univariate and multivariate logistic regression were performed to identify factors that differed significantly between patients with EAC arising from SSBE and LSBE. RESULTS: A total of 145 LSBE EAC and 179 SSBE EAC cases were identified. The LSBE EAC patients had a stronger association with having a hiatal hernia compared to the SSBE EAC patients. In contrast, inverse associations were observed in LSBE EAC patients with statin use and smoking pack-years relative to SSBE EAC patients. CONCLUSIONS: Patients who developed EAC on a background of LSBE were more likely to have a hiatus hernia compared to patients with SSBE EAC, who were more likely to have higher smoking pack-years and higher rates of statin use.

Pedunculated polyp of the ileum protruding from a large diverticulum.

INTRODUCTION: A 52-year-old woman presented with iron deficiency anaemia and postprandial right lower quadrant pain. Abdominal examination was unremarkable and laboratory results showed mild anaemia (haemoglobin 11.3 g/dL). Upper and lower endoscopies did not reveal any source of bleeding. Video capsule endoscopy was performed which showed a large polypoid lesion in the mid-ileum (figure 1). Abdominal contrast enhanced CT demonstrated a heterogeneously enhancing pedunculated polyp measuring approximately 6 cm (figure 2). Retrograde double-balloon enteroscopy was performed which revealed a large pedunculated polyp with hyperplastic-like mucosa protruding from a large diverticulum located approximately 70 cm proximal to the ileocaecal valve (figure 3A). The stalk appeared to arise from the base of the diverticulum (figure 3B). A technetium-99m pertechnetate scintigraphy revealed no ectopic gastric mucosa.Figure 1Video capsule endoscopy shows a large polypoid lesion.Figure 2CT shows a heterogeneously enhancing pedunculated polyp (arrow).Figure 3Retrograde double-balloon enteroscopy images. (A) Large pedunculated polyp protruding from a large diverticulum. (B) The stalk appears to arise from the base of the diverticulum. QUESTION: What is the diagnosis?

Fluorescence and spectral imaging.

Early identification of dysplasia remains a critical goal for diagnostic endoscopy since early discovery directly improves patient survival because it allows endoscopic or surgical intervention with disease localized without lymph node involvement. Clinical studies have successfully used tissue autofluorescence with conventional white light endoscopy and biopsy for detecting adenomatous colonic polyps, differentiating benign hyperplastic from adenomas with acceptable sensitivity and specificity. In Barrett's esophagus, the detection of dysplasia remains problematic because of background inflammation, whereas in the squamous esophagus, autofluorescence imaging appears to be more dependable. Point fluorescence spectroscopy, although playing a crucial role in the pioneering mechanistic development of fluorescence endoscopic imaging, does not seem to have a current function in endoscopy because of its nontargeted sampling and suboptimal sensitivity and specificity. Other point spectroscopic modalities, such as Raman spectroscopy and elastic light scattering, continue to be evaluated in clinical studies, but still suffer the significant disadvantages of being random and nonimaging. A recent addition to the fluorescence endoscopic imaging arsenal is the use of confocal fluorescence endomicroscopy, which provides real-time optical biopsy for the first time. To improve detection of dysplasia in the gastrointestinal tract, a new and exciting development has been the use of exogenous fluorescence contrast probes that specifically target a variety of disease-related cellular biomarkers using conventional fluorescent dyes and novel potent fluorescent nanocrystals (i.e., quantum dots). This is an area of great promise, but still in its infancy, and preclinical studies are currently under way.

Spectroscopy and fluorescence in esophageal diseases.

Malignant tumors of the esophagus continue to be a major health issue associated with high mortality primarily because most present with symptoms of dysphagia or anaemia. The disease at that stage is advanced and not likely curable. The big issue for squamous dysplasia and that associated with BE is that only a small proportion are discovered in surveillance programs when they are asymptomatic, either because the patient lives in a high-incidence geographical area, has a family history, previously diagnosed head and neck cancer or chronic reflux, as in Barrett's. Current endoscopic methods are hampered by the endoscopist's inability to recognize subtle topographic clues of dysplasia, sampling errors related to biopsy protocols, and confounding inflammation-induced artifacts both for the endoscopist and pathologist. What is desperately needed would be a biomarker (e.g. serological, fecal, urinary) that selects patients for endoscopy. However, such a test is not yet on the horizon. This article examines the current status in practice and research of novel optically based 'bioendoscopic' devices (i.e. fluorescence spectroscopy and imaging, confocal fluorescence microendoscopy (CFM), light scattering spectroscopy (LSS), Raman spectroscopy (RS), and immunophotodiagnostic endoscopy) which may enhance the diagnosis of dysplasia in all patients undergoing conventional white light endoscopy. Perhaps these new technologies will lead to more cost-effective diagnosis, mapping (e.g. surface), and staging (e.g. depth) of dysplasia, thereby allowing timely cure by endoscopic means (e.g. EMR and/or PDT), biological interventions (e.g. Cox-2 inhibitors) rather than esophajectomy.

Esophageal intramural pseudodiverticulosis with food impaction.

Esophageal intramural pseudodiverticulosis is a rare condition of unknown etiology originally described in 1960. It is characterized by multiple, flask-shaped outpouchings of pinhead size in the wall of the esophagus. Very small outpouchings on endoscopy and tiny collections of barium outside of the esophagus wall on esophagography are typical diagnostic findings. During the era of widespread endoscopic and radiological evaluation of esophageal disorders, approximately 200 cases were published in the literature. A 52-year-old man with esophageal intramural pseudodiverticulosis with food impaction is reported. The patient's symptoms of dysphagia resolved with endoscopic dilations and proton pump inhibitor therapy.

Gastric calcifying fibrous tumor.

Intramucosal gastric tumours are most commonly found to be gastrointestinal stromal tumours or leiomyomas (smooth muscle tumours); however, a variety of other uncommon mesenchymal tumours can occur in the stomach wall. A rare benign calcifying fibrous tumour is reported and the endoscopic appearance, ultrasound findings and morphology are documented. A review of the literature found only two similar cases.

Surveillance in Patients With Barrett's Esophagus for Early Detection of Esophageal Adenocarcinoma: A Systematic Review and Meta-Analysis.

OBJECTIVES: Although endoscopic surveillance of patients with Barrett's esophagus (BE) has been widely implemented for early detection of esophageal adenocarcinoma (EAC), its justification has been debated. This systematic review aimed to evaluate benefits, safety, and cost effectiveness of surveillance for patients with BE. METHODS: MEDLINE, EMBASE, EconLit, Scopus, Cochrane, and CINAHL were searched for published human studies that examined screening practices, benefits, safety, and cost effectiveness of surveillance among patients with BE. Reviewers independently reviewed eligible full-text study articles and conducted data extraction and quality assessment, with disagreements resolved by consensus. Random effects meta-analyses were performed to assess the incidence of EAC, EAC/high-grade dysplasia (HGD), and annual stage-specific transition probabilities detected among BE patients under surveillance, and relative risk of mortality among EAC patients detected during surveillance compared with those not under surveillance. RESULTS: A total of 51 studies with 11,028 subjects were eligible; the majority were of high quality based on the Newcastle-Ottawa quality scale. Among BE patients undergoing endoscopic surveillance, pooled EAC incidence per 1,000 person-years of surveillance follow-up was 5.5 (95% confidence interval (CI): 4.2-6.8) and pooled EAC/HGD incidence was 7.7 (95% CI: 5.7-9.7). Pooled relative mortality risk among surveillance-detected EAC patients compared with nonsurveillance-detected EAC patients was 0.386 (95% CI: 0.242-0.617). Pooled annual stage-specific transition probabilities from nondysplastic BE to low-grade dysplasia, high-grade dysplasia, and EAC were 0.019, 0.003, and 0.004, respectively. There was, however, insufficient scientific evidence on safety and cost effectiveness of surveillance for BE patients. CONCLUSIONS: Our findings confirmed a low incidence rate of EAC among BE patients undergoing surveillance and a reduction in mortality by 61% among those who received regular surveillance and developed EAC. Because of knowledge gaps, it is important to assess safety of surveillance and health-care resource use and costs to supplement existing evidence and inform a future policy decision for surveillance programs.

Fluorescence and Raman spectroscopy.

Table 2 provides a summary of selected in vivo fluorescence and Raman studies performed in BE. Although the findings from these studies appear promising, these techniques are still under development, and it is anticipated that technological refinements will further enhance their diagnostic accuracy. Ultimately, however, large-scale prospective clinical trials are required to determine their true diagnostic potential in BE and other sites. Ideally, the instrumentation of choice would be a real-time endoscopic system that combines excellent diagnostic accuracy with wide-area sampling. In this regard, fluorescence imaging is most appealing, although a variety of issues remain to be resolved, including the choice between autofluorescence versus drug-induced fluorescence and the problematic distinction between dysplastic (true positive) and confounding background metaplastic fluorescence (false positive), among others. It is also not clear whether exogenous fluorophores are necessary to achieve clinically useful sensitivity and specificity for lesion detection in BE. Point spectroscopic techniques, either fluorescence or Raman scattering, are inherently limited by the small volume of tissue (biopsy specimen size) they sample, but more detailed information can be extracted from the spectra, which may increase diagnostic accuracy. Moreover, it may be that the optimal system will be a combination of multiple optical spectroscopic or imaging techniques (multimodality approach), as suggested by Georgakoudi et al. For instance, a lesion could be detected by fluorescence imaging and its dysplastic nature characterized (graded) by Raman spectroscopy. In this era of cost containment, however, the critical challenge is to demonstrate whether an increase in diagnostic accuracy merits investment in costly technology, regardless of the technique used.

Photodynamic therapy in the esophagus.

Photodynamic therapy (PDT) involves in situ photo-activation of photosensitizers by light at appropriate wavelength, generating highly active singlet oxygen and free radicals. For esophageal mucosal dysplasia such as high-grade dysplasia or intramucosal cancer, curative endoluminal therapy including PDT is now a reality. We review the role of PDT in the esophagus for the past two decades. The light for PDT can be delivered endoluminally freehand by cylindrical diffusers, via inflatable balloon stabilizers or microlens fibers. Porfimer sodium (Photofrin(®)) is the only approved photosensitizer for PDT in the esophagus in North America, Europe and Japan. In addition, 5-aminolaevulinic acid (ALA), m-tetra(hydroxyphenyl)chlorin (m-THPC) and benzoporphyrin derivative monoacid ring A (BPD-MA) are other photosensitizers are being evaluated. More randomized clinical trials with long term follow up data are needed to further establish the role of PDT and other endoluminal ablative therapies either on their own or in combination to demonstrate survival benefits, quality of life advantages and cost-effectiveness. Changes in light delivery, timing, dosimetry and new endoscopic devices are needed to possibly improve all aspects of effectiveness. PDT was used mainly for palliation of advanced obstructing cancer of the esophagus at the gastrointestinal junction. More recently, because of the rising detection of the high-grade dysplasia in Barrett's esophagus, a curative role of PDT in being realized.

Wireless capsule endoscopy for obscure gastrointestinal bleeding: a single-centre, one-year experience.

BACKGROUND: Wireless capsule endoscopy (CE) is increasingly being used in the investigation of obscure gastrointestinal (GI) bleeding, but some studies have found that many of the bleeding lesions recognized by this technique are within the reach of conventional endoscopy. METHODS: The results of CE performed in the authors' centre in a 12 month period for obscure GI bleeding were retrospectively reviewed. RESULTS: Of the 46 patients with obscure GI bleeding, CE found a definite or probable cause in 19 (41%) and a possible cause in another 10 (22%), with an overall diagnostic yield of 63%. One of these lesions was found to be within reach of conventional gastroscopy, two were within reach of push enteroscopy, four were within reach of colonoscopy and one was within reach of retrograde enteroscopy through a stoma. The percentage of patients with a bleeding source within reach of routine endoscopy but missed during pre-CE endoscopy was significantly higher for those patients having endoscopy only in the community (30% [eight of 27]) versus in the authors' centre (0% [zero of 19]). CONCLUSIONS: CE was valuable for diagnosing bleeding lesions not only within the small bowel, but also in the stomach and colon. However, "second-look" endoscopy may be considered before ordering CE for obscure GI bleeding when local expertise is available.

Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps.

Colorectal cancers associated with Lynch syndrome are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR protein expression in Lynch syndrome-associated polyps. Sixty-two colorectal polyps--37 adenomatous polyps, 23 hyperplastic polyps, and 2 sessile serrated polyps (SSP)--from 34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 proteins by immunohistochemistry. High-level MSI (MSI-H) was seen in 15 of 37 (41%) adenomatous polyps, one of 23 (4%) hyperplastic polyps, and one of two (50%) SSPs. Loss of MMR protein expression was seen in 18 of 36 (50%) adenomatous polyps, zero of 21 hyperplastic polyps, and zero of two SSPs. Adenomatous polyps 8 mm or larger in size were significantly more likely to show MSI-H [OR, 9.98; 95% confidence interval (CI), 1.52-65.65; P = 0.02] and deficient MMR protein expression (OR, 3.17; 95% CI, 1.20-8.37; P = 0.02) compared with those less than 8 mm in size. All (six of six) adenomatous polyps 10 mm or larger in size showed both MSI-H and loss of MMR protein expression by immunohistochemistry. Our finding that the prevalence of MMR deficiency increases with the size of adenomatous polyps suggests that loss of MMR function is a late event in Lynch syndrome-associated colorectal neoplasia. Although testing large adenomatous polyps may be of value in the diagnostic evaluation of patients with suspected Lynch syndrome, the absence of an MMR-deficient phenotype in an adenoma cannot be considered as a strong evidence against Lynch syndrome, as it is with colorectal carcinomas.

Immunohistochemical staining for smoothelin in the duplicated versus the true muscularis mucosae of Barrett esophagus.

BACKGROUND: The muscularis mucosa underlying the metaplastic mucosa of Barrett esophagus is frequently duplicated, with an intervening layer of lamina propria between the superficial or neomuscularis mucosa (NMM) and the deep/true muscularis mucosa (TMM). This duplication causes difficulties with accurate staging of superficially invasive carcinoma in biopsy specimens and endoscopic mucosal resections (EMRs), as invasion underneath the superficial muscle layers may be mistaken for submucosal invasion. Mucosal resections or other ablative nonsurgical therapies can be curative in patients with esophageal intramucosal carcinoma, whereas patients with submucosal invasion are recommended for esophagectomy. Therefore, the accurate staging of such specimens is crucial. Smoothelin is a novel smooth muscle protein expressed only by fully differentiated smooth muscle cells and not by proliferative or noncontractile smooth muscle cells and fibroblasts. It has been suggested that in the bladder, immunohistochemistry for smoothelin may help separate hyperplastic muscularis mucosa from the true muscularis propria. We hypothesized that in the esophagus, immunohistochemistry for smoothelin would differentiate the NMM from the TMM. DESIGN: Thirty cases of EMRs for Barrett esophagus-related neoplasia were retrieved from the archives of the pathology department, St Michael's Hospital. Immunohistochemical staining for smoothelin was performed to evaluate differential staining in the TMM versus NMM. Fifteen cases were stained for smooth muscle actin and smooth muscle myosin. The staining score was evaluated on a scale from 0 to 3 according to the percentage and intensity of staining. RESULTS: Immunohistochemical staining results for smoothelin were as follows: the NMM showed weak focal staining (+1) in 23 of 30 cases (82%), and moderate staining (+2) in 7 of 30 cases (12%), and the TMM showed very strong and diffuse staining (+3) in 30 of 30 cases. No cases showed negative (0) staining in the NMM. With smooth muscle actin and myosin, strong and diffuse staining was observed with similar intensity in both the TMM and NMM in 15 of 15 cases. CONCLUSIONS: In our study, smoothelin staining in the NMM is significantly weaker than that seen in the true/deep muscularis mucosa. This pattern is similar to that reported for the muscularis mucosae of the urinary bladder. Although smoothelin can readily distinguish the 2 layers, its value might be limited by the need to simultaneously compare the 2 layers. Although this might be of use in EMR specimens in which both layers are visible, use in biopsies may be limited as the residual staining in the NMM may inhibit definitive evaluation. This issue may be resolved by the use of appropriate standard controls, individual optimization of the antibody, and the use of an automated digital assessment.

Rectal mucosal quantitative galactose oxidase-Schiff reaction as an early detection biomarker for colorectal cancer: comparison to fecal occult stool blood test.

The galactose oxidase-Schiff (GOS) reaction detects D-galactose-ß-[1,3]-N-acetyl-D-galactosamine. This is a T-antigen expressed in mucus from malignant cells and colonic mucosa adjacent to cancer but not in normal mucosa. Previous studies using a qualitative GOS assay proved to be of limited value for the detection of colorectal neoplasia. We used a newly developed quantitative GOS assay to determine its potential as an early detection biomarker for colorectal cancer. We completed a multi-center, prospective, cross-sectional cohort validation study consisting of 70 normal controls, 23 high-risk normal patients (polyp history or family history of colorectal cancer (CRC) with currently normal colonoscopy), 137 patients with adenomatous polyps, and 69 with colorectal cancers. Prior to colonoscopy, two samples of stool were collected via a rectal exam: one for FOBT, and one for GOS. The area under the ROC curve (AUC) for detecting colonic adenomas and cancer for normal colons, computed with logistic regression was 0.69 for GOS, 0.62 for FOBT, and 0.73 for GOS combined with FOBT. Adding GOS to FOBT did not significantly change the ROC of FOBT alone. GOS does not appear to be a suitable marker of colorectal neoplasia.

Missed adenomas during colonoscopic surveillance in individuals with Lynch Syndrome (hereditary nonpolyposis colorectal cancer).

BACKGROUND AND AIMS: Lynch syndrome (also known as hereditary nonpolyposis colon cancer) is associated with an increased risk for colorectal cancer, which can arise despite frequent colonoscopic exams. We evaluated the adenoma miss rate of conventional colonoscopy in patients with Lynch syndrome, and compared the sensitivity of chromoendoscopy versus intensive inspection for detecting polyps missed by conventional colonoscopy. METHODS: Fifty-four subjects with Lynch syndrome underwent tandem colonoscopies at four centers of the Great Lakes-New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. All participants first had a conventional colonoscopy with removal of all visualized polyps. The second endoscopy was randomly assigned as either pancolonic indigo carmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and number of polyps detected on each exam were recorded. RESULTS: After undergoing standard colonoscopy, 28 individuals were randomized to a second exam with chromoendoscopy and 26 underwent intensive inspection. The mean interval since last colonoscopy was 17.5 months. Seventeen polyps (10 adenomas and 7 hyperplastic polyps) were identified on the first standard colonoscopies. Twenty-three additional polyps (12 adenomas and 11 hyperplastic polyps) were found on the second exams, yielding an adenoma miss rate of 55%. Fifteen polyps (5 adenomas and 10 hyperplastic polyps) were found in subjects who had chromoendoscopy and 8 polyps (7 adenomas and 1 hyperplastic polyp) in those who had intensive inspection. Chromoendoscopy was associated with more normal tissue biopsies (11 versus 5) and longer procedure times compared with intensive inspection (29.8 +/- 9.5 versus 25.3 +/- 5.8 minutes; P = 0.04). Controlling for age, number of previous colonoscopies, procedure time, and prior colonic resection, chromoendoscopy detected more polyps (P = 0.04), but adenoma detection was not significantly different compared with intensive inspection (P = 0.27). CONCLUSIONS: Small adenomas are frequently missed in patients with Lynch syndrome. Although chromoendoscopy did not detect more missed adenomas than intensive inspection in this pilot study, larger trials are needed to determine optimal surveillance techniques in this high-risk population.

Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection without dye spraying.

Conventional colonoscopy misses some neoplastic lesions. We compared the sensitivity of chromoendoscopy and colonoscopy with intensive inspection for detecting adenomatous polyps missed by conventional colonoscopy. Fifty subjects with a history of colorectal cancer or adenomas underwent tandem colonoscopies at one of five centers of the Great Lakes New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. The first exam was a conventional colonoscopy with removal of all visualized polyps. The second exam was randomly assigned as either pan-colonic indigocarmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and numbers of polyps detected on each exam were recorded. Twenty-seven subjects were randomized to a second exam with chromoendoscopy and 23 underwent intensive inspection. Forty adenomas were identified on the first standard colonoscopies. The second colonoscopies detected 24 additional adenomas: 19 were found using chromoendoscopy and 5 were found using intensive inspection. Chromoendoscopy found additional adenomas in more subjects than did intensive inspection (44% versus 17%) and identified significantly more missed adenomas per subject (0.7 versus 0.2, P < 0.01). Adenomas detected with chromoendoscopy were significantly smaller (mean size 2.66 +/- 0.97 mm) and were more often right-sided. Chromoendoscopy was associated with more normal tissue biopsies and longer procedure times than intensive inspection. After controlling for procedure time, chromoendoscopy detected more adenomas and hyperplastic polyps compared with colonoscopy using intensive inspection alone. Chromoendoscopy detected more polyps missed by standard colonoscopy than did intensive inspection. The clinical significance of these small missed lesions warrants further study.