Efforts needed for preventing breast and colorectal cancer through changes in dietary patterns.

BACKGROUND: Prospective cohort studies on diet and cancer report risk associations as hazard ratios. But hazard ratios do not inform on the number of people who need to alter their dietary behaviours for preventing cancer. The objective of this study is to estimate the number of people that need to alter their diet for preventing one additional case of female breast or colorectal cancer. METHODS: Based on the largest prospective studies done in the USA and in Europe, we computed the number of subjects who need to alter their diet. RESULTS: For preventing one case of breast cancer, European women should increase their fruit consumption by 100 g/day during 33 000 person-years, and US women by 60 g/day during 10 600 person-years. For vegetables, European women should increase their consumption by 160 g/day during 26 900 person-years and US women by 100 g/day during 19 000 person-years. For preventing one case of colorectal cancer, European subjects should decrease their red meat consumption by 20 g/day during 26 100 person-years, and US subjects by 30 g/day during 8170 person-years. For processed meat, European subjects should decrease their consumption by 20 g/day during 17 400 person-years, and US subjects by 10 g/day during 7940 person-years. CONCLUSIONS: Large number of subjects would need to alter their intake of fruits, vegetables, red and processed meat during many years in order to prevent one additional breast or colorectal cancer.

Daily milk consumption and all-cause mortality, coronary heart disease and stroke: a systematic review and meta-analysis of observational cohort studies.

BACKGROUND: Observational studies and meta-analyses relating milk consumption by adults to all-cause mortality, coronary heart disease and stroke have obtained contradictory results. Some studies found a protective effect of milk consumption, whilst other found an increased risk. METHODS: We performed a systematic literature search until June 2015 on prospective studies that looked at milk consumption, all-cause mortality, coronary heart disease and stroke. Random-effect meta-analyses were performed with dose-response. RESULTS: Twenty-one studies involving 19 cohorts were included in this meta-analysis, 11 on all-cause mortality, 9 on coronary heart disease, and 10 on stroke. Milk intake ranged from 0 to 850 mL/d. The summary relative risk (SRR) for 200 mL/d milk consumption was 1.01 (95% CI: 0.96-1.06) for all-cause mortality, 1.01 (95% CI: 0.98-1.05) for fatal and non fatal coronary heart disease, and 0.91 (95% CI: 0.82-1.02) for fatal and non fatal stroke. Stratified analyses by age, Body Mass Index, total energy intake and physical acitivity did not alter the SRR estimates. The possibility of publication bias was found for all cause mortality and for stroke, indicating a gap in data that could have suggested a higher risk of these conditions with increased milk consumption. CONCLUSIONS: We found no evidence for a decreased or increased risk of all-cause mortality, coronary heart disease, and stroke associated with adult milk consumption. However, the possibility cannot be dismissed that risks associated with milk consumption could be underestimated because of publication bias.

Blood glucose concentrations and breast cancer risk in women without diabetes: a meta-analysis.

PURPOSE: Some studies have suggested an increased risk of breast cancer associated with elevated fasting serum glucose in nondiabetic subjects. Given how common both breast cancer and impaired glucose tolerance are in our aging societies, this is an important issue for public health. METHODS: We performed a systematic review of prospective cohort studies that examined the association between elevated serum glucose levels in nondiabetic subjects (levels below 7.0 mml/L) and the subsequent risk of breast cancer. We performed a systematic literature search and extracted relevant data in a standard way. We then computed summary relative risks (SRR) and 95 % confidence intervals using a random effects model applied on the risk of highest versus lowest quantile of serum glucose concentrations. RESULTS: Ten cohort studies were retrieved. The SRR for all studies was 1.11 (1.00-1.23), with no evidence of heterogeneity or publication bias. The SRR was not affected when the analysis was restricted to the 8 studies that reported results for fasting subjects (SRR = 1.11; 95 % CI 0.98-1.25). Three studies provided BMI-unadjusted and BMI-adjusted SRRs of 1.24 (95 % CI 0.60-2.56) and 1.20 (95 % CI 0.63-2.27), respectively. Similar magnitudes of associations were observed in sensitivity analyses, but statistical significance was lost. CONCLUSION: In nondiabetic subjects, the risk of breast cancer associated with fasting serum glucose levels seems to be small. Potential limitations to this meta-analysis include the fact that not all studies reported risks adjusted for adiposity and that serum glucose levels of comparison groups were variable across studies.

Next generation sequencing for molecular diagnosis of neuromuscular diseases.

Inherited neuromuscular disorders (NMD) are chronic genetic diseases posing a significant burden on patients and the health care system. Despite tremendous research and clinical efforts, the molecular causes remain unknown for nearly half of the patients, due to genetic heterogeneity and conventional molecular diagnosis based on a gene-by-gene approach. We aimed to test next generation sequencing (NGS) as an efficient and cost-effective strategy to accelerate patient diagnosis. We designed a capture library to target the coding and splice site sequences of all known NMD genes and used NGS and DNA multiplexing to retrieve the pathogenic mutations in patients with heterogeneous NMD with or without known mutations. We retrieved all known mutations, including point mutations and small indels, intronic and exonic mutations, and a large deletion in a patient with Duchenne muscular dystrophy, validating the sensitivity and reproducibility of this strategy on a heterogeneous subset of NMD with different genetic inheritance. Most pathogenic mutations were ranked on top in our blind bioinformatic pipeline. Following the same strategy, we characterized probable TTN, RYR1 and COL6A3 mutations in several patients without previous molecular diagnosis. The cost was less than conventional testing for a single large gene. With appropriate adaptations, this strategy could be implemented into a routine genetic diagnosis set-up as a first screening approach to detect most kind of mutations, potentially before the need of more invasive and specific clinical investigations. An earlier genetic diagnosis should provide improved disease management and higher quality genetic counseling, and ease access to therapy or inclusion into therapeutic trials.

Effectiveness of and overdiagnosis from mammography screening in the Netherlands: population based study.

Objective To analyse stage specific incidence of breast cancer in the Netherlands where women have been invited to biennial mammography screening since 1989 (ages 50-69) and 1997 (ages 70-75), and to assess changes in breast cancer mortality and quantified overdiagnosis.Design Population based study.Setting Mammography screening programme, the Netherlands.Participants Dutch women of all ages, 1989 to 2012.Main outcome measures Stage specific age adjusted incidence of breast cancer from 1989 to 2012. The extra numbers of in situ and stage 1 breast tumours associated with screening were estimated by comparing rates in women aged 50-74 with those in age groups not invited to screening. Overdiagnosis was estimated after subtraction of the lead time cancers. Breast cancer mortality reductions and overdiagnosis during 2010-12 were computed without (scenario 1) and with (scenario 2) a cohort effect on mortality secular trends.Results The incidence of stage 2-4 breast cancers in women aged 50 or more was 168 per 100 000 in 1989 and 166 per 100 000 in 2012. Screening would be associated with a 5% mortality reduction in scenario 1 and with no influence on mortality in scenario 2. In both scenarios, improved treatments would be associated with 28% reductions in mortality. Overdiagnosis has steadily increased over time with the extension of screening to women aged 70-75 and with the introduction of digital mammography. After deduction of clinical lead time cancers, 33% of cancers found in women invited to screening in 2010-12 and 59% of screen detected cancers would be overdiagnosed.Conclusions The Dutch mammography screening programme seems to have little impact on the burden of advanced breast cancers, which suggests a marginal effect on breast cancer mortality. About half of screen detected breast cancers would represent overdiagnosis.

Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials.

Randomised trials reported up to Dec 31, 2012, did not confirm that vitamin D supplementation could protect from non-skeletal health conditions affecting adults, as was expected on the basis of data from observational studies. To examine whether the more recently published meta-analyses and trials would change past conclusions, we systematically reviewed meta-analyses of vitamin D supplementation and non-skeletal disorders published between Jan 1, 2013, and May 31, 2017, that included study participants of all ages, including pregnant women. We also searched for randomised trials not included in meta-analyses. We identified 87 meta-analyses, of which 52 were excluded because they contained less recent literature or were of suboptimal quality. We retrieved 202 articles on trials that were not included in meta-analyses. Recent meta-analyses reinforce the finding that 10-20 µg per day of vitamin D can reduce all-cause mortality and cancer mortality in middle-aged and older people. Although vitamin D doses were greater than those assessed in the past, we found no new evidence that supplementation could have an effect on most non-skeletal conditions, including cardiovascular disease, adiposity, glucose metabolism, mood disorders, muscular function, tuberculosis, and colorectal adenomas, or on maternal and perinatal conditions. New data on cancer outcomes were scarce. The compilation of results from 83 trials showed that vitamin D supplementation had no significant effect on biomarkers of systemic inflammation. The main new finding highlighted by this systematic review is that vitamin D supplementation might help to prevent common upper respiratory tract infections and asthma exacerbations. There remains little evidence to suggest that vitamin D supplementation has an effect on most conditions, including chronic inflammation, despite use of increased doses of vitamin D, strengthening the hypothesis that low vitamin D status is a consequence of ill health, rather than its cause. We further hypothesise that vitamin D supplementation could exert immunomodulatory effects that strengthen resistance to acute infections, which would reduce the risk of death in debilitated individuals. We identified many meta-analyses of suboptimal quality, which is of concern. Future systematic reviews on vitamin D should be based on data sharing so that data for participants with the same outcomes measured in the same way can be pooled to generate stronger evidence.

Physical activity, hormone replacement therapy and breast cancer risk: A meta-analysis of prospective studies.

BACKGROUND: Lower risk of breast cancer has been reported among physically active women, but the risk in women using hormone replacement therapy (HRT) appears to be higher. We quantified the association between physical activity and breast cancer, and we examined the influence that HRT use and other risk factors had on this association. METHODS: After a systematic literature search, prospective studies were meta-analysed using random-effect models applied on highest versus lowest level of physical activity. Dose-response analyses were conducted with studies reporting physical activity either in hours per week or in hours of metabolic equivalent per week (MET-h/week). RESULTS: The literature search identified 38 independent prospective studies published between 1987 and 2014 that included 116,304 breast cancer cases. Compared to the lowest level of physical activity, the highest level was associated with a summary relative risk (SRR) of 0.88 (95% confidence interval [CI] 0.85, 0.90) for all breast cancer, 0.89 (95% CI 0.83, 0.95) for ER+/PR+ breast cancer and 0.80 (95% CI 0.69, 0.92) for ER-/PR- breast cancer. Risk reductions were not influenced by the type of physical activity (occupational or non-occupational), adiposity, and menopausal status. Risk reductions increased with increasing amounts of physical activity without threshold effect. In six studies, the SRR was 0.78 (95% CI 0.70, 0.87) in women who never used HRT and 0.97 (95% CI 0.88, 1.07) in women who ever used HRT, without heterogeneity in results. Findings indicate that a physically inactive women engaging in at least 150 min per week of vigorous physical activity would reduce their lifetime risk of breast cancer by 9%, a reduction that might be two times greater in women who never used HRT. CONCLUSION: Increasing physical activity is associated with meaningful reductions in the risk of breast cancer, but in women who ever used HRT, the preventative effect of physical activity seems to be cancelled out.

Trends in colorectal cancer mortality in Europe: retrospective analysis of the WHO mortality database.

OBJECTIVE: To examine changes in colorectal cancer mortality in 34 European countries between 1970 and 2011. DESIGN: Retrospective trend analysis. DATA SOURCE: World Health Organization mortality database. POPULATION: Deaths from colorectal cancer between 1970 and 2011. Profound changes in screening and treatment efficiency took place after 1988; therefore, particular attention was paid to the evolution of colorectal cancer mortality in the subsequent period. MAIN OUTCOMES MEASURES: Time trends in rates of colorectal cancer mortality, using joinpoint regression analysis. Rates were age adjusted using the standard European population. RESULTS: From 1989 to 2011, colorectal cancer mortality increased by a median of 6.0% for men and decreased by a median of 14.7% for women in the 34 European countries. Reductions in colorectal cancer mortality of more than 25% in men and 30% in women occurred in Austria, Switzerland, Germany, the United Kingdom, Belgium, the Czech Republic, Luxembourg, and Ireland. By contrast, mortality rates fell by less than 17% in the Netherlands and Sweden for both sexes. Over the same period, smaller or no declines occurred in most central European countries. Substantial mortality increases occurred in Croatia, the former Yugoslav republic of Macedonia, and Romania for both sexes and in most eastern European countries for men. In countries with decreasing mortality, reductions were more important for women of all ages and men younger than 65 years. In the 27 European Union member states, colorectal cancer mortality fell by 13.0% in men and 27.0% in women, compared with corresponding reductions of 39.8% and 38.8% in the United States. CONCLUSION: Over the past 40 years, there has been considerable disparity in the level of colorectal cancer mortality between European countries, as well as between men and women and age categories. Countries with the largest reductions in colorectal cancer mortality are characterised by better accessibility to screening services, especially endoscopic screening, and specialised care.

VaRank: a simple and powerful tool for ranking genetic variants.

Background. Most genetic disorders are caused by single nucleotide variations (SNVs) or small insertion/deletions (indels). High throughput sequencing has broadened the catalogue of human variation, including common polymorphisms, rare variations or disease causing mutations. However, identifying one variation among hundreds or thousands of others is still a complex task for biologists, geneticists and clinicians. Results. We have developed VaRank, a command-line tool for the ranking of genetic variants detected by high-throughput sequencing. VaRank scores and prioritizes variants annotated either by Alamut Batch or SnpEff. A barcode allows users to quickly view the presence/absence of variants (with homozygote/heterozygote status) in analyzed samples. VaRank supports the commonly used VCF input format for variants analysis thus allowing it to be easily integrated into NGS bioinformatics analysis pipelines. VaRank has been successfully applied to disease-gene identification as well as to molecular diagnostics setup for several hundred patients. Conclusions. VaRank is implemented in Tcl/Tk, a scripting language which is platform-independent but has been tested only on Unix environment. The source code is available under the GNU GPL, and together with sample data and detailed documentation can be downloaded from http://www.lbgi.fr/VaRank/.

Vitamin D status and ill health: a systematic review.

Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 µg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 µg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.