Marker Of Colorectal Cancer Risk Research Articles

Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats

Polyethylene glycol (PEG) is a frequently used osmotic laxative that accelerates gastrointestinal transit. It has remained unclear, however, whether PEG affects intestinal functions. We aimed to determine the effect of PEG treatment on intestinal sterol metabolism. Rats were treated with PEG in drinking water (7%) for 2 wk or left untreated (controls). We studied the enterohepatic circulation of the major bile salt (BS) cholate with a plasma stable isotope dilution technique and determined BS profiles and concentrations in bile, intestinal lumen contents, and feces. We determined the fecal excretion of cholesterol plus its intestinally formed metabolites. Finally, we determined the cytolytic activity of fecal water (a surrogate marker of colorectal cancer risk) and the amount and composition of fecal microbiota. Compared with control rats, PEG treatment increased the pool size (+51%; P < 0.01) and decreased the fractional turnover of cholate (-32%; P < 0.01). PEG did not affect the cholate synthesis rate, corresponding with an unaffected fecal primary BS excretion. PEG reduced fecal excretion of secondary BS and of cholesterol metabolites (each P < 0.01). PEG decreased the cytolytic activity of fecal water [54 (46-62) vs. 87 (85-92)% erythrocyte potassium release in PEG-treated and control rats, respectively; P < 0.01]. PEG treatment increased the contribution of Verrucomicrobia (P < 0.01) and decreased that of Firmicutes (P < 0.01) in fecal flora. We concluded that PEG treatment changes the intestinal bacterial composition, decreases the bacterial dehydroxylation of primary BS and the metabolism of cholesterol, and increases the pool size of the primary BS cholate in rats.

Can selenium levels act as a marker of colorectal cancer risk?

BackgroundSelenium has attracted attention because of its antioxidant properties. Antioxidants protects cells from damage. Certain breakdown products of selenium are believed to prevent tumor growth by enhancing the immune cell activity and suppressing the development of tumor blood vessels. In this observational study, selenium level was measured in a series of patients from Poland and Estonia to determine a correlation between levels of this microelement and colorectal cancer risk.MethodsA total of 169 colorectal cancer patients and 169 healthy controls were enrolled in the study after obtaining their informed consent. Selenium level in the blood serum was measured using Graphite Furnace Atomic Absorption Spectrometry (GFAAS). The statistical analysis was performed by Fisher’s exact test.ResultsThe threshold point of selenium level was 55 μg/l and 65 μg/l for Poland and Estonia respectively, for an increase in cancer risk. The lower levels of selenium were associated with greater risk of colorectal cancer.ConclusionsThe result reveals a significant strong association between low selenium level and the colorectal cancer risk in both Estonian and Polish populations.

Homocysteine, cysteine, and risk of incident colorectal cancer in the Women’s Health Initiative observational cohort

Inflammation underlies the etiology of colorectal cancer (CRC). Hyperhomocysteinemia is associated with inflammation and may be a risk marker for CRC. Cysteine is a metabolic product of homocysteine and a precursor of the antioxidant glutathione. It is unknown whether cysteine is associated with CRC. The objective was to assess the associations between homocysteine and cysteine and CRC incidence in postmenopausal women. Associations between homocysteine and cysteine and incident CRC in the Women's Health Initiative observational cohort were assessed by using a nested case-control design. Cases and controls (n = 988/group) were matched for age (mean ± SD age: 67 ± 7 y), ethnicity (85.2% white, 8.9% black, 2.2% Hispanic/Latina, and 3.6% other), hysterectomy status, and date of blood draw. Homocysteine and cysteine were measured by HPLC with postcolumn fluorimetric detection. Multivariate-adjusted ORs (95% CIs) for CRC were 1.46 (1.05, 2.04) for the highest quartile of homocysteine (>9.85 μmol/L) compared with the lowest quartile (≤6.74 μmol/L) (P = 0.02) and 0.57 (0.40, 0.82) for the highest quartile of cysteine (>309 μmol/L) compared with the lowest quartile (≤260 μmol/L) (P = 0.01). The association with homocysteine was significant for proximal colon tumors (P = 0.008) but not for distal or rectal tumors, whereas the association with cysteine was significant for rectal tumors (P = 0.02), borderline for proximal tumors (P = 0.06), and not significant for distal tumors. The associations with both homocysteine and cysteine were significant for localized tumors (P ≤ 0.01) but not for metastases. High plasma homocysteine is associated with increased risk of CRC, whereas high cysteine is associated with decreased risk. This trial was registered at clinicaltrials.gov as NCT 00000611.

PLZF Expression during Colorectal Cancer Development and in Normal Colorectal Mucosa according to Body Size, as Marker of Colorectal Cancer Risk

Promyelocytic leukemia zinc finger protein (PLZF) is a protein involved in various signaling, growth regulatory, and differentiation pathways, including development/function of some T cells. Here, we aimed at the detection of PLZF during colorectal carcinogenesis, using immunofluorescence, and at the evaluation of the colocalization of PLZF with CD2 and CD56 positive cells (T, γ δ, NK, and NKT cells), using confocal-microscopy, along colorectal carcinogenesis, since its earliest stages, that is, dysplastic aberrant crypt foci (ACF). Furthermore, we analyzed PLZF in the normal colonic mucosa (NM) according to anthropometric parameters of the subject. NM exhibited strong CD56 fluorescent staining. This infiltration was lost in both ACF and colorectal carcinoma (CRC), while PLZF presence increased from NM to ACF and CRC. Strong association was found between CD56+ colonic mucosa cell infiltration and body mass index. Interestingly, an increased stromal PLZF-reactivity was present in NM of obese subjects. This study shows that overexpression of PLZF and exclusion of NK cells in dysplastic microenvironment are very early events in the stepwise sequence leading to CRC and that lower levels of CD56+ cells in NM, together with increased levels of PLZF+ cells, can be a reflection of colon cancer risk due to obesity.

Novel Methylation Panel for the Early Detection of Neoplasia in High-risk Ulcerative Colitis and Crohnʼs Colitis Patients

Patients with ulcerative colitis and Crohn's colonic disease are at increased risk of developing colorectal cancer (CRC). The aim of the study was to analyze the methylation status of selected genes as a risk marker for CRC in inflammatory bowel disease (IBD) patients. We evaluated the methylation status of four genes (TGFB2, SLIT2, HS3ST2, and TMEFF2) in biopsies of four groups of patients: 60 patients with sporadic CRC, 32 patients with IBD-associated neoplasia, 85 patients with IBD without associated neoplasia (20 at high risk and 65 at low risk), and 28 healthy controls. Methylation-specific melting curve analysis (MS-MCA) was used. Methylation status of these genes was also assessed in stool DNA from 60 IBD patients without neoplasia. Methylation of the panel of genes analyzed was a very common phenomenon (78%) in IBD-associated neoplasia. The prevalence of methylation in adjacent nonneoplastic mucosa was also high (12/30). This prevalence was higher than in mucosa from healthy controls (2/28;7.1%; P < 0.05). Methylation of SLIT2 and TMEFF2 was more frequently detected in the mucosa of IBD patients at high risk of dysplasia or cancer (15/20) than patients at low risk (32/63) (P = 0.05 and P = 0.03, respectively). When stool samples were assessed, only SLIT2 gene methylation was more frequently methylated in the group of patients at high risk of dysplasia or cancer (4/16) compared to low risk (0/37) (P = 0.006). Analysis of a panel of methylation markers may help in the early identification of colorectal dysplasia or cancer in high-risk IBD patients.

Abstract A57: Randomized double-blind trial of a rational combination of anthocyanins and curcumin for colon cancer prevention in subjects with colorectal adenomas: MIRACOL study

Abstract Rationale: Colorectal cancer (CRC) is one of the most frequent malignant neoplasms in both sexes within developed countries. Colorectal carcinogenesis is a multistage process that occurs over a period of 10–20 years. Colorectal adenomas (CA) are well recognized CRC risk markers. Evidence from epidemiological studies and clinical trials, suggests that removal of CA decreases the incidence of CRC, supporting the hypothesis that regression or elimination of CA through chemopreventive strategies would also reduce CRC's incidence. Inflammation and oxidative stress appear to play a crucial role in the development of CRC; NF-kB activation has been associated with multiple pathways of oncogenesis, including apoptosis, cell cycle control, differentiation, angiogenesis and cell migration; interference with these mechanisms may represent a strategy in CRC chemoprevention. Anthocyanins and curcumin represent, so far, the two most reliable candidates mainly due to their integrated capacity of modulating key steps of inflammatory processes, cell proliferation and tumor progression. Anthocyanins are a group of natural occurring pigments responsible for the red-blue color of many fruits and vegetables and are provided with remarkable antiproliferative, apoptogenic, antiinflammatory and antioxidant effects and with the capacity of inhibiting tumor progression in experimental models of gastrointestinal cancerogenesis. In a recent pilot study in CRC patients, anthocyanins administered for 7 days were dose-dependently effective in reducing the proliferation index Ki-67. Curcumin is a polyphenolic compound obtained from turmeric (Curcuma longa L.) endowed with marked anti-inflammatory, antioxidant and antineoplastic effects; due to its peculiar proximal carbonyls, curcumin is also effective in interacting with the intracellular redox status contributing to modulate main steps of cellular activation and proliferation. In the present study, we propose to test a rational combination of a natural enriched source of anthocyanins from bilberry (Vaccinium myrtillus L.), MIRTOSELECT© (standardized to contain 36 % anthocyanins) with a bioavailable form of curcumin, MERIVA©. Based on previous experience in humans, the proposed daily dosages of 1g of MIRTOSELECT© and 1g of MERIVA© would assure an effective concentration of anthocyanins and curcumin in the target tissue; and at plasmatic level. Design: To assess the effects of MIRTOSELECT© and MERIVA© on cell proliferation in both adenomatous and unaffected colonic tissue, we designed a presurgical, double blind, placebo-controlled, randomized phase I/II trial in patients with colorectal adenomatous polyps. After a complete colonoscopy and biopsy of the index polyp, 100 subjects with histologically confirmed CA will be assigned (50 per arm) to either placebo or MIRTOSELECT© 1g/d + MERIVA© 1gr/die treatment for 4–6 weeks before polyp removal. Primary endpoint will be the nuclear transcriptional activation marker β-Catenin in adenoma tissue in subjects treated with the complex compared with placebo. The study is designed to have 85% power to detect an absolute difference of 10% between arms in β-Catenin expression levels in adenoma tissue after treatment, assuming 10% lost to follow-up. Secondary endpoints include treatment modulation of biomarkers of oxidative activation (NF-kB), proliferation and apoptosis (Ki67, TUNEL), phlogosis (u-CRP), circulating IGFs (IGF-1, IGFBP-3), genetic expression profile and tolerability. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A57.

Homocysteine, cysteine and risk of incident colorectal cancer in the Women's Health Initiative Observational Cohort

Inflammatory bowel disease (IBD) is a risk factor for colorectal cancer (CRC), as is low intake of folate. Hyperhomocysteinemia is highly prevalent in patients with IBD and is a marker of low folate status; thus homocysteine may serve as a risk marker for CRC. Cysteine is a metabolic product of homocysteine and a precursor for glutathione, an important intracellular antioxidant. It is unknown if cysteine is associated with CRC. We investigated the associations between homocysteine and cysteine and incident CRC in the Women's Health Initiative Observational Cohort using a nested case-control design. Cases and controls (n=988 per group) were matched for age (mean 67±7 yrs) and ethnicity. Multivariate-adjusted odds ratios (95% CI) for incident CRC were 1.4 (1.0, 1.9) for those subjects in the highest quartile of homocysteine (>9.8 μmol/L) compared with the lowest (≤6.8 μmol/L) (p=0.03), and 0.6 (0.4, 0.8) for those in the highest quartile of cysteine (>308 μmol/L) compared with the lowest (≤259 μmol/L) (p=0.007). The associations were statistically significant for proximal tumors (p≤0.04), but not for distal tumors, and were significant for localized tumors (p≤0.01), but not for metastases. These data indicate that high plasma homocysteine is associated with increased risk of CRC, while high cysteine is associated with decreased risk. Funding: NIH R01 CA120523, NIH N01 WH22110

Abstract ED05-04: Presurgical models to effectively screen preventive agents

Abstract ED05-04: Presurgical models to effectively screen preventive agents

Polymorphisms in RAD51, XRCC2 and XRCC3 genes of the homologous recombination repair in colorectal cancer—a case control study

XRCC2 and XRCC3 proteins are structurally and functionally related to RAD51 which play an important role in the homologous recombination, the process frequently involved in cancer transformation. In our previous work we show that the 135G>C polymorphism (rs1801320) of the RAD51 gene can modify the effect of the Thr241Met polymorphism (rs861539) of the XRCC3 gene. We tested the association between the 135G>C polymorphism of the RAD51 gene, the Thr241Met polymorphism of the XRCC3 gene and the Arg188His polymorphism (rs3218536) of the XRCC2 gene and colorectal cancer risk and clinicopathological parameters. Polymorphisms were evaluated by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) in 100 patients with invasive adenocarcinoma of the colon and in 100 sex, age and ethnicity matched cancer–free controls. We stratified the patients by genotypes, tumour Duke’s and TNM stage and calculated the linkage of each genotype with each stratum. Carriers of Arg188Arg/Me241tMet, His188His/Thr241Thr and His188His/G135G genotypes had an increased risk of colorectal cancer occurrence (OR 5.70, 95% CI 1.10–29.5; OR 12.4, 95% CI 1.63–94.9; OR 5.88, 95% CI 1.21–28.5, respectively). The C135C genotype decreased the risk of colorectal cancer singly (OR 0.06, 95% CI 0.02–0.22) as well as in combination with other two polymorphisms. TNM and Duke’s staging were not related to any of these polymorphisms. Our results suggest that the 135G>C polymorphism of the RAD51 gene can be an independent marker of colorectal cancer risk. The Thr241Met polymorphism of the XRCC3 gene and the Arg188His polymorphism of the XRCC2 gene can modify the risk of colorectal cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s11033-010-0430-6) contains supplementary material, which is available to authorized users.

Abstract 955: n-3 polyunsaturated fatty acids promote apoptosis in oxidatively stressed transgenic mouse models

Abstract Colorectal cancer is the second most common cause of cancer death in the United States. An increase in reactive oxygen species (ROS) generated from oxidative stress is generally associated with abnormal cancer cell growth and reflects a disruption of redox homeostasis. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. Interestingly, we have recently demonstrated that n-3 polyunsaturated fatty acids (PUFA) enhance apoptosis, a useful marker of colorectal cancer risk, in colonocytes by enhancing phospholipid oxidation. In order to elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed SOD2het, Gpx4het and Gpx4 over-expressing (Gpx4TG) transgenic mouse models diets containing either n-3 or n-6 PUFA (control). Animals were fed diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 wk. Apoptotic cells in the distal colon were enumerated in situ. Relative to their respective wild type siblings, Gpx4het and SOD2het mice had significantly (P&amp;lt;0.05) enhanced levels of colonocyte apoptosis, 63% and 20%, respectively. In contrast, apoptosis in Gpx4TG mice was significantly (P&amp;lt;0.05) reduced by 16% compared to wild type siblings. FO vs CO feeding further increased (P&amp;lt;0.05) apoptosis in Gpx4het and SOD2het mice by 42% and 18%, respectively. In addition, n-3 PUFA elevated apoptosis in Gpx4TG mice back to a level comparable with wild type (control) siblings. These data indicate that dietary and/or genetic pre-deposition to oxidative stress facilitates apoptosis in the colon, thereby reducing colon cancer risk. Supported in part by NIH grants CA59034, CA129444, P30ES09106, and USDA 2008-34402-19195, “Designing Foods for Health” through the Vegetable &amp; Fruit Improvement Center. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 955.

AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

The AGA Institute Medical Position Panel consisted of the authors of the technical review, a community-based gastroenterologist (Robert P. McCabe, MD, Minnesota Gastroenterology), academic-based gastroenterologists (Themistocles Dassopoulos, MD, James D. Lewis, MD, and Thomas A. Ullman, MD), an insurance provider representative (Tom James III, MD Physician Advisor, Strategic Advisory Group, Humana), a colon and rectal surgeon (Robin McLeod, MD, Mount Sinai Hospital-Canada), a pathologist (Lawrence J. Burgart, MD, Minnesota Gastroenterology), chair of the AGA Institute Clinical Practice and Quality Management Committee (John Allen, MD, Minnesota Gastroenterology), and chair of the Practice Management and Economics Committee (Joel V. Brill, MD, Predictive Health, LLC) .

DNA/RNA Markers for Colorectal Cancer Risk in Preserved Stool Specimens: A Pilot Study

Exfoliated cells in human stool offer excellent opportunities to non-invasively detect molecular markers associated with colorectal tumorigenesis, and to evaluate the effects of exposures to exogenous and endogenous carcinogenic or chemopreventive substances. This pilot study investigated the feasibility of determining DNA methylation and RNA expression simultaneously in stool specimens treated with a single type of nucleic acid preservatives. Stool specimens from 56 volunteers that were preserved up to a week with RNA later were used in this study. Bisulfite sequencing was used to determine methylation at 27 CpG loci on the estrogen receptor 1 (ESR1) promoter. Taqman assay was used for quantitative reverse transcription polymerase chain reactions to measure cyclooxygenase 2 (COX2) and epidermal growth factor receptor (EGFR) mRNA expression. Subjects' basic demographic and other selected risk factors for colorectal cancer were captured through questionnaires and correlated with the levels of these markers. Less than 10% of the samples failed in individual assays. Overall, 24.0% of the CpG loci on the ESR1 promoter were methylated. COX2 expression and alcohol use were positively correlated; an inverse association was present between EGFR expression and cigarette smoking; and subjects using anti-diabetic medication had higher ESR1 methylation. In addition, higher EGFR expression levels were marginally associated with history of polyps and family history of colorectal cancer. The present study demonstrates that simultaneous analyses for DNA and RNA markers are feasible in stool samples treated with a single type of nucleotide preservatives. Among several associations observed, the association between EGFR expression and polyps deserves further investigation as a potential target for colorectal cancer screening. Larger studies are warranted to confirm some of our observations.

Differences in Colon Adenomas and Carcinomas Among Women and Men

COLORECTAL CANCER REMAINS THE THIRD LEADING cause of cancer deaths among women and men in the United States, underscoring the need for more effective preventive strategies for both sexes. Many promising approaches are based on the adenoma-carcinoma paradigm of colon carcinogenesis. The clinical corollary to this model is that the presence of adenomas represents a robust marker of colon carcinogenesis. This leads to 2 distinct applications for colorectal cancer prevention: target for intervention and risk marker. Indeed, removing adenomas through colonoscopy has been shown to decrease future colorectal cancer occurrence by 75% to 90%. From a screening perspective, the colonoscopic adenoma identification is used clinically to gauge long-term risk and dictate the frequency of future colorectal cancer screening. Most data suggest that the effect of colorectal cancer is approximately equivalent in both sexes. In 2009, an estimated 71 380 women and 75 590 men will develop colorectal cancer. This is consistent with data from 1993-2003 in which women composed 50% of patients in an unselected cohort of 161 172 patients with colorectal cancer from US community cancer centers. Moreover, while estimates of incidence of colorectal cancer has suggested up to a 2-fold male predominance, the more robust lifetime risk estimates for US women and men are comparable (5.1% vs 5.5%, respectively). Taken together, this and other evidence would suggest that colorectal cancer is, by and large, a sex-neutral malignancy. Therefore, it would logically follow that colonic adenomas should also be equivalent in women and men. However, several large-scale studies have indicated that women have a substantially lower adenoma detection rate than men. For instance, in a cross-sectional analysis of 50 148 patients undergoing colonoscopybased screening program, Regula et al demonstrated that, compared with women, men had an adjusted odds ratio for advanced adenomas of 1.73 (95% confidence interval [CI], 1.52-1.98). Additionally, Schoenfeld et al noted that the relative risk (RR) of clinically significant neoplasia (advanced adenomas) in men was 1.91 (95% CI, 1.42-2.56) compared with women. In a recent metaanalysis including 924 932 adults, Nguyen et al reported that the RR of advanced neoplasia in men vs women was 1.83 (95% CI, 1.69-1.97). These findings would imply that adenomas (even those designated as advanced, ie, size 1 cm or high-grade dysplasia or 25% villous features) represent a less reliable marker of colorectal cancer risk in women than in men, and would lead to speculation that colonoscopic identification of adenomas may be less protective of colorectal cancer in women than in men. Although rigorous evidence for this hypothesis is lacking, an administrative database review by Bressler et al noted that women were 41% more likely than men to develop colorectal cancer despite undergoing colonoscopy (4.1% vs 2.9%, P .001). Other supportive evidence centers on the predilection for proximal lesions among women. Baxter et al demonstrated that even though having a colonoscopy was associated with decreased risk of subsequent colorectal cancer by two-thirds in the distal colon, no protective effect was found for lesions in the proximal colon. These studies suggest that the lower prevalence of adenomas in women may translate into possibly less efficacy of colonoscopy. There is biological precedence for the sex-related differential clinical behavior of colonic neoplasia. Randomized controlled studies have demonstrated the chemopreventive abilities of estrogens/progesterones, potentially mediated by the tumor suppressor role of estrogen receptor . Moreover, numerous studies have documented the higher proportion of microsatellite-unstable (MSI-high) lesion in women consonant with their slightly better prognosis. From a risk factor perspective, women appear to have differential sensitivity to the carcinogenic effect of cigarette smoking. From an epidemiological perspective, women develop more proximal colorectal cancer, but lesions generally occur somewhat later in life com-

Keeping Our Eye on the Ball: The American Society of Preventive Oncology in 2009

A common adage among those who play games that involve balls-baseball, for example-is that one must keep one's eye on the ball. The baseball player attempting to catch a grounder or fly ball must watch the ball-where it has been, where it is-into his or her glove; the player who diverts his or her

Fish consumption and markers of colorectal cancer risk: a multicenter randomized controlled trial

Background:Diet is a major factor in the etiology of colorectal cancer, with high fish consumption possibly decreasing colorectal cancer risk, as was shown in several observational studies. To date, no intervention trials have examined the possible beneficial effects of fish intake on colorectal cancer risk. Objective:The objective was to investigate the effects of a 6-mo intervention with oil-rich or lean fish on apoptosis and mitosis within the colonic crypt. Design:In a multicenter, randomized, controlled intervention trial, patients with colorectal polyps, inactive ulcerative colitis, or no macroscopic signs of disease were recruited (n = 242) and randomly allocated to receive dietary advice plus either 300 g oil-rich fish (salmon) per week (n = 82), 300 g lean fish (cod) per week (n = 78), or only dietary advice (DA) (n = 82). Apoptosis and mitosis were measured in colonic biopsy samples collected before and after intervention (n = 213). Results:The total number of apoptotic cells per crypt did not increase in the salmon or cod group: −0.10 (95% CI: −0.36, 0.16) and −0.06 (95% CI: −0.32, 0.20), respectively, compared with the DA group. The total number of mitotic cells per crypt decreased nonsignificantly in the salmon group (−0.87; 95% CI: −2.41, 0.68) and in the cod group (−1.04; 95% CI: −2.62, 0.53) compared with the DA group. Furthermore, the distribution of mitosis within the crypt did not significantly change in either group. Conclusion:An increase in the consumption of either oil-rich or lean fish to 2 portions weekly over 6 mo does not markedly change apoptotic and mitotic rates in the colonic mucosa. This trial was registered at www.clinicaltrials.gov as NCT00145015.

A Multicenter Study of Prevalence and Risk Factors for Aberrant Crypt Foci

Aberrant crypt foci (ACF) are the putative precursor of colorectal adenomas. However, there are limited data available on the prevalence and risk factors for ACF. Subjects from the Prostate, Lung, Colorectal and Ovarian cancer screening trial were recruited for an ACF study, with subjects with adenoma history being oversampled. By using a standardized protocol of magnified chromoendoscopy with methylene blue staining (up to the middle rectal fold), ACF were photo-documented and removed for histologic evaluation. A total of 505 (66% male; 55% > or =70 y) subjects from 4 institutions were examined; 42% had no adenoma, 32% had nonadvanced distal adenoma, and 25% had advanced distal adenoma at the baseline Prostate, Lung, Colorectal and Ovarian cancer screening trial examination (8.2 years before ACF examination on average). A total of 68% of this population had 1 or more ACF, 43% had 1 to 3, 19% had 4 to 6, and 5% had 7 or more. Baseline adenoma status was not associated with ACF prevalence (range, 66%-69%) or mean number of ACF (range, 3.1-3.5). Of 143 endoscopic ACF examined histologically, 68.5% were confirmed to be ACF. In a logistic model, current (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.2-5.6) and former smoking (OR, 1.6; 95% CI, 1.1-2.5) were associated with higher ACF prevalence; a body mass index greater than 30 was associated with lower prevalence (OR, 0.53; 95% CI, 0.35-0.8). Age, sex, family history of colorectal cancer, and aspirin/nonsteroidal anti-inflammatory drug use were not associated significantly with ACF prevalence. ACF prevalence and number were not associated with adenoma history, and only 68.5% of endoscopic ACF were confirmed histologically. These results raise concern about the use of ACF as a surrogate marker of colorectal cancer risk.

Myeloperoxidase-Positive Cell Infiltration in Colorectal Carcinogenesis as Indicator of Colorectal Cancer Risk

Colorectal mucosa is targeted by toxic agents, which can initiate or promote colon cancer. The mechanism of damage might be a focal irritation with loss of normal epithelial cell barrier function. Genetic alterations in tumors may also affect host inflammatory response. The aim of this study was to define the extent of inflammation in colorectal mucosa, along colorectal carcinogenesis, and in microsatellite stable and unstable colorectal carcinomas. We collected 103 samples of normal colorectal mucosa from 65 patients (35 with colorectal cancer or adenoma, 8 with inflammatory bowel diseases, and 22 controls with normal colonoscopy). We also examined 24 aberrant crypt foci, 14 hyperplastic polyps, 16 adenomas, and 67 samples of colorectal carcinoma. Immunohistochemistry was used to count myeloperoxidase (MPO)-positive cells (neutrophils and monocytes) in x100 optical fields under a light microscope. Patients with colorectal tumors had a higher mean number of MPO-positive cells in normal mucosa than controls (mean +/- SD, 2.7 +/- 2.0 versus 1.4 +/- 1.4; P = 0.017). MPO-positive cell number was tightly linked to dysplasia in aberrant crypt foci and adenomas, and it was higher in carcinomas microsatellite unstable than those microsatellite stable (21.6 +/- 15.5 versus 11.9 +/- 8.0; P < 0.01). MPO immunohistochemistry is a simple and reliable technique for the quantification of inflammation in colorectal mucosa., and it may be a potential marker of colorectal cancer risk. Microsatellite instability seems to influence host immune responses to colorectal carcinoma. These observations strongly support a key role of inflammation in colorectal carcinogenesis.

Fermented Milks, Probiotic Cultures, and Colon Cancer

: Colorectal cancer (CRC) is a major cause of death from cancer in the Western world. Approximately 70% of CRC is associated with environmental factors, probably mainly the diet. There is interest in the potential protective role of fermented milks containing probiotic cultures against CRC. This article analyzes the existing data from human, animal, and in vitro studies that explore whether consumption of milks fermented with probiotic cultures could play a role in colon cancer risk reduction. Cohort studies have failed to detect significant effects, but most case-control studies favor a protective role of fermented milks against colon cancer. Interventional studies have shown a shift of intermediate markers of CRC risk in human subjects from a high- to low-risk pattern after ingestion of fermented milks or probiotics. Animal studies consistently show a reduction in chemically induced colorectal tumor incidence and aberrant crypt formation accompanying probiotic administration. In vitro studies also provide evidence of protection, and permit a better understanding of active compounds involved, and of the mechanisms underlying their anticarcinogenic effects. Probiotics may beneficially modulate several major intestinal functions: detoxification, colonic fermentation, transit, and immune status, which may accompany the development of colon cancer. Although the evidence is not conclusive and much further research is required, the data reviewed constitute a promising body of evidence supporting the protective role of milks fermented with probiotic cultures in colon cancer risk reduction.

Plasma leptin and colorectal cancer risk: A prospective study in Northern Sweden

Obesity is associated with an increased risk of colorectal cancer. Circulating levels of leptin are high in obesity and strongly correlated to levels of insulin. Leptin stimulates growth of colon cancer cells. In a nested case-control study, we measured leptin levels in prediagnostic plasma from 75 men and 93 women who were diagnosed with colorectal cancer mean time 3.4 years (SD 2.4) after recruitment and among 327 control subjects. Logistic regression analyses showed increases in colorectal cancer risk in men with increasing levels of leptin, odds ratios (OR) were 1.00 (ref), 0.85 (95% C.I.=0.33-2.23), 1.04 (0.43-2.53), and 2.15 (0.89-5.22), (pfor trend=0.08). There was a distinct threshold between the third and fourth quartile of leptin, and the odds ratio for top quartile vs. three bottom quartiles was 2.28 (1.09-4.76). Adjustment for body mass index and insulin did not affect risk estimates. In separate analysis, odds ratio for top vs. bottom tertile of colon cancer was 1.96 (95% C.I.=0.72-5.29), whereas no increase was seen for rectal cancer. In women, no association between leptin and risk was seen. These data support the hypothesis that leptin is a risk marker for colorectal cancer in men, but not in women.

Colon carcinogenesis in inflammatory bowel disease: applying molecular genetics to clinical practice.

Although both sporadic colorectal cancer (CRC) and colitis-associated CRC arise from dysplastic precursor lesions and share several molecular alterations, the nature of the dysplasia and the frequency and timing of several of the key molecular changes differ enough to consider colitis-associated CRC a rather unique entity. To date, cancer surveillance in both ulcerative colitis and Crohn's colitis rests upon the detection of dysplasia. However, because there are considerable limitations to the detection and interpretation of dysplasia, there is a need for other molecular markers to complement the histologic analysis of dysplasia. Because patients with inflammatory bowel disease (IBD) undergo repeated, periodic surveillance colonoscopies, it affords an opportunity to study marker expression over time. Of the few markers that have been studied chronologically, aneuploidy, p53, and mucin-associated sialyl-Tn antigen expression each hold promise as markers of CRC risk in IBD. It will be important to study whether these markers, or other panels of gene or protein expression, can identify patients at highest risk for developing CRC in future clinical studies.