Marta Carrillo

Clinical validation of the European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE) II criteria in an open-access unit: a prospective study.

BACKGROUND AND STUDY AIMS The European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE I) criteria were recently updated (EPAGE II), but no prospective studies have used these criteria in clinical practice. The aim of the current study was to validate the EPAGE II criteria in an open-access endoscopy unit. PATIENTS AND METHODS A prospective observational study was conducted in an open-access endoscopy unit at a tertiary care referral center. Consecutive outpatients (n = 1004; mean age 58.9 ± 13.1 years; 45 % men) were referred for diagnostic colonoscopy between September 2009 and February 2010. The appropriateness of colonoscopy was assessed based on EPAGE II criteria, and the relationship between appropriateness and both referral doctor and detection of significant lesions was examined. The effectiveness of EPAGE II criteria in assessing appropriateness was measured by means of sensitivity, specificity, and positive and negative predictive values for detecting significant lesions. RESULTS Colonoscopic cecal intubation was achieved in 956 patients (95.2 %). Most referral doctors were gastroenterologists (58.0 %) and the most common indication was colorectal cancer (CRC) screening (35.2 %). EPAGE II criteria were applicable in 968 patients (96.4 %); of these patients, the indication was appropriate in 778 (80.4 %), inappropriate in 102 (10.5 %), and uncertain in 88 (9.1 %). Patients with appropriate or uncertain indications based on EPAGE II criteria had more relevant endoscopic findings than those with inappropriate indications (38.8 % vs. 24.5 %; OR 1.95, 95 %CI 1.22 - 3.13; P < 0.005). Sensitivity and negative predictive value of EPAGE II criteria for detecting significant lesions were 93.1 % (95 %CI 90 % - 96 %) and 75.5 % (95 %CI 67 % - 84 %), respectively, whereas for advanced neoplastic lesions these values were 98.0 % (95 %CI 95 % - 100 %) and 98.0 % (95 % CI 95 % - 100 %), respectively. Adherence to EPAGE II recommendations was an independent predictor of finding a significant lesion (OR 1.93, 95 %CI 1.20 - 3.11; P = 0.007). CONCLUSIONS EPAGE II is a simple, valid score for detecting inappropriate colonoscopies in clinical practice.

Uptake of Colon Capsule Endoscopy vs Colonoscopy for Screening Relatives of Patients With Colorectal Cancer

BACKGROUND & AIMS The efficacy of screening colonoscopy in first-degree relatives (FDRs) of patients with colorectal cancer (CRC) is limited by suboptimal uptake. We compared screening uptake of colon capsule endoscopy (CCE) vs colonoscopy in this population. METHODS We performed a prospective study of 329 asymptomatic FDRs of patients with CRC who were randomly assigned to groups examined by CCE (PillCam, second generation; n = 165) or colonoscopy (n = 164) at a tertiary hospital in Spain from July 2012 through December 2013. Crossover was permitted for patients who did not wish to undergo the assigned procedure. Subjects assigned to CCE who had a significant lesion (polyp ≥ 10 mm, >2 polyps of any size, or CRC) were invited to undergo colonoscopy. RESULTS One hundred twenty subjects in the CCE group and 113 in the colonoscopy group were eligible for inclusion. In the intention-to-screen analysis, uptake was similar between groups (55.8% CCE vs 52.2% colonoscopy; odds ratio [OR], 0.86; 95% confidence interval [CI], 0.51-1.44; P = .57); 57.4% of subjects crossed over from the CCE group, and 30.2% crossed over from the colonoscopy group (OR, 3.11; 95% CI, 1.51-6.41; P = .002). Unwillingness to repeat bowel preparation in the case of a positive result was the main reason that subjects assigned to the CCE group crossed over; fear of colonoscopy was the reason that most patients in this group crossed over. A significant lesion was detected in 14 subjects (11.7%) in the CCE group and 13 subjects (11.5%) in the colonoscopy group (OR, 1.02; 95% CI, 0.45-2.26; P = .96). CONCLUSIONS In a prospective study, similar numbers of FDRs of patients with CRC assigned to undergo CCE or colonoscopy agreed to participate, but most preferred to undergo colonoscopy. CCE was as effective as colonoscopy in detecting significant lesions; it could be a valid rescue strategy for subjects who reject screening colonoscopy. ClinicalTrials.gov number: NCT01557101.

Comparison of Two Intensive Bowel Cleansing Regimens in Patients With Previous Poor Bowel Preparation: A Randomized Controlled Study

Objectives:Inadequate bowel cleansing is a major burden for endoscopy units. The aim of this study was to compare two intensive bowel cleansing regimens in patients with previous colonoscopy with inadequate bowel preparation.Methods:Patients with inadequate cleansing at index colonoscopy were randomized to 4-L split-dose polyethylene-glycol (PEG) regimen vs. 2-L split-dose PEG plus ascorbic acid (PEG+Asc) regimen. All individuals underwent a 3-day low-residue diet and received 10 mg of bisacodyl, the day before colonoscopy. Cleansing was considered to be adequate if the Boston Bowel Preparation Scale scored ≥2 at each colonic segment. A non-inferiority analysis was performed to demonstrate that colonic cleansing with 2-L PEG+Asc was not inferior to 4-l PEG, considering a non-inferiority margin of 10%.Results:Adequate bowel cleansing was significantly higher in patients assigned to 4-L PEG regimen (n=127) vs. those randomized to 2-L PEG+Asc regimen (n=129) by intention-to-treat analysis (81.1 vs. 67.4%, odds ratio (OR) 2.07, 95% confidence interval (CI) (1.163–3.689)) and by per-protocol analysis (86.6 vs. 71.7%, OR: 2.55, 95% CI: (1.316–4.922)). The study was terminated for futility after the interim analysis, because the 95% CI of the difference of proportions was 3.13–24.27% in the intention-to-treat analysis and 3.33–26.47% in the per-protocol analysis, confirming the superiority of 4-L PEG preparation.Conclusions:After 3-day low-residue diet and oral bisacodyl before colonoscopy, colon cleansing with 4-L split-dose PEG was superior to 2-L split-dose PEG+Asc in patients with previous inadequate cleansing. (EUDRACT: 2013-002506-31, NCT02073552).

Risk factors for inadequate bowel preparation: a validated predictive score

Background and study aim Inadequate bowel cleansing negatively affects the efficiency of colonoscopy in routine clinical practice. The aim of this study was to design and validate a predictive model for inadequate bowel cleanliness. Patients and methods The model was built from 667 consecutive outpatients (development cohort) who were prospectively scheduled for colonoscopy between June and September 2014. The validation cohort included 409 outpatients who underwent colonoscopy between October and December 2014. Cleansing was evaluated using the Boston Bowel Preparation Scale (BBPS). Bowel preparation was administered on the same day as the examination. Results In the development cohort, BBPS was adequate in 541 patients (81.1 %). At multivariate analysis, antidepressants (odds ratio [OR] 4.25, 95 % confidence interval [CI] 1.91 - 9.47), co-morbidity (OR 3.35, 95 %CI 2.16 - 5.18), constipation (OR 2.09, 95 %CI 1.29 - 3.40), and abdominal/pelvic surgery (OR 1.60, 95 %CI 1.03 - 2.47) were independent predictors for inadequate cleansing. The model built with these variables showed an area under the curve of 0.72 in the development cohort and 0.70 in the validation cohort. A cutoff of 1.225 predicted inadequate bowel preparation with a sensitivity, specificity, positive predictive value, and negative predictive value of 60.3 % (95 %CI 51.6 - 68.4), 75.4 % (95 %CI 71.6 - 78.9), 36.4 % (95 %CI 30.1 - 43.1), and 89.1 % (95 %CI 85.9 - 91.6) in the development cohort, and 50.0 % (95 %CI 38.1 - 61.9), 80.0 % (95 %CI 75.3 - 84.2), 35.7 % (95 %CI 26.4 - 45.6), and 87.9 % (95 %CI 83.7 - 91.3) in the validation cohort. Conclusion A simple score may assist the clinician in predicting which patients are at high risk of inadequate bowel cleanliness. This may guide changes in bowel preparation strategy accordingly.

Risk of Advanced Neoplasia in First-Degree Relatives with Colorectal Cancer: A Large Multicenter Cross-Sectional Study

Background First-degree relatives (FDR) of patients with colorectal cancer have a higher risk of developing colorectal cancer than the general population. For this reason, screening guidelines recommend colonoscopy every 5 or 10 y, starting at the age of 40, depending on whether colorectal cancer in the index-case is diagnosed at <60 or ≥60 y, respectively. However, studies on the risk of neoplastic lesions are inconclusive. The aim of this study was to determine the risk of advanced neoplasia (three or more non-advanced adenomas, advanced adenoma, or invasive cancer) in FDR of patients with colorectal cancer compared to average-risk individuals (i.e., asymptomatic adults 50 to 69 y of age with no family history of colorectal cancer). Methods and Findings This cross-sectional analysis includes data from 8,498 individuals undergoing their first lifetime screening colonoscopy between 2006 and 2012 at six Spanish tertiary hospitals. Of these individuals, 3,015 were defined as asymptomatic FDR of patients with colorectal cancer (“familial-risk group”) and 3,038 as asymptomatic with average-risk for colorectal cancer (“average-risk group”). The familial-risk group was stratified as one FDR, with one family member diagnosed with colorectal cancer at ≥60 y (n = 1,884) or at <60 y (n = 831), and as two FDR, with two family members diagnosed with colorectal cancer at any age (n = 300). Multiple logistic regression analysis was used for between-group comparisons after adjusting for potential confounders (age, gender, and center). Compared with the average-risk group, advanced neoplasia was significantly more prevalent in individuals having two FDR with colorectal cancer (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.36–2.66, p < 0.001), but not in those having one FDR with colorectal cancer diagnosed at ≥60 y (OR 1.03; 95% CI 0.83–1.27, p = 0.77) and <60 y (OR 1.19; 95% CI 0.90–1.58, p = 0.20). After the age of 50 y, men developed advanced neoplasia over two times more frequently than women and advanced neoplasia appeared at least ten y earlier. Fewer colonoscopies by 2-fold were required to detect one advanced neoplasia in men than in women. Major limitations of this study were first that although average-risk individuals were consecutively included in a randomized control trial, this was not the case for all individuals in the familial-risk cohort; and second, the difference in age between the average-risk and familial-risk cohorts. Conclusions Individuals having two FDR with colorectal cancer showed an increased risk of advanced neoplasia compared to those with average-risk for colorectal cancer. Men had over 2-fold higher risk of advanced neoplasia than women, independent of family history. These data suggest that screening colonoscopy guidelines should be revised in the familial-risk population.

Plasma matrix metalloproteinase 9 as an early surrogate biomarker of advanced colorectal neoplasia

INTRODUCTION Matrix metalloproteinases (MMPs) are overexpressed at different stages of colorectal carcinogenesis and could serve as early surrogate biomarkers of colorectal neoplasia. OBJECTIVE To assess the utility of plasma MMP2 and MMP9 levels in the detection of advanced colorectal neoplasia and their correlation with tissue levels. METHODS We analysed blood and tissue samples from patients with non-advanced adenomas (n=25), advanced adenomas (n=25), colorectal cancer (n=25) and healthy controls (n=75). Plasma and tissue gelatinase levels were determined by Luminex XMAP technology and gelatin zymography. Receiver operating characteristic (ROC) curve analysis was used to calculate the optimum cut-off for the detection of advanced colorectal neoplasia. RESULTS Plasma MMP2 levels were similar between groups whatever the type of lesion. Plasma MMP9 levels were significantly higher in patients with neoplastic lesions than in healthy controls (median 292.3ng/ml vs. 139.08ng/ml, P<0.001). MMP9 levels were also higher in colorectal cancer than in non-advanced adenomas (median 314.6ng/ml vs. 274.3ng/ml, P=0.03). There was a significant correlation between plasma and tissue levels of MMP9 (r=0.5, P<0.001). The plasma MMP9 cut-off range with the highest diagnostic accuracy was between 173ng/ml and 204ng/ml (AUC=0.80 [95% CI: 0.72-0.86], P<0.001; sensitivity, 80-86% and specificity, 57-67%). CONCLUSION Plasma MMP9 could be a surrogate biomarker for the early detection of advanced colorectal neoplasia, although its diagnostic performance could be increased by combination with other biomarkers.

Genetic susceptibility in the development of colorectal adenomas according to family history of colorectal cancer: Genetic susceptibility to colorectal adenomas

Our study aimed to evaluate the relevance of genetic susceptibility in the development of colorectal adenomas (CRA) and its relationship with the presence of family history of colorectal cancer (CRC). Genomic DNA from 750 cases (first degree relatives of patients with CRC) and 750 controls (subjects with no family history of CRC) was genotyped for 99 single nucleotide polymorphisms (SNPs) previously associated with CRC/CRA risk by GWAS and candidate gene studies by using the MassArray™ (Sequenom) platform. Cases and controls were matched by gender, age and histological lesion. Eight hundred and fifty‐eight patients showed no neoplastic lesions, whereas 288 patients showed low‐risk adenomas, and 354 patients presented high‐risk adenomas. Two SNPs (rs10505477, rs6983267) in the CASC8 gene were associated with a reduced risk of CRA in controls (log‐additive models, OR: 0.67, 95%CI:0.54–0.83, and OR:0.66, 95%CI:0.54–0.84, respectively). Stratified analysis by histological lesion revealed the association of rs10505477 and rs6983267 variants with reduced risk of low‐ and high‐risk adenomas in controls, being this effect stronger in low‐risk adenomas (log‐additive models, OR:0.63, 95%CI:0.47–0.84 and OR:0.64, 95%CI:0.47–0.86, respectively). Moreover, 2 SNPs (rs10795668, rs11255841) in the noncoding LINC00709 gene were significantly associated with a reduced risk of low‐risk adenomas in cases (recessive models, OR:0.22, 95%CI:0.06–0.72, and OR:0.08, 95%CI:0.03–0.61) and controls (dominant models, OR:0.50, 95%CI:0.34–0.75, and OR:0.52, 95%CI:0.35–0.78, respectively). In conclusion, some variants associated with CRC risk (rs10505477, rs6983267, rs10795668 and rs11255841) are also involved in the susceptibility to CRA and specific subtypes. These associations are influenced by the presence of family history of CRC.

Colorectal cancer screening in the familial risk population: Is colonoscopy still the strategy of choice?

First-degree relatives of patients with colorectal cancer (CRC) are at high risk of this disease. For this reason, medical organizations and clinical guidelines recommend more intensive screening and surveillance for such first-degree relatives than for the average-risk population. Colonoscopy has been the cornerstone of CRC screening in this setting. Although colonoscopy is the most sensitive technique for the detection of neoplastic lesions (especially non-advanced adenomas), its role is less clear for CRC. In addition, screening colonoscopy has several limitations that may affect the success of a screening campaign, such as poor participant acceptance, the need for skilled endoscopists, participant access to screening colonoscopy, overburdened endoscopy units, potential complications, and procedure-related costs. In addition, recent evidence has cast doubt on the advantage of colonoscopy over other strategies for the detection of advanced neoplastic lesions. Despite being less sensitive in general, other screening methods frequently recommended in the average-risk population may be more acceptable and thus help increase CRC screening uptake. This review discusses recent evidence on the risk of CRC in first-degree relatives, the advantages and disadvantages of each screening technique, participation rates depending on the technique, patient preferences, and barriers to screening.