Aspirin and cancer treatment: systematic reviews and meta-analyses of evidence: for and against.

Aspirin as a possible treatment of cancer has been of increasing interest for over 50 years, but the balance of the risks and benefits remains a point of contention. We summarise the valid published evidence 'for' and 'against' the use of aspirin as a cancer treatment and we present what we believe are relevant ethical implications. Reasons for aspirin include the benefits of aspirin taken by patients with cancer upon relevant biological cancer mechanisms. These explain the observed reductions in metastatic cancer and vascular complications in cancer patients. Meta-analyses of 118 observational studies of mortality in cancer patients give evidence consistent with reductions of about 20% in mortality associated with aspirin use. Reasons against aspirin use include increased risk of a gastrointestinal bleed though there appears to be no valid evidence that aspirin is responsible for fatal gastrointestinal bleeding. Few trials have been reported and there are inconsistencies in the results. In conclusion, given the relative safety and the favourable effects of aspirin, its use in cancer seems justified, and ethical implications of this imply that cancer patients should be informed of the present evidence and encouraged to raise the topic with their healthcare team.

A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling.

Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (ß = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.

Amateur Boxing and Dementia: Cognitive Impairment Within the 35-Year Caerphilly Cohort Study.

OBJECTIVE: To examine the long-term effects of amateur boxing in a representative population sample of men. DESIGN: The sample was examined every 5 years for 35 years. Cognition was assessed repeatedly from the third examination. Previous boxing experience and dementia were assessed at the fifth examination, and dementia assessed subsequently through medical records. SETTING AND ASSESSMENT OF RICK FACTORS: The Caerphilly Prospective Study investigates risk factors for a range of chronic diseases of diseases. These include life style and behavior, together with biological factors relevant to vascular disease. PARTICIPANTS: 1123 adult men aged 45 to 59 years at baseline, followed for 35 years. MAIN OUTCOME MEASURES: Cognitive impairment. RESULTS: A report by a subject of having boxed "seriously" when younger was associated with a 2-fold increase in cognitive impairment [odds ratio (OR) = 2.27; 95% confidence intervals = 1.18-4.38]. For amnestic (Alzheimer-like) impairment, this rises to OR = 2.78 (95% confidence limits 1.37-5.65). Having boxed is associated with an "advancement" in the onset of the dementia (4.8 years; 95% confidence limits 0.9-8.8 years). CONCLUSIONS: Amateur boxing is associated with an increased risk and an earlier onset of cognitive impairment and dementia.

Association between egg consumption and cardiovascular disease events, diabetes and all-cause mortality.

PURPOSE: The association between egg consumption and cardiovascular disease (CVD) or type 2 diabetes (T2D) remains controversial. We investigated the association between egg consumption and risk of CVD (primary outcome), T2D and mortality in the Caerphilly prospective cohort study (CAPS) and National Diet and Nutritional Survey (NDNS). METHODS: CAPS included 2512 men aged 45-59 years (1979-1983). Dietary intake, disease incidence and mortality were updated at 5-year intervals. NDNS included 754 adults aged 19-64 years from 2008 to 2012. RESULTS: Men free of CVD (n = 1781) were followed up for a mean of 22.8 years, egg consumption was not associated with new incidence of CVD (n = 715), mortality (n = 1028) or T2D (n = 120). When stroke (n = 248), MI (n = 477), heart failure (n = 201) were investigated separately, no associations between egg consumption and stroke and MI were identified, however, increased risk of stroke in subjects with T2D and/or impaired glucose tolerance (IGT, fasting plasma glucose ≥ 6.1 mmol/L), adjusted hazard ratios (95% CI) were 1.0 (reference), 1.09 (0.41, 2.88), 0.96 (0.37, 2.50), 1.39 (0.54, 3.56) and 2.87 (1.13, 7.27) for egg intake (n) of 0 ≤ n ≤ 1, 1 < n ≤ 2, 2 < n ≤ 3, 3 < n < 5, and n ≥ 5 eggs/wk, respectively (P = 0.01). In addition, cross-sectional analyses revealed that higher egg consumption was significantly associated with elevated fasting glucose in those with T2D and/or IGT (CAPS: baseline P = 0.02 and 5-year P = 0.04; NDNS: P = 0.05). CONCLUSIONS: Higher egg consumption was associated with higher blood glucose in subjects with T2D and/or IGT. The increased incidence of stroke with higher egg consumption among T2D and/or IGT sub-group warrants further investigation.

Association of apolipoprotein E gene polymorphisms with blood lipids and their interaction with dietary factors.

BACKGROUND: Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. METHODS: The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi-quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country. RESULTS: There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (P = 4 × 10- 4 and P = 0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54 ± 0.97 mmol/L) than those with the E3 (5.98 ± 1.05 mmol/L) (P = 0.001) and E4 (6.09 ± 1.06 mmol/L) (P = 2 × 10- 4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (P = 2 × 10- 6 and P = 3 × 10- 4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (P = 4 × 10- 4 and P = 0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes. CONCLUSION: In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene-diet interactions on lipids require further investigation in larger cohorts.

Vitamin D intake and risk of CVD and all-cause mortality: evidence from the Caerphilly Prospective Cohort Study.

OBJECTIVE: Prospective data on the associations between vitamin D intake and risk of CVD and all-cause mortality are limited and inconclusive. The aim of the present study was to investigate the associations between vitamin D intake and CVD risk and all-cause mortality in the Caerphilly Prospective Cohort Study. DESIGN: The associations of vitamin D intake with CVD risk markers were examined cross-sectionally at baseline and longitudinally at 5-year, 10-year and >20-year follow-ups. In addition, the predictive value of vitamin D intake for CVD events and all-cause mortality after >20 years of follow-up was examined. Logistic regression and general linear regression were used for data analysis. SETTING: Participants in the UK. SUBJECTS: Men (n 452) who were free from CVD and type 2 diabetes at recruitment. RESULTS: Higher vitamin D intake was associated with increased HDL cholesterol (P=0·003) and pulse pressure (P=0·04) and decreased total cholesterol:HDL cholesterol (P=0·008) cross-sectionally at baseline, but the associations were lost during follow-up. Furthermore, higher vitamin D intake was associated with decreased concentration of plasma TAG at baseline (P=0·01) and at the 5-year (P=0·01), but not the 10-year examination. After >20 years of follow-up, vitamin D was not associated with stroke (n 72), myocardial infarctions (n 142), heart failure (n 43) or all-cause mortality (n 281), but was positively associated with increased diastolic blood pressure (P=0·03). CONCLUSIONS: The study supports associations of higher vitamin D intake with lower fasting plasma TAG and higher diastolic blood pressure.

Aspirin and cancer: biological mechanisms and clinical outcomes.

Evidence on aspirin and cancer comes from two main sources: (1) the effect of aspirin upon biological mechanisms in cancer, and (2) clinical studies of patients with cancer, some of whom take aspirin. A series of systematic literature searches identified published reports relevant to these two sources. The effects of aspirin upon biological mechanisms involved in cancer initiation and growth appear to generate reasonable expectations of effects upon the progress and mortality of cancer. Clinical evidence on aspirin appears overall to be favourable to the use of aspirin, but evidence from randomized trials is limited, and inconsistent. The main body of evidence comes from meta-analyses of observational studies of patients with a wide range of cancers, about 25% of whom were taking aspirin. Heterogeneity is large but, overall, aspirin is associated with increases in survival and reductions in metastatic spread and vascular complications of different cancers. It is important that evaluations of aspirin used as an adjunct cancer treatment are based upon all the available relevant evidence, and there appears to be a marked harmony between the effects of aspirin upon biological mechanisms and upon the clinical progress of cancer.

Associations between dairy consumption and body weight: a review of the evidence and underlying mechanisms.

As the incidence of obesity is reaching 'epidemic' proportions, there is currently widespread interest in the impact of dietary components on body-weight and food intake regulation. The majority of data available from both epidemiological and intervention studies provide evidence of a negative but modest association between milk and dairy product consumption and BMI and other measures of adiposity, with indications that higher intakes result in increased weight loss and lean tissue maintenance during energy restriction. The purported physiological and molecular mechanisms underlying the impact of dairy constituents on adiposity are incompletely understood but may include effects on lipolysis, lipogeneis and fatty acid absorption. Furthermore, accumulating evidence indicates an impact of dairy constituents, in particular whey protein derivatives, on appetite regulation and food intake. The present review summarises available data and provides an insight into the likely contribution of dairy foods to strategies aimed at appetite regulation, weight loss or the prevention of weight gain.

Aspirin bleeding in perspective.

Aspirin therapy should be an adjunct to the medical management of patients who have had a vascular event but the role of aspirin prophylaxis in the primary prevention of vascular events is less clear. This benefit-versus-risk balance may, however, be influenced by evidence that aspirin reduces bowel cancer risk. Wider aspirin use could lead to more advice being sought on its use from community pharmacists and general practitioners. Yet 10% of those taking aspirin experience symptoms that negatively affect their daily quality of life. These symptoms, such as heartburn, may discourage more individuals from taking aspirin than would the risk of bleeding.

Aspirin and cancer survival: a systematic review and meta-analyses of 118 observational studies of aspirin and 18 cancers.

BACKGROUND: Despite the accumulation of research papers on aspirin and cancer, there is doubt as to whether or not aspirin is an acceptable and effective adjunct treatment of cancer. The results of several randomised trials are awaited, and these should give clear evidence on three common cancers: colon, breast and prostate. The biological effects of aspirin appear likely however to be of relevance to cancer generally, and to metastatic spread, rather than just to one or a few cancers, and there is already a lot of evidence, mainly from observational studies, on the association between aspirin and survival in a wide range of cancers. AIMS: In order to test the hypothesis that aspirin taking is associated with an increase in the survival of patients with cancer, we conducted a series of systematic literature searches to identify clinical studies of patients with cancer, some of whom took aspirin after having received a diagnosis of cancer. RESULTS: Three literature searches identified 118 published observational studies in patients with 18 different cancers. Eighty-one studies report on aspirin and cancer mortality and 63 studies report on all-cause mortality. Within a total of about a quarter of a million patients with cancer who reported taking aspirin, representing 20%-25% of the total cohort, we found aspirin to be associated with a reduction of about 20% in cancer deaths (pooled hazard ratio (HR): 0.79; 95% confidence intervals: 0.73, 0.84 in 70 reports and a pooled odds ratio (OR): 0.67; 0.45, 1.00 in 11 reports) with similar reductions in all-cause mortality (HR: 0.80; 0.74, 0.86 in 56 studies and OR: 0.57; 0.36, 0.89 in seven studies). The relative safety of aspirin taking was examined in the studies and the corresponding author of every paper was written to asking for additional information on bleeding. As expected, the frequency of bleeding increased in the patients taking aspirin, but fatal bleeding was rare and no author reported a significant excess in fatal bleeds associated with aspirin. No author mentioned cerebral bleeding in the patients they had followed. CONCLUSIONS: There is a considerable body of evidence suggestive of about a 20% reduction in mortality in patients with cancer who take aspirin, and the benefit appears not to be restricted to one or a few cancers. Aspirin, therefore, appears to deserve serious consideration as an adjuvant treatment of cancer, and patients with cancer, and their carers, have a right to be informed of the available evidence.

Aspirin, salicylates, and cancer.

Evidence from a wide range of sources suggests that individuals taking aspirin and related non-steroidal anti-inflammatory drugs have reduced risk of large bowel cancer. Work in animals supports cancer reduction with aspirin, but no long-term randomised clinical trials exist in human beings, and randomisation would be ethically unacceptable because vascular protection would have to be denied to a proportion of the participants. However, opportunistic trials of aspirin, designed to test vascular protection, provide some evidence of a reduction in cancer, but only after at least 10 years. We summarise evidence for the potential benefit of aspirin and natural salicylates in cancer prevention. Possible mechanisms of action and directions for further work are discussed, and implications for clinical practice are considered.

The survival advantage of milk and dairy consumption: an overview of evidence from cohort studies of vascular diseases, diabetes and cancer.

OBJECTIVES: To conduct a detailed evaluation, with meta-analyses, of the published evidence on milk and dairy consumption and the incidence of vascular diseases and diabetes. Also to summarise the evidence on milk and dairy consumption and cancer reported by the World Cancer Research Fund and then to consider the relevance of milk and dairy consumption to survival in the UK, a typical Western community. Finally, published evidence on relationships with whole milk and fat-reduced milks was examined. METHODS: Prospective cohort studies of vascular disease and diabetes with baseline data on milk or dairy consumption and a relevant disease outcome were identified by searching MEDLINE, and reference lists in the relevant published reports. Meta-analyses of relationships in these reports were conducted. The likely effect of milk and dairy consumption on survival was then considered, taking into account the results of published overviews of relationships of these foods with cancer. RESULTS: From meta-analysis of 15 studies the relative risk of stroke and/or heart disease in subjects with high milk or dairy consumption was 0.84 (95% CI 0.76, 0.93) and 0.79 (0.75, 0.82) respectively, relative to the risk in those with low consumption. Four studies reported incident diabetes as an outcome, and the relative risk in the subjects with the highest intake of milk or diary foods was 0.92 (0.86, 0.97). CONCLUSIONS: Set against the proportion of total deaths attributable to the life-threatening diseases in the UK, vascular disease, diabetes and cancer, the results of meta-analyses provide evidence of an overall survival advantage from the consumption of milk and dairy foods.

Dairy Foods and Body Mass Index over 10-Year: Evidence from the Caerphilly Prospective Cohort Study.

The association between dairy product consumption and body mass index (BMI) remains controversial. The aim of the present study was to investigate the association between total dairy, milk, cheese, cream and butter consumption and BMI change over a 10-year follow-up by using long-term follow-up cohort data from the Caerphilly Prospective Cohort Study (CAPS). The CAPS included 2512 men aged 45⁻59 years at baseline, who were followed up at 5-year intervals for over 20-year. A semi-quantitative food frequency questionnaire estimated the intake of dairy consumption, including milk, cheese, cream and butter at baseline, 5-year and 10-year follow-up. In total, men free of cardiovascular disease, diabetes and cancer (n = 1690) were included in current analysis. General linear regression and logistic regression were used for data analysis. The results showed higher cheese consumption was associated with lower BMI at the 5-year follow-up (p = 0.013). There was no evidence that higher consumption of total dairy, milk, cream and butter were significantly associated with BMI during the over the 10-year following-up. This study suggest that cheese consumption have beneficial effects on lowering BMI, which needs further investigation.

Systematic review update of observational studies further supports aspirin role in cancer treatment: Time to share evidence and decision-making with patients?

BACKGROUND: Evidence is growing that low-dose aspirin used as an adjuvant treatment of cancer is associated with an increased survival and a reduction in metastatic spread. We therefore extended up to August 2017 an earlier systematic search and meta-analyses of published studies of low-dose aspirin taken by patients with a diagnosis of cancer. METHODS: Searches were completed in Medline and Embase to August 2017 using a pre-defined search strategy to identify reports of relevant studies. References in all the selected papers were scanned. Two reviewers independently applied pre-determined eligibility criteria and extracted data on cause-specific cancer deaths, overall mortality and the occurrence of metastatic spread. Meta-analyses were then conducted for different cancers and heterogeneity and publication bias assessed. Sensitivity analyses and attempts to reduce heterogeneity were conducted. RESULTS: Analyses of 29 studies reported since an earlier review up to April 2015 are presented in this report, and these are then pooled with the 42 studies in our earlier publication. Overall meta-analyses of the 71 studies are presented, based on a total of over 120 thousand patients taking aspirin. Ten of the studies also give evidence on the incidence of metastatic cancer spread. There are now twenty-nine observational studies describing colorectal cancer (CRC) and post-diagnostic aspirin. Pooling the estimates of reduction by aspirin which are reported as hazard ratios (HR), gives an overall HR for aspirin and CRC mortality 0.72 (95% CI 0.64-0.80). Fourteen observational studies have reported on aspirin and breast cancer mortality and pooling those that report the association with aspirin as a hazard ratio gives HR 0.69 (0.53-0.90). Sixteen studies report on aspirin and prostate cancer mortality and a pooled estimate yields an HR of 0.87 (95% CI 0.73-1.05). Data from 12 reports relating to other cancers are also listed. Ten studies give evidence of a reduction in metastatic spread; four give a pooled HR 0.31 (95% CI 0.18, 0.54) and five studies which reported odds ratio of metastatic spread give OR 0.79 (0.66 to 0.95). CONCLUSION: Being almost entirely from observational studies, the evidence of benefit from aspirin is limited. There is heterogeneity between studies and the results are subject to important biases, only some of which can be identified. Nevertheless, the evidence would seem to merit wide discussion regarding whether or not it is adequate to justify the recommendation of low-dose therapeutic aspirin, and if it is, for which cancers?

Healthy living and cancer: evidence from UK Biobank.

CONTEXT: UK Biobank is a prospective study of half a million subjects, almost all aged 40-69 years, identified in 22 centres across the UK during 2006-2010. OBJECTIVE: A healthy lifestyle has been described as 'better than any pill, and no side effects [5]. We therefore examined the relationships between healthy behaviours: low alcohol intake, non-smoking, healthy BMI, physical activity and a healthy diet, and the risk of all cancers, colon, breast and prostate cancers in a large dataset. METHOD: Data on lifestyle behaviours were provided by 343,150 subjects, and height and weight were measured at recruitment. 14,285 subjects were diagnosed with cancer during a median of 5.1 years of follow-up. RESULTS: Compared with subjects who followed none or a single healthy behaviour, a healthy lifestyle based on all five behaviours was associated with a reduction of about one-third in incident cancer (hazard ratio [HR] 0.68; 95% confidence intervals [CI] 0.63-0.74). Colorectal cancer was reduced in subjects following the five behaviours by about one-quarter (HR 0.75; 95% CI 0.58-0.97), and breast cancer by about one-third (HR 0.65; 95% CI 0.52-0.83). The association between a healthy lifestyle and prostate cancer suggested a significant increase in risk, but this can be attributed to bias consequent on inequalities in the uptake of the prostate specific antigen screening test. CONCLUSIONS: Taken together with reported reductions in diabetes, vascular disease and dementia, it is clearly important that every effort is taken to promote healthy lifestyles throughout the population, and it is pointed out that cancer and other screening clinics afford 'teachable moments' for the promotion of a healthy lifestyle.

Milk and dairy consumption, diabetes and the metabolic syndrome: the Caerphilly prospective study.

OBJECTIVES: To report a negative association between milk or dairy consumption and the metabolic syndrome and to examine associations within the Caerphilly cohort. SETTING: A representative sample of men aged 45-59 years in Caerphilly, UK. PARTICIPANTS AND DATA: Data on fasting blood glucose and plasma insulin, fasting plasma triglycerides and high-density lipoprotein cholesterol, body mass index, and blood pressure were used to define the metabolic syndrome in terms of levels of two or more variates within the top 10%. The clinical importance of the syndrome was assessed from 20-year incidence of diabetes, vascular events and deaths. The relationships between the syndrome and the consumption of milk and dairy products was examined using data from both a semiquantitative food frequence questionnaire, and from a 7-day weighed intake record which had been kept by a 1:3 subsample of the men. MAIN RESULTS: There were 2,375 men without diabetes in the cohort. The prevalence of the metabolic syndrome was 15%. Men with the syndrome had significantly increased risks of a subsequent ischaemic heart disease event, death or diabetes. Negative relationships were shown between both the consumption of milk and dairy produce, and the syndrome. Adjusted odds ratio in men who regularly drank a pint of milk or more daily was 0.38 (0.18 to 0.78) and that for dairy food consumption was 0.44 (0.21 to 0.91). Milk intake showed no significant trend with incident diabetes. CONCLUSIONS: The consumption of milk and dairy products is associated with a markedly reduced prevalence of the metabolic syndrome, and these items therefore fit well into a healthy eating pattern.

Cortisol, testosterone, and coronary heart disease: prospective evidence from the Caerphilly study.

BACKGROUND: There is a popular belief that chronic stress causes heart disease through psychoneuroendocrine mechanisms. We have examined whether an elevated circulating cortisol-to-testosterone ratio increases the risk of ischemic heart disease. METHODS AND RESULTS: We undertook a prospective cohort study of 2512 men aged 45 to 59 years between 1979 and 1983 from Caerphilly, South Wales, with a mean follow-up of 16.5 years. Subjects underwent a clinical examination, and morning fasting blood samples were taken for analysis of cortisol levels, testosterone levels, and other cardiovascular risk factors. The ratio of cortisol to testosterone showed weak associations with potential confounding factors but strong positive associations with components of the insulin resistance syndrome (P<0.001). A positive linear trend was seen across quintiles of cortisol:testosterone ratio for incident ischemic heart disease (age-adjusted OR per z score change in ratio 1.22, 95% CI 1.07 to 1.38, P=0.003). This was markedly attenuated after adjustment for components of the insulin resistance syndrome (age-adjusted OR per z score change in ratio 1.10, 95% CI 0.96 to 1.25, P=0.18). There was no association between the cortisol:testosterone ratio and other causes of death (age-adjusted hazard ratio 0.99, 95% CI 0.88 to 1.11, P=0.81). CONCLUSIONS: This is the first population-based prospective study that has found a specific association between cortisol:testosterone ratio and incident ischemic heart disease, apparently mediated through the insulin resistance syndrome. Whether this reflects the effects of chronic stress, behavioral factors, or genetic influences remains to be determined.

Sleep disturbance, stroke, and heart disease events: evidence from the Caerphilly cohort.

OBJECTIVE: To test the hypothesis that sleep disorders are relevant to the risk of ischaemic stroke and ischaemic heart disease events in older men. DESIGN: A cohort study. SETTING: The Caerphilly cohort, a representative population sample of older men in South Wales, UK. PARTICIPANTS: 1986 men aged 55-69 years completed a questionnaire on sleep patterns with help from their partners. This asked about symptoms of disturbed sleep: insomnia, snoring, restless legs, obstructive sleep apnoea, and about daytime sleepiness. During the following 10 years 107 men experienced an ischaemic stroke and 213 had an ischaemic heart disease event. MAIN RESULTS: Up to one third of the men reported at least one symptom suggestive of sleep disturbance, and one third reported daytime sleepiness. Compared with men who reported no such symptoms, the adjusted relative odds of an ischaemic stroke were significantly increased in men with any sleep disturbance, the strongest association being with sleep apnoea (relative odds 1.97; 1.26 to 3.09). The association with daytime sleepiness was not significant for stroke. Relations with ischaemic heart disease events were all raised in men with symptoms of sleep disturbance, but none was significant, other than daytime sleepiness (relative odds: 1.41; 1.04 to 1.92). There were no significant relations with blood pressure. CONCLUSION: The risk of an ischaemic stroke is increased in men whose sleep is frequently disturbed, and daytime sleepiness is associated with a significant increase in ischaemic heart disease events.

Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies.

BACKGROUND: Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain. OBJECTIVES: We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses. METHODS: Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned. RESULTS: Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79-0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76-0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available. CONCLUSIONS AND IMPLICATIONS: The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin. SYSTEMATIC REVIEW PROTOCOL NUMBER: CRD42015014145.