Maria Elena Martinez

Lack of Effect of a High-Fiber Cereal Supplement on the Recurrence of Colorectal Adenomas

BACKGROUND The risks of colorectal cancer and adenoma, the precursor lesion, are believed to be influenced by dietary factors. Epidemiologic evidence that cereal fiber protects against colorectal cancer is equivocal. We conducted a randomized trial to determine whether dietary supplementation with wheat-bran fiber reduces the rate of recurrence of colorectal adenomas. METHODS We randomly assigned 1429 men and women who were 40 to 80 years of age and who had had one or more histologically confirmed colorectal adenomas removed within three months before recruitment began to a supervised program of dietary supplementation with either high amounts (13.5 g per day) or low amounts (2 g per day) of wheat-bran fiber. The primary end point was the presence or absence of new adenomas at the time of follow-up colonoscopy. Subjects and physicians, including colonoscopists, were unaware of the group assignments. RESULTS Of the 1303 subjects who completed the study, 719 had been randomly assigned to the high-fiber group and 584 to the low-fiber group. The median times from randomization to the last follow-up colonoscopy were 34 months in the high-fiber group and 36 months in the low-fiber group. By the time of the last follow-up colonoscopy, at least one adenoma had been identified in 338 subjects in the high-fiber group (47.0 percent) and in 299 subjects in the low-fiber group (51.2 percent). The multivariate adjusted odds ratio for recurrent adenoma in tile high-fiber group, as compared with the low-fiber group, was 0.88 (95 percent confidence interval, 0.70 to 1.11; P=0.28), and the relative risk of recurrence according to the number of adenomas, in the high-fiber group as compared with the low-fiber group, was 0.99 (95 percent confidence interval, 0.71 to 1.36; P=0.93). CONCLUSIONS As used in this study, a dietary supplement of wheat-bran fiber does not protect against recurrent colorectal adenomas.

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.

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.

Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene

Most sporadic colon adenomas acquire mutations in the adenomatous polyposis coli gene (APC) and show defects in APC-dependent signaling. APC influences the expression of several genes, including the c-myc oncogene and its antagonist Mad1. Ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is a transcriptional target of c-myc and a modifier of APC-dependent tumorigenesis. A single-nucleotide polymorphism exists in intron 1 of the human ODC gene, which lies between two myc-binding domains. This region is known to affect ODC transcription, but no data exist on the relationship of this polymorphism to risk of colorectal neoplasia in humans. We show that individuals homozygous for the minor ODC A-allele who reported using aspirin are ≈0.10 times as likely to have an adenoma recurrence as non-aspirin users homozygous for the major G-allele. Mad1 selectively suppressed the activity of the ODC promoter containing the A-allele, but not the G-allele, in a human colon cancer-derived cell line (HT29). Aspirin (≥10 μM) did not affect ODC allele-specific promoter activity but did activate polyamine catabolism and lower polyamine content in HT29 cells. We propose that the ODC polymorphism and aspirin act independently to reduce the risk of adenoma recurrence by suppressing synthesis and activating catabolism, respectively, of colonic mucosal polyamines. These findings confirm the hypothesis that the ODC polymorphism is a genetic marker for colon cancer risk, and support the use of ODC inhibitors and aspirin, or other nonsteroidal antiinflammatory drugs (NSAIDs), in combination as a strategy for colon cancer prevention.

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.

Case–Control Study of Overweight, Obesity, and Colorectal Cancer Risk, Overall and by Tumor Microsatellite Instability Status

BACKGROUND Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%-20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status. METHODS The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (> or =30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided. RESULTS Recent BMI, modeled in 5 kg/m(2) increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m(2), was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31). CONCLUSION The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.

Primary Prevention of Colorectal Cancer: Lifestyle, Nutrition, Exercise

The past two decades have provided a vast amount of literature related to the primary prevention of colorectal cancer. Large international variation in colorectal cancer incidence and mortality rates and the prominent increases in the incidence of colorectal cancer in groups that migrated from low- to high-incidence areas provided important evidence that lifestyle factors influence the development of this malignancy. Moreover, there is convincing evidence from epidemiological and experimental studies that dietary intake is an important etiological factor in colorectal neoplasia. Although the precise mechanisms have not been clarified, several lifestyle factors are likely to have a major impact on colorectal cancer development. Physical inactivity and to a lesser extent, excess body weight, are consistent risk factors for colon cancer. Exposure to tobacco products early in life is associated with a higher risk of developing colorectal neoplasia. Diet and nutritional factors are also clearly important. Diets high in red and processed meat increase risk. Excess alcohol consumption, probably in combination with a diet low in some micronutrients such as folate and methionine, appear to increase risk. There is also recent evidence supporting a protective effect of calcium and vitamin D in the etiology of colorectal neoplasia. The relationship between intake of dietary fiber and risk of colon cancer has been studied for three decades but the results are still inconclusive. However, some micronutrients or phytochemicals in fiber-rich foods may be important; folic acid is one such micronutrient that has been shown to protect against the development of colorectal neoplasia and is currently being studied in intervention trials of adenoma recurrence. The overwhelming evidence indicates that primary prevention of colon cancer is feasible. Continued focus on primary prevention of colorectal cancer, in combination with efforts aimed at screening and surveillance, will be vital in attaining the greatest possible progress against this complex, yet highly preventable disease.

Reproductive risk factors and breast cancer subtypes: a review of the literature

AbstractAside from age, sex, and family history, risk of developing breast cancer is largely linked to reproductive factors, which characterize exposure to sex hormones. Given that, molecular testing at the tumor level is currently possible, clinical characterization of tumor subtypes is routinely conducted to guide treatment decisions. However, despite the vast amount of published data from observational studies on reproductive factor associations and breast cancer risk, relatively fewer reports have been published on associations specific to breast tumor subtypes. We conducted a review of the literature and summarized the results of associations between reproductive factors and risk or odds of three distinct tumor subtypes: estrogen receptor/progesterone receptor positive (hormone receptor positive, HR+ tumors), tumors overexpressing the human epidermal receptor 2 protein (HER2+), and triple negative breast cancer (TNBC), which lacks the three markers. Results show that the most consistent evidence for associations with reproductive risk factors exists for HR+ breast cancers, with nulliparity, current use of menopausal hormone therapy, and prolonged interval between menarche and age at first birth being the strongest risk factors; increased age at first birth and decreased age at menarche were fairly consistently associated with HR+ cancers; and though less consistent, older age at menopause was also positively associated, while lactation was inversely associated with HR+ tumors. Fewer consistent associations have been reported for TNBC. The single protective factor most consistently associated with TNBC was longer duration of breastfeeding. Increased parity, younger age at first birth, older age at menarche, and oral contraceptive use were less consistently shown to be associated with TNBC. No remarkable associations for HER2+ breast cancers were evident, although this was based on relatively scarce data. Findings suggest heterogeneity in reproductive risk factors for the distinct subtypes of breast tumors, which may have implications for recommended prevention strategies.

Nutrition and physical activity cancer prevention guidelines, cancer risk, and mortality in the women's health initiative.

Healthy lifestyle behaviors are recommended to reduce cancer risk and overall mortality. Adherence to cancer-preventive health behaviors and subsequent cancer risk has not been evaluated in a diverse sample of postmenopausal women. We examined the association between the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines score and risk of incident cancer, cancer-specific mortality, and all-cause mortality in 65,838 postmenopausal women enrolled in the Womens Health Initiative Observational Study. ACS guidelines scores (0–8 points) were determined from a combined measure of diet, physical activity, body mass index (current and at age 18 years), and alcohol consumption. After a mean follow-up of 12.6 years, 8,632 incident cancers and 2,356 cancer deaths were identified. The highest ACS guidelines scores compared with the lowest were associated with a 17% lower risk of any cancer [HR, 0.83; 95% confidence interval (CI), 0.75–0.92], 22% lower risk of breast cancer (HR, 0.78; 95% CI, 0.67–0.92), 52% lower risk of colorectal cancer (HR, 0.48; 95% CI, 0.32–0.73), 27% lower risk of all-cause mortality, and 20% lower risk of cancer-specific mortality (HR, 0.80; 95% CI, 0.71–0.90). Associations with lower cancer incidence and mortality were generally strongest among Asian, black, and Hispanic women and weakest among non-Hispanic whites. Behaviors concordant with Nutrition and Physical Activity Cancer Prevention Guidelines were associated with lower risk of total, breast, and colorectal cancers and lower cancer-specific mortality in postmenopausal women. Cancer Prev Res; 7(1); 42–53. ©2014 AACR.

Plasma levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer

In the US, prostate cancer (PCa) has the highest incidence rate of all cancers in males, with few known modifiable risk factors. Some studies support an association between the Vitamin D metabolites, 1,25-dihydroxyvitamin D (1alpha,25(OH)(2)D(3)) and/or 25-hydroxyvitamin D (25(OH)D(3)), and prostate cancer, while others have yielded conflicting results. 1alpha,25(OH)(2)D(3) has anti-proliferative and pro-differentiating effects in prostate cancer cell lines, and levels of circulating 25(OH)D(3) may be important as PCa cells possess 1-alpha-hydroxylase activity. Using a nested case-control design, we evaluated whether plasma levels of 25(OH)D(3) and 1alpha,25(OH)(2)D(3) were associated with prostate cancer risk in participants from the Nutritional Prevention of Cancer (NPC) trial. With 83 cases and 166 matched controls, we calculated the adjusted odds ratios for increasing plasma levels of 25(OH)D(3) and 1alpha,25(OH)(2)D(3). Compared to the lowest tertile of plasma 25(OH)D(3) levels, the adjusted odds ratios were 1.71 (0.68-4.34) and 0.75 (0.29-1.91); the corresponding odds ratios for 1alpha,25(OH)(2)D(3) were 1.44 (0.59-3.52) and 1.06 (0.42-2.66). Given the pivotal effects of the Vitamin D receptor on gene transcription, it is likely that the anti-carcinogenic effects of Vitamin D that have previously been described are related to the activity and expression of the Vitamin D receptor and should be investigated further.