A partially hydrolyzed formula with synbiotics supports adequate growth and is well tolerated in healthy, Chinese term infants: A double-blind, randomized controlled trial.

OBJECTIVES: The aim of this study was to evaluate growth and gastrointestinal tolerance in infants fed a partially hydrolyzed protein formula (pHF) with a synbiotic mixture of short-chain galacto-oligosaccharides and long-chain fructooligosaccharides (scGOS/lcFOS; 9:1) and Bifidobacterium breve M-16V (test formula) compared with an intact protein infant formula (IF) with scGOS/lcFOS (control formula). METHODS: This randomized, double-blind, controlled, multicenter trial enrolled healthy, fully formula-fed Chinese infants (≤44 d) who received either the test (n = 112) or control formula (n = 112) until 17 wk of age. Fully breastfed infants served as a reference (n = 60). Anthropometrics, gastrointestinal symptoms, and adverse events were assessed monthly. Primary outcome was weight gain in grams per day from baseline to 17 wk of age. RESULTS: Equivalence in daily weight gain (primary outcome) was demonstrated between the test and control groups (estimated mean difference [SE]: -0.36 [0.93] g/d, 90% confidence interval [CI], -1.90 to 1.18) as well as between each IF group and the breastfed reference group (test: 0.02 [1.05] g/d, 90% CI, -1.71 to 1.75; control: 0.36 [1.04] g/d, 90% CI, -1.35 to 2.08). There were no clinically relevant differences in gastrointestinal tolerance or adverse events between the formula groups. CONCLUSION: A pHF with synbiotics supports adequate growth and is well tolerated in healthy, term-born Chinese infants. Additionally, infant growth and gastrointestinal tolerance measures of both IF groups were comparable to the breastfed group and can be considered suitable and well tolerated for use.

Polymorphisms in the Angiogenesis-Related Genes EFNB2, MMP2 and JAG1 Are Associated with Survival of Colorectal Cancer Patients.

An individual's inherited genetic variation may contribute to the 'angiogenic switch', which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p < 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome.

Association of CD4+ Radiation-Induced Lymphocyte Apoptosis with Fibrosis and Telangiectasia after Radiotherapy in 272 Breast Cancer Patients with >10-Year Follow-up.

PURPOSE: Radiation-induced lymphocyte apoptosis (RILA) has been suggested as a predictive assay for adverse late reactions after radiotherapy. Thus, low RILA values of T-lymphocyte subpopulations have been associated with increased risk for various endpoints at 2 to 3 years of follow-up. The purpose was to test if such associations persist for specific endpoints (subcutaneous fibrosis, telangiectasia) in breast cancer patients with at least 10 years of follow-up.Experimental Design: Two hundred and seventy-two female patients who had received breast-conserving therapy within the German ISE study were included (median follow-up: 11.6 years). Radiotherapy-induced side effects were scored according to the Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic (LENT-SOMA) classification system. RILA in the CD4+, CD8+, and natural killer (NK) subpopulations from peripheral blood was analyzed by flow cytometry. Multivariate predictive modeling was performed including relevant clinical risk factors. RESULTS: Low CD4+ RILA was associated with increased risk for both fibrosis (P = 0.011) and telangiectasia (P < 0.001). For fibrosis, the association was stronger outside the surgical area (Fibout; P = 0.004) than within (Fibin; P = 0.17). Predictive multivariate modeling including clinical risk factors yielded OR of 3.48 (95% confidence interval, 1.84-6.58) for any fibrosis and 8.60 (2.71-27.3) for telangiectasia. Addition of CD4+ RILA to the clinical variables improved discrimination (c statistics) from 0.62 to 0.68 for any fibrosis, 0.62 to 0.66 for Fibin, 0.61 to 0.69 for Fibout, and from 0.65 to 0.76 for telangiectasia. CD8+ and NK RILA were not significantly associated with radiotherapy-related late reactions. CONCLUSIONS: The results provide first evidence that low CD4+ RILA is associated with increased subcutaneous fibrosis and telangiectasia even after 10 years. This supports the potential usefulness for predicting individual clinical risk.

Pathway analysis of genetic variants in folate-mediated one-carbon metabolism-related genes and survival in a prospectively followed cohort of colorectal cancer patients.

Folate-mediated one-carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5-fluorouracil (5-FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM-related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM-related genes for associations with overall- (OS) and disease-free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5-FU-based chemotherapy and assessed pathway-specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow-up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HRhet  = 0.81, 95% CI: 0.67-0.97; TYMS: rs1001761: HRhet  = 0.82, 95% CI: 0.68-0.99 and rs2847149: HRhet  = 0.82, 95% CI: 0.68-0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HRhet  = 1.28, 95% CI: 1.07-1.53; HRhzv  = 2.02, 95% CI:1.46-2.80; HRlogAdd  = 1.31, pFDR  = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P < 0.01) with significant gene-chemotherapy interactions, including PON1 rs3917538. This study supports the concept that FOCM-related genes could be associated with CRC survival and may modify effects of 5-FU-based chemotherapy in genes in pyrimidine and fluorouracil metabolism, which are relevant targets for therapeutic response and prognosis in CRC. These results require confirmation in additional clinical studies.

Pitfalls in Prediction Modeling for Normal Tissue Toxicity in Radiation Therapy: An Illustration With the Individual Radiation Sensitivity and Mammary Carcinoma Risk Factor Investigation Cohorts.

PURPOSE: To identify the main causes underlying the failure of prediction models for radiation therapy toxicity to replicate. METHODS AND MATERIALS: Data were used from two German cohorts, Individual Radiation Sensitivity (ISE) (n=418) and Mammary Carcinoma Risk Factor Investigation (MARIE) (n=409), of breast cancer patients with similar characteristics and radiation therapy treatments. The toxicity endpoint chosen was telangiectasia. The LASSO (least absolute shrinkage and selection operator) logistic regression method was used to build a predictive model for a dichotomized endpoint (Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer score 0, 1, or ≥2). Internal areas under the receiver operating characteristic curve (inAUCs) were calculated by a naïve approach whereby the training data (ISE) were also used for calculating the AUC. Cross-validation was also applied to calculate the AUC within the same cohort, a second type of inAUC. Internal AUCs from cross-validation were calculated within ISE and MARIE separately. Models trained on one dataset (ISE) were applied to a test dataset (MARIE) and AUCs calculated (exAUCs). RESULTS: Internal AUCs from the naïve approach were generally larger than inAUCs from cross-validation owing to overfitting the training data. Internal AUCs from cross-validation were also generally larger than the exAUCs, reflecting heterogeneity in the predictors between cohorts. The best models with largest inAUCs from cross-validation within both cohorts had a number of common predictors: hypertension, normalized total boost, and presence of estrogen receptors. Surprisingly, the effect (coefficient in the prediction model) of hypertension on telangiectasia incidence was positive in ISE and negative in MARIE. Other predictors were also not common between the 2 cohorts, illustrating that overcoming overfitting does not solve the problem of replication failure of prediction models completely. CONCLUSIONS: Overfitting and cohort heterogeneity are the 2 main causes of replication failure of prediction models across cohorts. Cross-validation and similar techniques (eg, bootstrapping) cope with overfitting, but the development of validated predictive models for radiation therapy toxicity requires strategies that deal with cohort heterogeneity.

Aspirin Reduces Plasma Concentrations of the Oncometabolite 2-Hydroxyglutarate: Results of a Randomized, Double-Blind, Crossover Trial.

BACKGROUND: Aspirin use is an effective strategy for the chemoprevention of colorectal cancer, even at low doses. However, in order to implement aspirin interventions, risk-benefit balances and biologic mechanisms need to be better defined; to further this aim, we used a metabolomics approach. METHODS: We metabolically profiled 40 healthy, nonsmoking men and women ages 20 to 45 years enrolled in a randomized, double-blind, crossover trial of 325 mg aspirin/day over a period of 60 days. Gas and liquid chromatography-mass spectrometry were used to comprehensively profile participants' plasma samples after aspirin and placebo interventions. RESULTS: A total of 363 metabolites, covering most human biochemical pathways, were measured. Compared with placebo-treated participants, plasma concentrations of the oncometabolite 2-hydroxyglutarate (R+S) decreased after aspirin treatment in both men and women (P = 0.005). This signal proved robust during 20-fold random splitting of the data using 80% of the samples in each split. We subsequently performed functional follow-up studies using targeted, enantiospecific detection in human colorectal cancer cell lines and observed an aspirin-induced reduction of (R)-2-hydroxyglutarate. We further showed that salicylate, the primary aspirin metabolite, inhibits the hydroxyacid-oxoacid transhydrogenase mediated production of (R)-2-hydroxyglutarate, thereby providing mechanistic evidence for the clinically observed effects of aspirin on total-2-hydroxyglutarate. CONCLUSIONS: Using a metabolomics approach with functional follow-up, we propose that a decrease in the oncometabolite (R)-2-hydroxyglutarate may identify an additional mechanism for aspirin or its metabolites in cancer prevention. IMPACT: Reduction of the oncometabolite (R)-2-hydroxyglutarate identifies a novel, non-COX-inhibition-mediated mechanism of aspirin.

Phyto-oestrogens and colorectal cancer risk: a systematic review and dose-response meta-analysis of observational studies.

Epidemiological studies suggest that soya consumption as a source of phyto-oestrogens and isoflavones may be associated with a reduced risk of colorectal cancer. However, findings have not yet been synthesised for all groups of phyto-oestrogens. A meta-analysis was conducted to quantify the association between phyto-oestrogens and colorectal cancer risk. Relevant observational studies published up to June 2016 were identified by searching MEDLINE, EMBASE and Cochrane Library databases. Study-specific relative risks (RR) were pooled in both categorical and dose-response meta-analyses. Out of seventeen identified studies, sixteen were included in the meta-analysis. Comparing the highest with the lowest intake category, inverse associations for phyto-oestrogens overall and by subgroup were observed but were statistically significant in case-controls studies and not in cohort studies. The pooled RR in case-control studies were 0·76 (95 % CI 0·69, 0·84), 0·77 (95 % CI 0·69, 0·85) and 0·70 (95 % CI 0·56, 0·89) for phyto-oestrogens, isoflavones and lignans, respectively, whereas the corresponding pooled RR were 0·95 (95 % CI 0·85, 1·06), 0·94 (95 % CI 0·84, 1·05) and 1·00 (95 % CI 0·64, 1·57) in cohort studies. Dose-response analysis yielded an 8 % reduced risk of colorectal neoplasms for every 20 mg/d increase in isoflavones intake in Asians (pooled RR 0·92; 95 % CI 0·86, 0·97). A non-linear inverse association with colorectal cancer risk was found for lignans intake, but no association for circulating enterolactone concentrations was observed. Thus, study heterogeneity precludes a rigorous conclusion regarding an effect of high exposure to isoflavones on risk of colorectal cancer. Current evidence for an association with lignans exposure is limited. Further prospective studies, particularly evaluating lignans, are warranted to clarify the association between different phyto-oestrogens and colorectal cancer risk.

Dietary B vitamin and methionine intake and MTHFR C677T genotype on risk of colorectal tumors in Lynch syndrome: the GEOLynch cohort study.

PURPOSE: Dietary intake of B vitamins and methionine, essential components of DNA synthesis and methylation pathways, may influence colorectal tumor (CRT) development. The impact of B vitamins on colorectal carcinogenesis in individuals with Lynch syndrome (LS) is unknown but is important given their high lifetime risk of developing neoplasms. The role of MTHFR C677T genotype in modifying these relationships in LS individuals is also unclear. We investigated associations between dietary intakes of folate, vitamins B2, B6, B12, and methionine and CRT development in a prospective cohort study of 470 mismatch repair gene mutation carriers. METHODS: Dietary intakes were assessed by food frequency questionnaire. Cox regression models with robust sandwich covariance estimation, adjusted for age, sex, physical activity, number of colonoscopies during person-time, NSAID use, and mutual vitamins were used to calculate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs). Analyses were also stratified by MTHFR C677T genotype. RESULTS: During a median person-time of 28.0 months, 131 persons developed a CRT. Fifty-one of these persons developed an incident colorectal adenoma, while there were four persons who developed an incident colorectal carcinoma. Compared to the lowest tertile of intake, adjusted HRs (95 % CIs) for CRT development in the highest tertile were 1.06 (0.59-1.91) for folate, 0.77 (0.39-1.51) for vitamin B2, 0.98 (0.59-1.62) for vitamin B6, 1.24 (0.77-2.00) for vitamin B12, and 1.36 (0.83-2.20) for methionine. Low vitamin B2 and low methionine intake were statistically significantly associated with an increased risk of CRT in MTHFR 677TT individuals compared to a combined reference of persons with low intake and CC genotype. CONCLUSIONS: There was no suggestion that intake of any dietary B vitamin or methionine was associated with CRT development among those with LS.

Dietary Supplement Use and Colorectal Adenoma Risk in Individuals with Lynch Syndrome: The GEOLynch Cohort Study.

BACKGROUND AND AIMS: Individuals with Lynch syndrome have a high lifetime risk of developing colorectal tumors. In this prospective cohort study of individuals with Lynch syndrome, we examined associations between use of dietary supplements and occurrence of colorectal adenomas. MATERIALS AND METHODS: Using data of 470 individuals with Lynch syndrome in a prospective cohort study, associations between dietary supplement use and colorectal adenoma risk were evaluated by calculating hazard ratios (HR) and 95% confidence intervals (CI) using cox regression models adjusted for age, sex, and number of colonoscopies during person time. Robust sandwich covariance estimation was used to account for dependency within families. RESULTS: Of the 470 mismatch repair gene mutation carriers, 122 (26.0%) developed a colorectal adenoma during an overall median person time of 39.1 months. 40% of the study population used a dietary supplement. Use of any dietary supplement was not statistically significantly associated with colorectal adenoma risk (HR = 1.18; 95%CI 0.80-1.73). Multivitamin supplement use (HR = 1.15; 95%CI 0.72-1.84), vitamin C supplement use (HR = 1.57; 95%CI 0.93-2.63), calcium supplement use (HR = 0.69; 95%CI 0.25-1.92), and supplements containing fish oil (HR = 1.60; 95%CI 0.79-3.23) were also not associated with occurrence of colorectal adenomas. CONCLUSION: This prospective cohort study does not show inverse associations between dietary supplement use and occurrence of colorectal adenomas among individuals with Lynch syndrome. Further research is warranted to determine whether or not dietary supplement use is associated to colorectal adenoma and colorectal cancer risk in MMR gene mutation carriers.

Do lifestyle factors influence colorectal cancer risk in Lynch syndrome?

Lynch syndrome (LS) is one of the inherited colorectal cancer (CRC) syndromes and is due to germline mutations in one of the mismatch repair (MMR) genes. Within LS affected-families the expression of the syndrome varies, which suggests that other factors, such as lifestyle factors, have an influence on the LS phenotype. This review gives an overview of studies that assessed the role of lifestyle factors in the development of CRC in LS. Several published studies investigated smoking habits or body fatness (BMI) in relation to colorectal tumours. Those studies fairly consistently suggest that smoking and a high BMI markedly increase the risk of CRC in persons with LS. Other lifestyle factors, such as physical activity, alcohol or diet have not or only scarcely been studied. Lifestyle factors may indeed affect CRC risk in LS. However, more prospective studies with only confirmed MMR gene mutation carriers should be done to further elucidate the role of all lifestyle factors in CRC and in other types of cancer in persons with LS. Information on the role of lifestyle factors in the development of LS-associated cancers may help in establishing lifestyle and dietary recommendations with the ultimate goal of decreasing cancer risk in persons with LS.

Dietary supplement use is not associated with recurrence of colorectal adenomas: a prospective cohort study.

Diet and lifestyle influence colorectal adenoma recurrence. The role of dietary supplement use in colorectal adenoma recurrence remains controversial. In this prospective cohort study, we examined the association between dietary supplement use, total colorectal adenoma recurrence and advanced adenoma recurrence. Colorectal adenoma cases (n = 565) from a former case-control study, recruited between 1995 and 2002, were prospectively followed until 2008. Adenomas with a diameter of ≥1 cm and/or (tubulo)villous histology and/or with high grade dysplasia and/or ≥3 adenomas detected at the same colonic examination were considered advanced adenomas. Hazard ratios (HRs) and 95% confidence intervals (CIs) for dietary supplement users (use of any supplement during the past year) compared to nonusers and colorectal adenoma recurrence were calculated using stratified Cox proportional hazard models for counting processes and were adjusted for age, sex, educational level and number of colonoscopies during follow-up. Robust sandwich covariance estimation was used to adjust for the within subject correlation. A number of 165 out of 565 adenoma patients had at least one colorectal adenoma recurrence during a median person-time of 5.4 years and of these, 37 patients had at least one advanced adenoma. One-third of the total study population (n = 203) used a dietary supplement. Compared to no use, dietary supplement use was neither statistically significantly associated with total colorectal adenoma recurrence (HR = 1.03; 95% CI 0.79-1.34) nor with recurrent advanced adenomas (HR = 1.59; 95% CI 0.88-2.87). This prospective cohort study did not suggest an association between dietary supplement use and colorectal adenoma recurrence.

Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch cohort study.

BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in LS patients was assessed. METHODS: In the GEOLynch cohort of 486 persons with LS, dietary information was collected, using a food frequency questionnaire. Dietary pattern scores were obtained by principal components analysis. Hazard ratios (HR) between dietary patterns and colorectal adenomas were calculated using Cox regression models. Robust sandwich variance estimates were used to control for dependency within families. Final models were adjusted for age, sex, smoking habits, colorectal adenoma history, and extent of colon resection. RESULTS: During a median follow-up of 20 months, colorectal adenomas were detected in 58 persons. Four dietary patterns were identified: a "Prudent," "Meat," "Snack," and "Cosmopolitan" pattern. Individuals within the highest tertile of the "Prudent" pattern had a HR of 0.73 (95% confidence interval [CI], 0.32-1.66) for colorectal adenomas, compared with the lowest tertile. Those with high "Meat" pattern scores had a HR of 1.70 (95% CI, 0.83-3.52). A high "Snack" pattern was associated with an increased risk of colorectal adenomas (HR, 2.16; 95% CI, 1.03-4.49). A HR of 1.25 (95% CI, 0.61-2.55) was observed for persons in the highest tertile of the "Cosmopolitan" pattern. CONCLUSIONS: These findings suggest that dietary patterns may be associated with development of colorectal adenoma in patients with Lynch syndrome. The directions of these findings are corroborative with those observed in studies investigating sporadic colorectal cancer.

Plasma B vitamins and LINE-1 DNA methylation in leukocytes of patients with a history of colorectal adenomas.

SCOPE: Low concentrations of folate, other B vitamins, and methionine are associated with colorectal cancer risk, possibly by changing DNA methylation patterns. Here, we examine whether plasma concentrations of B vitamins and methionine are associated with methylation of long interspersed nuclear element-1 (LINE-1) among those at high risk of colorectal cancer, i.e. patients with at least one histologically confirmed colorectal adenoma (CRA) in their life. METHODS AND RESULTS: We used LINE-1 bisulfite pyrosequencing to measure global DNA methylation levels in leukocytes of 281 CRA patients. Multivariable linear regression was used to assess associations between plasma B vitamin concentrations and LINE-1 methylation levels. Plasma folate was inversely associated with LINE-1 methylation in CRA patients, while plasma methionine was positively associated with LINE-1 methylation. CONCLUSION: This study does not provide evidence that in CRA patients, plasma folate concentrations are positively related to LINE-1 methylation in leukocytes but does suggest a direct association between plasma methionine and LINE-1 methylation in leukocytes.

Smoking increases the risk for colorectal adenomas in patients with Lynch syndrome.

BACKGROUND & AIMS: Individuals with Lynch syndrome have a high risk of developing colorectal carcinomas and adenomas at a young age, due to inherited mutations in mismatch repair genes. We investigated whether modifiable lifestyle factors, such as smoking and alcohol intake, increase this risk. METHODS: Using data from the GeoLynch cohort study, a prospective analysis of 386 subjects with Lynch syndrome, we calculated hazard ratios for the association between smoking and alcohol intake and development of colorectal adenoma. We used robust variance estimates in the calculation of 95% confidence intervals to account for dependency within families and adjusted for confounding by age, sex, smoking (in the analyses of alcohol intake), number of colonoscopies during the follow-up, colonic resection, and body mass index. RESULTS: During a median follow-up of 10 months, 58 subjects developed a histologically confirmed colorectal adenoma. The hazard ratio for current smokers was 6.13 (95% confidence interval, 2.84-13.22) and for former smokers was 3.03 (95% confidence interval, 1.49-6.16) compared with never smokers. Among ever smokers, a higher number of pack-years was associated with an increased risk for colorectal adenoma (P for trend = .03). There was a trend of alcohol intake increasing the risk of colorectal adenomas, although this was not statistically significant; the hazard ratio for the highest tertile of intake (median, 22 g/day) vs the lowest tertile (median, 0.4 g/day) was 1.56 (95% confidence interval, 0.71-3.43). CONCLUSIONS: Among people with Lynch syndrome, current smokers have an increased risk of colorectal adenomas. Former smokers have a lower risk than current smokers, but greater risk than never smokers. Individuals with Lynch syndrome should be encouraged to avoid smoking.

Body mass index increases risk of colorectal adenomas in men with Lynch syndrome: the GEOLynch cohort study.

PURPOSE: High body mass index (BMI) is an established risk factor for sporadic colorectal cancer. Still, the influence of BMI on hereditary colorectal cancer (eg, Lynch syndrome [LS]), is unknown. The objective of this study was to assess whether BMI is associated with colorectal adenoma occurrence in persons with LS. PATIENTS AND METHODS: A prospective cohort study of 486 patients with LS was conducted. Cox regression models with robust sandwich estimates controlling for age, sex, extent of colon surgery, smoking, and alcohol intake were used to evaluate associations between BMI, height, weight, weight change, and risk of colorectal adenomas. Analyses were performed separately for those without (incident cohort; n = 243) and those with (prevalent cohort; n = 243) a history of colorectal cancer neoplasms at baseline. RESULTS: A statistically significant association between current overweight (≥ 25 kg/m(2)) and developing colorectal adenomas was seen among men in the incident cohort (overweight v normal weight hazard ratio [HR], 8.72; 95% CI, 2.06 to 36.96). This association was not observed among women (overweight v normal weight HR, 0.75; 95% CI, 0.19 to 3.07), nor was it observed in the prevalent cohort. In the incident cohort, height was statistically significantly associated with a decreased risk of adenomatous polyps among men (per 5 cm HR, 0.43; 95% CI, 0.23 to 0.83), but the association between weight and adenomatous polyps among men was of marginal significance (per 5 kg HR, 1.17; 95% CI, 1.00 to 1.37). No statistically significant associations were observed among women in either the incident cohort or the prevalent cohort. CONCLUSION: Excess body weight increased the risk of incident colorectal adenomas in people with LS. This increased risk was seen only in men.

Desmoid tumors in a dutch cohort of patients with familial adenomatous polyposis.

BACKGROUND & AIMS: Desmoid tumors are a severe extracolonic manifestation in familial adenomatous polyposis (FAP). Identification of risk factors might be helpful in the management of FAP patients with such tumors. The aim of this study was to assess potential risk factors for the development of desmoids in a cohort of Dutch FAP patients. METHODS: The medical records of 735 FAP patients were analyzed for the occurrence of desmoids. Relative risks and survival times were calculated to assess the influence of potential risk factors (female sex, family history, mutation site, abdominal surgery, and pregnancy) on desmoid development. RESULTS: Desmoid tumors were identified in 66 of the 735 patients (9%). The cumulative risk of developing desmoids was 14%. No correlation was found between specific adenomatous polyposis coli mutation sites and desmoid development. Patients with a positive family history for desmoids had a significant increased risk to develop this tumor (30% vs 6.7%, P < .001). No association was found between female sex or pregnancy and desmoid development. Most desmoid patients (95%) had undergone previous abdominal surgery. In a substantial proportion of patients with an ileorectal anastomosis, it was impossible to convert the ileorectal anastomosis to an ileal pouch-anal anastomosis as a result of desmoid development. CONCLUSIONS: A positive family history of desmoids is an evident risk factor for developing desmoids. Most desmoids develop after colectomy. No correlation was found between desmoids and the adenomatous polyposis coli gene mutation site, female sex, and pregnancy. Ileal pouch-anal anastomosis is the appropriate type of surgery in FAP patients with a positive family history for desmoids.

Long-term risk of cardiovascular disease in 10-year survivors of breast cancer.

BACKGROUND: Radiotherapy for breast cancer as delivered in the 1970s has been associated with increased risk of cardiovascular disease, but recent studies of associations with modern regimens have been inconclusive. Few data on long-term cardiovascular disease risk according to specific radiation fields are available, and interaction with known cardiovascular risk factors has not been examined. METHODS: We studied treatment-specific incidence of cardiovascular disease in 4414 10-year survivors of breast cancer who were treated from 1970 through 1986. Risk of cardiovascular disease in these patients was compared with general population rates and evaluated in Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: After a median follow-up of 18 years, 942 cardiovascular events were observed (standardized incidence ratio = 1.30, 95% confidence interval [CI] = 1.22 to 1.38; corresponding to 62.9 excess cases per 10,000 patient-years). Breast irradiation only was not associated with increased risk of cardiovascular disease. However, radiotherapy to either the left or right side of the internal mammary chain was associated with increased cardiovascular disease risk for the treatment period 1970-1979 (for myocardial infarction, hazard ratio [HR] = 2.55, 95% CI = 1.55 to 4.19; P<.001; for congestive heart failure, HR = 1.72, 95% CI = 1.22 to 2.41; P = .002) compared with no radiotherapy. Among patients who received internal mammary chain radiotherapy after 1979, risk of myocardial infarction declined over time toward unity, whereas the risks of congestive heart failure (HR = 2.66, 95% CI = 1.27 to 5.61; P = .01) and valvular dysfunction (HR = 3.17, 95% CI = 1.90 to 5.29; P<.001) remained increased. Patients who underwent radiotherapy plus adjuvant chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) after 1979 had a higher risk of congestive heart failure than patients who were treated with radiotherapy only (HR = 1.85, 95% CI = 1.25 to 2.73; P = .002). Smoking and radiotherapy together were associated with a more than additive effect on risk of myocardial infarction (HR = 3.04, 95% CI = 2.03 to 4.55; P for departure from additivity = .039). CONCLUSIONS: Radiotherapy as administered from the 1980s onward is associated with an increased risk of cardiovascular disease. Irradiated breast cancer patients should be advised to refrain from smoking to reduce their risk for cardiovascular disease.