The "diagnose and leave in" strategy for diminutive rectosigmoid polyps in Lynch syndrome: a post hoc analysis from a randomized controlled trial.

BACKGROUND: The "diagnose-and-leave-in" policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. METHODS : We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard. RESULTS: Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %-98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %-93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. CONCLUSION: In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.

White-Light Endoscopy Is Adequate for Lynch Syndrome Surveillance in a Randomized and Noninferiority Study.

BACKGROUND & AIMS: Dye-based pancolonic chromoendoscopy is recommended for colorectal cancer surveillance in patients with Lynch syndrome. However, there is scarce evidence to support its superiority to high-definition white-light endoscopy. We performed a prospective study assess whether in the hands of high detecting colonoscopists, high-definition, white-light endoscopy is noninferior to pancolonic chromoendoscopy for detection of adenomas in patients with Lynch syndrome. METHODS: We conducted a parallel controlled study, from July 2016 through January 2018 at 14 centers in Spain of adults with pathogenic germline variants in mismatch repair genes (60% women; mean age, 47 ± 14 years) under surveillance. Patients were randomly assigned to groups that underwent high-definition white-light endoscopy (n = 128) or pancolonic chromoendoscopy (n = 128) evaluations by 24 colonoscopists who specialized in detection of colorectal lesions in high-risk patients for colorectal cancer. Adenoma detection rates (defined as the proportion of patients with at least 1 adenoma) were compared between groups, with a noninferiority margin (relative difference) of 15%. RESULTS: We found an important overlap of confidence intervals (CIs) and no significant difference in adenoma detection rates by pancolonic chromoendoscopy (34.4%; 95% CI 26.4%-43.3%) vs white-light endoscopy (28.1%; 95% CI 21.1%-36.4%; P = .28). However, pancolonic chromoendoscopy detected serrated lesions in a significantly higher proportion of patients (37.5%; 95% CI 29.5-46.1) than white-light endoscopy (23.4%; 95% CI 16.9-31.4; P = .01). However, there were no significant differences between groups in proportions of patients found to have serrated lesions of 5 mm or larger (9.4% vs 7.0%; P = .49), of proximal location (11.7% vs 10.2%; P = .68), or sessile serrated lesions (3.9% vs 5.5%; P = .55), respectively. Total procedure and withdrawal times with pancolonic chromoendoscopy (30.7 ± 12.8 minutes and 18.3 ± 7.6 minutes, respectively) were significantly longer than with white-light endoscopy (22.4 ± 8.7 minutes and 13.5 ± 5.6 minutes; P < .001). CONCLUSIONS: In a randomized parallel trial, we found that for Lynch syndrome surveillance, high-definition white-light endoscopy is not inferior to pancolonic chromoendoscopy if performed by experienced and dedicated endoscopists. ClinicalTrials.gov no: NCT02951390.

Accuracy of the Narrow-Band Imaging International Colorectal Endoscopic Classification System in Identification of Deep Invasion in Colorectal Polyps.

BACKGROUND & AIMS: T1 colorectal polyps with at least 1 risk factor for metastasis to lymph node should be treated surgically and are considered endoscopically unresectable. Optical analysis, based on the Narrow-Band Imaging International Colorectal Endoscopic (NICE) classification system, is used to identify neoplasias with invasion of the submucosa that require endoscopic treatment. We assessed the accuracy of the NICE classification, along with other morphologic characteristics, in identifying invasive polyps that are endoscopically unresectable (have at least 1 risk factor for metastasis to lymph node). METHODS: We performed a multicenter, prospective study of data collected by 58 endoscopists, from 1634 consecutive patients (examining 2123 lesions) at 17 university and community hospitals in Spain from July 2014 through June 2016. All consecutive lesions >10 mm assessed with narrow-band imaging were included. The primary end point was the accuracy of the NICE classification for identifying lesions with deep invasion, using findings from histology analysis as the reference standard. Conditional inference trees were fitted for the analysis of diagnostic accuracy. RESULTS: Of the 2123 lesions analyzed, 89 (4.2%) had features of deep invasion and 91 (4.3%) were endoscopically unresectable. The NICE classification system identified lesions with deep invasion with 58.4% sensitivity (95% CI, 47.5-68.8), 96.4% specificity (95% CI, 95.5-97.2), a positive-predictive value of 41.6% (95% CI, 32.9-50.8), and a negative-predictive value of 98.1% (95% CI, 97.5-98.7). A conditional inference tree that included all variables found the NICE classification to most accurately identify lesions with deep invasion (P < .001). However, pedunculated morphology (P < .007), ulceration (P = .026), depressed areas (P < .001), or nodular mixed type (P < .001) affected accuracy of identification. Results were comparable for identifying lesions that were endoscopically unresectable. CONCLUSIONS: In an analysis of 2123 colon lesions >10 mm, we found the NICE classification and morphologic features identify those with deep lesions with >96% specificity-even in non-expert hands and without magnification. ClinicalTrials.gov number NCT02328066.

Colon capsule endoscopy versus CT colonography in FIT-positive colorectal cancer screening subjects: a prospective randomised trial-the VICOCA study.

BACKGROUND: Colon capsule endoscopy (CCE) and CT colonography (CTC) are minimally invasive techniques for colorectal cancer (CRC) screening. Our objective is to compare CCE and CTC for the identification of patients with colorectal neoplasia among participants in a CRC screening programme with positive faecal immunochemical test (FIT). Primary outcome was to compare the performance of CCE and CTC in detecting patients with neoplastic lesions. METHODS: The VICOCA study is a prospective, single-centre, randomised trial conducted from March 2014 to May 2016; 662 individuals were invited and 349 were randomised to CCE or CTC before colonoscopy. Endoscopists were blinded to the results of CCE and CTC. RESULTS: Three hundred forty-nine individuals were included: 173 in the CCE group and 176 in the CTC group. Two hundred ninety individuals agreed to participate: 147 in the CCE group and 143 in the CTC group. In the intention-to-screen analysis, sensitivity, specificity and positive and negative predictive values for the identification of individuals with colorectal neoplasia were 98.1%, 76.6%, 93.7% and 92.0% in the CCE group and 64.9%, 95.7%, 96.8% and 57.7% in the CTC group. In terms of detecting significant neoplastic lesions, the sensitivity of CCE and CTC was 96.1% and 79.3%, respectively. Detection rate for advanced colorectal neoplasm was higher in the CCE group than in the CTC group (100% and 93.1%, respectively; RR = 1.07; p = 0.08). Both CCE and CTC identified all patients with cancer. CCE detected more patients with any lesion than CTC (98.6% and 81.0%, respectively; RR = 1.22; p = 0.002). CONCLUSION: Although both techniques seem to be similar in detecting patients with advanced colorectal neoplasms, CCE is more sensitive for the detection of any neoplastic lesion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02081742 . Registered: September 16, 2013.

Panchromoendoscopy Increases Detection of Polyps in Patients With Serrated Polyposis Syndrome.

BACKGROUND & AIMS: Serrated polyposis syndrome (SPS), characterized by multiple and/or large proximal serrated lesions, increases the risk of colorectal cancer. Serrated lesions often are missed during colonoscopy but panchromoendoscopy can increase their detection in an average-risk population. We performed a randomized controlled study to determine the efficacy of panchromoendoscopy in detection of polyps in patients with SPS. METHODS: Patients with SPS (n = 86 patients) underwent tandem high-definition (HD) colonoscopies from February 2015 through July 2016 at 7 centers in Spain. Patients were assigned randomly to groups that received 2 HD white-light endoscopy examinations (HD-WLE group; n = 43) or HD-WLE followed by 0.4% indigo carmine panchromoendoscopy (HD-CE group; n = 43). For each procedure, polyps detected were described, removed, and analyzed by histology. The primary outcome was additional polyp detection rate, defined as the number of polyps detected during the second inspection divided by the total number of polyps detected during the first and the second examination. RESULTS: A total of 774 polyps were detected (362 in the HD-WLE group and 412 in the HD-CE group); 54.2% were hyperplastic, 13.8% were adenomas, and 10.9% were sessile serrated polyps. There was a significantly higher additional polyp detection rate in the HD-CE group (0.39; 95% CI, 0.35-0.44) than in the HD-WLE group (0.22; 95% CI, 0.18-0.27) (P < .001). A higher additional rate of serrated lesions proximal to the sigmoid colon were detected in the second inspection with HD-CE (0.40; 95% CI, 0.33-0.47) than with HD-WLE (0.24; 95% CI, 0.19-0.31) (P = .001). Detection of adenomas and serrated lesions greater than 10 mm did not differ significantly between groups. In a multivariate logistic regression analysis, only use of HD-CE was associated independently with increased polyp detection throughout the colon. CONCLUSIONS: In a randomized controlled trial, we found that panchromoendoscopy increases detection of polyps (mostly of small serrated lesions) and should be considered the standard of care in patients with SPS. Studies are needed to determine the effects of this strategy on the incidence of advanced neoplasia during long-term follow-up evaluation. ClinicalTrials.gov no: NCT03476434.

Computer-aided prediction of polyp histology on white light colonoscopy using surface pattern analysis.

BACKGROUND: This study aimed to evaluate a new computational histology prediction system based on colorectal polyp textural surface patterns using high definition white light images. METHODS: Textural elements (textons) were characterized according to their contrast with respect to the surface, shape, and number of bifurcations, assuming that dysplastic polyps are associated with highly contrasted, large tubular patterns with some degree of bifurcation. Computer-aided diagnosis (CAD) was compared with pathological diagnosis and the diagnosis made by endoscopists using Kudo and Narrow-Band Imaging International Colorectal Endoscopic classifications. RESULTS: Images of 225 polyps were evaluated (142 dysplastic and 83 nondysplastic). The CAD system correctly classified 205 polyps (91.1 %): 131/142 dysplastic (92.3 %) and 74/83 (89.2 %) nondysplastic. For the subgroup of 100 diminutive polyps (≤ 5 mm), CAD correctly classified 87 polyps (87.0 %): 43/50 (86.0 %) dysplastic and 44/50 (88.0 %) nondysplastic. There were no statistically significant differences in polyp histology prediction between the CAD system and endoscopist assessment. CONCLUSION: A computer vision system based on the characterization of the polyp surface in white light accurately predicted colorectal polyp histology.

High incidence of advanced colorectal neoplasia during endoscopic surveillance in serrated polyposis syndrome.

BACKGROUND: Serrated polyposis syndrome (SPS) has been associated with an increased risk of colorectal cancer (CRC). Accordingly, intensive surveillance with annual colonoscopy is advised. The aim of this multicenter study was to describe the risk of advanced lesions in SPS patients undergoing surveillance, and to identify risk factors that could guide the prevention strategy. METHODS: From March 2013 to April 2015, 296 patients who fulfilled criteria I and/or III for SPS were retrospectively recruited at 18 centers. We selected patients in whom successful clearing colonoscopy had been performed and who underwent subsequent endoscopic surveillance. Advanced neoplasia was defined as CRC, advanced adenoma, or advanced serrated lesion that were ≥ 10 mm and/or with dysplasia. Cumulative incidence of advanced neoplasia was calculated and independent predictors of advanced neoplasia development were identified. RESULTS: In 152 SPS patients a total of 315 surveillance colonoscopies were performed (median 2, range 1 - 7). The 3-year cumulative incidence of CRC and advanced neoplasia were 3.1 % (95 % confidence interval [CI] 0 - 6.9) and 42.0 % (95 %CI 32.4 - 51.7), respectively. Fulfilling both I + III criteria and the presence of advanced serrated lesions at baseline colonoscopy were independent predictors of advanced neoplasia development (odds ratio [OR] 1.85, 95 %CI 1.03 - 3.33, P  = 0.04 and OR 2.62, 95 %CI 1.18 - 5.81, P  = 0.02, respectively). During follow-up, nine patients (5.9 %) were referred for surgery for invasive CRC (n = 4, 2.6 %) or because of polyp burden (n = 5, 3.3 %). After total colectomy, 17.9 % patients developed advanced neoplasia in the retained rectum. CONCLUSIONS: Patients with SPS have a substantial risk of developing advanced neoplasia under endoscopic surveillance, whereas CRC incidence is low. Personalized endoscopic surveillance based on polyp burden and advanced serrated histology could help to optimize prevention in patients with SPS.

Real-life chromoendoscopy for neoplasia detection and characterisation in long-standing IBD.

OBJECTIVE: Outside clinical trials, the effectiveness of chromoendoscopy (CE) for long-standing IBD surveillance is controversial. We aimed to assess the effectiveness of CE for neoplasia detection and characterisation, in real-life. DESIGN: From June 2012 to 2014, patients with IBD were prospectively included in a multicentre cohort study. Each colonic segment was evaluated with white light followed by 0.4% indigo carmine CE. Specific lesions' features were recorded. Optical diagnosis was assessed. Dysplasia detection rate between expert and non-expert endoscopists and learning curve were ascertained. RESULTS: Ninety-four (15.7%) dysplastic (1 cancer, 5 high-grade dysplasia, 88 low-grade dysplasia) and 503 (84.3%) non-dysplastic lesions were detected in 350 patients (47% female; mean disease duration: 17 years). Colonoscopies were performed with standard definition (41.5%) or high definition (58.5%). Dysplasia miss rate with white light was 40/94 (57.4% incremental yield for CE). CE-incremental detection yield for dysplasia was comparable between standard definition and high definition (51.5% vs 52.3%, p=0.30). Dysplasia detection rate was comparable between expert and non-expert (18.5% vs 13.1%, p=0.20). No significant learning curve was observed (8.2% vs 14.2%, p=0.46). Sensitivity, specificity, and positive and negative predictive values for dysplasia optical diagnosis were 70%, 90%, 58% and 94%, respectively. Endoscopic characteristics predictive of dysplasia were: proximal location, loss of innominate lines, polypoid morphology and Kudo pit pattern III-V. CONCLUSIONS: CE presents a high diagnostic yield for neoplasia detection, irrespectively of the technology and experience available in any centre. In vivo, CE optical diagnosis is highly accurate for ruling out dysplasia, especially in expert hands. Lesion characteristics can aid the endoscopist for in situ therapeutic decisions. TRIAL REGISTRATION NUMBER: NCT02543762.

Reassessment colonoscopy to diagnose serrated polyposis syndrome in a colorectal cancer screening population.

Background and study aims Serrated polyposis syndrome (SPS) is a high risk condition for colorectal cancer (CRC). Surveillance strategies for patients with serrated lesions remain controversial. We aimed to evaluate a diagnostic strategy to detect SPS consistently during reassessment colonoscopy in patients with proximal serrated lesions. Methods This was a retrospective study of all individuals from a fecal immunochemical test (FIT)-based CRC screening program (2010 - 2013) with one or more serrated lesions of ≥ 5 mm proximal to the sigmoid colon on baseline colonoscopy. We analyzed all individuals empirically scheduled for a reassessment colonoscopy aimed at diagnosing SPS within 1 year. Reassessment colonoscopy was performed with standard white-light or chromoendoscopy ±â€Šhigh definition endoscopy depending on availability. SPS diagnosis was based on the cumulative number of polyps in both the baseline and reassessment colonoscopies. Factors associated with SPS diagnosis were analyzed. Results From 3444 screening colonoscopies, 196 patients met the study entry criteria, of whom 11 patients (0.32 %) met the criteria for SPS on baseline colonoscopy. Reassessment colonoscopies were performed in 71 patients at 11.9 ±â€Š1.7 months and detected 20 additional patients with SPS, a tripling of the rate of SPS up to 0.90 %. Independent factors associated with SPS diagnosis were: having five or more proximal serrated lesions (odds ratio [OR] 4.01 [95 % confidence interval 1.20 - 13.45]; P = 0.02) or two or more sessile serrated polyps ≥ 10 mm (OR 6.35 [1.40 - 28.81]; P = 0.02) on baseline colonoscopy and the use of chromoendoscopy ±â€Šhigh definition endoscopy during reassessment colonoscopy (OR 4.99 [1.11 - 22.36]; P = 0.04). Conclusions A 1-year reassessment colonoscopy using chromoendoscopy and high definition endoscopes substantially improves SPS detection in individuals from a FIT-based screening program with proximal serrated lesions. Five or more proximal serrated lesions or two or more sessile serrated polyps ≥ 10 mm could be thresholds for requiring a reassessment colonoscopy. Prospective studies are required to validate these results and adjust surveillance recommendations in patients with serrated lesions.

Endoscopic tattooing of early colon carcinoma enhances detection of lymph nodes most prone to harbor tumor burden.

BACKGROUND: Colorectal cancer (CRC) screening programs result in the detection of early-stage asymptomatic carcinomas suitable to be surgically cured. Lymph nodes (LN) from early CRC are usually small and may be difficult to collect. Still, at least 12 LNs should be analyzed from colectomies, to ensure a reliable pN0 stage. Presurgical endoscopic tattooing improves LN procurement. In addition, molecular detection of occult LN tumor burden in histologically pN0 CRC patients is associated with a decreased survival rate. We aimed to study the impact of presurgical endoscopic tattooing on the molecular detection of LN tumor burden in early colon neoplasms. METHODS: A prospective cohort study from a CRC screening-based population was performed at a tertiary academic hospital. LNs from colectomies with and without preoperative endoscopic tattooing were assessed by two methods, hematoxylin and eosin (HE), and RT-LAMP, to detect tumor cytokeratin 19 (CK19) mRNA. We compared the amount of tumor burden and LN yields from tattooed and non-tattooed specimens. RESULTS: HE and RT-LAMP analyses of 936 LNs were performed from 71 colectomies containing early carcinomas and endoscopically unresectable adenomas (8 pT0, 17 pTis, 27 pT1, 19 pT2); 47 out of 71 (66.2 %) were tattooed. Molecular positivity correlated with the presence of tattoo in LN [p < 0.001; OR 3.1 (95 % CI 1.7-5.5)]. A significantly higher number of LNs were obtained in tattooed specimens (median 17 LN vs. 14.5 LN; p = 0.019). CONCLUSIONS: Endoscopic tattooing enables the analysis of those LNs most prone to harbor tumor cells and improves the number of LN harvested.

Colorectal cancer risk factors in patients with serrated polyposis syndrome: a large multicentre study.

OBJECTIVE: Serrated polyposis syndrome (SPS) is associated with an increased colorectal cancer (CRC) risk, although the magnitude of the risk remains uncertain. Whereas intensive endoscopic surveillance for CRC prevention is advised, predictors that identify patients who have high CRC risk remain unknown. We performed a multicentre nationwide study aimed at describing the CRC risk in patients with SPS and identifying clinicopathological predictors independently associated with CRC. DESIGN: From March 2013 through September 2014, patients with SPS were retrospectively recruited at 18 Spanish centres. Data were collected from medical, endoscopy and histopathology reports. Multivariate logistic regression was performed to identify CRC risk factors. RESULTS: In 296 patients with SPS with a median follow-up time of 45 months (IQR 26-79.7), a median of 26 (IQR 18.2-40.7) serrated polyps and 3 (IQR 1-6) adenomas per patient were detected. Forty-seven patients (15.8%) developed CRC at a mean age of 53.9±12.8, and 4 out of 47 (8.5%) tumours were detected during surveillance (cumulative CRC incidence 1.9%). Patients with >2 sessile serrated adenomas/polyps (SSA/Ps) proximal to splenic flexure and ≥1 proximal SSA/P with high-grade dysplasia were independent CRC risk factors (incremental OR=2, 95% CI 1.22 to 3.24, p=0.006). Patients with no risk factors showed a 55% decrease in CRC risk (OR=0.45, 95% CI 0.24 to 0.86, p=0.01). CONCLUSIONS: Patients with SPS have an increased risk of CRC, although lower than previously published. Close colonoscopy surveillance in experienced centres show a low risk of developing CRC (1.9% in 5 years). Specific polyp features (SSA/P histology, proximal location and presence of high-grade dysplasia) should be used to guide clinical management.

Exploring the clinical potential of an automatic colonic polyp detection method based on the creation of energy maps.

BACKGROUND AND AIMS: Polyp miss-rate is a drawback of colonoscopy that increases significantly for small polyps. We explored the efficacy of an automatic computer-vision method for polyp detection. METHODS: Our method relies on a model that defines polyp boundaries as valleys of image intensity. Valley information is integrated into energy maps that represent the likelihood of the presence of a polyp. RESULTS: In 24 videos containing polyps from routine colonoscopies, all polyps were detected in at least one frame. The mean of the maximum values on the energy map was higher for frames with polyps than without (P < 0.001). Performance improved in high quality frames (AUC = 0.79 [95 %CI 0.70 - 0.87] vs. 0.75 [95 %CI 0.66 - 0.83]). With 3.75 set as the maximum threshold value, sensitivity and specificity for the detection of polyps were 70.4 % (95 %CI 60.3 % - 80.8 %) and 72.4 % (95 %CI 61.6 % - 84.6 %), respectively. CONCLUSION: Energy maps performed well for colonic polyp detection, indicating their potential applicability in clinical practice.

Clinical utility of one versus two faecal immunochemical test samples in the detection of advanced colorectal neoplasia in symptomatic patients.

BACKGROUND: The utility of faecal immunochemical tests (FIT) in assessment of symptomatic patients with lower gastrointestinal symptoms has not been well explored. The aims of this study were to evaluate the diagnostic yield for advanced colorectal neoplasia (ACRN) in symptomatic patients using the first of two FIT samples (FIT/1) and the higher concentration of two FIT samples (FIT/max). METHODS: Samples from two consecutive bowel motions from 208 symptomatic patients who required colonoscopy were analysed using the HM-JACKarc analyser (Kyowa Medex Co., Ltd., Tokyo, Japan). Patients were categorised into two groups: patients with any ACRN and individuals with other diagnoses or normal colonoscopy. RESULTS: Colonoscopy detected ACRN in 29 patients. In these patients, FIT/1 and FIT/max were significantly higher than in patients with low-risk adenoma (p=0.006 and p=0.024), other findings (p=0.002 and p=0.002) and normal colonoscopy (p<0.001 and p<0.001). The areas under the curves (AUC) of FIT/1 and FIT/max were 0.71 and 0.69, respectively. Undetectable FIT/1 rules out 96.6% of ACRN and the specificity was 10.6%. Increasing the FIT/1 cut-off to 10 µg Hb/g faeces, sensitivity and specificity were 34.5% and 87.2%, respectively. Similar results were obtained using FIT/max with 20 µg Hb/g faeces cut-off, providing a sensitivity and specificity of 34.5% and 85.6%, respectively. CONCLUSIONS: Undetectable FIT is a good strategy to rule-out ACRN in symptomatic patients. The diagnostic yield of collecting two samples for FIT can be achieved with one sample, but a lower faecal haemoglobin concentrations (f-Hb) cut-off is required.

Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer.

BACKGROUND: Colorectal cancers (CRCs) that have microsatellite instability (MSI) and mutL homolog 1 (MLH1) immunoloss are observed in 3 clinical scenarios: Lynch syndrome (LS), sporadic MSI CRC, and Lynch-like syndrome (LLS). v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational analysis is used to differentiate LS from sporadic MSI CRC. The role of MLH1 promoter methylation status for the differential diagnosis of these clinical forms is not well established. The objectives of this study were: 1) to analyze MLH1 promoter methylation in MLH1-deficient CRCs by pyrosequencing, and 2) to assess its role in the differential diagnosis of MLH1-deficient CRCs. METHODS: In total, 165 CRCs were analyzed, including LS (n = 19), MSI BRAF-mutated CRC (n = 37), MSI BRAF wild-type CRC (n = 60), and a control group of CRCs without MSI (microsatellite stable [MSS] CRC; n = 49). MLH1 promoter methylation status was analyzed by pyrosequencing, and the ability of different strategies to identify LS was assessed. RESULTS: The average ± standard deviation methylation in LS (9% ± 7%) was significantly lower than that in MSI BRAF-mutated CRC (42% ± 17%; P < .001) and in MSI BRAF wild-type CRC (25% ± 19%; P = .002). Somatic MLH1 hypermethylation was detected in 3 patients (15.8%) with LS, in 34 patients (91.9%) with MSI BRAF-mutated CRC, and in 37 patients (61.7%) with MSI BRAF wild-type tumors. Patients with MSI BRAF wild-type, unmethylated tumors (ie, LLS) had a stronger family history of CRC than those who had tumors with MLH1 methylation (P < .05). The sensitivity for ruling out LS was 100% for BRAF analysis, 84.2% for MLH1 methylation analysis, and 84.2% for the combination of both analyses. CONCLUSIONS: Somatic MLH1 promoter methylation occurs in up to 15% of LS CRCs. Somatic BRAF analysis is the most sensitive strategy for ruling out LS. Patients who have CRCs with loss of MLH1 protein expression and neither BRAF mutation nor MLH1 methylation resemble patients with LS.

Risk stratification for advanced colorectal neoplasia according to fecal hemoglobin concentration in a colorectal cancer screening program.

BACKGROUND & AIMS: The latest generation of fecal immunochemical tests (FIT) allows for quantitation of hemoglobin in feces, allowing for selection of optimal cut-off concentrations. We investigated whether individuals with positive results from quantitative FITs, in combination with other factors, could be identified as being at greatest risk for advanced colorectal neoplasia. METHODS: In a retrospective study, we analyzed data from a consecutive series of 3109 participants with positive results from FITs (≥20 µg/g of feces) included in the first round of the Barcelona colorectal cancer screening program, from December 2009 through February 2012. All participants underwent colonoscopy and were assigned to groups with any advanced colorectal neoplasia or with nonadvanced colorectal neoplasia (but with another diagnosis or normal examination findings). RESULTS: Median fecal hemoglobin concentrations were significantly higher in participants with advanced colorectal neoplasia (105 µg/g; interquartile range, 38-288 µg/g) compared with participants with nonadvanced colorectal neoplasia (47 µg/g; interquartile range, 23-119 µg/g) (P < .001). Positive predictive values for advanced colorectal neoplasia, determined using arbitrary fecal hemoglobin concentrations, differed with sex and age. Multivariate logistic regression analysis identified sex (men: odds ratio [OR], 2.07; 95% confidence interval, 1.78-2.41), age (60-69 y: OR, 1.24; 95% confidence interval, 1.07-1.44), and fecal hemoglobin concentration (>177 µg/g: OR, 3.80; 95% confidence interval, 3.07-4.71) as independent predictive factors for advanced colorectal neoplasia. Combining these factors, we identified 16 risk categories associated with different probabilities of identifying advanced colorectal neoplasia. Risk for advanced colorectal neoplasia increased 11.46-fold among individuals in the highest category compared with the lowest category; positive predictive values ranged from 21.3% to 75.6%. CONCLUSIONS: Fecal hemoglobin concentration, in addition to sex and age, in individuals with positive results from FITs can be used to stratify probability for the detection of advanced colorectal neoplasia. These factors should be used to prioritize individuals for colonoscopy examination.

Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer.

PURPOSE: Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APC, MUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutations in new genes is a likely explanation for the underlying predisposition in some of these familial cases. METHODS: Exome sequencing was performed in 43 patients with colorectal cancer from 29 families with strong disease aggregation without mutations in known hereditary colorectal cancer genes. Data analysis selected only very rare variants (0-0.1%), producing a putative loss of function and located in genes with a role compatible with cancer. Variants in genes previously involved in hereditary colorectal cancer or nearby previous colorectal cancer genome-wide association study hits were also chosen. RESULTS: Twenty-eight final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, and BARD1. CONCLUSION: We identified new potential colorectal cancer predisposition variants in genes that have a role in cancer predisposition and are involved in DNA repair and the cell cycle, which supports their putative involvement in germ-line predisposition to this neoplasm.

Incidence of bacteremia in cirrhotic patients undergoing upper endoscopic ultrasonography.

BACKGROUND: The incidence of bacteremia after endoscopic ultrasonography (EUS) or EUS-guided fine-needle aspiration (EUS-FNA) is between 0% and 4%, but there are no data on this topic in cirrhotic patients. AIM: To prospectively assess the incidence of bacteremia in cirrhotic patients undergoing EUS and EUS-FNA. PATIENTS AND METHODS: We enrolled 41 cirrhotic patients. Of these, 16 (39%) also underwent EUS-FNA. Blood cultures were obtained before and at 5 and 30 min after the procedure. When EUS-FNA was used, an extra blood culture was obtained after the conclusion of radial EUS and before the introduction of the sectorial echoendoscope. All patients were clinically followed up for 7 days for signs of infection. RESULTS: Blood cultures were positive in 16 patients. In 10 patients, blood cultures grew coagulase-negative Staphylococcus, Corynebacterium species, Propionibacterium species or Acinetobacterium Lwoffii, which were considered contaminants (contamination rate 9.8%, 95% CI: 5.7-16%). The remaining 6 patients had true positive blood cultures and were considered to have had true bacteremia (15%, 95% CI: 4-26%). Blood cultures were positive after diagnostic EUS in five patients but were positive after EUS-FNA in only one patient. Thus, the frequency of bacteremia after EUS and EUS-FNA was 12% and 6%, respectively (95% CI: 2-22% and 0.2-30%, respectively). Only one of the patients who developed bacteremia after EUS had a self-limiting fever with no other signs of infection. CONCLUSION: Asymptomatic Gram-positive bacteremia developed in cirrhotic patients after EUS and EUS-FNA at a rate higher than in non-cirrhotic patients. However, this finding was not associated with any clinically significant infections.

The role of high-resolution endoscopy and narrow-band imaging in the evaluation of upper GI neoplasia in familial adenomatous polyposis.

BACKGROUND: The Spigelman classification stratifies cancer risk in familial adenomatous polyposis (FAP) patients with duodenal adenomatosis. High-resolution endoscopy (HRE) and narrow-band imaging (NBI) may identify lesions at high risk. OBJECTIVE: To compare HRE and NBI for the detection of duodenal and gastric polyps and to characterize duodenal adenomas harboring advanced histology with HRE and NBI. DESIGN: Prospective, nonrandomized, comparative study. Retrospective image evaluation study. SETTING: Tertiary-care center. PATIENTS: Thirty-seven FAP patients undergoing surveillance upper endoscopies. INTERVENTION: HRE endoscopy was followed by NBI. The number of gastric polyps and Spigelman staging were compared. Duodenal polyp images were systematically reviewed in a learning and validation phase. MAIN OUTCOME MEASUREMENTS: Number of gastric and duodenal polyps detected by HRE and NBI and prevalence of specific endoscopic features in duodenal adenomas with advanced histology. RESULTS: NBI did not identify additional gastric polyps but detected more duodenal adenomas in 16 examinations, resulting in upgrades of the Spigelman stage in 2 cases (4.4%). Pictures of 168 duodenal adenomas (44% advanced histology) were assessed. In the learning phase, 3 endoscopic features were associated with advanced histology: white color, enlarged villi, and size ≥1 cm. Only size ≥1 cm was confirmed in the validation phase (odds ratio 3.0; 95% confidence interval, 1.2-7.4). LIMITATIONS: Nonrandomized study, scant number of high-grade dysplasia adenomas. CONCLUSION: Inspection with NBI did not lead to a clinically relevant upgrade in the Spigelman classification and did not improve the detection of gastric polyps in comparison with HRE. The only endoscopic feature that predicted advanced histology of a duodenal adenoma was size ≥1 cm.

Endoscopic features of sessile serrated adenomas: validation by international experts using high-resolution white-light endoscopy and narrow-band imaging.

BACKGROUND: Sessile serrated adenomas/polyps (SSAs/Ps) are premalignant lesions susceptible to being easily overlooked by endoscopists. A detailed description of the endoscopic appearance of SSAs/Ps might help endoscopists to recognize these lesions to improve the effectiveness of colonoscopy. OBJECTIVE: To identify various endoscopic features of SSAs/Ps using high-resolution white-light endoscopy (HR-WLE) and narrow-band imaging (NBI). DESIGN: Retrospective image evaluation study. SETTING: Single tertiary referral center. PATIENTS: Forty-5 patients with serrated polyposis syndrome undergoing surveillance colonoscopies. INTERVENTION: HR-WLE and NBI images of 150 polyps (50 SSAs/Ps, 50 hyperplastic polyps [HPs], and 50 adenomas) were systematically assessed by 5 experts using various endoscopic descriptors. MAIN OUTCOME MEASUREMENTS: The prevalence of specific endoscopic features observed in SSAs/Ps versus HPs. RESULTS: Multivariate analysis demonstrated that indistinct borders (OR, 3.11; 95% CI, 1.57-6.15) and a cloud-like surface (OR, 2.65; 95% CI, 1.21-5.78) were associated with SSA/P histology on HR-WLE. On NBI, a cloud-like surface (OR, 4.91; 95% CI, 2.42-9.97), indistinct borders (OR, 2.38; 95% CI, 1.14-4.96), irregular shape (OR, 3.17; 95% CI, 1.59-6.29), and dark spots inside the crypts (OR, 2.05; 95% CI, 1.02-4.11) were found to be endoscopic predictors of SSA/P histology. The sensitivity, specificity, and accuracy of NBI for differentiating serrated polyps containing either none or all 4 endoscopic SSA/P features were, respectively, 89%, 96%, and 93%. LIMITATIONS: Retrospective, image evaluation analysis. CONCLUSIONS: The current study demonstrates that SSAs/Ps possess several specific endoscopic features compared with HPs. Recognition of these characteristics might assist endoscopists in the differentiation of these lesions and could possibly facilitate endoscopic detection of these rather subtle lesions.

[Timing of polyethylene glycol administration is a key factor in the tolerability and efficacy of colon preparation in colorectal cancer screening]. / La hora de ingesta del polietilenglicol es un factor clave en la tolerancia y eficacia de la preparación del colon en individuos de un programa poblacional de cribado de cáncer colorrectal.

INTRODUCTION: The quality and tolerability of antegrade gut lavage bowel preparation are key elements in the success of population-based colorectal cancer screening. OBJECTIVES: To evaluate cleansing quality and tolerability according to the timing of polyethylene glycol administration in persons undergoing colorectal cancer screening. METHOD: Participants in colorectal cancer screening were randomized to two groups: a) control group (colonoscopy scheduled at 9-12 h); preparation with polyethylene glycol on the previous afternoon; b) study group (colonoscopy scheduled at 12-15 h): preparation with polyethylene glycol on the morning of the colonoscopy, with the option of a split dose. The quality of cleansing was evaluated with the Boston scale and tolerability through a questionnaire. RESULTS: A total of 282 participants were included: preparation was carried out the day before the procedure in 134 and on the same day in 148, of which 26 received a split dose. Cleansing was adequate in 95% (n=268) of the participants. The quality of cleansing was higher in the study group (P=.045). The interval between the end of administration and the beginning of the procedure was inversely correlated with the Boston scale score (P=.036; r=-0.125). Tolerability was unrelated to the time of administration (P>.2). Acceptance of the timing of administration was lower in the study group than in the control group (26% vs 10%, respectively; P=.001). CONCLUSIONS: Preparation as close as possible to the colonoscopy improves the quality of cleansing with no detrimental effects on tolerability, although this option is less comfortable.