Distal Colorectal Cancer Research Articles

Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial

Colorectal cancer is the third most common cancer worldwide and has a high mortality rate. We tested the hypothesis that only one flexible sigmoidoscopy screening between 55 and 64 years of age can substantially reduce colorectal cancer incidence and mortality. This randomised controlled trial was undertaken in 14 UK centres. 170 432 eligible men and women, who had indicated on a previous questionnaire that they would accept an invitation for screening, were randomly allocated to the intervention group (offered flexible sigmoidoscopy screening) or the control group (not contacted). Randomisation by sequential number generation was done centrally in blocks of 12, with stratification by trial centre, general practice, and household type. The primary outcomes were the incidence of colorectal cancer, including prevalent cases detected at screening, and mortality from colorectal cancer. Analyses were intention to treat and per protocol. The trial is registered, number ISRCTN28352761. 113 195 people were assigned to the control group and 57 237 to the intervention group, of whom 112 939 and 57 099, respectively, were included in the final analyses. 40 674 (71%) people underwent flexible sigmoidoscopy. During screening and median follow-up of 11.2 years (IQR 10.7-11.9), 2524 participants were diagnosed with colorectal cancer (1818 in control group vs 706 in intervention group) and 20 543 died (13 768 vs 6775; 727 certified from colorectal cancer [538 vs 189]). In intention-to-treat analyses, colorectal cancer incidence in the intervention group was reduced by 23% (hazard ratio 0.77, 95% CI 0.70-0.84) and mortality by 31% (0.69, 0.59-0.82). In per-protocol analyses, adjusting for self-selection bias in the intervention group, incidence of colorectal cancer in people attending screening was reduced by 33% (0.67, 0.60-0.76) and mortality by 43% (0.57, 0.45-0.72). Incidence of distal colorectal cancer (rectum and sigmoid colon) was reduced by 50% (0.50, 0.42-0.59; secondary outcome). The numbers needed to be screened to prevent one colorectal cancer diagnosis or death, by the end of the study period, were 191 (95% CI 145-277) and 489 (343-852), respectively. Flexible sigmoidoscopy is a safe and practical test and, when offered only once between ages 55 and 64 years, confers a substantial and longlasting benefit. Medical Research Council, National Health Service R&D, Cancer Research UK, KeyMed.

Antioxidant and DNA methylation-related nutrients and risk of distal colorectal cancer

To investigate the relationship between antioxidant nutrients (vitamins C and E, beta-carotene, selenium) and DNA methylation-related nutrients (folate, vitamins B6 and B12) and distal colorectal cancer risk in whites and African Americans and to examine intakes from food only versus total (food plus dietary supplements) intakes. Data are from the North Carolina Colon Cancer Study-Phase II, a case-control study of 945 distal colorectal cancer (including sigmoid, rectosigmoid, and rectum) cases and 959 controls. In-person interviews captured usual dietary intake and various covariates. Multivariate logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). High intakes of each antioxidant and DNA methylation-related nutrient were significantly associated with lower risk in whites. In African Americans, the highest category of selenium from food only had a marginally significant inverse association with distal colorectal cancer risk (Q4 vs. Q1 OR: 0.55, 95% CI 0.29-1.02). Supplements did not provide additional risk reduction beyond intakes from food. Our findings provide evidence that antioxidant and DNA methylation-related nutrients may lower the risk of distal colorectal cancer in whites, and selenium may lower risk in African Americans. Optimal micronutrient intakes from food alone may be more beneficial than supplementation.

Preventing colorectal cancer and cancer mortality with colonoscopy: what we know and what we don’t know

The goal of most colonoscopies is the prevention of incident colorectal cancer and especially death from colorectal cancer. The effectiveness of colonoscopy is now justly under attack following the publication of studies showing that colonoscopy reduces the risk of distal colorectal cancer and advanced neoplasms but has no [1] [2] or limited [3] effect on the incidence of proximal neoplasms. The reasons for no or limited proximal colon protection by colonoscopy are uncertain, but there are two broad categories of possible explanations. One category is altered biology in the proximal colon. Interval cancers in the proximal colon are more likely to be microsatellite unstable (MSI) and to bear the CpG Island Methylator Phenotype (CIMP) [4]. MSI is known to push tumors through the adenoma–carcinoma sequence rapidly, and CIMP tumors are believed to be the end product of serrated polyps, a group of lesions that are endoscopically subtle and about which little is known compared with adenomas.

Location-related differences in sporadic microsatellite unstable colorectal cancer

Background Microsatellite unstable CRC is associated with female gender, large tumours, and poor differentiation. However, there are few reports about the characteristics and differences of sporadic microsatellite unstable CRC based on tumour location. Aims Site-specific heterogeneity of sporadic microsatellite unstable colorectal cancer (CRC) based on location was elucidated. Methods We enrolled 164 CRC patients with high-frequency microsatellite instability (MSI-H) from the prospective database of 2686 consecutive CRC patients who underwent surgical resection. We analysed microsatellite instability (MSI) and expression of mismatch repair (MMR) proteins (MLH1, MSH2, and MSH6). Results Among the 164 MSI-H CRC, 105 (64.0%) were located in the proximal colon and 59 (36.0%) were located in the distal colon. The proximal MSI-H CRC was predominantly in female ( p = 0.014), had a more aggressive differentiation ( p = 0.001), was of advanced stage ( p = 0.035), and had a frequent loss of MLH1 expression ( p = 0.005) compared to the distal MSI-H CRC. Conclusion There were different clinicopathologic characteristics and MMR protein expression between proximal and distal MSI-H CRC. These findings suggest that the underlying carcinogenic pathway or molecular background differs according to location, despite being microsatellite unstable CRC.

Factors that contribute to faecal cyclooxygenase-2 mRNA expression in subjects with colorectal cancer

Background:We previously reported that a faecal cyclooxygenase-2 (COX-2) mRNA assay was useful for identifying colorectal cancer (CRC). This study sought to investigate the factors that contribute to faecal COX-2 mRNA expression in subjects with CRC.Methods:The study cohort comprised 78 patients with CRC and 36 control subjects. The expressions of COX-2, β-2-microglobulin (B2M), carcinoembryonic antigen (CEA), E-cadherin (E-cad), and CD45 mRNA in faeces and COX-2 mRNA expression in tissue were determined by quantitative real-time RT–PCR.Results:The level of faecal expression of COX-2 mRNA in CRC was significantly higher than that in controls. A significant correlation was found between faecal COX-2 mRNA expression and faecal B2M, CEA, E-cad, or CD45 mRNAs, markers of exfoliated total cells, colonocytes, and leukocytes, respectively. A significant correlation was found between the expression of COX-2 mRNA in faeces and tumour surface area, COX-2 mRNA expression in primary tumour. There was no difference in faecal COX-2 mRNA expression between proximal CRC and distal CRC.Conclusion:COX-2 mRNA expression in faeces seems to originate from tumour lesion and to be affected by factors such as the number of exfoliated cells, exfoliation of inflammatory cells, COX-2 mRNA expression in tumour, and tumour size.

Apical lymph nodes at the root of the inferior mesenteric artery in distal colorectal cancer: an analysis of the risk of tumor involvement and the impact of high ligation on anastomotic integrity

What level of arterial ligation is best in left-sided colon cancer and rectal cancer remains controversial. This study aims to assess the necessity and risk of high ligation from an oncological and technical perspective. The lymph nodes at the origin of the inferior mesenteric artery (IMA) were separated as apical nodes in all patients operated for distal colorectal cancer in our department. The number and status of the nodes were prospectively assessed, and demographic and tumor-related variables were evaluated as risk factors for apical tumor invasion. Anastomotic leaks were also evaluated. A hundred and three patients (52 [50.5%] males, 60.3+/-12.9 years old) were included. The number of non-apical lymph nodes harvested was 14.5+/-7.1 with an additional 4.4+/-3.2 apical nodes at the high ligation site. Tumor invasion of apical nodes was observed in 6 (5.8%) patients. Two of these (1.9%) had no other positive nodes (skip metastases). Although none of the variables evaluated was found significant for predicting apical node positivity, tumor invasion was detected in 8.5 and 22.2% of patients with pT3 and pN2 cancers, respectively. Among patients, who had an anastomosis (n = 84, 81.6%), anastomotic leak was observed in 7(8.3%) and 1 (1.2%) of these patients required emergency relaparotomy. There was no mortality related to high ligation. High ligation of IMA may be routinely performed in patients with distal colorectal cancer, since tumor invasion of apical lymph nodes is neither rare (>5%) nor predictable, and skip metastases may also occur. This is especially true in case of an advanced disease for which apical node positivity peaks. The anastomotic leak rate is less than 10%, and mortality is low after high ligation of IMA.

Difference Between Proximal and Distal Microsatellite-Unstable Sporadic Colorectal Cancers: Analysis of Clinicopathological and Molecular Features and Prognoses

Distal microsatellite instability (MSI)-high colorectal cancers (CRCs) have been investigated by few studies and are generally regarded as having similar features to proximal MSI-high CRCs. In the present study, we aimed to elucidate whether distal sporadic MSI-high CRCs displayed distinguished clinicopathological and molecular features from proximal MSI-high CRCs. All patients who underwent their first surgical resections for stage I-IV sporadic CRCs between August 2003 and August 2006 were initially considered for enrollment, and their MSI data were prospectively collected. Among them, 135 patients with MSI-high CRCs (86 proximal and 49 distal CRCs) were finally identified. The clinicopathological and molecular characteristics, and prognosis of these cases with MSI-high CRCs were reviewed and compared according to tumor site (proximal versus distal). Distal MSI-high CRCs showed significantly more frequent association with younger age, male gender, differentiated histology, small tumor size, distant metastasis, stability in BAT25 and BAT26, and hMLH1 expression on immunohistochemical staining as compared with proximal MSI-high CRCs. In addition, distal MSI-high CRCs demonstrated significantly worse 3-year overall and disease-free survival rates than proximal MSI-high CRCs (87.0% versus 97.4%; 81.6% versus 95.9%). For stage III-IV CRCs, distal MSI-high CRCs also showed significantly worse 3-year overall and disease-free survival rates than proximal MSI-high CRCs (72.2% vs. 90.5%; 58.3% vs. 94.4%). These results indicated that distal sporadic MSI-high CRCs formed a distinct subgroup with distinguished clinicopathological and molecular features from proximal MSI-high CRCs. In addition, this study demonstrated that distal MSI-high CRCs had worse prognosis than proximal MSI-high CRCs.

Trans-Fatty acid consumption and its association with distal colorectal cancer in the North Carolina Colon Cancer Study II

trans-Fatty acid consumption and its association with distal colorectal cancer in the North Carolina Colon Cancer Study II

Antioxidant and DNA methylation-related nutrients and risk of distal colorectal cancer

Antioxidant and DNA methylation-related nutrients and risk of distal colorectal cancer

Associations of Red Meat, Fat, and Protein Intake With Distal Colorectal Cancer Risk

Associations of Red Meat, Fat, and Protein Intake With Distal Colorectal Cancer Risk

A case‐control study of colorectal cancer detection by quantification of DNA isolated from directly collected exfoliated colonocytes

This pilot study aimed to assess an original test based on the analysis of exfoliated colonocytes as a new approach to colorectal cancer (CRC) detection. DNA was isolated from exfoliated cells collected from the surface of the rectal mucosa by a standardized minimally invasive procedure in a case-control trial involving 66 patients with CRC diagnosis and 110 healthy volunteers (age 50-70). PicoGreen staining and quantitative real-time PCR (QRTPCR) were used for DNA quantification. Mean DNA scores in microg/ml obtained for the control and cancer groups were 2.1 (95% CI 1.7-2.5) and 9.0 (CI 6.7-11.2) respectively (p < 0.001) for PicoGreen and 0.8 (CI 0.6-0.9) and 3.8 (CI 1.9-5.7) respectively (p = 0.003) for QRTPCR. The PicoGreen assay better detected CRC presence. At DNA score cut-off point of 2.5 microg/ml this assay gave sensitivities of 77.8% (CI 52.4-93.6) for proximal tumours, 91.4% (CI 76.9-98.2) for distal CRC and 86.8% (CI 74.7-94.5) for all CRC with specificity at 74.0% (CI 64.0-82.4). Increasing the cut-off point to 5.0 microg/ml resulted in sensitivities of 38.9% (CI 17.3-64.3) for proximal tumours, 71.4% (CI 53.7-85.4) for distal CRC and 60.4% (CI 46.0-73.5) for all CRC. Specificity for this cut-off point increased to 94.8% (CI 88.3-98.3). The new procedure of exfoliated cell collection from the surface of the rectal mucosa is a simple, safe and well-tolerated technique providing high quality cells. These early results suggest that exfoliated cell collection in combination with DNA quantification can potentially be employed as a tool for CRC early detection.

Trans-Fatty acid consumption and its association with distal colorectal cancer in the North Carolina Colon Cancer Study II

Recently, the potential health effects of trans-fatty acid consumption have raised concerns. A few studies have examined the risk of colorectal cancer with increasing consumption of trans-fatty acids, but none investigated the risk of rectal cancer, which may have different risk factors than colon cancer. Our objective was to explore the relationship between trans-fatty acid consumption and distal colorectal (sigmoid, rectosigmoid, and rectal) cancer using a case-control study of Whites (n = 1,516) and African Americans (n = 392) in North Carolina from 2001 to 2006. Matched cases and controls were interviewed about demographic information, lifestyle factors, and diet. White cases reported higher mean consumption of trans-fatty acid than White controls, but mean consumption was similar for African American cases and controls. Relative to the lowest quartile, the highest quartiles of energy-adjusted trans-fatty acid consumption were positively associated with distal colorectal cancer for Whites [adjusted ORs for the third and fourth quartiles are 1.54 (95%CI: 1.12, 2.13) and 1.45 (95%CI: 1.04, 2.03), respectively]. Consumption was not associated with distal colorectal cancer in African Americans [adjusted ORs for the third and fourth quartiles are 0.98 (95%CI: 0.47, 2.05) and 0.87 (95%CI 0.42, 1.81), respectively]. In conclusion, high consumption of trans-fatty acids was positively associated with distal colorectal cancer among Whites.

Are prediction models for Lynch syndrome valid for probands with endometrial cancer?

Currently, three prediction models are used to predict a patient's risk of having Lynch syndrome (LS). These models have been validated in probands with colorectal cancer (CRC), but not in probands presenting with endometrial cancer (EMC). Thus, the aim was to determine the performance of these prediction models in women with LS presenting with EMC. Probands with EMC and LS were identified. Personal and family history was entered into three prediction models, PREMM(1,2), MMRpro, and MMRpredict. Probabilities of mutations in the mismatch repair genes were recorded. Accurate prediction was defined as a model predicting at least a 5% chance of a proband carrying a mutation. From 562 patients prospectively enrolled in a clinical trial of patients with EMC, 13 (2.2%) were shown to have LS. Nine patients had a mutation in MSH6, three in MSH2, and one in MLH1. MMRpro predicted that 3 of 9 patients with an MSH6, 3 of 3 with an MSH2, and 1 of 1 patient with an MLH1 mutation could have LS. For MMRpredict, EMC coded as "proximal CRC" predicted 5 of 5, and as "distal CRC" three of five. PREMM(1,2) predicted that 4 of 4 with an MLH1 or MSH2 could have LS. Prediction of LS in probands presenting with EMC using current models for probands with CRC works reasonably well. Further studies are needed to develop models that include questions specific to patients with EMC with a greater age range, as well as placing increased emphasis on prediction of LS in probands with MSH6 mutations.

Outcomes of endoluminal stenting for distal colorectal cancer: An institutional experience

Aim: The present article aims to review the results of the use of the self‐expanding metallic stent (SEMS) in our institution for distal colorectal tumours, defined as tumours distal to the splenic flexure.Patients and methods: SEMS was selectively offered to the following patients with distal colorectal tumours: (i) patients with clinically obstructed tumours; (ii) patients undergoing palliative treatment; and (iii) patients planned for neoadjuvant chemotherapy. All data, including outcomes and complications, were entered prospectively into a database. A review was carried out for those patients who underwent endoluminal stenting between February 2002 and August 2008.Results: Sixty‐eight patients were evaluated with a median age of 68 years (range 39–91). The median follow up was 11 months. Of these, 53 patients received emergency stenting for acute intestinal obstruction, 12 had palliative stenting for endoscopically obstructive cancer and three had pre‐emptive stenting of locally advanced, stenotic rectal cancer before neoadjuvant chemo‐irradiation. The overall technical success and clinical success rates were 81% and 65%, respectively. Complications included four stent‐related perforations (5.9%) and seven distal migrations (10.3%). Twenty‐seven patients from the intestinal obstruction group and the three patients from the neoadjuvant chemo‐irradiation group subsequently underwent laparoscopic tumour resection with success.Conclusion: In conclusion, our experience showed that SEMS is a useful adjunct in the management of distal colorectal cancer. Apart from being an alternative measure for palliation, SEMS is an effective and non‐invasive way for relieving obstruction in patients with obstructed tumours, allowing them to undergo subsequent one‐stage laparoscopic tumour resection. It is also useful in patients with locally advanced rectal cancer, in whom neoadjuvant chemo‐irradiation is planned.

Prospective evaluation oftrans-fatty acid intake and colorectal cancer risk in the Iowa Women's Health Study

Concerns regarding the safety of dietary trans-fatty acids (tFAs) have generated recent public interest, scientific discussion and legislative action. Although most widely recognized as a risk factor for cardiovascular disease, associations between tFA intake and incident cancer have also been proposed. With respect to colorectal cancer (CRC), existing observational data remain limited and inconclusive. Therefore, we conducted a prospective evaluation of tFA intake and CRC risk, overall and by anatomic subsite, among participants in the Iowa Women's Health Study (IWHS), a population-based cohort of older women (ages 55-69 years at enrollment). Exposure data were collected at baseline using a semiquantitative food-frequency questionnaire. Incident CRC cases were identified through annual linkage to the Iowa Cancer Registry. CRC risks were estimated using Cox proportional hazards regression models. In total, 35,216 women met our inclusion criteria and 1,229 CRC cases (631 proximal, 571 distal, 27 site not specified) were observed through 18 years of follow-up. Adjusting for age and total energy consumption, tFA intake in the 4th versus 1st quartile was not significantly associated with overall CRC risk [relative risk (RR) = 1.12; 95% confidence interval (CI) = 0.96-1.32]. Similarly, risk estimates based on proximal (RR = 1.09; 95% CI = 0.87-1.37) and distal (RR = 1.18; 95% CI = 0.93-1.49) CRC subsites did not differ from unity. Multivariable adjustment yielded slightly attenuated risk estimates, but the observed associations were not meaningfully altered. Given these findings, tFA intake does not appear to be a major CRC risk factor, at least among older women.

Exam 1: Risk of Developing Proximal Versus Distal Colorectal Cancer After a Negative Colonoscopy: a Population Based Study

Exam 1: Risk of Developing Proximal Versus Distal Colorectal Cancer After a Negative Colonoscopy: a Population Based Study

MLH1 −93G&gt;A promoter polymorphism and risk of mismatch repair deficient colorectal cancer

Rare inherited mutations in the mutL homolog 1 (MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (-93G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 -93A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG = 3.30, 95% CI 1.46-7.47, n = 1392, p = 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG=1.68, 95% confidence interval (CI) 1.00-2.83, n = 1,518, p = 0.05, proximal vs distal CRC). These findings suggest that the MLH1 -93G>A polymorphism defines a low penetrance risk allele for CRC.

Risk of Developing Proximal Versus Distal Colorectal Cancer After a Negative Colonoscopy: A Population-Based Study

The incidence of colorectal cancer (CRC) overall is reduced for up to 10 years after a negative colonoscopy. The objective of this research was to determine the incidence of proximal and distal CRC after a negative complete colonoscopy. A cohort of Ontario residents aged 50 to 80 years who had a negative complete colonoscopy between January 1, 1992, and December 31, 1997, was identified by using linked administrative databases. Cohort members had no prior history of CRC, inflammatory bowel disease, or recent colonic resection. Each individual was followed up through December 31, 2005, and the relative rate (RR) of overall CRC, distal CRC, and proximal CRC was compared with the remaining Ontario population. A cohort of 110,402 individuals with a negative complete colonoscopy was identified. The RR of CRC overall and the RR of distal CRC remained significantly lower than the Ontario population. For example, at year 14 the RR of distal CRC was 0.21 (95% confidence interval, 0.05-0.36). The RR of proximal CRC was significantly lower than the Ontario population in half of the follow-up years, mainly after 7 years of follow-up. Over a 14-year follow-up period, negative complete colonoscopy was associated with a subsequent reduced incidence of CRC overall, and of incident CRC in the distal colon. However, the reduction in incidence of proximal CRC differed in magnitude and timing, and occurred in half the follow-up years, mainly after 7 years of follow-up. These results highlight an important limitation of colonoscopy in usual clinical practice.

Risk of Proximal and Distal Colorectal Cancer Following Flexible Sigmoidoscopy: A Population-Based Cohort Study

Little is known about the risk of proximal and distal colorectal cancer (CRC) following flexible sigmoidoscopy (FS) in usual clinical practice. Our objective was to estimate the annual incidence of CRC within 7 yr following FS and to identify factors associated with incident CRC in those with a negative FS. In this population-based retrospective cohort study, we included men and women 50-80 yr of age who had a negative or positive FS during 1996-1998 in Ontario. We followed each individual through December 31, 2005 and calculated the age- and sex-standardized incidence rates (SIRs) and 95% confidence intervals (CIs) for distal and proximal CRC. We compared the relative rate (RR) and 95% CIs of incident CRC between the negative and positive FS cohorts and the remaining Ontario population. Cox models were used to evaluate factors associated with incident cancers. The RR for distal CRC was significantly lower among those with a negative FS than in the Ontario population during each year of follow-up except the first year. For example, at 7 yr, the SIR for distal CRC following negative FS was 0.74 cancers/1,000 persons (95% CI 0.46-1.13) compared with 1.07/1,000 (95% CI 1.02-1.11) in the Ontario population (RR = 0.69, 95% CI 0.40-0.99). The RR for proximal CRC, except for year 2, did not differ between the negative FS cohort and the Ontario population during follow-up. In the positive FS cohort, the RR for distal CRC was significantly higher in the first year of follow-up compared with the Ontario population, but not thereafter. The results were similar for the RR for proximal CRC in the positive FS cohort. Only age was significantly associated with incident CRC following negative FS. Following negative FS, the incidence of distal but not proximal CRC was reduced for up to 7 yr. Following a positive FS, the incidence of distal and proximal cancer after the first year of follow-up did not differ from the Ontario population. The benefit of FS was confined to the distal colon, emphasizing the potential limitation of FS in practice.

IGF-I, IGFBP-3, and IGF-I/IGFBP-3 Ratio: No Association with Incident Colorectal Cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

The insulin-like growth factor (IGF) signaling system is thought to affect tissue growth and development ([1][1]), with IGF-I and IGF binding protein-3 (IGFBP-3) having putative procarcinogenic and anticarcinogenic properties, respectively. A recent meta-analysis of four prospective studies found