Evaluation of global and intragenic hypomethylation in colorectal adenomas improves patient stratification and colorectal cancer risk prediction.

BACKGROUND: Aberrant DNA hypomethylation of the long interspersed nuclear elements (LINE-1 or L1) has been recognized as an early event of colorectal transformation. Simultaneous genetic and epigenetic analysis of colorectal adenomas may be an effective and rapid strategy to identify key biological features leading to accelerated colorectal tumorigenesis. In particular, global and/or intragenic LINE-1 hypomethylation of adenomas may represent a helpful tool for improving colorectal cancer (CRC) risk stratification of patients after surgical removal of polyps. To verify this hypothesis, we analyzed a cohort of 102 adenomas derived from 40 high-risk patients (who developed CRC in a post-polypectomy of at least one year) and 43 low-risk patients (who did not develop CRC in a post-polypectomy of at least 5 years) for their main pathological features, the presence of hotspot variants in driver oncogenes (KRAS, NRAS, BRAF and PIK3CA), global (LINE-1) and intragenic (L1-MET) methylation status. RESULTS: In addition to a significantly higher adenoma size and an older patients' age, adenomas from high-risk patients were more hypomethylated than those from low-risk patients for both global and intragenic LINE-1 assays. DNA hypomethylation, measured by pyrosequencing, was independent from other parameters, including the presence of oncogenic hotspot variants detected by mass spectrometry. Combining LINE-1 and L1-MET analyses and profiling the samples according to the presence of at least one hypomethylated assay improved the discrimination between high and low risk lesions (p = 0.005). Remarkably, adenomas with at least one hypomethylated assay identified the patients with a significantly (p < 0.001) higher risk of developing CRC. Multivariable analysis and logistic regression evaluated by the ROC curves proved that methylation status was an independent variable improving cancer risk prediction (p = 0.02). CONCLUSIONS: LINE-1 and L1-MET hypomethylation in colorectal adenomas are associated with a higher risk of developing CRC. DNA global and intragenic hypomethylation are independent markers that could be used in combination to successfully improve the stratification of patients who enter a colonoscopy surveillance program.

Computer-aided detection for computed tomographic colonography screening: a prospective comparison of a double-reading paradigm with first-reader computer-aided detection against second-reader computer-aided detection.

OBJECTIVES: The objective of this study was to prospectively compare diagnostic performance and time efficiency of a double-reading paradigm in which a first-reader computer-aided detection (CAD) is followed by a fast 2-dimensional review (DR FR-CAD) with those of a double reading with second-reader CAD (SR CAD). MATERIALS AND METHODS: The local ethical committee approved this study. Consecutive immunological patients who have positive results for fecal immunological test who were scheduled for colonoscopy were enrolled for a 10-month period. Computed tomographic colonography studies were read with CAD (CAD COLON-1.20; im3D, Turin, Italy) by using both SR CAD (applied after unassisted interpretation primary 2-dimensional) and DR FR-CAD (CAD-prompts evaluation followed by a fast 2-dimensional review) in randomized order with the radiologist for each reading paradigm masked to the other reader's results.Per-patient sensitivity and specificity of unassisted and CAD-assisted readings for detecting 6-mm adenomas or larger were calculated by using unblinding colonoscopy as reference standard. Reporting times were also calculated. Pairwise comparisons were performed. RESULTS: A total of 182 participants (median age, 65 years; range, 58-76) were included in the final analysis. Of these, 93 (51%) had at least 1 cancer or a 6-mm adenoma or larger. At the 6-mm threshold, sensitivity of unassisted reading (79.6%; 95% confidence interval [CI], 69.9-87.2) increased significantly with the use of both SR CAD (86.0%; 95% CI, 77.3%-92.3%) and DR FR-CAD (89.2%; 95% CI, 81.1%-94.7%), without differences between CAD readings (P = 0.500). No significant differences in specificity among the 3 paradigms were observed. Double reading with first-reader CAD required less reading time than that for SR CAD (378 vs 496; Δ118 seconds; P < 0.001) and was 59 seconds longer than the unassisted reading (P = 0.058). CONCLUSIONS: When compared with unassisted reading, a double-reading paradigm in which first-reader CAD is followed by a fast 2-dimensional review improves the adenoma detection rate to the same level achieved by a second-reader CAD while decreasing reporting times.

Efficacy of computer-aided detection as a second reader for 6-9-mm lesions at CT colonography: multicenter prospective trial.

PURPOSE: To assess the effect of computer-aided detection (CAD) as a second reader on the sensitivity and specificity of computed tomographic (CT) colonography in detecting 6-9-mm colorectal cancer (CRC) lesions. MATERIALS AND METHODS: Individuals with clinical indications for colonoscopy--either for symptoms or as part of participating in a surveillance program or CRC screening--were prospectively enrolled at one of 10 academic centers between July 2007 and May 2009. Institutional review board approval was obtained at each clinical site, and all participants provided written informed consent. All participants underwent CT colonography and colonoscopy on the same day. Experienced readers interpreted the CT colonography images unassisted and then reviewed all colorectal lesion-like structures pinpointed by the CAD algorithm. Segmental unblinding of CT colonoscopy findings at colonoscopy was utilized. The sensitivity and specificity of unassisted and CAD-assisted reading in identifying individuals with 6-9-mm lesions were calculated and compared by means of pairwise analysis. RESULTS: A total of 618 participants (mean age, 57.9 years; 54.5% male) were included in the final analysis. Of these participants, 464 (75.1%) had no lesions 6 mm or larger, and 52 (8.4%) had 6-9-mm lesions. The sensitivity of CT colonography with unassisted reading and that with CAD-assisted reading in identifying individuals with 6-9-mm lesions was 65.4% (95% confidence interval [CI]: 50.9%, 78.0%) and 76.9% (95% CI: 63.2%, 87.5%; P = .016), respectively. No significant change in specificity was observed: The specificity of CT colonography with unassisted and that with CAD-assisted reading was 91.8% (95% CI: 88.9%, 94.1%) and 90.9% (95% CI: 88.0%, 93.4%; P = .063), respectively. Evaluation of CAD candidates required an additional 1.6 minutes (25th-75th percentile: 1.0 minute to 3.4 minutes). CONCLUSION: The addition of CAD to reading performed by experienced readers resulted in a significant benefit in the detection of 6-9-mm polyps at CT colonography in this cohort. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120376/-/DC1.

Diagnostic accuracy of computed tomographic colonography for the detection of advanced neoplasia in individuals at increased risk of colorectal cancer.

CONTEXT: Computed tomographic (CT) colonography has been recognized as an alternative for colorectal cancer (CRC) screening in average-risk individuals, but less information is available on its performance in individuals at increased risk of CRC. OBJECTIVE: To assess the accuracy of CT colonography in detecting advanced colorectal neoplasia in asymptomatic individuals at increased risk of CRC using unblinded colonoscopy as the reference standard. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, cross-sectional study. Individuals at increased risk of CRC due to either family history of advanced neoplasia in first-degree relatives, personal history of colorectal adenomas, or positive results from fecal occult blood tests (FOBTs) were recruited in 11 Italian centers and 1 Belgian center between December 2004 and May 2007. Each participant underwent CT colonography followed by colonoscopy on the same day. MAIN OUTCOME MEASURES: Sensitivity and specificity of CT colonography in detecting individuals with advanced neoplasia (ie, advanced adenoma or CRC) 6 mm or larger. RESULTS: Of 1103 participants, 937 were included in the final analysis: 373 cases in the family-history group, 343 in the group with personal history of adenomas, and 221 in the FOBT-positive group. Overall, CT colonography identified 151 of 177 participants with advanced neoplasia 6 mm or larger (sensitivity, 85.3%; 95% confidence interval [CI], 79.0%-90.0%) and correctly classified results as negative for 667 of 760 participants without such lesions (specificity, 87.8%; 95% CI, 85.2%-90.0%). The positive and negative predictive values were 61.9% (95% CI, 55.4%-68.0%) and 96.3% (95% CI, 94.6%-97.5%), respectively; after group stratification, a significantly lower negative predictive value was found for the FOBT-positive group (84.9%; 95% CI, 76.2%-91.3%; P < .001). CONCLUSIONS: In a group of persons at increased risk for CRC, CT colonography compared with colonoscopy resulted in a negative predictive value of 96.3% overall. When limited to FOBT-positive persons, the negative predictive value was 84.9%.

Abdominal bowel ultrasound can predict the risk of surgery in Crohn's disease: proposal of an ultrasonographic score.

OBJECTIVE: Abdominal bowel ultrasound (US) is widely used in the management of Crohn's disease (CD). The aim of this study was to evaluate the prognostic role of bowel-wall US morphology on the short-term risk of surgery. MATERIAL AND METHODS: The 147 CD patients recruited in a case-control study comprised 49 cases operated on within 30 days after US examination and 98 matched non-operated controls. Clinical and US characteristics were analysed. Bowel-wall thickness was recorded, bowel-wall patterns were grouped into five types, but for final analysis they were grouped as "preserved" or "disrupted stratification". RESULTS: Wall thickness and US patterns were significantly different between cases and controls (p<0.0001). A wall thickness >4.5 mm was observed in 45/49 cases and 47/98 controls (OR = 12.21), while "disrupted stratification" was observed in 34/49 cases and 12/98 controls (OR = 16.24). Among the clinical and US characteristics recorded, only 4 US variables were independently associated with surgery (pattern, thickness, presence of fistulae/abscesses and stenoses) and considered for the US score=(2.5*US pattern)+(1.5*Bowel thickness)+(3*Presence of fistulae/abscesses)+(1.5*Presence of stenoses). Based on this score, up to 84% of patients were correctly classified according to actual status (operated/non-operated). CONCLUSIONS: Although it needs further prospective validation, the score we propose seems to be a reliable prognostic marker for the short-term risk of surgery in CD. In particular, the score points out those patients with an impending risk of surgery who need careful and frequent control in order to decide on the right time for surgery.