Resistance-associated substitutions after sofosbuvir/velpatasvir/voxilaprevir triple therapy failure.

Direct-acting antivirals (DAAs) resolve chronic HCV infection in >95% of patients, but a small percentage do not respond to DAA-based therapy. These may be difficult to treat because of resistance-associated substitutions (RAS) emerging after treatment failure. Triple therapy with sofosbuvir (SOF)/velpatasvir (VEL)/voxilaprevir (VOX) is the recommended retreatment after DAA-based failure. However, in rare cases, failure to triple therapy occurs, and there is little information characterizing the viruses that relapse. To determine the RAS profile after failing SOF/VEL/VOX, and seek suitable alternatives for retreatment, samples from 5 patients were analysed using MiSeq Illumina deep sequencing before and after triple therapy. All patients were men, aged 59-78 years, 2 HCV genotype (G) 1b and 3 G3a. The most prevalent NS3 substitutions after SOF/VEL/VOX failure were Y56F and A166T. Four patients had the NS5A RAS, Y93H, after triple failure, and Y93H was observed in both G1b patients before retreatment and after SOF/ledipasvir failure. In 2 G3a patients, Y93H appeared at triple failure, and on the other G3a, A30K persisted in 100% of viral genomes. Finally, G1b patients showed C316N in NS5B, associated with SOF failure, but G3a patients had no known NS5B substitutions. HCV RAS analysis identified the following substitutions present at higher rates after triple failure: Y56F in NS3 (G1b), A166T in NS3 (G3a), A30K or Y93H in NS5A, and C316N in NS5B (G1b). A RAS-based salvage treatment (SOF + glecaprevir/pibrentasvir + RBV) was successfully used in one G3a patient.

Diagnostic performance of fecal immunochemical test and sigmoidoscopy for advanced right-sided colorectal neoplasms.

BACKGROUND: Colorectal cancer screening effect on right-sided colorectal neoplasia is limited. We compared fecal immunochemical test and simulated sigmoidoscopy diagnostic accuracy for advanced right-sided neoplasia detection. METHODS: We analyzed 1,292 individuals with complete screening colonoscopy with a fecal immunochemical test determination before colonoscopy. Sigmoidoscopy and "hybrid strategy" (sigmoidoscopy or fecal hemoglobin concentration ≥ 20 µg hemoglobin/g) diagnostic yield were simulated according to UK Flexible Sigmoidoscopy, Screening for COlon REctum (SCORE), and Norwegian Colorectal Cancer Prevention (NORCCAP) trials criteria to complete colonic examination. We compared sensitivity and specificity of both strategies and of "hybrid strategy" for advanced right-sided neoplasia with McNemar test. RESULTS: An advanced right-sided neoplasia was detected in 47 (3.6 %) subjects. A fecal hemoglobin concentration ≥ 20 µg hemoglobin/g was determined in 6.6 % of the subjects and 10.1, 12.7, and 23.5 % met UK, SCORE, and NORCCAP criteria, respectively. Fecal immunochemical test was statistically more specific than sigmoidoscopy strategies (93.8 %, UK 90.3 %, SCORE 87.7 %, NORCCAP 77.8 %; p < 0.001). In contrast, fecal immunochemical test sensitivity for advanced right-sided neoplasia (17 %) was not statistically different than UK (21.3 %; p = 0.7) or SCORE (23.4 %; p = 0.5), although it was inferior than NORCCAP strategy (42.5 %; p < 0.001). Adding fecal immunochemical test to sigmoidoscopy increased number of positives (8.5-25.7 %), sensitivity (10-30 %), and significantly reduced advanced right-sided neoplasia specificity (p < 0.001). CONCLUSIONS: Fecal immunochemical test and sigmoidoscopy diagnostic yield for advanced right-sided neoplasia are low. Fecal immunochemical test is more specific than sigmoidoscopy but less sensitive than sigmoidoscopy according to NORCCAP criteria.

Diagnostic accuracy of fecal immunochemical test in average- and familial-risk colorectal cancer screening.

BACKGROUND: There is little information about the fecal immunochemical test (FIT) in familial-risk colorectal cancer (CRC) screening. OBJECTIVES: The objective of this article is to investigate whether FIT diagnostic accuracy for advanced neoplasia (AN) differs between average and familial-risk (first-degree relative) patients. METHODS: A total of 1317 consecutive participants (595 familial) who collected one stool sample before performing a colonoscopy as a CRC screening test were included. FIT diagnostic accuracy for AN was evaluated with Chi-square test at a 20 µg hemoglobin/g of feces cut-off value. Finally, we determined which variables were independently related to AN. RESULTS: An AN was found in 151 (11.5%) patients. The overall accuracy was not statistically different between both cohorts for AN (88.4%, 91.7%; p = 0.051). At the cut-off stablished, differences in FIT sensitivity (31.1%, 40.6%; p = 0.2) or specificity (96.5%, 97.3%; p = 0.1) were not statistically significant. Finally, independent variables such as sex (male) (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.4-3.1), age (50-65, >65 years) (OR 2.1, 95% CI 1.1-4.3; OR 2.7, 95% CI 1.2-6.1), previous colonoscopy (OR 0.4, 95% CI 0.2-0.9) and FIT ≥20 µg/g feces (OR 17.7, 95% CI 10.8-29.1) were associated with AN diagnosis. CONCLUSIONS: FIT accuracy for AN detection is equivalent in average and familial-risk CRC screening cohorts.

Characteristics of adenomas detected by fecal immunochemical test in colorectal cancer screening.

BACKGROUND: Fecal immunochemical test (FIT) diagnostic accuracy for colorectal adenoma detection in colorectal cancer screening is limited. METHODS: We analyzed 474 asymptomatic subjects with adenomas detected on colonoscopy in two blinded diagnostic tests studies designed to assess FIT diagnostic accuracy. We determined the characteristics of adenomas (number, size, histology, morphology, and location) and the risk of metachronous lesions (according to European guidelines). Finally, we performed a logistic regression to identify those variables independently associated with a positive result. RESULTS: Advanced adenomas were found in 145 patients (75.6% distal and 24.3% only proximal to splenic flexure). Patients were classified as low (59.5%), intermediate (30.2%), and high risk (10.3%) according to European guidelines. At a 100-ng/mL threshold, FIT was positive in 61 patients (12.8%). Patients with advanced adenomas [odds ratio (OR), 8.8; 95% confidence interval (CI), 4.76-16.25], distal advanced adenomas (OR, 6.7; 95% CI, 1.9-8.8), high risk (OR, 20.1; 95% CI, 8.8-45.8), or intermediate risk lesions (OR, 6; 95% CI, 2.9-12.4) had more probabilities to have a positive test. The characteristics of adenomas independently associated were number of adenomas (OR, 1.22; 95% CI, 1.04-1.42), distal flat adenomas (OR, 0.44; 95% CI, 0.21-0.96), pedunculated adenomas (OR, 2.28; 95% CI, 1.48-3.5), and maximum size of distal adenomas (mm; OR, 1.24; 95% CI, 1.16-1.32). CONCLUSIONS: European guidelines classification and adenoma location correlates with the likelihood of a positive FIT result. IMPACT: This information allows us to understand the FIT impact in colorectal cancer prevention. Likewise, it should be taken into account in the development of new colorectal adenomas biomarkers.

Fecal immunochemical test accuracy in average-risk colorectal cancer screening.

AIM: To assess the fecal immunochemical test (FIT) accuracy for colorectal cancer (CRC) and advanced neoplasia (AN) detection in CRC screening. METHODS: We performed a multicentric, prospective, double blind study of diagnostic tests on asymptomatic average-risk individuals submitted to screening colonoscopy. Two stool samples were collected and the fecal hemoglobin concentration was determined in the first sample (FIT1) and the highest level of both samples (FITmax) using the OC-sensor™. Areas under the curve (AUC) for CRC and AN were calculated. The best FIT1 and FITmax cut-off values for CRC were determined. At this threshold, number needed to scope (NNS) to detect a CRC and an AN and the cost per lesion detected were calculated. RESULTS: About 779 individuals were included. An AN was found in 97 (12.5%) individuals: a CRC in 5 (0.6%) and an advanced adenoma (≥ 10 mm, villous histology or high grade dysplasia) in 92 (11.9%) subjects. For CRC diagnosis, FIT1 AUC was 0.96 (95%CI: 0.95-0.98) and FITmax AUC was 0.95 (95%CI: 0.93-0.97). For AN, FIT1 and FITmax AUC were similar (0.72, 95%CI: 0.66-0.78 vs 0.73, 95%CI: 0.68-0.79, respectively, P = 0.34). Depending on the number of determinations and the positivity threshold cut-off used sensitivity for AN detection ranged between 28% and 42% and specificity between 91% and 97%. At the best cut-off point for CRC detection (115 ng/mL), the NNS to detect a CRC were 10.2 and 15.8; and the cost per CRC was 1814€ and 2985€ on FIT1 and FITmax strategies respectively. At this threshold the sensitivity, NNS and cost per AN detected were 30%, 1.76, and 306€, in FIT1 strategy, and 36%, 2.26€ and 426€, in FITmax strategy, respectively. CONCLUSION: Performing two tests does not improve diagnostic accuracy, but increases cost and NNS to detect a lesion.

Relationship of colonoscopy-detected serrated polyps with synchronous advanced neoplasia in average-risk individuals.

BACKGROUND: Serrated cancers account for 10% to 20% of all colorectal cancers (CRC) and more than 30% of interval cancers. The presence of proximal serrated polyps and large (≥10 mm) serrated polyps (LSP) has been correlated with colorectal neoplasia. OBJECTIVE: To evaluate the prevalence of serrated polyps and their association with synchronous advanced neoplasia in a cohort of average-risk population and to assess the efficacy of one-time colonoscopy and a biennial fecal immunochemical test for reducing CRC-related mortality. This study focused on the sample of 5059 individuals belonging to the colonoscopy arm. DESIGN: Multicenter, randomized, controlled trial. SETTING: The ColonPrev study, a population-based, multicenter, nationwide, randomized, controlled trial. PATIENTS: A total of 5059 asymptomatic men and women aged 50 to 69 years. INTERVENTION: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Prevalence of serrated polyps and their association with synchronous advanced neoplasia. RESULTS: Advanced neoplasia was detected in 520 individuals (10.3%) (CRC was detected in 27 [0.5%] and advanced adenomas in 493 [9.7%]). Serrated polyps were found in 1054 individuals (20.8%). A total of 329 individuals (6.5%) had proximal serrated polyps, and 90 (1.8%) had LSPs. Proximal serrated polyps or LSPs were associated with male sex (odds ratio [OR] 2.08, 95% confidence interval [CI], 1.76-4.45 and OR 1.65, 95% CI, 1.31-2.07, respectively). Also, LSPs were associated with advanced neoplasia (OR 2.49, 95% CI, 1.47-4.198), regardless of their proximal (OR 4.15, 95% CI, 1.69-10.15) or distal (OR 2.61, 95% CI, 1.48-4.58) locations. When we analyzed subtypes of serrated polyps, proximal hyperplasic polyps were related to advanced neoplasia (OR 1.61, 95% CI, 1.13-2.28), although no correlation with the location of the advanced neoplasia was observed. LIMITATIONS: Pathology criteria for the diagnosis of serrated polyps were not centrally reviewed. The morphology of the hyperplasic polyps (protruded or flat) was not recorded. Finally, because of the characteristics of a population-based study carried out in average-risk patients, the proportion of patients with CRC was relatively small. CONCLUSION: LSPs, but not proximal serrated polyps, are associated with the presence of synchronous advanced neoplasia. Further studies are needed to determine the risk of proximal hyperplastic polyps.

Artificial intelligence techniques for colorectal cancer drug metabolism: ontology and complex network.

Colorectal cancer is one of the most frequent types of cancer in the world and generates important social impact. The understanding of the specific metabolism of this disease and the transformations of the specific drugs will allow finding effective prevention, diagnosis and treatment of the colorectal cancer. All the terms that describe the drug metabolism contribute to the construction of ontology in order to help scientists to link the correlated information and to find the most useful data about this topic. The molecular components involved in this metabolism are included in complex network such as metabolic pathways in order to describe all the molecular interactions in the colorectal cancer. The graphical method of processing biological information such as graphs and complex networks leads to the numerical characterization of the colorectal cancer drug metabolic network by using invariant values named topological indices. Thus, this method can help scientists to study the most important elements in the metabolic pathways and the dynamics of the networks during mutations, denaturation or evolution for any type of disease. This review presents the last studies regarding ontology and complex networks of the colorectal cancer drug metabolism and a basic topology characterization of the drug metabolic process sub-ontology from the Gene Ontology.