20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment

A proposal for reducing the effect of one of many causes of publication bias.

In order to avoid publication bias, all trials should be registered at initiation and their results made easily accessible. However, some trial results are more difficult to publish than others. This report describes one such trial and highlights the need for a way of making results of trials widely available even if not presented in the traditional format. Until such time as it is required by law both to register all trials and enter their final results into the database, a lack of resources will mean that some trial results are never published. The scale of the problem of non-publication is unknown and for valid trial results any form of publication is better than none. Therefore it is essential that a quick and easy way is available to act as a safety net to catch trial results that would otherwise be lost

Body-mass index, blood pressure, diabetes and cardiovascular mortality in Cuba: prospective cohort study of 146,665 participants

Background Cardiovascular disease (CVD) is a leading cause of premature death in Cuba, accounting for about one third of all deaths under age 70 years. Substantial uncertainty remains, however, about the relevance of major metabolic risk factors to CVD mortality in this population. Purpose To relate body-mass index (BMI), systolic blood pressure (SBP), and diabetes to risk of CVD death in Cuba. Methods In a prospective cohort study, 146,665 adults were recruited from the general population in five areas of Cuba between 1996 and 2002. Participants were interviewed, measured (height, weight and blood pressure) and followed up by electronic linkage to Cuban national death registries to Jan 1 2017; 24,345 participants were resurveyed between 2006 and 2008. After excluding all with missing data or chronic disease at recruitment or, to further limit reverse causality, those who died in the first 5 years, Cox regression (adjusted for age, sex, education, smoking, alcohol and, where appropriate, BMI) was used to relate mortality rate ratios (RRs) at ages 35–79 years to BMI, SBP and diabetes. Correlations of baseline and resurvey values were used to corrected RRs for regression dilution, and thereby estimate associations with long-term average (“usual”) levels of SBP and BMI. Results After exclusions, there were 117,008 participants age 35–79 (mean age 52 [SD 12]; 55% women). At recruitment, mean SBP was 124 mm Hg (SD 15), mean BMI was 24.2 kg/m2 (SD 3.6) and 5% had diabetes; mean SBP and diabetes prevalence were both strongly related to BMI. Correlations of resurvey and baseline measurements were 0.48 for SBP and 0.60 for BMI. At ages 35–79 years, there were 3780 CVD deaths (1871 ischaemic heart disease [IHD], 766 stroke, and 1143 other). CVD mortality was positively associated with BMI (down to about 22–23 kg/m2; figure), SBP and diabetes: 10 kg/m2 higher usual BMI approximately doubled CVD mortality (RR 1.90, 95% CI 1.61–2.24), as did 20 mmHg higher usual SBP (2.03, 1.88–2.20), and a prior diagnosis of diabetes (2.18, 1.97–2.42). The associations were similar in men and women. Given these associations, about one quarter (27%) of CVD deaths in this study were attributable to these metabolic risk factors combined. Conclusion These associations differ to those reported from other parts of Latin America, and are more consistent with studies in Europe and North America, highlighting the need for many more large-scale prospective studies in low and middle income countries. This study provides direct evidence for the expected benefit on CVD mortality of addressing major metabolic risk factors in Cuba. As the levels of these metabolic risk factors are increasing in Cuba, so too is their importance as determinants of premature CVD death

Association between smoking and mortality: Khon Kaen cohort study, Thailand.

BACKGROUND: Despite anti-smoking campaigns, smoking prevalence among Thai males aged 30 or older is high, at around 50%. The purpose of this study was to determine the relationship between smoking and mortality in a rural Thai community. MATERIALS AND METHODS: Subjects enrolled into the Khon Kaen cohort study between 1990 and 2001 were followed up for their vital status until 16th March 2012. The death resource was from the Bureau of Policy and Strategy, Ministry of Interior, Thailand. A Cox proportional hazards model was used to analyse the association between smoking and death, controlling for age, education level and alcohol drinking, and confidence intervals were calculated using the floating risk method. RESULTS: The study recruited 5,962 male subjects, of whom 1,396 died during a median 13.5 years of follow-up. Current smokers were more likely to die than never smokers after controlling for age, education level and alcohol drinking (HR, 95%CI: 1.41, 1.32- 1.51), and the excess mortality was greatest for lung cancer (HR, 95%CI: 3.51, 2.65-4.66). However, there was no increased risk with increasing dose of tobacco, and no difference in risk between smokers of yamuan (hand- rolled cigarettes) and manufactured tobacco. CONCLUSION: Mortality from cancer, particularly lung cancer, and from all causes combined is dependent on smoking status among men in rural Thailand, but the relative risks are lower than have been reported from studies in high income countries, where the tobacco epidemic is more established

Educational inequalities and premature mortality: the Cuba Prospective Study

Background Although socioeconomic status is a major determinant of premature mortality in many populations, the impact of social inequalities on premature mortality in Cuba, a country with universal education and health care, remains unclear. We aimed to assess the association between educational level and premature adult mortality in Cuba. Methods The Cuba Prospective Study (a cohort study) enrolled 146 556 adults aged 30 years and older from the general population in five provinces from Jan 1, 1996, to Nov 24, 2002. Participants were followed up until Jan 1, 2017, for cause-specific mortality. Deaths were identified through linkage to the Cuban Public Health Ministry's national mortality records. Cox regression models yielded rate ratios (RRs) for the effect of educational level (a commonly used measure for social status) on mortality at ages 35–74 years, with assessment for the mediating effects of smoking, alcohol consumption, and BMI. Findings A total of 127 273 participants aged 35–74 years were included in the analyses. There was a strong inverse association between educational level and premature mortality. Compared with a university education, men who did not complete primary education had an approximately 60% higher risk of premature mortality (RR 1·55, 95% CI 1·40–1·72), while the risk was approximately doubled in women (1·96, 1·81–2·13). Overall, 28% of premature deaths could be attributed to lower education levels. Excess mortality in women was primarily due to vascular disease, while vascular disease and cancer were equally important in men. 31% of the association with education in men and 18% in women could be explained by common modifiable risk factors, with smoking having the largest effect. Interpretation This study highlights the value of understanding the determinants of health inequalities in different populations. Although many major determinants lie outside the health system in Cuba, this study has identified the diseases and risk factors that require targeted public health interventions, particularly smoking. Funding UK Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen)

Alcohol consumption and cause-specific mortality in Cuba: prospective study of 120 623 adults

Background The associations of cause-specific mortality with alcohol consumption have been studied mainly in higher-income countries. We relate alcohol consumption to mortality in Cuba. Methods In 1996-2002, 146 556 adults were recruited into a prospective study from the general population in five areas of Cuba. Participants were interviewed, measured and followed up by electronic linkage to national death registries until January 1, 2017. After excluding all with missing data or chronic disease at recruitment, Cox regression (adjusted for age, sex, province, education, and smoking) was used to relate mortality rate ratios (RRs) at ages 35–79 years to alcohol consumption. RRs were corrected for long-term variability in alcohol consumption using repeat measures among 20 593 participants resurveyed in 2006-08. Findings After exclusions, there were 120 623 participants aged 35-79 years (mean age 52 [SD 12]; 67 694 [56%] women). At recruitment, 22 670 (43%) men and 9490 (14%) women were current alcohol drinkers, with 15 433 (29%) men and 3054 (5%) women drinking at least weekly; most alcohol consumption was from rum. All-cause mortality was positively and continuously associated with weekly alcohol consumption: each additional 35cl bottle of rum per week (110g of pure alcohol) was associated with ∼10% higher risk of all-cause mortality (RR 1.08 [95%CI 1.05-1.11]). The major causes of excess mortality in weekly drinkers were cancer, vascular disease, and external causes. Non-drinkers had ∼10% higher risk (RR 1.11 [1.09-1.14]) of all-cause mortality than those in the lowest category of weekly alcohol consumption (<1 bottle/week), but this association was almost completely attenuated on exclusion of early follow-up. Interpretation In this large prospective study in Cuba, weekly alcohol consumption was continuously related to premature mortality. Reverse causality is likely to account for much of the apparent excess risk among non-drinkers. The findings support limits to alcohol consumption that are lower than present recommendations in Cuba. Funding Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen)

Sympatric speciation in palms on an oceanic island.

The origin of species diversity has challenged biologists for over two centuries. Allopatric speciation, the divergence of species resulting from geographical isolation, is well documented. However, sympatric speciation, divergence without geographical isolation, is highly controversial. Claims of sympatric speciation must demonstrate species sympatry, sister relationships, reproductive isolation, and that an earlier allopatric phase is highly unlikely. Here we provide clear support for sympatric speciation in a case study of two species of palm (Arecaceae) on an oceanic island. A large dated phylogenetic tree shows that the two species of Howea, endemic to the remote Lord Howe Island, are sister taxa and diverged from each other well after the island was formed 6.9 million years ago. During fieldwork, we found a substantial disjunction in flowering time that is correlated with soil preference. In addition, a genome scan indicates that few genetic loci are more divergent between the two species than expected under neutrality, a finding consistent with models of sympatric speciation involving disruptive/divergent selection. This case study of sympatric speciation in plants provides an opportunity for refining theoretical models on the origin of species, and new impetus for exploring putative plant and animal examples on oceanic islands

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer : meta-analysis of individual patient data from ten randomised trials

Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21.4% for NACT versus 15.9% for adjuvant chemotherapy (5.5% increase [95% CI 2.4-8.6]; rate ratio 1.37 [95% CI 1.17-1.61]; p = 0.0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38.2% for NACT vs 38.0% for adjuvant chemotherapy; rate ratio 1.02 [95% CI 0.92-1.14]; p = 0.66), breast cancer mortality (34.4% vs 33.7%; 1.06 [0.95-1.18]; p = 0.31), or death from any cause (40.9% vs 41.2%; 1.04 [0.94-1.15]; p = 0.45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. Copyright (c) The Author(s). Published by Elsevier Ltd.Peer reviewe