Colorectal cancers soon after colonoscopy: a pooled multicohort analysis.

OBJECTIVE: Some individuals are diagnosed with colorectal cancer (CRC) despite recent colonoscopy. We examined individuals under colonoscopic surveillance for colonic adenomas to assess possible reasons for diagnosing cancer after a recent colonoscopy with complete removal of any identified polyps. DESIGN: Primary data were pooled from eight large (>800 patients) North American studies in which participants with adenoma(s) had a baseline colonoscopy (with intent to remove all visualised lesions) and were followed with subsequent colonoscopy. We used an algorithm based on the time from previous colonoscopy and the presence, size and histology of adenomas detected at prior exam to assign interval cancers as likely being new, missed, incompletely resected (while previously an adenoma) or due to failed biopsy detection. RESULTS: 9167 participants (mean age 62) were included in the analyses, with a median follow-up of 47.2 months. Invasive cancer was diagnosed in 58 patients (0.6%) during follow-up (1.71 per 1000 person-years follow-up). Most cancers (78%) were early stage (I or II); however, 9 (16%) resulted in death from CRC. We classified 30 cancers (52%) as probable missed lesions, 11 (19%) as possibly related to incomplete resection of an earlier, non-invasive lesion and 14 (24%) as probable new lesions. The cancer diagnosis may have been delayed in three cases (5%) because of failed biopsy detection. CONCLUSIONS: Despite recent colonoscopy with intent to remove all neoplasia, CRC will occasionally be diagnosed. These cancers primarily seem to represent lesions that were missed or incompletely removed at the prior colonoscopy and might be avoided by increased emphasis on identifying and completely removing all neoplastic lesions at colonoscopy.

Epidemiology of Helicobacter pylori infection in six Latin American countries (SWOG Trial S0701).

OBJECTIVE: To investigate the potential determinants of Helicobacter pylori infection between adults 21-65 years old. METHODS: Data are from the initial screening visit of a randomized clinical trial of three antibiotic regimens to eradicate H. pylori, conducted in seven sites (Santiago-Chile, Túquerres-Colombia, Guanacaste-Costa Rica, Copán-Honduras, Obregón and Tapachula-México, León-Nicaragua). Thousand eight hundred and fifty-nine adults from the general population were screened for H. pylori infection using an urea breath test (UBT) and were interviewed to assess socioeconomic-, demographic-, and symptom-related characteristics. Logistic regression was used to assess the relationship between these characteristics and H. pylori positivity at enrollment. RESULTS: Among the 1,852 eligible participants for whom a conclusive UBT result was obtained, H. pylori prevalence was 79.4 %, ranging from 70.1 to 84.7 % among the seven centers. Prevalence did not differ by sex (female: 78.4, male: 80.9; p = 0.20) or age (p = 0.08). H. pylori positivity increased with increasing number of siblings (p trend <0.0001). Participants with education beyond 12 years were less likely to be UBT-positive (OR 0.4: 0.3-0.6, compared to participants with 0-6 years of schooling) as were those employed outside the home (OR 0.7: 0.6-1.0). Odds of H. pylori infection increased with the presence of certain living conditions during childhood including having lived in a household with an earth floor (OR 1.8: 1.4-2.4), lack of indoor plumbing (OR 1.3: 1.0-1.8) and crowding (OR 1.4: 1.0-1.8, for having more than two persons per bedroom). Regarding current household conditions, living with more than 3 children in the household (OR 1.7: 1.2-2.5) and crowding (OR 1.8: 1.3-2.3) were associated with H. pylori infection. CONCLUSIONS: The prevalence of H. pylori in adults was high and differed significantly among the six Latin American countries studied (p < 0.001). Our findings confirm the strong link between poor socioeconomic conditions and H. pylori infection.

Helicobacter pylori eradication in the prevention of gastric cancer: are more trials needed?

The incidence of gastric cancer has decreased in much of the world, but gastric cancer remains the second leading cause of cancer death globally, and the burden is growing in many countries in East Asia and Latin America. Chronic infection with Helicobacter pylori is the dominant cause of gastric cancer, and two recent randomized trials showed that H. pylori eradication significantly decreased gastric cancer risk. Population screening and treating individuals for H. pylori also appears to be cost-effective. Nevertheless, current clinical guidelines differ as to whether asymptomatic adults should be screened and treated for H. pylori, and no countries have yet implemented eradication programs. Some of this inaction may reflect lingering doubts about the effectiveness of H. pylori eradication in preventing gastric cancer, but there is also uncertainty about possible risks of mass antibiotic treatment and its impact on gut flora. Appropriately designed studies will help address these issues and hasten the implementation of population-wide prevention programs.

One-year risk for advanced colorectal neoplasia: U.S. versus U.K. risk-stratification guidelines.

BACKGROUND: Guidelines from the United Kingdom and the United States on risk stratification after polypectomy differ, as do recommended surveillance intervals. OBJECTIVE: To compare risk for advanced colorectal neoplasia at 1-year colonoscopy among patients cross-classified by U.S. and U.K. surveillance guidelines. DESIGN: Pooled analysis of 4 prospective studies between 1984 and 1998. SETTING: Academic and private clinics in the United States. PATIENTS: 3226 postpolypectomy patients with 6- to 18-month follow-up colonoscopy. MEASUREMENTS: Rates of advanced neoplasia (an adenoma ≥1 cm, high-grade dysplasia, >25% villous architecture, or invasive cancer) at 1 year, compared across U.S. and U.K. risk categories. RESULTS: Advanced neoplasia was detected 1 year after polypectomy in 3.8% (95% CI, 2.7% to 4.9%) of lower-risk patients and 11.2% (CI, 9.8% to 12.6%) of higher-risk patients by U.S. criteria. According to U.K. criteria, 4.4% (CI, 3.3% to 5.4%) of low-risk patients, 9.9% (CI, 8.3% to 11.5%) of intermediate-risk patients, and 18.7% (CI, 14.8% to 22.5%) of high-risk patients presented with advanced neoplasia; U.K. high-risk patients comprised 12.1% of all patients. All U.S. lower-risk patients were low-risk by U.K. criteria; however, more patients were classified as low-risk, because the U.K. guidelines do not consider histologic features. Higher-risk U.S. patients were distributed across the 3 U.K. categories. Among all patients with advanced neoplasia, 26.3% were reclassified by the U.K. criteria to a higher-risk category and 7.0% to a lower-risk category, with a net 19.0% benefiting from detection 2 years earlier. Overall, substitution of U.K. for U.S. guidelines resulted in an estimated 0.03 additional colonoscopy every 5 years per patient. LIMITATIONS: Patients were enrolled 15 to 20 years ago, and quality measures for colonoscopy were unavailable. Patients lacking follow-up colonoscopy or with surveillance colonoscopy after 6 to 18 months and those with cancer or insufficient baseline adenoma characteristics were excluded (2076 of 5302). CONCLUSION: Application of the U.K. guidelines in the United States could identify a subset of high-risk patients who may warrant a 1-year clearing colonoscopy without substantially increasing rates of colonoscopy. PRIMARY FUNDING SOURCE: European Union Public Health Programme.

Risk of recurrent Helicobacter pylori infection 1 year after initial eradication therapy in 7 Latin American communities.

IMPORTANCE: The long-term effectiveness of Helicobacter pylori eradication programs for preventing gastric cancer will depend on recurrence risk and individual and community factors. OBJECTIVE: To estimate risk of H. pylori recurrence and assess factors associated with successful eradication 1 year after treatment. DESIGN, SETTING, AND PARTICIPANTS: Cohort analysis of 1463 randomized trial participants aged 21 to 65 years from 7 Latin American communities, who were treated for H. pylori and observed between September 2009 and July 2011. INTERVENTIONS: Randomization to 1 of 3 treatment groups: 14-day lansoprazole, amoxicillin, and clarithromycin (triple therapy); 5-day lansoprazole and amoxicillin followed by 5-day lansoprazole, clarithromycin, and metronidazole (sequential); or 5-day lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant). Participants with a positive (13)C-urea breath test (UBT) 6 to 8 weeks posttreatment were offered voluntary re-treatment with 14-day bismuth-based quadruple therapy. MEASUREMENTS: Recurrent infection after a negative posttreatment UBT and factors associated with successful eradication at 1-year follow-up. RESULTS: Among participants with UBT-negative results who had a 1-year follow-up UBT (n=1091), 125 tested UBT positive, a recurrence risk of 11.5% (95% CI, 9.6%-13.5%). Recurrence was significantly associated with study site (P = .03), nonadherence to initial therapy (adjusted odds ratio [AOR], 2.94; 95% CI, 1.31-6.13; P = .01), and children in the household (AOR, 1.17; 95% CI, 1.01-1.35 per child; P = .03). Of the 281 with positive posttreatment UBT results, 138 completed re-treatment, of whom 93 tested UBT negative at 1 year. Among the 1340 who had a 1-year UBT, 80.4% (95% CI, 76.4%-83.9%), 79.8% (95% CI, 75.8%-83.5%), and 77.8% (95% CI, 73.6%-81.6%) had UBT-negative results in the triple, sequential, and concomitant groups, respectively (P = .61), with 79.3% overall effectiveness (95% CI, 77.1%-81.5%). In a single-treatment course analysis that ignored the effects of re-treatment, the percentage of UBT-negative results at 1 year was 72.4% (95% CI, 69.9%-74.8%) and was significantly associated with study site (P < .001), adherence to initial therapy (AOR, 0.26; 95% CI, 0.15-0.42; P < .001), male sex (AOR, 1.63; 95% CI, 1.25-2.13; P < .001), and age (AOR, 1.14; 95% CI, 1.02-1.27 per decade; P = .02). One-year effectiveness among all 1463 enrolled participants, considering all missing UBT results as positive, was 72.7% (95% CI, 70.3%-74.9%). CONCLUSIONS AND RELEVANCE: One year after treatment for H. pylori infection, recurrence occurred in 11.5% of participants who had negative posttreatment UBT results. Recurrence determinants (ie, nonadherence and demographics) may be as important as specific antibiotic regimen in determining the long-term success of H. pylori eradication interventions. Study findings are relevant to the feasibility of programs for the primary prevention of gastric cancer in high-incidence regions of Latin America. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01061437.

14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial.

BACKGROUND: Evidence from Europe, Asia, and North America suggests that standard three-drug regimens of a proton-pump inhibitor plus amoxicillin and clarithromycin are significantly less effective for eradication of Helicobacter pylori infection than are 5-day concomitant and 10-day sequential four-drug regimens that include a nitroimidazole. These four-drug regimens also entail fewer antibiotic doses than do three-drug regimens and thus could be suitable for eradication programmes in low-resource settings. Few studies in Latin America have been done, where the burden of H pylori-associated diseases is high. We therefore did a randomised trial in Latin America comparing the effectiveness of four-drug regimens given concomitantly or sequentially with that of a standard 14-day regimen of triple therapy. METHODS: Between September, 2009, and June, 2010, we did a randomised trial of empiric 14-day triple, 5-day concomitant, and 10-day sequential therapies for H pylori in seven Latin American sites: Chile, Colombia, Costa Rica, Honduras, Nicaragua, and Mexico (two sites). Participants aged 21-65 years who tested positive for H pylori by a urea breath test were randomly assigned by a central computer using a dynamic balancing procedure to: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy); 5 days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy); or 5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole (sequential therapy). Eradication was assessed by urea breath test 6-8 weeks after randomisation. The trial was not masked. Our primary outcome was probablity of H pylori eradication. Our analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, registration number NCT01061437. FINDINGS: 1463 participants aged 21-65 years were randomly allocated a treatment: 488 were treated with 14-day standard therapy, 489 with 5-day concomitant therapy, and 486 with 10-day sequential therapy. The probability of eradication with standard therapy was 82·2% (401 of 488), which was 8·6% higher (95% adjusted CI 2·6-14·5) than with concomitant therapy (73·6% [360 of 489]) and 5·6% higher (-0·04% to 11·6) than with sequential therapy (76·5% [372 of 486]). Neither four-drug regimen was significantly better than standard triple therapy in any of the seven sites. INTERPRETATION: Standard 14-day triple-drug therapy is preferable to 5-day concomitant or 10-day sequential four-drug regimens as empiric therapy for H pylori infection in diverse Latin American populations. FUNDING: Bill & Melinda Gates Foundation, US National Institutes of Health.

A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy.

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.

Using the results of a baseline and a surveillance colonoscopy to predict recurrent adenomas with high-risk characteristics.

BACKGROUND: Suggested intervals for postpolypectomy surveillance colonoscopy are currently based on the adenoma findings from the most recent examination. OBJECTIVE: To determine the risk for clinically significant adenoma recurrence on the basis of the results of 2 previous colonoscopies. DESIGN: Prospective cohort study. SETTING: Academic and private centers in North America. PATIENTS: Participants in an adenoma chemoprevention trial in which all participants had 1 or more adenoma found on complete colonoscopy at entry. For this analysis, only participants whose qualifying adenoma was their first were included. All participants then underwent second and third study colonoscopies at roughly 3-year intervals. MEASUREMENTS: Proportion of patients with high-risk findings at the third study colonoscopy--either at least 1 advanced (> or = 1 cm or advanced histology) adenoma or multiple (> or = 3) adenomas. RESULTS: Fifty-eight of 564 participants (10.3%) had high-risk findings at the third study examination. If the second examination showed high-risk findings, then results from the first examination added no significant information about the probability of high-risk findings on the third examination (18.2% for high-risk findings on the first examination vs. 20.0% for low-risk findings on the first examination; P = 0.78). If the second examination showed no adenomas, then the results from the first examination added significant information about the probability of high-risk findings on the third examination (12.3% if the first examination had high-risk findings vs. 4.9% if the first examination had low-risk findings; P = 0.015). LIMITATION: This observational study cannot specifically examine adenoma recurrence risk at intervals suggested for patients with low-risk adenomas (for example, 5 years vs. 10 years). CONCLUSION: Information from 2 previous examinations may help identify low-risk populations that benefit little from intense surveillance. Surveillance guidelines might be tailored in selected patients to use information from 2 previous examinations, not just the most recent one. PRIMARY FUNDING SOURCE: National Institutes of Health.

Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study.

A direct relation between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses by sex, family history, colorectal subsite, or features of metachronous lesions. Data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas were pooled to assess whether the association between BMI and metachronous neoplasia varied by these factors. A statistically significant direct association between BMI and the odds of nonadvanced adenomas (P(trend) < 0.001) was observed, while the relation for advanced adenomas was of marginal significance (P(trend) < 0.07). In sex-stratified analyses, obesity was statistically significantly associated with the odds of any metachronous lesion among men (odds ratio = 1.36, 95% confidence interval: 1.17, 1.58) but not among women (odds ratio = 1.10, 95% confidence interval: 0.89, 1.37). The associations with BMI appeared to be limited to proximal neoplasia, with statistically significant results for BMI and proximal (P(trend) < 0.001), but not distal (P(trend) < 0.85), neoplasia. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages.

Gastrin, Helicobacter pylori, and colorectal adenomas.

BACKGROUND & AIMS: Hypergastrinemia and Helicobacter pylori (Hp) infection have been associated with an increased risk for colorectal neoplasia in some studies. However, data from large prospective studies of both associations are lacking. The aim of this study was to evaluate whether serum gastrin levels and/or infection with Hp are associated with the subsequent development of colorectal adenomas. METHODS: Subjects (all with a history of adenoma formation) were drawn from 2 previously completed adenoma chemoprevention trials. Participants underwent clearing colonoscopy at baseline with follow-up colonoscopy 1 and 4 years after enrollment. We used commercially available assays on fasting blood specimens to measure serum gastrin levels and Hp serologies 1 year after randomization. Risk ratios for adenoma and advanced adenoma development during the subsequent 3 years were computed by generalized linear regression. RESULTS: Of the 1794 subjects randomized in the 2 trials, 685 had available serum and were included in the analyses. Gastrin levels were significantly higher in the 239 subjects with Hp titers indicating infection (mean, 88.3 pg/mL) than in those not infected (mean, 73.9 pg/mL; P < .001). In fully adjusted models, gastrin levels were not associated with incident adenoma development (risk ratio [RR], 1.10; 95% confidence interval [CI], 0.78-1.54) or advanced adenoma formation (RR, 0.82; 95% CI, 0.33-2.03). A positive Hp serology was associated with a decreased risk for adenoma formation (RR, 0.76; 95% CI, 0.60-0.96). CONCLUSIONS: Neither hypergastrinemia nor serologic evidence of Hp infection were associated with an increased risk for recurrent adenoma development. These results do not support the notion that gastrin promotes colorectal carcinogenesis, at least at the stage of adenoma development.

A randomized trial of aspirin to prevent colorectal adenomas.

BACKGROUND: Laboratory and epidemiologic data suggest that aspirin has an antineoplastic effect in the large bowel. METHODS: We performed a randomized, double-blind trial of aspirin as a chemopreventive agent against colorectal adenomas. We randomly assigned 1121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81 mg of aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to the protocol, follow-up colonoscopy was to be performed approximately three years after the qualifying endoscopy. We compared the groups with respect to the risk of one or more neoplasms (adenomas or colorectal cancer) at least one year after randomization using generalized linear models to compute risk ratios and 95 percent confidence intervals. RESULTS: Reported adherence to study medications and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up colonoscopy was performed at least one year after randomization in 1084 patients (97 percent). The incidence of one or more adenomas was 47 percent in the placebo group, 38 percent in the group given 81 mg of aspirin per day, and 45 percent in the group given 325 mg of aspirin per day (global P=0.04). Unadjusted relative risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg group (95 percent confidence interval, 0.69 to 0.96) and 0.96 in the 325-mg group (95 percent confidence interval, 0.81 to 1.13). For advanced neoplasms (adenomas measuring at least 1 cm in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer), the respective relative risks were 0.59 (95 percent confidence interval, 0.38 to 0.92) and 0.83 (95 percent confidence interval, 0.55 to 1.23). CONCLUSIONS: Low-dose aspirin has a moderate chemopreventive effect on adenomas in the large bowel.

Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women's Healthy Eating and Living (WHEL) randomized trial.

CONTEXT: Evidence is lacking that a dietary pattern high in vegetables, fruit, and fiber and low in total fat can influence breast cancer recurrence or survival. OBJECTIVE: To assess whether a major increase in vegetable, fruit, and fiber intake and a decrease in dietary fat intake reduces the risk of recurrent and new primary breast cancer and all-cause mortality among women with previously treated early stage breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Multi-institutional randomized controlled trial of dietary change in 3088 women previously treated for early stage breast cancer who were 18 to 70 years old at diagnosis. Women were enrolled between 1995 and 2000 and followed up through June 1, 2006. INTERVENTION: The intervention group (n = 1537) was randomly assigned to receive a telephone counseling program supplemented with cooking classes and newsletters that promoted daily targets of 5 vegetable servings plus 16 oz of vegetable juice; 3 fruit servings; 30 g of fiber; and 15% to 20% of energy intake from fat. The comparison group (n = 1551) was provided with print materials describing the "5-A-Day" dietary guidelines. MAIN OUTCOME MEASURES: Invasive breast cancer event (recurrence or new primary) or death from any cause. RESULTS: From comparable dietary patterns at baseline, a conservative imputation analysis showed that the intervention group achieved and maintained the following statistically significant differences vs the comparison group through 4 years: servings of vegetables, +65%; fruit, +25%; fiber, +30%, and energy intake from fat, -13%. Plasma carotenoid concentrations validated changes in fruit and vegetable intake. Throughout the study, women in both groups received similar clinical care. Over the mean 7.3-year follow-up, 256 women in the intervention group (16.7%) vs 262 in the comparison group (16.9%) experienced an invasive breast cancer event (adjusted hazard ratio, 0.96; 95% confidence interval, 0.80-1.14; P = .63), and 155 intervention group women (10.1%) vs 160 comparison group women (10.3%) died (adjusted hazard ratio, 0.91; 95% confidence interval, 0.72-1.15; P = .43). No significant interactions were observed between diet group and baseline demographics, characteristics of the original tumor, baseline dietary pattern, or breast cancer treatment. CONCLUSION: Among survivors of early stage breast cancer, adoption of a diet that was very high in vegetables, fruit, and fiber and low in fat did not reduce additional breast cancer events or mortality during a 7.3-year follow-up period. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003787.

Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.

CONTEXT: Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine. OBJECTIVE: To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, placebo-controlled, 2-factor, phase 3, randomized clinical trial conducted at 9 clinical centers between July 6, 1994, and October 1, 2004. Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma. INTERVENTION: Participants were randomly assigned in a 1:1 ratio to receive 1 mg/d of folic acid (n = 516) or placebo (n = 505), and were separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of 2 colonoscopic surveillance cycles (the first interval was at 3 years and the second at 3 or 5 years later). MAIN OUTCOME MEASURES: The primary outcome measure was occurrence of at least 1 colorectal adenoma. Secondary outcomes were the occurrence of advanced lesions (> or =25% villous features, high-grade dysplasia, size > or =1 cm, or invasive cancer) and adenoma multiplicity (0, 1-2, or > or =3 adenomas). RESULTS: During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n = 221) and 42.4% for placebo (n = 206) (unadjusted risk ratio [RR], 1.04; 95% confidence interval [CI], 0.90-1.20; P = .58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n = 57) and 8.6% for placebo (n = 42) (unadjusted RR, 1.32; 95% CI, 0.90-1.92; P = .15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n = 127) and 37.2% for placebo (n = 113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P = .23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n = 35) and 6.9% for placebo (n = 21) (unadjusted RR, 1.67; 95% CI, 1.00-2.80; P = .05). Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation. CONCLUSIONS: Folic acid at 1 mg/d does not reduce colorectal adenoma risk. Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00272324.

Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma.

PURPOSE: The primary purpose of this study was to compare the neuropsychologic functioning of long-term survivors of breast cancer and lymphoma who had been treated with standard-dose systemic chemotherapy or local therapy only. PATIENTS AND METHODS: Long-term survivors (5 years postdiagnosis, not presently receiving cancer treatment, and disease-free) of breast cancer or lymphoma who had been treated with systemic chemotherapy (breast cancer: n = 35, age, 59.1 +/- 10.7 years; lymphoma: n = 36, age, 55.9 +/- 12.1 years) or local therapy only (breast cancer: n = 35, age, 60.6 +/- 10.5 years; lymphoma: n = 22, age, 48.7 +/- 11.7 years) completed a battery of neuropsychologic and psychologic tests (Center for Epidemiological Study-Depression, Spielberger State-Trait Anxiety Inventory, and Fatigue Symptom Inventory). RESULTS: Multivariate analysis of variance, controlling for age and education, revealed that survivors who had been treated with systemic chemotherapy scored significantly lower on the battery of neuropsychologic tests compared with those treated with local therapy only (P <.04), particularly in the domains of verbal memory (P <.01) and psychomotor functioning (P <.03). Survivors treated with systemic chemotherapy were also more likely to score in the lower quartile on the Neuropsychological Performance Index (39% v 14%, P <.01) and to self-report greater problems with working memory on the Squire Memory Self-Rating Questionnaire (P <.02). CONCLUSION: Data from this study support the hypothesis that systemic chemotherapy can have a negative impact on cognitive functioning as measured by standardized neuropsychologic tests and self-report of memory changes. However, analysis of the Neuropsychological Performance Index suggests that only a subgroup of survivors may experience long-term cognitive deficits associated with systemic chemotherapy.

Risk of prostate cancer in a randomized clinical trial of calcium supplementation.

BACKGROUND: In some studies, high calcium intake has been associated with an increased risk of prostate cancer, but no randomized studies have investigated this issue. METHODS: We randomly assigned 672 men to receive either 3 g of calcium carbonate (1,200 mg of calcium), or placebo, daily for 4 years in a colorectal adenoma chemoprevention trial. Participants were followed for up to 12 years and asked periodically to report new cancer diagnoses. Subject reports were verified by medical record review. Serum samples, collected at randomization and after 4 years, were analyzed for 1,25-(OH)2 vitamin D, 25-(OH) vitamin D, and prostate-specific antigen (PSA). We used life table and Cox proportional hazard models to compute rate ratios for prostate cancer incidence and generalized linear models to assess the relative risk of increases in PSA levels. RESULTS: After a mean follow-up of 10.3 years, there were 33 prostate cancer cases in the calcium-treated group and 37 in the placebo-treated group [unadjusted rate ratio, 0.83; 95% confidence interval (95% CI), 0.52-1.32]. Most cases were not advanced; the mean Gleason's score was 6.2. During the first 6 years (until 2 years post-treatment), there were significantly fewer cases in the calcium group (unadjusted rate ratio, 0.52; 95% CI, 0.28-0.98). The calcium risk ratio for conversion to PSA >4.0 ng/mL was 0.63 (95% CI, 0.33-1.21). Baseline dietary calcium intake, plasma 1,25-(OH)2 vitamin D and 25-(OH) vitamin D levels were not materially associated with risk. CONCLUSION: In this randomized controlled clinical trial, there was no increase in prostate cancer risk associated with calcium supplementation and some suggestion of a protective effect.

Prediagnostic serum selenium concentration and the risk of recurrent colorectal adenoma: a nested case-control study.

Several studies have suggested that selenium may help to prevent colorectal neoplasia. To investigate the relation between prediagnostic serum selenium concentrations and colorectal adenomas, we conducted a nested case-control study using data from a large, multicenter, adenoma prevention trial. Cases comprised a total of 276 patients who developed a colorectal adenoma between the year 1 and year 4 follow-up exam. Controls were 276 patients who did not develop an adenoma during this time interval, matched to case subjects on age, sex, and clinical center. Total and bound selenium concentrations were measured from baseline or year 1 serum samples using instrumental neutron activation analysis. We estimated the odds ratios of colorectal adenoma in relation to serum selenium concentrations adjusting for age, clinical center, and sex. Compared with the lowest quintile, the odds ratio for the highest quintile was 0.76 (95% confidence interval, 0.44-1.30) for total selenium and 0.60 (95% confidence interval, 0.34-1.05) for bound selenium, and there was no apparent trend in risk (P for trend = 0.50 for total selenium and P for trend = 0.20 for bound selenium). Thus, our findings do not indicate a clear association between serum selenium concentrations and adenoma recurrence.

Early life factors in relation to breast cancer risk in postmenopausal women.

We evaluated the role of early life factors in a large, population-based, case-control study of breast cancer risk in postmenopausal women. Case women in Massachusetts, New Hampshire, and Wisconsin were ascertained through state cancer registries; control women were randomly selected from drivers license lists (50-65 years of age) or Medicare beneficiary lists (65-79 years of age). Information concerning factors of interest was obtained through structured telephone interviews. Overall, 83% of eligible cases and 78% of eligible controls participated, and data from more than 2900 women were available for this analysis. We observed a weak J-shaped relationship between birth weight and breast cancer risk; the increased risk was not statistically significant for either the lowest or the highest birth weight. Parental smoking during the pregnancy was not associated with risk of breast cancer in the adult daughter. Breast cancer risk increased significantly with father's education (P = 0.01). Risk also increased with greater age of the mother at the time of the subject's birth (P = 0.04). The subject's birth rank was inversely associated with risk (P = 0.03), as was the number of older sisters (P = 0.03), but the number of older brothers, number of younger siblings, sibship gender ratio, and total sibship size were unrelated to risk. Overall, our results are consistent with previous studies and suggest that these early life factors have a modest influence on breast cancer risk in postmenopausal women.

Project ENABLE: a palliative care demonstration project for advanced cancer patients in three settings.

At the end of the 1990s, based on data from two major studies of end-of-life (EOL) care, the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT), and the Hospitalized Elderly Longitudinal Project (HELP), a consensus panel report documented the problems and needs of patients with cancer and other life-limiting diagnoses at end-of-life. A national program of The Robert Wood Johnson Foundation (RWJF), Promoting Excellence in End-of-Life Care, attempted to address these needs by funding demonstration projects to test various approaches to improve identified deficits. In 1998, Project ENABLE (Educate, Nurture, Advise Before Life Ends), one of four RWJF-funded cancer center/hospice collaborations of the Promoting Excellence program, began to address these issues. The jointly sponsored Norris Cotton Cancer Center (NCCC)/Hospice of Vermont and New Hampshire (Hospice VNH) program provided an integrated approach to the management of life-limiting cancer. Project ENABLE was aimed at alleviating the symptoms of disease and treatment, enhancing clinician and patient/family communication, offering support for families, friends and other caregivers, addressing emotional and spiritual needs of dying people and providing conceptual and administrative structure to provide EOL care consistent with patients' values and preferences. Although patient symptom data is not yet available, other measures of success included improved access to hospice and palliative care services from the time of diagnosis and a sustained palliative care program at two of the three sites in which the program was implemented.