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Background: It is unclear whether the higher burden from colorectal cancer among blacks is due to an increased biological susceptibility., Objective: To determine whether non-Hispanic blacks (blacks) have a higher risk of adenoma recurrence than non-Hispanic whites (whites) after removal of colorectal adenoma., Design: Secondary analysis of the Polyp Prevention Trial (PPT) data., Setting: United States., Patients: Patients were 1668 self-identified whites and 153 blacks who completed the 4-year trial. Of these, 688 whites and 55 blacks enrolled in a posttrial, passive Polyp Prevention Trial Continued Follow-up Study (PPT-CFS) and underwent another colonoscopy., Main Outcome Measurements: Recurrence and location of the adenoma and advanced adenoma by race-ethnicity during PPT and cumulative recurrence over a mean follow-up of 8.3 years (range, 4.9-12.4 years) among PPT-CFS enrollees., Results: Blacks had similar risk of recurrence of adenoma (39.2% vs 39.4%; incidence risk ratio [RR] = .98; 95% CI, .80-1.20) and advanced adenoma (8.5% vs 6.4%; RR = 1.18; 95% CI, .68-2.05) as whites at the end of PPT. Recurrence risk did not differ by colon subsite. Among PPT-CFS enrollees, the cumulative recurrence rate over a maximal follow-up period of 12 years was similar for blacks and whites for adenoma (67.3% vs 67.0%; RR = 1.01; 95% CI, .84-1.21) and advanced adenoma (14.5% vs 16.9%; RR = 1.03; 95% CI, .60-1.79)., Limitation: There were few blacks in the long-term follow-up study., Conclusions: Adenoma and advanced adenoma recurrence did not differ by race. Our study does not support more frequent surveillance colonoscopies for blacks with a personal history of adenoma as an intervention to reduce colorectal cancer disparity., (Copyright © 2013 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background and Study Aims: Obesity is a risk factor for colorectal neoplasia. Lifestyle modifications, including weight loss, have been advocated to reduce the risk. However, no prospective study has evaluated whether weight loss actually affects adenoma recurrence. The aim of this study was to examine whether weight change (loss or gain) over 4 years is associated with adenoma recurrence., Patients and Methods: A total of 1826 patients with colorectal adenoma in the Polyp Prevention Trial had their height and weight measured at baseline. Adenoma recurrence was determined by end of trial colonoscopy 4 years after study entry when patients' weights were re-measured. Poisson regression models were used to evaluate body mass index (BMI), weight change over 4 years, and the risk of any adenoma and advanced adenoma recurrence., Results: Adenoma recurrence was observed in 723 patients (39.6%), 118 (6.5%) of whom had advanced adenoma recurrence. Among those with baseline BMI < 25 kg/m² (n = 466), BMI 25-29 kg/m² (n = 868), and BMI ≥ 30 kg/m² (n = 492), the recurrence rate was 34.5%, 41.0%, and 41.9%, respectively. Obesity was associated with an increased risk of adenoma recurrence (RR = 1.19; 95%CI 1.01-1.39) and advanced adenoma recurrence (RR = 1.62; 95%CI 1.01-2.57). However, when compared with those with relatively stable weight (weight change < 5 lb) over the 4-year trial, weight gain or loss was not associated with adenoma recurrence. This was consistent, regardless of the baseline BMI., Conclusions: Weight loss or gain over 4 years does not affect adenoma recurrence. This study does not support weight loss alone as an effective intervention for reducing adenoma recurrence., (© Georg Thieme Verlag KG Stuttgart · New York.)

Lignans and proanthocyanidins are plant polyphenols that have shown protective properties against colorectal neoplasms in some human studies. Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to prospectively evaluate the association between lignan and proanthocyanidin intake, estimated from databases linked to a food frequency questionnaire, and adenoma recurrence in 1,859 participants of the Polyp Prevention Trial. Overall, individual or total lignans or proanthocyanidins were not associated with colorectal adenoma recurrence. However, in sex-specific analyses, total lignan intake was positively associated with any adenoma recurrence in women (highest vs. lowest lignan intake quartile OR = 2.07, 95% CI: 1.22-3.52, p trend = 0.004) but not in men (p interaction = 0.04). To conclude, dietary lignan and proanthocyanidin consumption were not generally related to colorectal adenoma recurrence; however, high lignan intake may increase the risk of adenoma recurrence in women., (Copyright © 2011 UICC.)

Chemopreventive dietary compounds, such as flavonols, may inhibit colorectal carcinogenesis partly by altering cytokine expression and attenuating inflammation. Single nucleotide polymorphisms (SNPs) in the promoter regions of genes encoding cytokines may influence flavonol-induced changes in cytokine expression and consequently cancer risk. Using logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between SNPs of interleukin (IL)-1β, 6, 8, and 10 alone or combined with flavonol intake or serum IL concentration changes, and adenoma recurrence in 808 participants from the intervention arm of the Polyp Prevention Trial, a 4-year intervention study evaluating the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence. Overall, SNPs in genes encoding IL-1β, 6, 8, and 10 were not associated with their corresponding serum concentrations or adenoma recurrence. However, individuals homozygous for IL-10 -592 C (OR=2.23, 95% CI: 1.07-4.66, P(interaction)=0.03) orIL-10 -819 C (OR=2.18, 95% CI: 1.05-4.51, P(interaction)=0.05) had an elevated risk of high-risk adenoma recurrence when their serum IL-10 concentrations increased during the trial. In addition, IL-6 -174 GG in combination with above median flavonol intake (OR=0.14, 95% CI: 0.03-0.66) or with decreased IL-6 concentrations (OR=0.14, 95% CI: 0.03-0.65) reduced the risk of advanced adenoma recurrence, although the interaction term was not statistically significant. In conclusion, our results suggest that IL SNPs, in combination with a flavonol-rich diet or decreased serum IL, may lower the risk of adenoma recurrence.

Background: Serum cytokine concentrations may reflect inflammatory processes occurring during the development of colorectal neoplasms. Flavonols, bioactive compounds found in plant-based foods and beverages, may inhibit colorectal neoplasms partly by attenuating inflammation., Methods: Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to investigate the association between serum concentrations of interleukin (IL) β, 2, 8, 10, 12p70, granulocyte macrophage colony stimulating factor, interferon-γ, and tumour necrosis factor-α, measured over time, flavonol intake, estimated from a flavonol database used in conjunction with a food frequency questionnaire, and adenoma recurrence in 872 participants from the intervention arm of the Polyp Prevention Trial., Results: Decreased IL-2 concentration during the trial increased the risk of any adenoma recurrence (4th vs 1st quartile, OR=1.68, 95% CI=1.13-2.49), whereas decreased IL-1β or IL-10 reduced the risk of advanced adenoma recurrence (OR=0.37, 95% CI=0.15-0.94; OR=0.39, 95% CI=0.15-0.98, respectively). Individuals with flavonol intake above the median (29.7 mg per day) and decreased cytokine concentrations had the lowest risk of advanced adenoma recurrence., Conclusion: Overall, no consistent associations were observed between serum cytokine profile and colorectal adenoma recurrence; however, decreased cytokine concentrations during high flavonol consumption may indicate prevention of colorectal neoplasms.

Background: Serum adiponectin, leptin, C-peptide, and homocysteine are indicators for obesity, hyperinsulinemia, and chronic inflammation, which have all been associated with colorectal cancer., Aims: To determine whether serum adiponectin, leptin, C-peptide, and homocysteine are associated with fat, fiber, fruit and vegetable, flavonol, or dry bean intake and colorectal adenoma recurrence., Methods: Using logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (95% CI) for adenoma recurrence in 627 participants from the control arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence., Results: Serum concentrations of C-peptide and homocysteine were inversely related to fiber, fruit and vegetable, and flavonol intake and positively related to percentage of calories from fat (all P(trend) < or = 0.01). High homocysteine concentrations were associated with any (4th versus 1st quartile: OR, 2.26; 95% CI, 1.30-3.94) and more than one adenoma recurrence (OR, 2.11; 95% CI, 1.01-4.40). Individuals in the highest, versus lowest, tertile of serum leptin concentration had a decreased risk of advanced adenoma recurrence (OR, 0.22; 95% CI, 0.06-0.79)., Conclusion: Our results suggest that serum homocysteine may serve as an indicator of dietary exposure, including a low-fat and high-fiber, high-fruit and vegetable, and high-flavonol diet, as well as colorectal adenoma recurrence., Impact: Discovering biomarkers that are both modifiable and can predict cancer risk is critical. We identified serum homocysteine as a novel indicator that is modified by diet and predicts risk of adenoma recurrence., (Copyright 2010 AACR.)

The Legume Inflammation Feeding Experiment is, to our knowledge, the first randomized crossover feeding trial testing the effects of a legume-enriched, low-glycemic index (GI) diet among men characterized for colorectal adenomas and insulin resistance (IR) status. This study was designed to test the effects of a legume-enriched diet compared with a healthy American (HA) diet under weight-stable conditions. The primary objective was to assess effects on C-reactive protein (CRP) and C-peptide levels. The secondary objective was to assess changes by IR status or history of adenomas. A total of 64 men who completed a colonoscopy within the previous 2 y consumed 2 diets in random order each for 4 wk separated by a washout period. The diets were a legume-enriched (250 g/d), low-GI (GI 38) diet and a high-GI (GI 69) HA diet. We measured fasting glucose, insulin, C-peptide, CRP, and soluble tumor necrosis factor-alpha receptors I and II (sTNFRI/II) at the beginning and end of the diet periods. Participants who consumed both the legume and HA diets had favorably improved CRP (-20.2 and -18.3%) and sTNFRI (-3.7 and -4.4%) concentrations, respectively. The sTNFRII concentrations declined marginally during the legume diet period (-3.8%; P = 0.060) and significantly during the HA diet period (-5.1%; P < 0.001). Fasting glucose increased significantly during both the legume (+1.8%) and HA (-2.2%) diet periods. Only the changes in glucose differed between the diet periods. Serum C-peptide and plasma insulin levels did not change in participants consuming either diet. Healthful dietary changes can improve biomarkers of IR and inflammation.

Background: Despite regular colonoscopy, interval colorectal cancer (CRC) may occur. Long-term studies examining CRC rates in patients with previous colonoscopy are lacking., Objective: We examined the rate of interval CRC in the Polyp Prevention Trial Continued Follow-up Study (PPT-CFS), an observational study of PPT participants that began after the PPT ended., Design: Prospective., Setting: A national U.S. community-based polyp prevention trial., Main Outcome Measurements: Medical records of patients with CRC were collected, reviewed, and abstracted in a standardized fashion., Results: Among 2079 PPT participants, 1297 (62.4%) agreed to participate in the PPT-CFS. They were followed for a median of 6.2 years after 4.3 years of median follow-up in the main PPT. Nine cases of CRC were diagnosed over 7626 person-years of observation (PYO), for an incidence rate of 1.2/1000 PYO. The ratio of CRCs observed compared with that expected by Surveillance, Epidemiology, and End Results was 0.64 (95% CI, 0.28-1.06). Including all CRCs (N = 22) since the beginning of the PPT, the observed compared with expected rate by Surveillance, Epidemiology, and End Results was 0.74 (95% CI, 0.47-1.05). Of patients in whom CRC developed in the PPT-CFS, 78% had a history of an advanced adenoma compared with only 43% of patients who remained cancer free (P = .04)., Limitation: A relatively small number of interval cancers were detected., Conclusions: Despite frequent colonoscopy during the PPT, in the years after the trial, there was a persistent ongoing risk of cancer. Subjects with a history of advanced adenoma are at increased risk of subsequent cancer and should be followed closely with continued surveillance., (2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

We have developed novel molecular methods using a stool sample, which contains intact sloughed colon cells, to quantify colonic gene expression profiles. In this study, our goal was to identify diagnostic gene sets (combinations) for the noninvasive classification of different phenotypes. For this purpose, the effects of a legume-enriched, low glycemic index, high fermentable fiber diet was evaluated in subjects with four possible combinations of risk factors, including insulin resistance and a history of adenomatous polyps. In a randomized crossover design controlled feeding study, each participant (a total of 23; 5-12 per group) consumed the experimental diet (1.5 cups of cooked dry beans) and a control diet (isocaloric average American diet) for 4 weeks with a 3-week washout period between diets. Using prior biological knowledge, the complexity of feature selection was reduced to perform an exhaustive search on all allowable feature (gene) sets of size 3, and among these, 27 had (unbiased) error estimates of 0.15 or less. Linear discriminant analysis was successfully used to identify the best single genes and two- to three-gene combinations for distinguishing subjects with insulin resistance, a history of polyps, or exposure to a chemoprotective legume-rich diet. These results support our premise that gene products (RNA) isolated from stool have diagnostic value in terms of assessing colon cancer risk.

Epidemiological evidence suggests that obesity may be causally associated with colorectal cancer. Dopamine and the dopaminergic reward pathway have been implicated in drug and alcohol addiction as well as obesity. Polymorphisms within the D2 dopamine receptor gene (DRD2) have been shown to be associated with colorectal cancer risk. We investigated the association between DRD2 genotype at these loci and the risk of colorectal adenoma recurrence in the Polyp Prevention Trial. Odds ratios (OR) and 95% confidence intervals (CI) for risk of adenoma recurrence were calculated using unconditional logistic regression. Individuals with any, multiple (>or=2) or advanced adenoma recurrence after 4 years were compared to those without adenoma recurrence. Variation in intake of certain dietary components according to DRD2 genotype at 3 loci (rs1799732; rs6277; rs1800497) was also investigated. The DRD2 rs1799732 CT genotype was significantly associated with all adenoma recurrence (OR: 1.30; 95% CI: 1.01, 1.69). The rs1800497 TT genotype was also associated with a significantly increased risk of advanced adenoma recurrence (OR: 2.40; 95% CI: 1.11, 5.20). The rs1799732 CT and rs1800497 TT genotypes were significantly associated with adenoma recurrence in the Polyp Prevention Trial. Increased risk of adenoma recurrence as conferred by DRD2 genotypes may be related to difference in alcohol and fat intake across genotypes., ((c) 2008 Wiley-Liss, Inc.)

Background & Aims: Limited data exist regarding the actual risk of developing advanced adenomas and cancer after polypectomy or the factors that determine risk., Methods: We pooled individual data from 8 prospective studies comprising 9167 men and women aged 22 to 80 with previously resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer as well as identify factors associated with the development of advanced colorectal neoplasms during surveillance., Results: During a median follow-up period of 47.2 months, advanced colorectal neoplasia was diagnosed in 1082 (11.8%) of the patients, 58 of whom (0.6%) had invasive cancer. Risk of a metachronous advanced adenoma was higher among patients with 5 or more baseline adenomas (24.1%; standard error, 2.2) and those with an adenoma 20 mm in size or greater (19.3%; standard error, 1.5). Risk factor patterns were similar for advanced adenomas and invasive cancer. In multivariate analyses, older age (P < .0001 for trend) and male sex (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.19-1.65) were associated significantly with an increased risk for metachronous advanced neoplasia, as were the number and size of prior adenomas (P < .0001 for trend), the presence of villous features (OR, 1.28; 95% CI, 1.07-1.52), and proximal location (OR, 1.68; 95% CI, 1.43-1.98). High-grade dysplasia was not associated independently with metachronous advanced neoplasia after adjustment for other adenoma characteristics., Conclusions: Occurrence of advanced colorectal neoplasia is common after polypectomy. Factors that are associated most strongly with risk of advanced neoplasia are patient age and the number and size of prior adenomas.

Background and Aims: Recent studies have suggested that some hyperplastic polyps may be associated with an increased risk of colorectal cancer. Prospective information on the risk of adenoma recurrence associated with hyperplastic polyps is limited. We sought to investigate whether the coexistence of hyperplastic polyps with adenomas increases the risk of adenoma recurrence., Methods: We used unconditional logistic regression models to examine the association between baseline hyperplastic polyps and subsequent adenoma recurrence during a 3-year follow-up evaluation, among 1637 participants in the Polyp Prevention Trial., Results: A total of 437 participants (26.7%) had hyperplastic polyps coexisting with adenomas at baseline. Of these, 132 (30.2%) had at least one hyperplastic polyp in the proximal colon, whereas 305 (69.8%) had only distal hyperplastic polyps. When compared with subjects without any hyperplastic polyps at baseline, there was no statistically significant association between the presence of baseline hyperplastic polyps and recurrence of any adenoma (odds ratio [OR], 1.19; 95% confidence interval [CI], 0.94-1.51) or advanced adenoma (OR, 1.25; 95% CI, 0.78-2.03). Also, there was no association between hyperplastic polyp location and adenoma recurrence (OR, 1.01; 95% CI, 0.69-1.48) for any proximal hyperplastic polyp (OR, 1.26; 95% CI, 0.96-1.65) and for distal hyperplastic polyps., Conclusions: The coexistence of hyperplastic polyps with adenomas, irrespective of location, does not confer an increased risk of adenoma recurrence beyond that of adenomas alone within 3 years of follow-up evaluation. Prospective long-term studies on adenoma recurrence risk associated with hyperplastic polyps in screening populations are needed.

Background: Low dietary folate intake has been associated with colorectal cancer risk and adenoma recurrence. A C/T transition at position 677 in the gene encoding methlylenetetrahydrofolate reductase (MTHFR C677T) has been reported to interact with folate intake to modulate colorectal adenoma recurrence or cancer risk., Methods: We investigated the association between MTHFR, total folate, and the risk of colorectal adenoma recurrence in the Polyp Prevention Trial. We compared 625 individuals with any adenoma recurrence after 4 years (266 individuals with multiple (> or =2) recurrent adenomas and 101 individuals with advanced adenoma recurrence) to 978 individuals with no adenoma recurrence. Odds ratios (OR) and 95% confidence intervals (CI) for risk of adenoma recurrence were calculated using unconditional logistic regression. We also investigated effect modification of the MTHFR genotype associations by total folate intake., Results: In general, no statistically significant associations were found between quartile of folate intake (dietary or total) and adenoma recurrence. The MTHFR CT genotype was associated with a significantly increased risk of multiple adenoma recurrence (OR: 1.34, 95% CI: 1.00, 1.81). No significant interaction was noted for total folate and MTHFR genotype, though an increased risk of recurrence noted for the MTHFR CT genotype was statistically significant only for those individuals with below median intake of total folate., Conclusion: We report that the MTHFR 677 CT genotype was associated with increased risk of adenoma recurrence (specifically multiple adenoma recurrence) 4 years after polypectomy.

Insulin-like growth factor I (IGF-I) and its primary binding protein, IGFBP-3, have been associated with colorectal cancer incidence in prior epidemiologic studies. High concentrations of IGF-I generally result in increasing risk and high concentrations of IGFBP-3 in decreasing risk. Only one prior study of IGF-I and IGFBP-3 and adenoma recurrence has been reported. We assayed fasting serum from 375 subjects with and 375 subjects without a recurrent adenoma during the course of the Polyp Prevention Trial to determine baseline concentrations of IGF-I and IGFBP-3. To estimate relative risk of adenoma recurrence over the course of 4 years of follow-up for each of these serum measures, we calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable logistic regression models adjusting for age, gender, body mass index, intervention group, aspirin, smoking, ethnicity, and education. For both IGF-I and IGFBP-3, we found trends indicating decreased risk for subjects in the high compared with the low quartile (for IGF-I: OR, 0.65; 95% CI 0.41-1.01; for IGFBP-3: OR, 0.66; 95% CI, 0.42-1.05). The associations were even greater for advanced adenomas (for IGF-I: OR, 0.51; 95% CI, 0.21-1.29; for IGFBP-3: OR, 0.32; 95% CI, 0.13-0.82). These results showed an unexpected null association, or even the suggestion of a reduction in risk for recurrent adenoma, with not just high IGFBP-3 concentration but also with high levels of IGF-I. Why IGF-I would decrease risk of recurrent adenoma (as distinct from incident adenoma or colorectal cancer) is not clear.

Two recent case-control studies suggested that some flavonoid subgroups may play a role in preventing colorectal cancer. Previous prospective cohort studies generally reported no association; however, only a small subset of flavonoids was evaluated and partial flavonoid databases were used. We used the newly constructed U.S. Department of Agriculture flavonoid database to examine the association between consumption of total flavonoids, 6 flavonoid subgroups, and 29 individual flavonoids with adenomatous polyp recurrence in the Polyp Prevention Trial. The Polyp Prevention Trial was a randomized dietary intervention trial, which examined the effectiveness of a low-fat, high-fiber, high-fruit, and high-vegetable diet on adenoma recurrence. Intakes of flavonoids were estimated from a food frequency questionnaire. Multivariate logistic regression models (adjusted for age, body mass index, sex, regular non-steroidal anti-inflammatory use, and dietary fiber intake) were used to estimate odds ratios and 95% confidence intervals for both any and advanced adenoma recurrence within quartiles of energy-adjusted flavonoid intake (baseline, during the trial, and change during the trial). Total flavonoid intake was not associated with any or advanced adenoma recurrence. However, high intake of flavonols, which are at greater concentrations in beans, onions, apples, and tea, was associated with decreased risk of advanced adenoma recurrence (4th versus 1st quartile during the trial; odds ratio, 0.24; 95% confidence interval, 0.11, 0.53; P(trend) = 0.0006). Similar inverse associations were observed to a smaller extent for isoflavonoids, the flavonol kaempferol, and the isoflavonoids genistein and formononetin. Our data suggest that a flavonol-rich diet may decrease the risk of advanced adenoma recurrence.

Background: Lack of confidence in postpolypectomy surveillance guidelines may be a factor in the observed low adherence rates among providers., Objective: To assess the 2006 postpolypectomy colonoscopy surveillance guidelines, which recommend 3-year follow-up colonoscopy for individuals with high-risk adenomas (defined as > or =3 adenomas or any advanced adenomas) and 5- to 10-year follow-up for patients with 2 or fewer nonadvanced adenomas, who are considered to be at low risk., Design: Analysis of prospective data from the Polyp Prevention Trial., Setting: United States., Participants: 1905 patients who had colorectal adenomas removed at baseline screening or diagnostic colonoscopy and completed the trial., Measurements: Baseline adenoma characteristics, risk-stratified according to definitions used in the guidelines, were examined as predictors for advanced adenoma recurrence., Results: 125 patients (6.6%) had advanced and 629 (33.0%) had nonadvanced adenoma recurrence; 1151 (60.4%) had no recurrence within 4 years of follow-up. The probability of advanced adenoma recurrence was 0.09 (95% CI, 0.07 to 0.11) among patients with high-risk adenomas at baseline and 0.05 (CI, 0.04 to 0.06) among those with low-risk adenomas at baseline. The relative risk for advanced adenoma recurrence for patients with high-risk adenomas versus those with low-risk adenomas at baseline was 1.68 (CI, 1.19 to 2.38) when advanced adenoma recurrence was compared with no advanced adenoma recurrence and 1.76 (CI, 1.26 to 2.46) when advanced adenoma recurrence was compared with no adenoma recurrence. The c-statistics for these 2 comparisons were 0.68 and 0.72, respectively., Limitation: Participants were self-selected and had restrictions on the degree of obesity., Conclusion: Although the risk for recurrence of advanced adenoma within 4 years is greater for patients with high-risk adenomas at baseline than for those with low-risk adenomas, the discrimination of this risk stratification scheme is relatively low.

Background & Aims: Indicators of insulin resistance have been hypothesized to promote colorectal cancer., Methods: We assayed fasting serum from 375 subjects with and 375 subjects without a recurrent adenoma during the course of the Polyp Prevention Trial to determine baseline concentrations of insulin and glucose, as well as changes in these measurements over the course of 4 years of follow-up evaluation. To estimate the relative risk of adenoma recurrence for each of these serum measures, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models adjusting for age, sex, body mass index, intervention group, and an interaction term for sex and intervention group., Results: For both insulin and glucose, we found higher risk for subjects in the high quartile compared with the low quartile (OR, 1.56; 95% CI, 1.00-2.43 for insulin; OR, 1.49; 95% CI, 0.95-2.31 for glucose). The association for glucose was most apparent for advanced adenomas (OR, 2.43; 95% CI, 1.23-4.79) but for insulin, we did not observe this pattern. When we restricted the analysis to those without a family history of colorectal cancer, we observed an even stronger association between increased glucose at study entry and adenoma recurrence (OR, 1.78; 95% CI, 1.06-3.01 for all adenomas; OR, 3.52; 95% CI, 1.47-8.42 for advanced adenoma)., Conclusions: Our findings suggest that patients with increased insulin and glucose are at higher risk of adenoma recurrence, and for those with increased glucose, the increase in risk for recurrence of advanced adenomas is even greater.

The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), and low-fat (20% of total energy) diet on the recurrence of adenomatous polyps in the large bowel over a period of 4 years. Although intervention participants reported a significantly reduced intake of dietary fat, and increased fiber, fruit, and vegetable intakes, their risk of recurrent adenomas was not significantly different from that of the controls. Since the PPT intervention lasted only 4 years, it is possible that participants need to be followed for a longer period of time before treatment differences in adenoma recurrence emerge, particularly if diet affects early events in the neoplastic process. The PPT-Continued Follow-up Study (PPT-CFS) was a post-intervention observation of PPT participants for an additional 4 years from the completion of the trial. Of the 1,905 PPT participants, 1,192 consented to participate in the PPT-CFS and confirmed colonoscopy reports were obtained on 801 participants. The mean time between the main trial end point colonoscopy and the first colonoscopy in the PPT-CFS was 3.94 years (intervention group) and 3.87 years (control group). The baseline characteristics of 405 intervention participants and 396 control participants in the PPT-CFS were quite similar. Even though the intervention group participants increased their fat intake and decreased their intakes of fiber, fruits, and vegetables during the PPT-CFS, they did not go back to their prerandomization baseline diet (P < 0.001 from paired t tests) and intake for each of the three dietary goals was still significantly different from that in the controls during the PPT-CFS (P < 0.001 from t tests). As the CFS participants are a subset of the people in the PPT study, the nonparticipants might not be missing completely at random. Therefore, a multiple imputation method was used to adjust for potential selection bias. The relative risk (95% confidence intervals) of recurrent adenoma in the intervention group compared with the control group was 0.98 (0.88-1.09). There were no significant intervention-control group differences in the relative risk for recurrence of an advanced adenoma (1.06; 0.81-1.39) or multiple adenomas (0.92; 0.77-1.10). We also used a multiple imputation method to examine the cumulative recurrence of adenomas through the end of the PPT-CFS: the intervention-control relative risk (95% confidence intervals) for any adenoma recurrence was 1.04 (0.98-1.09). This study failed to show any effect of a low-fat, high-fiber, high-fruit and -vegetable eating pattern on adenoma recurrence even with 8 years of follow-up. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1745-52).

Adequate fruit and vegetable intake was suggested to protect against colorectal cancer and colorectal adenomas; however, several recent prospective studies reported no association. We examined the association between fruits and vegetables and adenomatous polyp recurrence in the Polyp Prevention Trial (PPT). The PPT was a low-fat, high-fiber, high-fruit, and vegetable dietary intervention trial of adenoma recurrence, in which there were no differences in the rate of adenoma recurrence in participants in the intervention and control arms of the trial. In this analysis of the entire PPT trial-based cohort, multiple logistic regression analysis was used to estimate the odds ratio (OR) of advanced and nonadvanced adenoma recurrence within quartiles of baseline and change (baseline minus the mean over 3 y) in fruit and vegetable intake, after adjustment for age, total energyy intake, use of nonsteroidal anti-inflammatory drugs, BMI, and gender. There were no significant associations between nonadvanced adenoma recurrence and overall change in fruit and vegetable consumption; however, those in the highest quartile of change in dry bean intake (greatest increase) compared with those in the lowest had a significantly reduced OR for advanced adenoma recurrence (OR = 0.35; 95% CI, 0.18-0.69; P for trend = 0.001). The median in the highest quartile of change in dry bean intake was 370% higher than the baseline intake. The PPT trial-based cohort provides evidence that dry beans may be inversely associated with advanced adenoma recurrence.

Background: Pro- and anti-inflammatory cytokine genes may be important in the maintenance and progression of colorectal cancer. It is possible that single-nucleotide polymorphisms in inflammatory genes may play a role in chronic colonic inflammation and development of colorectal adenomas. Furthermore, common variants in cytokine genes may modify the anti-inflammatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of colorectal cancer., Methods: We examined the association between cytokine gene polymorphisms and risk of recurrent adenomas among 1,723 participants in the Polyp Prevention Trial. We used logistic regression to calculate odds ratios (OR) for the association between genotype, NSAID use, and risk of adenoma recurrence., Results: Cytokine gene polymorphisms were not statistically significantly associated with risk of adenoma recurrence in our study. We observed statistically significant interactions between NSAID use, IL-10 -1082 G>A genotype, and risk of adenoma recurrence (P = 0.01) and multiple adenoma recurrence (P = 0.01). Carriers of the IL-10 -1082 G>A variant allele who were non-NSAID users had a statistically significant decreased risk of multiple adenoma recurrence (OR, 0.43; 95% confidence interval, 0.24-0.77) as well as a nonsignificant 30% decreased risk of any adenoma recurrence. In contrast, NSAID users who were carriers of the IL-10 -1082 G>A variant allele were at an increased risk of any adenoma recurrence (OR, 1.55; 95% confidence interval, 1.00-2.43)., Conclusion: These findings suggest that individuals who are carriers of the IL-10 -1082 G>A variant allele may not benefit from the chemoprotective effect of NSAIDs on adenoma polyp recurrence.

Background: Evidence for an association between dietary fiber and colorectal neoplasia has been equivocal, and some data suggest that there may be sex differences in response to fiber., Objective: We sought to determine whether fiber affects colorectal adenoma recurrence differently in men and women by combining the study populations of 2 large clinical intervention trials: the Wheat Bran Fiber Trial and the Polyp Prevention Trial., Design: Data from 3209 participants combined from 2 trials were analyzed with logistic regression models to examine the effect of a dietary intervention on colorectal adenoma recurrence in the pooled population as a whole and by sex., Results: The adjusted odds ratio for adenoma recurrence for those in the intervention group of either the Wheat Bran Fiber Trial or the Polyp Prevention Trial was 0.91 (95% CI: 0.78, 1.06). For men, the intervention was associated with statistically significantly reduced odds of recurrence with an odds ratio of 0.81 (95% CI: 0.67, 0.98); for women, no significant association was observed. Using a likelihood-ratio test, we found a statistically significant interaction between intervention group and sex (P = 0.03)., Conclusion: The results of the current analyses indicate that men may experience more benefit from dietary fiber than do women and may help to explain some of the discrepant results reported in the literature.

The Polyp Prevention Trial was designed to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), low-fat (20% energy) diet on recurrence of adenomatous polyps. Participants > or =35 years of age, with histologically confirmed colorectal adenoma(s) removed in the prior 6 months, were randomized to the intervention or control group. Demographic, dietary, and clinical information, including use of nonsteroidal anti-inflammatory drugs (NSAID), was collected at baseline and four annual visits. Adenoma recurrence was found in 754 of 1,905 participants and was not significantly different between groups. NSAID use was associated with a significant reduction in recurrence [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.63-0.95]. In this analysis, NSAIDs modified the association between the intervention and recurrence at baseline (P = 0.02) and throughout the trial (P = 0.008). Among participants who did not use NSAIDs, the intervention was in the protective direction but did not achieve statistical significance (OR, 0.87; 95% CI, 0.69-1.09). The intervention was protective among males who did not use NSAIDs at baseline (OR, 0.71; 95% CI, 0.54-0.94), but not among NSAIDs users (OR, 1.09; 95% CI, 0.74-1.62). For females, corresponding OR estimates were 1.28 (95% CI, 0.86-1.90) and 2.30 (95% CI, 1.24-4.27), respectively. The protective association observed for NSAID use was stronger among control (OR, 0.63; 95% CI, 0.47-0.84) than for intervention group participants (OR, 0.97; 95% CI, 0.74-1.28). These results should be interpreted cautiously given that they may have arisen by chance in the course of examining multiple associations and Polyp Prevention Trial study participants were not randomly assigned to both dietary intervention and NSAID use. Nevertheless, our results suggest that adopting a low-fat, high-fiber diet rich in fruits and vegetables may lower the risk of colorectal adenoma recurrence among individuals who do not regularly use NSAIDs.

Background: Interval colorectal cancer (CRC) occasionally is detected in patients who have recently undergone colonoscopy. Systematic evaluation of CRC detected after colonoscopy could identify ways to improve the quality and the outcome of colonoscopy., Methods: This study examined cancer diagnoses in the course of the dietary Polyp Prevention Trial, a randomized study of a dietary intervention on recurrence of adenomatous polyps. An algorithm was developed to classify each cancer into one of 4 etiologies: (1) incomplete removal (cancer at the site of previous adenoma), (2) failed biopsy detection (cancer in an area of suspected neoplasia with negative biopsy specimens), (3) missed cancer (large, advanced stage cancer found at a short interval after colonoscopy), or (4) new cancer (small, early stage cancer after a longer time interval)., Results: Of 2079 patients, 13 had cancer detected over 5810 person years of observation (PYO) (2.2 cases/1000 PYO); 7/13 or 53.8% of patients had either a potentially "avoidable" cancer or one detectable at an earlier time interval because of incomplete removal (4/13) or missed cancer (3/13)., Conclusions: Interval cancer occurs despite colonoscopy. Improved quality of colonoscopy may have reduced cancer prevalence or resulted in earlier cancer detection in over 50% of prevalent cancers in the dietary Polyp Prevention Trial.

Background: Secondary analyses of data from a large randomized clinical trial have suggested that intake of the trace element selenium reduces risk of colorectal neoplasia, but epidemiologic studies have not shown a consistent protective association., Methods: We conducted a combined analysis of data from three randomized trials--the Wheat Bran Fiber Trial, the Polyp Prevention Trial, and the Polyp Prevention Study--which tested the effects of various nutritional interventions for colorectal adenoma prevention among participants who recently had an adenoma removed during colonoscopy. Selenium concentrations were measured from blood specimens from a total of 1763 trial participants, and quartiles of baseline selenium were established from the pooled data. To estimate the association between baseline selenium and colorectal adenoma risk, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression modeling. All statistical tests were two-sided., Results: Individual study results among participants whose blood selenium concentrations were in the highest versus the lowest quartile varied in magnitude (Polyp Prevention Trial: OR = 0.67, 95% CI = 0.43 to 1.05; P(trend) = .21; Wheat Bran Fiber Trial: OR = 0.66, 95% CI = 0.40 to 1.10; P(trend) = .13, and Polyp Prevention Study: OR = 0.57, 95% CI = 0.34 to 0.95, P(trend) = .04). Analyses of the pooled data showed that individuals whose blood selenium values were in the highest quartile (median = 150 ng/mL) had statistically significantly lower odds of developing a new adenoma compared with those in the lowest quartile (OR = 0.66, 95% CI = 0.50 to 0.87; P(trend) = .006)., Conclusions: The inverse association between higher blood selenium concentration and adenoma risk supports previous findings indicating that higher selenium status may be related to decreased risk of colorectal cancer.

A large multicenter randomized controlled trial was re-assessed to check whether meat intake and a reduction in its consumption are associated with recurrence of adenomatous polyps of the large bowel, which are precursors of most colorectal malignancies. All subjects (n = 1905; 958 interventions and 947 controls) had one or more histologically confirmed colorectal adenomas removed during a colonoscopy within 6 months before randomization. The subjects were followed-up for approximately 4 years after randomization and a colonoscopy for detecting adenomas was conducted at the 1st and 4th year after randomization. Dietary variables were assessed at baseline (T0) and in conjunction with annual visits at the end of the 1st (T1), 2nd (T2), 3rd (T3) and 4th (T4) years. Odds ratios using logistic regression models for meat variables were estimated based on the average intake at T0, T1, T2, T3 and T4 (prior to the T4 colonoscopy) as well as change (T0-T4) in intake. In the intervention group, the total reduction in median intake of red meat from T0 to T4 was observed by the end of 1st year itself (30 and 31% for men and women, respectively). The analysis provide no evidence to suggest that lower intake or reduction in total and in red meat consumption during a period of 4 years reduces the risk of adenoma recurrence (including multiple or advanced adenoma), whereas the data suggest that high intake of fish is associated with lower risk of adenoma recurrence.

Objectives: Insulin is a growth factor for colorectal cancer. Visceral adipose tissue (VAT) is strongly associated with insulin levels, and insulin and visceral obesity have been associated in cohort studies with colorectal cancer. The aim of this investigation was to determine whether VAT is associated with recurrence of adenomatous polyps, the precursor to colorectal cancer., Methods: As an ancillary study to the Polyp Prevention Trial, a randomized clinical trial that evaluated the effect of a low-fat, high-fiber, high vegetable and fruit diet on adenomatous polyp recurrence, subjects at one clinical center underwent measurement of VAT with a single-slice CT scan through the L4-L5 interspace. The scan was performed around the time of the subject's year 4 colonoscopy that determined adenoma recurrence., Results: Of 119 subjects, 44 of 84 men (52%) and 16 of 35 women (46%) had a recurrent adenoma (p= 0.51). Body mass index (BMI) and weight at baseline and at year 4 colonoscopy were unrelated to adenoma recurrence. In a multivariate model including visceral fat quartile, remote history of polyps, gender, age, and randomization group, only remote history of polyps was statistically significantly associated with recurrent adenoma with a relative risk of 4.6 (95% CI 1.7, 12.4, p= 0.001). There was no consistent monotonic trend of increased or decreased risk of recurrence as one ascended quartiles of adipose tissue for visceral, subcutaneous, or total abdominal fat., Conclusion: In this study, no association between visceral adipose tissue and adenomatous polyp recurrence was observed. Further study and exploration of the role of VAT in adenoma progression is required.

Objective: To prospectively examine the association between non-steroidal anti-inflammatory drugs (NSAIDs) use (including dose and dosage schedule) and the recurrence of colorectal adenomas among individuals who were diagnosed with an adenoma at entry into a clinical trial., Methods: For this analysis, participants who completed the full follow-up (n = 1905) for the Polyp Prevention Trial (PPT) were evaluated. Information on current use and dose of NSAIDs and other drugs was obtained at baseline and at each subsequent study visit over the duration of the trial. The study endpoint was the recurrence of colorectal adenomas in the 3 years between the 1-year trial colonoscopy (T1) and the end of the trial colonoscopy (T4)., Results: There was a significant reduction in overall adenoma recurrence among NSAIDs users (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.63-0.95), with the greatest effect seen in advanced polyps (OR = 0.51; CI: 0.33-0.79). Among aspirin users, we observed a significant dose response for overall adenoma recurrence, with a 40% reduction in the OR association (OR = 0.56; 95% CI: 0.31-0.99) among those taking more than 325 mg per day., Conclusion: This prospective study provides further evidence that NSAIDs may play an important role in the chemoprevention of recurrent colorectal adenomas, even those with advanced features.

Background: Epidemiologic studies have suggested that estrogen may protect against the development of colorectal cancers and adenomatous polyps. We conducted a prospective study to evaluate the association between hormone replacement therapy (HRT) and adenoma recurrence among perimenopausal and postmenopausal women participating in the Polyp Prevention Trial, a randomized dietary intervention study of individuals with colorectal adenomas., Methods: We used a questionnaire and interviews to collect detailed information, at baseline and at each of four annual study visits, from 620 women regarding hormone use, menopausal status, diet, alcohol consumption, and other risk factors. Adenoma recurrence was ascertained by complete colonoscopy at baseline and after 1 and 4 years. Logistic regression models were used to evaluate the association between hormone use and adenoma recurrence after adjusting for intervention group and for age and body mass index at baseline. All statistical tests were two-sided., Results: Adenomas recurred in 200 women. There was no overall association between adenoma recurrence and either overall hormone use (odds ratio [OR] = 1.01; 95% confidence interval [CI] = 0.70 to 1.45), combined estrogen and progestin use (OR = 0.94; 95% CI = 0.57 to 1.56), or unopposed estrogen use (OR = 1.04; 95% CI = 0.68 to 1.59). HRT use was associated with a reduction in risk for recurrence of distal adenomas (OR = 0.56; 95% CI = 0.32 to 1.00) and a statistically nonsignificant increase in risk for recurrence of proximal adenomas (OR = 1.39; 95% CI = 0.85 to 2.26). We observed a statistically significant interaction between the HRT-adenoma recurrence association and age (P =.02). HRT was associated with a 40% reduced risk of adenoma recurrence among women older than 62 years (OR = 0.58; 95% CI = 0.35 to 0.97) but with an increased risk among women younger than 62 years (OR = 1.99; 95% CI = 1.11 to 3.55)., Conclusions: HRT was not associated with a reduced risk for overall adenoma recurrence in this trial cohort, although there was a suggestion of an age interaction. The effect of age on the association needs to be confirmed in other adenoma recurrence trials.

Cell proliferation in the human colorectum can be measured using bromodeoxyuridine (BrdU) or proliferating cell nuclear antigen (PCNA) assays. Using data from the National Cancer Institute's Polyp Prevention Trial, these two assays are compared using correlation coefficients and variance components analysis. Adjusting for fixed as well as for the random effects of between-biopsy and scoring variation, the estimated correlation is 0.46 for the log labeling index and 0.45 for log proliferative height. This is an estimate of the highest correlation that can be achieved by taking multiple biopsies scored by multiple scorers. For single biopsies, the estimated correlation is 0.16 and 0.10, respectively. There are significant differences between the variance components for the two assays. For example, for log labeling index, PCNA has a lower variation between biopsies than BrdU, but higher variation between scorings. When used in a clinical or epidemiological setting, it is important to take multiple biopsies at multiple time points.

Background: We tested the hypothesis that dietary intervention can inhibit the development of recurrent colorectal adenomas, which are precursors of most large-bowel cancers., Methods: We randomly assigned 2079 men and women who were 35 years of age or older and who had had one or more histologically confirmed colorectal adenomas removed within six months before randomization to one of two groups: an intervention group given intensive counseling and assigned to follow a diet that was low in fat (20 percent of total calories) and high in fiber (18 g of dietary fiber per 1000 kcal) and fruits and vegetables (3.5 servings per 1000 kcal), and a control group given a standard brochure on healthy eating and assigned to follow their usual diet. Subjects entered the study after undergoing complete colonoscopy and removal of adenomatous polyps; they remained in the study for approximately four years, undergoing colonoscopy one and four years after randomization., Results: A total of 1905 of the randomized subjects (91.6 percent) completed the study. Of the 958 subjects in the intervention group and the 947 in the control group who completed the study, 39.7 percent and 39.5 percent, respectively, had at least one recurrent adenoma; the unadjusted risk ratio was 1.00 (95 percent confidence interval, 0.90 to 1.12). Among subjects with recurrent adenomas, the mean (+/-SE) number of such lesions was 1.85+/-0.08 in the intervention group and 1.84+/-0.07 in the control group. The rate of recurrence of large adenomas (with a maximal diameter of at least 1 cm) and advanced adenomas (defined as lesions that had a maximal diameter of at least 1 cm or at least 25 percent villous elements or evidence of high-grade dysplasia, including carcinoma) did not differ significantly between the two groups., Conclusions: Adopting a diet that is low in fat and high in fiber, fruits, and vegetables does not influence the risk of recurrence of colorectal adenomas.