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The implementation of FIT programs reduces incidence and mortality from CRC in the screened subjects. The ultimate efficacy for CRC morbidity and mortality prevention in a FIT program depends on the colonoscopy in FIT+ subjects that has the task of detecting and removing these advanced lesions. Recently, there has been growing evidence on factors that influence the quality of colonoscopy specifically withing organized FIT programs, prompting to dedicated interventions in order to maximize the benefit/harm ratio of post-FIT colonoscopy. This document focuses on the diagnostic phase of colonoscopy, providing indications on how to standardise colonoscopy in FIT+ subjects, regarding timing of examination, management of antithrombotic therapy, bowel preparation, competence and sedation., Competing Interests: Conflict of Interest None., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

In the last years, the field of nanomedicine and drug delivery has grown exponentially, providing new platforms to carry therapeutic agents into the target sites. Extracellular vesicles (EVs) are ready-to-use, biocompatible, and non-toxic nanoparticles that are revolutionizing the field of drug delivery. EVs are involved in cell-cell communication and mediate many physiological and pathological processes by transferring their bioactive cargo to target cells. Recently, nanovesicles from plants (PDNVs) are raising the interest of the scientific community due to their high yield and biocompatibility. This study aims to evaluate whether PDNVs may be used as drug delivery systems. We isolated and characterized nanovesicles from tangerine juice (TNVs) that were comparable to mammalian EVs in size and morphology. TNVs carry the traditional EV marker HSP70 and, as demonstrated by metabolomic analysis, contain flavonoids, organic acids, and limonoids. TNVs were loaded with DDHD1-siRNA through electroporation, obtaining a loading efficiency of 13%. We found that the DDHD1-siRNA complex TNVs were able to deliver DDHD1-siRNA to human colorectal cancer cells, inhibiting the target expression by about 60%. This study represents a proof of concept for the use of PDNVs as vehicles of RNA interference (RNAi) toward mammalian cells.

Background and Aims: Granular mixed laterally spreading tumors (GM-LSTs) have an intermediate level of risk for submucosal invasive cancer (SMICs) without clear signs of invasion (covert); the optimal resection method is uncertain. We aimed to determine the risk of covert SMIC in GM-LSTs based on clinical and endoscopic factors., Methods: We collected data from 693 patients (50.6% male; median age, 69 years) with colorectal GM-LSTs, without signs of invasion, who underwent endoscopic resection (74.2%) or endoscopic submucosal dissection (25.2%) at 7 centers in Italy from 2016 through 2019. We performed multivariate and univariate analyses to identify demographic and endoscopic factors associated with risk of SMIC. We developed a multivariate model to calculate the number needed to treat (NNT) to detect 1 SMIC., Results: Based on pathology analysis, 66 patients (9.5%) had covert SMIC. In multivariate analyses, increased risk of covert SMIC were independently associated with increasing lesion size (odds ratio per mm increase, 1.02, 95% CI, 1.01-1.03; P = .003) and rectal location (odds ratio, 3.08; 95% CI, 1.62-5.83; P = .004). A logistic regression model based on lesion size (with a cutoff of 40 mm) and rectal location identified patients with covert SMIC with 47.0% sensitivity, 82.6% specificity, and an area under the curve of 0.69. The NNT to identify 1 patient with a nonrectal SMIC smaller than 4 cm was 20; the NNT to identify 1 patient with a rectal SMIC of 4 cm or more was 5., Conclusions: In an analysis of data from 693 patients, we found the risk of covert SMIC in patients with GM-LSTs to be approximately 10%. GM-LSTs of 4 cm or more and a rectal location are high risk and should be treated by en-bloc resection. ClinicalTrials.gov, Number: NCT03836131., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Inpatients are at risk for inadequate colon cleansing. Experts recommend 4L-polyethylene-glycol (PEG) solution. A higher colon cleansing adequacy rate for a hyperosmolar 1L-PEG plus ascorbate prep has been recently reported., Aims: We aimed to determine whether 1L-PEG outperforms 4L-PEG among inpatients., Methods: post-hoc analysis of a large Italian multicenter prospective observational study among inpatients (QIPS study). We performed a propensity score matching between 1L-PEG and 4L-PEG group. The primary outcome was the rate of adequate colon cleansing as assessed by unblinded endoscopists through Boston scale. Secondary outcome was the safety profile., Results: Among 1,004 patients undergoing colonoscopy, 724 (72%) were prescribed 4L-PEG and 280 (28%) 1L-PEG. The overall adequate colon cleansing rate was 69.2% (n = 695). We matched 274 pairs of patients with similar distribution of confounders. The rate of patients with adequate colon cleansing was higher in 1L-PEG than in 4L-PEG group (84.3% vs. 77.4%, p = 0.039). No different shift in serum concentration of electrolytes (namely Na + , K + , Ca 2+ ), creatinine and hematocrit were observed for both preparations., Conclusion: We found a higher rate of adequate colon cleansing for colonoscopy with the 1L-PEG bowel prep vs. 4L-PEG, with apparent similar safety profile, among inpatients. A confirmatory randomized trial is needed. (ClinicalTrials.gov no: NCT04310332)., (Copyright © 2020. Published by Elsevier Ltd.)

Background and Aim: Endoscopic full-thickness resection(EFTR) with FTRD ® in colo-rectum may be useful for several indications.The aim was to assess its efficacy and safety., Material and Methods: In this retrospective multicenter study 114 patients were screened; 110 (61M/49F, mean age 68 ± 11 years, range 20-90) underwent EFTR using FTRD ® . Indications were:residual/recurrent adenoma (39), incomplete resection at histology (R1 resection) (26), non-lifting lesion (12), adenoma involving the appendix (2) or diverticulum (2), subepithelial lesions(10), suspected T1 carcinoma (16), diagnostic resection (3). Technical success (TS: lesion reached and resected), R0 resection (negative lateral and deep margins),EFTR rate(all layers documented in the specimen) and safety have been evaluated., Results: TS was achieved in 94.4% of cases. EFTR was achieved in 91% with lateral and deep R0 resection in 90% and 92%. Mean size of specimens was 20 mm (range 6-42). In residual/recurrent adenomas, final analysis revealed: low-risk T1 (11), adenoma with low-grade dysplasia (LGD) (24) and high-grade dysplasia (HGD) (3), scar tissue (1). Histology reports of R1 resections were: adenoma with LGD (6), with HGD (1), low-risk (6) and high-risk (1) T1, scar tissue (12). Non-lifting lesions were diagnosed as: adenoma with HGD (3), low-risk (7) and high risk (2) T1. Adverse clinical events occurred in 12 patients (11%),while adverse technical events in11%. Three-months follow-up was available in 100 cases and residual disease was evident in only seven patients., Conclusions: EFTR using FTRD ® seems to be a feasible, effective and safe technique for treating selected colo-rectal lesions. Comparative prospective studies are needed to confirm these promising results., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: Although split regimen is associated with higher adenoma detection and is recommended for elective colonoscopy, its adoption remains suboptimal. The identification of patient-related barriers may improve its implementation. Our aim was to assess patients' attitude towards split regimen and patient-related factors associated with its uptake., Design: In a multicentre, prospective study, outpatients undergoing colonoscopy from 8:00 to 14:00 were given written instructions for 4 L polyethylene glycol bowel preparation, offering the choice between split-dose and day-before regimens and emphasising the superiority of split regimen on colonoscopy outcomes. Uptake of split regimen and association with patient-related factors were explored by a 20-item questionnaire., Results: Of the 1447 patients (mean age 59.2±13.5 years, men 54.3%), 61.7% and 38.3% chose a split-dose and day-before regimens, respectively. A linear correlation was observed between time of colonoscopy appointments and split-dose uptake, from 27.3% in 8:00 patients to 96% in 14:00 patients (p<0.001, χ 2 for linear trend). At multivariate analysis, colonoscopy appointment before 10:00 (OR 0.14, 95% CI 0.11 to 0.18), travel time to endoscopy service >1 h (OR 0.55, 95% CI 0.38 to 0.79), low education level (OR 0.72, 95% CI 0.54 to 0.96) and female gender (OR 0.74, 95% CI 0.58 to 0.95) were inversely correlated with the uptake of split-dose. Overall, the risk of travel interruption and faecal incontinence was slightly increased in split regimen patients (3.0% vs 1.4% and 1.5% vs 0.9%, respectively; p=NS). Split regimen was an independent predictor of adequate colon cleansing (OR 3.34, 95% CI 2.40 to 4.63) and polyp detection (OR 1.46, 95% CI 1.11 to 1.92)., Conclusion: Patient attitude towards split regimen is suboptimal, especially for early morning examinations. Interventions to improve patient compliance (ie, policies to reorganise colonoscopy timetable, educational initiatives for patient and healthcare providers) should be considered., Trial Registration Number: NCT02287051; pre-result., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: This study aimed to explore the relationship between K-ras status, anti-tumour treatments, and the complications of colorectal self-expandable metallic stenting in colorectal cancer., Methods: This is a retrospective, multicentre study of 91 patients with obstructive advanced colorectal cancer palliated with enteral stents between 2007 and 2011., Results: K-ras wild-type tumours were diagnosed in 44 patients (48.4%); 82 (90.1%) received chemotherapy and 45 (49.4%) had additional biological therapy (34 bevacizumab, 11 cetuximab). Twenty-one (23.1%) experienced stent-related complications: 11 (52.4%) occurred in the K-ras mutant group (P=0.9). K-ras wild-type patients were not less likely to develop adverse events than K-ras mutant patients (OR, 0.99; 95% CI: 0.4-2.7). Overall mean time to complication was 167.6 days (range 4-720 days), with no difference between the two groups (141 vs. 197 days; P=0.5). Chemotherapy did not influence the risk of complications (OR, 0.56; 95% CI: 0.14-2.9), and there was no evidence that patients treated with chemotherapy and cetuximab were more likely to experience stent-related complications than patients treated with chemotherapy alone, or untreated (OR, 1.2; 95% CI: 0.2-5.9). Although perforation rates were higher with bevacizumab-based treatment (11.8% vs. 7%), this result was not statistically significant (P=0.69)., Conclusions: K-ras mutation status, chemotherapy, and biological treatments should not influence colorectal stent-related complication rates., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Aberrant activation of canonical Wnt signaling is a hallmark event in colorectal carcinogenesis. The Dickkopf-1 (DKK1) and Secreted Frizzled Related Protein 1 (SFRP1) genes encode extracellular inhibitors of Wnt signaling that are frequently silenced by promoter hypermethylation in colorectal cancer (CRC). These methylation events have been identified as prognostic markers of patient outcome and tumor subtype in several cancers but similar roles in CRC have not been comprehensively examined. In CRC, the microsatellite instability (MSI) subtype associates with favorable disease outcome but the molecular events that are responsible remain poorly understood. Consequently, we quantified promoter methylation status of the Wnt antagonist genes DKK1 and SFRP1 in a large population-based cohort of CRCs from Ontario (n = 549) and Newfoundland (n = 696) stratified by MSI status. We examined the association between methylation status and clinicopathological features including tumor MSI status and patient survival. DKK1 and SFRP1 were methylated in 13 and 95% of CRCs, respectively. In Ontario, DKK1 methylation was strongly associated with MSI tumors after adjustment for age, sex and tumor location [odds ratio (OR) = 13.7, 95% confidence interval (CI) = 7.8-24.2, P < 0.001]. Conversely, SFRP1 methylation was inversely associated with MSI tumors after these adjustments (OR = 0.3, 95% CI = 0.1-0.9, P = 0.009). Similar results were obtained in Newfoundland. There were no independent associations with recurrence-free survival. This is the first large study to identify associations between Wnt antagonist promoter hypermethylation and CRC MSI subtype. These events provide insight into subtype-specific epigenetic mediation of Wnt signaling in CRC.

ApoE single nucleotide polymorphisms (SNPs) Cys112Arg (Epsilon-4), and Arg158Cys (Epsilon-2) have been implicated in cardiovascular and Alzheimer's disease, but their role in colorectal cancer (CRC) has not been extensively studied. We investigated whether ApoE polymorphisms alone or in combination with dietary factors selectively contribute to mismatch-repair (MMR) proficient (microsatellite stable/low or MSS/L) vs deficient (microsatellite unstable or MSI-H) CRCs. We carried out a case-control study with 906 CRC cases and 911 unaffected controls to examine the associations between ApoE polymorphisms and dietary factors and assessed their contribution to MSS/L and MSI-H CRCs. We used unconditional logistic regression to evaluate the associations between ApoE SNPs, tumour MSI status, and dietary factors after adjusting for age and sex. All statistical tests were two-sided. No significant differences in ApoE genotype frequencies were observed between CRC cases and unaffected controls. We observed that increased dietary intake of total fat, saturated fat, cholesterol, and red meat was significantly associated with CRC. Among non-ApoE4 carriers, 2-4 and >4 red meat servings/week were associated with developing MSS/L CRC (OR=1.51, 95% CI 1.10-2.07 and OR=1.80, 95% CI 1.30-2.48, respectively), whereas among ApoE4 allele carriers, four or more red meat servings/week were associated with MSI-H CRC (OR=4.62, 95% CI 1.20-17.77) when compared with the controls. ApoE isoforms modulate the risk of MSI-H and MSS/L CRCs among high red meat consumers.

Colorectal cancer literature regarding the interaction between polymorphisms in carcinogen-metabolizing enzymes and red meat intake/doneness is inconsistent. A case-control study was conducted to evaluate the interaction between red meat consumption, doneness, and polymorphisms in carcinogen-metabolizing enzymes. Colorectal cancer cases diagnosed 1997 to 2000, ages 20 to 74 years, were identified through the population-based Ontario Cancer Registry and recruited by the Ontario Family Colorectal Cancer Registry. Controls were sex-matched and age group-matched random sample of Ontario population. Epidemiologic and food questionnaires were completed by 1,095 cases and 1,890 controls; blood was provided by 842 and 1,251, respectively. Multivariate logistic regression was used to obtain adjusted odds ratio (OR) estimates. Increased red meat intake was associated with increased colorectal cancer risk [OR (> 5 versus < or = 2 servings/wk), 1.67 (1.36-2.05)]. Colorectal cancer risk also increased significantly with well-done meat intake [OR (> 2 servings/wk well-done versus < or = 2 servings/wk rare-regular), 1.57 (1.27-1.93)]. We evaluated interactions between genetic variants in 15 enzymes involved in the metabolism of carcinogens in overcooked meat (cytochrome P450, glutathione S-transferase, UDP-glucuronosyltransferases, SULT, NAT, mEH, and AHR). CYP2C9 and NAT2 variants were associated with colorectal cancer risk. Red meat intake was associated with increased colorectal cancer risk regardless of genotypes; however, CYP1B1 combined variant and SULT1A1-638G>A variant significantly modified the association between red meat doneness intake and colorectal cancer risk. In conclusion, well-done red meat intake was associated with an increased risk of colorectal cancer regardless of carcinogen-metabolizing genotype, although our data suggest that persons with CYP1B1 and SULT1A1 variants had the highest colorectal cancer risk.

Hereditary non-polyposis colorectal cancer (HNPCC) represents about 1-3% of all cases of colorectal cancer (CRC). The objectives of the study were to examine motivational factors, expectations and psychosocial functioning in a sample of CRC survivors undergoing genetic testing for HNPCC. A cross-sectional survey of 314 colorectal cancer patients recruited through a population-based colon cancer family registry was conducted. Motivations for genetic testing for hereditary cancer were similar to those of clinic-based samples of CRC patients and included learning of the increased risk to offspring and finding out if additional screening was needed. While age at diagnosis and sex were associated with psychological functioning, significant predictors of post-counseling distress were perceived lower satisfaction with social support, an escape-avoidant coping style and the anticipation of becoming depressed if a mutation was present. Most cancer survivors anticipated disclosing test results to relatives and physicians. Cancer survivors reported several motivations for genetic testing for HNPCC that varied by sex. A subgroup of survivors with lower satisfaction with social support and an escape-avoidant coping style were worried about the potential impact of genetic test results and demonstrated more distress following counseling. Findings have implications for future research and potential support needs during the genetic counseling and testing process.

Evidence suggests dietary phytoestrogens may reduce the risk of certain hormonal cancers (e.g. breast and prostate). There is a paucity of data regarding phytoestrogens and colorectal cancer risk. Phytoestrogens are plant compounds with estrogen-like activities. Main classes include isoflavones (found in legumes such as soy) and lignans (found in grains, seeds, nuts, fruits, and vegetables). Although isoflavones have dominated phytoestrogen cancer research, lignans may be more relevant to North American diets. Food questionnaires and analytic databases have recently been modified to incorporate some lignan information. We conducted a case-control study to evaluate the association between phytoestrogen intake and colorectal cancer risk. Colorectal cancer cases were diagnosed in 1997-2000, aged 20-74 y, identified through the population-based Ontario Cancer Registry, and recruited by the Ontario Familial Colorectal Cancer Registry. Controls were a sex and age-group matched random sample of the population of Ontario. Epidemiologic and food frequency questionnaires were completed by 1095 cases and 1890 control subjects. Multivariate logistic regression analysis was used to obtain adjusted odds ratio (OR) estimates. Dietary lignan intake was associated with a significant reduction in colorectal cancer risk [OR (T3 vs. T1) = 0.73; 95% CI: 0.56, 0.94], as was isoflavone intake [OR (T3 vs. T1) = 0.71; 95% CI: 0.58, 0.86]. We evaluated interactions between polymorphic genes that encode enzymes possibly involved in metabolism of phytoestrogens (CYPs, catechol O-methyl transferase, GSTs, and UGTs) and found no significant effect modification with respect to phytoestrogen intake. This finding that phytoestrogen intake may reduce colorectal cancer risk is important, because dietary intake is potentially modifiable.

Objective: This is the first study to evaluate the association between colonic screening and colorectal cancer risk among Canadians., Methods: A case-control study was conducted. Cases were diagnosed with cancer of the colorectum, between 1997 and 2000, aged 20 to 74 years, identified through the population-based Ontario Cancer Registry and recruited by the Ontario Familial Colorectal Cancer Registry. Controls were a sex- and age-matched random sample of the population of Ontario. 971 cases and 1944 controls completed questionnaires (including colorectal screening history and many risk factors). Multivariate logistic regression analysis was used to obtain adjusted odds ratios (OR) estimates., Results: Having had a fecal occult blood screen was associated with reduced colorectal cancer risk (OR=0.76; 95% confidence interval (CI): 0.59, 0.97). Having had a screening sigmoidoscopy was associated with a halving of colorectal cancer risk (OR = 0.52; 95% CI: 0.34, 0.80). Having had a screening colonoscopy did not significantly reduce colorectal cancer risk (OR = 0.69; 95% CI: 0.44, 1.07); however, having had either screening endoscopy was associated with a significant reduction in colorectal cancer risk (OR = 0.62; 95% CI: 0.44, 0.87). Findings differed slightly by anatomic sub-site (proximal and distal colorectum)., Conclusions: We report a reduction in colorectal cancer risk among persons who underwent colorectal cancer screening; in particular, sigmoidoscopy. Findings are of great importance for the prevention of colorectal cancer.

Colorectal cancer screening reduces colorectal cancer incidence and mortality. This population-based study was conducted to evaluate (i) the association between subject factors and colorectal screening participation and (ii) the lifetime prevalence of colorectal screening among the general population of Ontario, Canada. Population-based controls were recruited by the Ontario Familial Colorectal Cancer Registry during 1998-2000. The 1944 persons completed an epidemiologic questionnaire. Descriptive statistics were computed and step-wise multivariate logistic regression was used to estimate odds ratios and 95% confidence intervals. Overall, 23% of persons greater than 50 years of age reported ever having had colorectal cancer screening; 17% reported fecal occult blood test (FOBT), 6% sigmoidoscopy, and 4% colonoscopy. Family history of colorectal cancer, increased age, higher household income, and use of hormone replacement therapy (among women) were all significantly associated with ever having had colorectal cancer screening. The low prevalence of colorectal cancer screening among the target population suggests the need for an increased awareness of the public health importance of colorectal cancer screening.

The MutY human homologue (MYH) gene encodes a member of the base excision repair pathway that is involved in repairing oxidative damage to DNA. Two germline MYH gene mutations that result in Myh proteins containing amino acid substitutions Y165C and G382D (hereafter called the Y165C and G382D mutations) are associated with adenomatous poly-posis and colorectal cancer among patients from several European poly-posis registries. We used a population-based series of 1238 colorectal cancer patients and 1255 healthy control subjects from Ontario, Canada, to examine the risk of colorectal cancer among biallelic and monoallelic germline MYH Y165C and G382D mutation carriers. The entire MYH gene coding region was screened in all MYH Y165C and G382D mutation carriers. Compared with noncarriers, biallelic and monoallelic germline MYH gene mutation carriers had an increased risk of colorectal cancer and were more likely to have first-or second-degree relatives with colorectal cancer (relative risk = 1.54, 95% confidence interval = 1.10 to 2.16). The increased risk of colorectal cancer in biallelic and monoallelic MYH gene mutation carriers was not consistently associated with the development of multiple adenomatous polyps. Loss of heterozygosity in at least one of four loci in MYH was detected in eight (47%) of 17 colorectal tumors from monoallelic MYH gene mutation carriers but in only two (20%) of 10 colorectal tumors from biallelic MYH gene mutation carriers. These two MYH gene mutations may account for a substantial fraction of hereditary colorectal cancer.