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To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. National Foundation for Alzheimer's disease and related disorders Institut Pasteur de Lille Centre National de Genotypage Inserm FRC (fondation pour la recherche sur le cerveau) Rotary LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) MEDIALZ Project - ERDF (European Regional Development Fund) 11001003 Conseil Regional Nord Pas de Calais Fondation pour la Recherche Medicale Caisse Nationale Maladie des Travailleurs Salaries Direction Generale de la Sante MGEN Institut de la Longevite Agence Francaise de Securite Sanitaire des Produits de Sante Aquitaine and Bourgogne Regional Councils Fondation de France joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program Eisai Wellcome Trust British Heart Foundation Chief Scientist Office of the Scottish Executive NIA N01-AG-12100 National Heart, Lung and Blood Institute Contracts HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C R01HL70825 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute U01HG004402 NIH Roadmap for Medical Research Austrian Science Fond (FWF) P20545-P05 P13180 Intramural Research Program of the NIH, National Institute on Aging NHLBI HHSN268201200036C HHSN268200800007C N01HC55222 N01HC85079 N01HC85080 N01HC85081 N01HC85082 N01HC85083 N01HC850863 U01HL080295 R01HL087652 R01HL105756 R01HL103612 R01HL120393 National Institute of Neurological Disorders and Stroke (NINDS) National Institute on Aging (NIA) R01AG023629 R01AG15928 R01AG20098 R01AG027058 National Center for Advancing Translational Sciences CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) DK063491 Medical Research Council (UK) European Commission Framework 6 project EUROSPAN LSHG-CT-2006-018947 Republic of Croatia Ministry of Science, Education and Sports 108-1080315-0302 Netherlands Organization for Scientific Research (NWO) Internationale Stichting Alzheimer Onderzoek (ISAO) Hersenstichting Nederland (HSN) Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) Russian Foundation for Basic Research (RFBR) National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc N02-HL-6-4278 U01 HL096917 R01 HL093029 Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine Boston Medical Center National Institute of Neurological Disorders and Stroke NS17950 National Institute of Aging U01 AG049505 AG033193 AG008122 AG16495 Agence National de la Recherche Leducq Foundation National Heart, Lung and Blood Institute HL054464 HL054457 HL054481 HL071917 HL87660 HL043851 HL080467 National Institute of Neurological Disorders and Stroke of the National Institutes of Health NS041558 Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 Scottish Funding Council HR03006 Academy of Finland Finnish Diabetes Research Society Folkhalsan Research Foundation Novo Nordisk Foundation Finska Lakaresallskapet Signe and Ane Gyllenberg Foundation University of Helsinki Ministry of Education Ahokas Foundation Emil Aaltonen Foundation Juho Vainio Foundation Wellcome Trust WT089062 University of Newcastle's Strategic Initiative Fund Vincent Fairfax Family Foundation Hunter Medical Research Institute Italian Ministry of Health ICS 110.1RS97.71 US National Institute on Aging N01[AG]916413 N01[AG]821336 263 MD 9164 13 263 MD 821336 Intramural Research Program, National Institute on Aging, National Institutes of Health BBSRC Royal Society Chief Scientist Office of the Scottish Government Research Into Ageing UK Biotechnology and Biological Sciences Research Council (BBSRC) Engineering and Physical Sciences Research Council (EPSRC) Economic and Social Research Council (ESRC) MRC NHMRC 401184 Australian National Health & Medical Research Council 350833 568969 Capacity Building Grant 568940 NHMRC Project 525453 National Institutes of Health CA87969 CA49449 HL34594 U01HG004399 DK058845 CA65725 CA67262 CA50385 5UO1CA098233 EY09611 EY015473 HG004728 HL35464 CA55075 CA134958 DK070756 MRC Human Genetics Unit Arthritis Research UK European Union LSHG-CT-2006-018947 Bristol-Myers Squibb Netherlands Heart Foundation 2001 D 032 European commission 223004 Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) 050-060-810 Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project 050-060-810 Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission 49 (DG XII) Municipality of Rotterdam ZonMW Veni Grant 916.13.054 NIA Grants P30AG10161 R01AG15819 R01AG17917 R01AG30146 K08AG34290 K25AG41906 Federal Ministry of Education and Research 01ZZ9603 01ZZ0103 01ZZ0403 Ministry of Cultural Affairs Social Ministry of the Federal State of Mecklenburg-West Pomerania National Cancer Institute CA047988 Donald W Reynolds Foundation Fondation Leducq Amgen info:eu-repo/grantAgreement/EC/FP7/223004

Aim According to established guidelines, patients with stage III colon cancer should receive adjuvant chemotherapy. However, a significant proportion do not. This study assessed factors associated with the administration of adjuvant chemotherapy and causes of death. Methods Patients with stage III colon cancer, who underwent surgery between 2000 and 2009, were selected from two hospitals in the Netherlands. Patient characteristics, including co-morbidities and treatment preferences, tumour characteristics, and follow-up were extracted from the medical records. The patient and tumour characteristics of patients who did receive chemotherapy were compared with those who did notusing chi-squared analysis.. Differences between the groups in causes of death were recorded together with the duration of follow-up. Results A total of 348 patients were included. The median value of age was 73 years (range 33 to 93). Over half of the patients received adjuvant chemotherapy (50.6%). Patients who did not receive adjuvant chemotherapy were significantly older (p

In this review, the results of the FOCUS (Female breast cancer in the elderly: Optimizing Clinical guidelines USing clinico-pathological and molecular data) program are summarized. This study was originally designed with the aim to define guidelines for the treatment of older women with breast cancer. With data from several studies within FOCUS, a prediction model can be constructed. Such a model helps to define individualized treatment for older patients with breast cancer, taking into account tumour characteristics and patient-related factors. At a clinical level, this model can provide the physician and the patient with accurate prediction to assist on the decision making of treatment strategies: this results into individualized treatment, not based on one individual marker, but on different pillars related to the patient, the tumour and the most suitable, appropriate treatment.

With the ongoing ageing of western societies, the proportion of older breast cancer patients will increase. For several years, clinicians and researchers in geriatric oncology have urged for new clinical trials that address patient-related endpoints such as functional decline after treatment of older patients. The aim of this study was to present an overview of trial characteristics and endpoints of all currently running clinical trials in breast cancer, particularly in older patients. The clinical trial register of the United States National Institutes of Health Differences was searched for all current clinical trials on breast cancer treatment. Trial characteristics and endpoints were retrieved from the register and differences in characteristics between studies in older patients specifically (defined as a lower age-limit of 60 years or older) and trials in all patients were assessed using chi(2) tests. We included 463 clinical trials. Nine trials (2 %) specifically investigated breast cancer treatment in older patients. Ninety-one breast cancer trials included any patient-related endpoint (20 %), while five trials specifically addressing older patients included any patient-related endpoint (56 %, P = 0.02). Five of the trials in older patients incorporated a geriatric assessment (56 %). Clinical trials still rarely incorporate patient-related endpoints, even in trials that specifically address older patients. Trials that are specifically designed for older patients do not often incorporate a geriatric assessment in their design. This implicates that current clinical studies are not expected to fill the gap in knowledge concerning treatment of older breast cancer patients in the next decade

Cardiovascular disease (CVD) remains the leading cause of death in developed countries, despite the decline of CVD mortality over the last two decades. From observational, predictive research, efforts have been made to find causal risk factors for CVD. However, in recent years, some of these findings have been shown to be mistaken. Possible explanations for the discrepant findings are confounding and reverse causation. Genetic epidemiology has tried to address these problems through the use of Mendelian randomisation. In this paper, we discuss the promise and limitations of using genetic variation for establishing causality of cardiovascular risk factors.

BACKGROUND AND PURPOSE: Small vessel disease is a major cause of neurocognitive dysfunction in the elderly. Small vessel disease may manifest as white matter hyperintensities, lacunar infarcts, cerebral microbleeds, and atrophy, all of which are visible on conventional MR imaging or as microstructural changes determined by diffusion tensor imaging. This study investigated whether microstructural integrity is associated with neurocognitive dysfunction in older individuals, irrespective of the conventional features of small vessel disease. MATERIALS AND METHODS: The study included 195 participants (75 years of age or older) who underwent conventional 3T MR imaging with DTI to assess fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. Cognitive tests were administered to assess cognitive domains, and the Geriatric Depression Scale-15 and Apathy Scale of Starkstein were used to assess symptoms of depression and apathy, respectively. The association between DTI measures and neurocognitive function was analyzed by using linear regression models. RESULTS: In gray matter, a lower fractional anisotropy and higher mean diffusivity, axial diffusivity, and radial diffusivity were associated with worse executive function, psychomotor speed, and overall cognition and, in white matter, also with memory. Findings were independent of white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. However, after additional adjustment for normalized brain volume, only lower fractional anisotropy in white and gray matter and higher gray matter radial diffusivity remained associated with executive functioning. DTI measures were not associated with scores on the Geriatric Depression Scale-15 or the Apathy Scale of Starkstein. CONCLUSIONS: Microstructural integrity was associated with cognitive but not psychological dysfunction. Associations were independent of the conventional features of small vessel disease but attenuated after adjusting for brain volume.

Background Insulin-like growth factor (IGF)-1 is a growth factor that can influence fibroblast functioning, with effects including the inhibition of collagenases and the induction of collagen expression. Objectives To assess whether serum IGF-1, IGF-binding protein (IGFBP)3 and the ratio between IGF-1 and IGFBP3, as a measure of IGF-1 bioavailability, are associated with facial ageing and skin wrinkling. Methods From a random sample comprising 617 subjects from the Leiden Longevity Study, perceived age and skin wrinkling were assessed from facial photographs, and IGF-1 and IGFBP3 were measured in serum. The associations were assessed using linear regression models, adjusted for chronological age, sex, body mass index, smoking and sun exposure. Results Across tertiles of the ratio of IGF-1 to IGFBP3, and after adjusting for all potential confounding factors, the mean perceived age decreased from 60AE6 years in the lowest tertile to 59AE5 years in the highest (Ptrend =0 AE045). Similarly, the mean skin wrinkling grade decreased from 4AE8 in the lowest tertile to 4AE 5i n the highest (Ptrend =0 AE011). Adding skin wrinkling as a covariate in the analysis between IGF-1 and perceived age diminished this association. Conclusions This study demonstrates that a higher ratio of IGF-1 to IGFBP3 associates with a lower perceived age, via its association with reduced skin wrinkling. Whether high IGF-1 levels actually delay the accumulation of skin wrinkling now needs investigating.

SummaryBackground Multiple biomarkers have been associated with hair loss in women, but studies have shown inconsistent results. Objectives We investigated the associations between markers of cardiovascular disease risk (e.g. serum lipid levels and hypertension) and ageing [e.g. 25-hydroxyvitamin D and insulin-like growth factor (IGF)] with hair loss in a population of middle-aged women. Methods In a random subgroup of 323 middle-aged women (mean age 61·5 years) from the Leiden Longevity Study, hair loss was graded by three assessors using the Sinclair scale; women with a mean score > 1·5 were classified as cases with hair loss. Results Every 1 SD increase in high-density lipoprotein (HDL) cholesterol was associated with a 0·65-times lower risk [95% confidence interval (CI) 0·46–0·91] of hair loss. For IGF-1 the risk was 0·68 times lower (95% CI 0·48–0·97) per 1 SD increase, independently of the other studied variables. Women with both IGF-1 and HDL cholesterol levels below the medians of the study population had a 3·47-times higher risk (95% CI 1·30–9·25) of having hair loss. Conclusions Low HDL cholesterol and IGF-1 were associated with a higher risk of hair loss in women. However, further studies are required to infer causal relationships.

Background: Predicting breast cancer outcome in older patients is challenging, as it has been shown that the available tools are not accurate in older patients. The PREDICT tool may serve as an alternative tool, as it was developed in a cohort that included almost 1800 women aged 65 years or over. The aim of this study was to assess the validity of the online PREDICT tool in a population-based cohort of unselected older patients with breast cancer. Methods: Patients were included from the population-based FOCUS-cohort. Observed 5- and 10-year overall survival were estimated using the Kaplan–Meier method, and compared with predicted outcomes. Calibration was tested by composing calibration plots and Poisson Regression. Discriminatory accuracy was assessed by composing receiver-operator-curves and corresponding c-indices. Results: In all 2012 included patients, observed and predicted overall survival differed by 1.7%, 95% confidence interval (CI)=−0.3–3.7, for 5-year overall survival, and 4.5%, 95% CI=2.3–6.6, for 10-year overall survival. Poisson regression showed that 5-year overall survival did not significantly differ from the ideal line (standardised mortality ratio (SMR)=1.07, 95% CI=0.98–1.16, P=0.133), but 10-year overall survival was significantly different from the perfect calibration (SMR=1.12, 95% CI=1.05–1.20, P=0.0004). The c-index for 5-year overall survival was 0.73, 95% CI=0.70–0.75, and 0.74, 95% CI=0.72–0.76, for 10-year overall survival. Conclusions: PREDICT can accurately predict 5-year overall survival in older patients with breast cancer. Ten-year predicted overall survival was, however, slightly overestimated.

AIMS For several types of cancer, including colon cancer, the survival gap between middle-aged patients and elderly patients widened between 1988 and 1999 in Europe. The aim of our study was to describe treatments and compare survival rates over time (1991-2005) between middle-aged (

In medical curricula, considerable effort is put into scientific education and research training. The output of these efforts, however, is not known. To assess the number of students who published at least one scientific paper during the course of their medical studies. Names and initials of all students who received their medical degree in 2006 or 2007 in one of the six participating university medical centers in the Netherlands were searched in the Web of Science database using a well-validated algorithm. Of the 2973 students, 14.5% had published at least one scientific paper during the last three years of their medical studies. These papers were of good quality, as the average number of citations per paper is above the average for papers published in their field. Based on the results of our survey, we conclude that medical students in the Netherlands are productively involved in research during their studies. Due to publication delay, the true number of papers is likely to be higher than we counted, but the bibliometric index chosen gives a robust estimate of the effect on the output of the scientific climate of a medical school. Using such an index on a larger scale may stimulate medical faculties to recognize and cultivate academic talent among their students. (Eyk HJ van, Hooiveld MHW, Leeuwen TN van, Wurff BLJ van der, Craen AJM de, Dekker FW. Scientific output of Dutch medical students. Netherlands Journal of Medical Education 2011;30(3):72–79.)

A central paradigm in life-history theory is the trade-off between offspring number and quality. Several studies have investigated this trade-off in humans, but data are inconclusive, perhaps because prosperous socio-cultural factors mask the trade-off. Therefore, we studied 2461 offspring groups in an area under adverse conditions in northern Ghana with high fertility and mortality rates. In a linear mixed model controlling for differences in age and tribe of the mother and socioeconomic status, each additional child in the offspring group resulted in a 2.3% (95% CI 1.9-2.6%, P < 0.001) lower proportional survival of the offspring. Furthermore, we made use of the polygamous population structure and compared offspring of co-wives in 388 households, thus controlling for variation in resources between compounds. Here, offspring survival decreased 2.8% (95% CI 2.3-4.0%, P < 0.001) for each increase in offspring number. We interpret these data as an apparent quality-quantity trade-off in human offspring.

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the C804A polymorphism and the primary endpoint (p = 0.03). After stratification for gender, this association was found only in males. Furthermore, we found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes (p = 0.02). The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm our results.

BACKGROUND: The metabolic syndrome is a cluster of risk factors including hypertension, obesity, dyslipidemia, and impaired glucose metabolism, associated with cardiovascular disease. The metabolic syndrome also appears to predispose to cognitive dysfunction and dementia. In this study the association between the metabolic syndrome and cognitive function was examined in a population of the oldest old.METHODS: The Leiden 85-Plus Study is a population-based study of 599 persons from age 85 onward. Cognitive function was assessed annually from age 85 to 90 by means of four neuropsychological tests. The presence (n = 237) or absence (n = 325) of the metabolic syndrome was recorded at baseline. Cross-sectional and prospective associations between the metabolic syndrome and cognitive function were analyzed with linear mixed models, adjusted for sex and level of education.RESULTS: At age 85 the metabolic syndrome was not associated with lower cognitive performance. The metabolic syndrome was associated with a decelerated cognitive decline from age 85 to 90 on the Mini-Mental State Examination (additional annual effect 0.18 [0.07], p = 0.01), the Stroop Test (-1.49 [0.59], p = 0.01), and the Letter Digit Coding Test (0.26 [0.09], p = 0.005). This effect was mainly attributable to glucose, body mass index, and, to a lesser extent, blood pressure.CONCLUSION: The association between the metabolic syndrome and accelerated cognitive decline, which has been reported in persons up to age 75, is not evident in a population of the oldest old. The concept of the metabolic syndrome may be less valid in this age group.

Proinflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), are implicated in the development of atherosclerosis. The role of anti-inflammatory cytokines, like IL-10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (4259AG, -1082GA, -592CA, and -2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the -592A variant allele) and risk of coronary events (P = 0.019). Moreover, analysis of separate SNPs found a significant association between -2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04-2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti-inflammatory cytokines may play an important role.

The relationship between structural variants of the apolipoprotein E gene, APOE epsilon2/epsilon3/epsilon4, and dementia is well established, whereas the relationship of plasma apoE levels with dementia is less clear. Plasma apoE levels are under tight genetic control but vary widely within the various genotypes indicating that the APOE epsilon2/epsilon3/epsilon4 locus explains only a small fraction of this variation. Here we studied the association of plasma apolipoprotein E (apoE) levels with cognitive function in the elderly population at large. Within the Leiden 85-plus Study, a prospective population-based study of subjects aged 85 years, we measured plasma apoE level and genotype at base line. During a 5-year follow-up period, cognitive function was annually assessed using the Mini Mental State Examination (MMSE) and a standardized neuropsychological test battery. Among epsilon3epsilon3 carriers (n = 324), high plasma apoE levels associated with impaired global cognitive function (-1.10 points change in MMSE score per one standard deviation increase of plasma apoE level, P = 0.001), as well as lower attention (P = 0.064), speed and memory function (all P

This paper describes the results of classifying document types in various electronic representations of the same scientific literature. Research evaluation assessment procedures at the Leiden University Medical Centre have shown that the classifications of research letters in the highly prolific general medicine journals occurs in various ways, resulting in discrepancies in representation of these documents. these discrepancies create problems, if “research letters” are classified sometimes as articles, or sometimes as letters. And although the representations of these documents in the citation indexes do vary with the original journal, the classification of research letters in the citation indexes follows certain specific guidelines that do right by the specific characteristics of these publications. Copyright , Beech Tree Publishing.

Solid evidence of treatment effects in older women with breast cancer is lacking, as they are generally underrepresented in randomized clinical trials on which guideline recommendations are based. An alternative way to study treatment effects in older patients could be to use data from observational studies. However, using appropriate methods in analyzing observational data is a key condition in order to draw valid conclusions, as directly comparing treatments generally results in biased estimates due to confounding by indication. The aim of this systematic review was to investigate the methods that have been used in observational studies that assessed the effects of breast cancer treatment on survival, breast cancer survival and recurrence in older patients (aged 65 years and older). Studies were identified through systematic review of the literature published between January 1st 2009 and December 13th 2013 in the PubMed database and EMBASe. Finally, 31 studies fulfilled the inclusion criteria. Of these, 22 studies directly compared two treatments. Fifteen out of these 22 studies addressed the problem of confounding by indication, while seven studies did not. Nine studies used some form of instrumental variable analysis. In conclusion, the vast majority of observational studies that investigate treatment effects in older breast cancer patients compared treatments directly. These studies are therefore likely to be biased. Observational research will be essential to improve treatment and outcome of older breast cancer patients, but the use of accurate methods is essential to draw valid conclusions from this type of data.

Interleukin-10 (IL10) is assumed beneficial for a successful pregnancy; it may increase fertility and fecundity. Allele frequencies of IL10 polymorphisms at position -2849, -1082 and -592 were analyzed in association with a past history of fertility and fecundity in men and women of at least 85 years old. Fertility was decreased in association with the -2849 A allele in females; 27% of the AA genotype carriers produced no offspring in marriage compared to 14% of the G allele carriers (odds ratio (OR): 2.2, 95% confidence interval (CI): 1.2-4.2, P=0.01). Effective fecundability was decreased in association with the -2849 A allele in females; 7% of female -2849 AA genotype carriers had a child within 371 days of marriage (therefore, conceived within 3 months of marriage) compared to 28% of female G allele carriers (OR: 0.2, 95% CI: 0.04-0.7, P=0.01). This suggests an association between the -2849 AA genotype and a decreased fertility and fecundity in females.

Diabetes mellitus is a risk factor for the development of cognitive impairment and dementia in the general population up to 75 years of age. As part of the Leiden 85-plus Study we studied the effects of diabetes on cognition in the oldest old. The Leiden 85-plus Study is a prospective population-based study of 599 persons from age 85 onward. Cognitive function was assessed each year from ages 85 to 90 by means of four neuropsychological tests. The presence of diabetes and vascular disease was recorded at baseline, HbA1c was assessed by means of a blood sample at ages 85 and 90. The cross-sectional and prospective associations between diabetes and cognitive function were analysed with linear mixed models, adjusted for sex and level of education. At age 85, diabetes was associated with a lower level of cognitive functioning on the Letter Digit Coding test and the Stroop Test. Diabetes was not associated with accelerated cognitive decline during follow-up. Within the group of diabetic patients, macrovascular disease was the most important determinant of cognitive dysfunction. The association between diabetes and accelerated cognitive decline, which has been documented previously in patients up to 75 years of age, may be less evident after age 85. This suggests that the damage occurs in previous years and that therapies aimed at preventing cognitive decline and dementia should focus on the younger old.

Background A multicentre randomized controlled trial with or without hysterosalpingography (HSG) was conducted to assess the usefulness of HSG as a routine investigation in the fertility workup prior to laparoscopy and dye. Methods From 1 April 1997 to 1 April 2002, subfertile women were allocated by a computer-based 1 : 1 ratio randomization procedure, either for an HSG followed by laparoscopy and dye (the intervention group) of for laparoscopy and dye only (the control group) as a part of their fertility workup. Cumulative pregnancy rate (CPR) within 18 months after randomization was the primary outcome of interest. Results 344 women were randomized to the intervention group (n = 169) and the control group (n = 175). There was no significant difference in CPR at 18 months in the intervention group (49.1%) [95% confidence interval (CI) 41.6 to 56.6] and the control group (50.3%) (95% CI 42.8 to 57.8), a difference of -1.2% (95% CI -11.8% to 9.5%). Conclusion The routine use of HSG at an early stage in the fertility workup prior to laparoscopy and dye does not influence CPR, compared with the routine use of laparoscopy and dye without HSG.

Objective: To investigate the influence of deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH) on progression of cognitive decline in non-demented elderly people. Methods: All data come from the nested MRI sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We performed a 3 year follow up study on 554 subjects of the PROSPER study using both repeated magnetic resonance imaging and cognitive testing. Cognitive decline and its dependency on WMH severity was assessed using linear regression models adjusted for sex, age, education, treatment group, and test version when applicable. Results: We found that the volume of PVWMH at baseline was longitudinally associated with reduced mental processing speed (p = 0.0075). In addition, we found that the progression in PVWMH volume paralleled the decline in mental processing speed (p = 0.024). In contrast, neither presence nor progression of DWMH was associated with change in performance on any of the cognitive tests. Conclusion: PVWMH should not be considered benign but probably underlie impairment in cognitive processing speed.

BACKGROUND: Factor V Leiden (FVL, Arg506Gln) mutation may facilitate embryo implantation and increase fertility and fecundity. This was studied in subjects who were of childbearing age in a time with minimal fertility control without modern contraceptive methods. METHODS: From 1986 to 1999, 1502 inhabitants of Leiden, The Netherlands, reaching the age of 85 years were enrolled in the Leiden 85-Plus Study. Of 1176 subjects the FVL status was analysed, in 365 male and 811 female subjects. RESULTS: The FVL carrier rate was 4.3%. Fertility was not affected by FVL status. In male subjects, fecundity (interval between marriage and birth of first child) was significantly increased in FVL carriers; 67% of male FVL carriers had a child within 371 days of marriage (therefore conceived within 3 months of marriage), compared with 19% of male non-carriers [relative risk (RR), 3.5; 95% confidence interval (CI), 2.1-5.7; P < 0.001]. Within 6 months of marriage, 75% of male FVL carriers had conceived a child compared with 34% male non-carriers (RR, 2.2; 95% CI, 1.5-3.2; P = 0.01). In female subjects, fecundity was not influenced by FVL status. CONCLUSION: Fecundity is increased in male FVL carriers; in female subjects, no such association was observed.

Background Cerebral white matter hyperintensities on magnetic resonance imaging (MRI) scans have been associated with vascular disease and late-life depression, both in the general population and in psychiatric patients. Therefore, a cerebrovascular etiology for late-onset depression has been hypothesized. However, longitudinal studies on the causal role of white matter hyperintensities in the development of depressive symptoms in elderly adults are lacking. Objective To investigate the relation between white matter hyperintensities and depressive symptoms in elderly subjects at risk of cardiovascular disease. Methods In the Dutch sample of the PROSPER (PROspective Study of Pravastatine in the Elderly at Risk of cardiovascular disease) cohort, 527 non-demented elderly, all aged 70 years or older, received a cranial MRI scan and the 15-item Geriatric Depression Scale, at baseline and 33 months (SD 1.6) later. Results Presence of white matter hyperintensities at baseline was not related to baseline depressive symptoms nor to the development of depressive symptoms during follow-up. Moreover, no association was found between progression of white matter lesion volume and progression of depressive symptoms. Conclusion This longitudinal study does not confirm the involvement of cerebrovascular disease expressed as MRI white matter hyperintensities in the development of depressive symptoms in elderly subjects. Copyright © 2006 John Wiley & Sons, Ltd.

BACKGROUND: The primary objective of this study was to investigate whether subfertility explains poor perinatal outcome after assisted conception. A secondary objective was to test the hypothesis that ovarian hyperstimulation rather than the IVF procedure may influence the perinatal outcome. METHODS: Using data from a Dutch population-based historical cohort of women treated for subfertility, we compared perinatal outcome of singletons conceived after controlled ovarian hyperstimulation (COHS) and IVF (IVF + COHS; n = 2239) with perinatal outcome in subfertile women who conceived spontaneously (subfertile controls; n = 6343) and in women who only received COHS (COHS only; n = 84). Furthermore, we compared perinatal outcome of singletons conceived after the transfer of thawed embryos with (Stim + Cryo; n = 66) and without COHS (Stim - Cryo; n = 73). RESULTS: The odds ratios (ORs) for very low birthweight (

Through its ability to induce the enhanced release and production of cytokines, amyloid-β is responsible for the chronic inflammatory response that contributes to Alzheimer's disease (AD). Determining whether the response of monocytes to amyloid-β stimulation is under genetic control may help understand the basis of why some people are more prone to develop neuronal degeneration than others. In the current study we investigated the heritability of the cytokine (IL-10, IL-6, IL-1β, IL-1ra, TNF-α) production capacity upon ex vivo stimulation with amyloid-β in whole blood samples of 222 twins and 85 singleton siblings from 139 extended twin families. It was found that individual differences in amyloid-β- induced cytokine production capacity are to a large extent of genetic origin, with heritability estimates ranging from 55% (IL-1β) to 68% (IL-6). We conclude that genes influencing amyloid-β-induced cytokine response may provide clues to the progression of AD pathology.

Background:In older persons, a relationship between both higher and lower blood pressure and depression has inconsistently been reported. Blood pressure may be differentially associated with distinct symptom domains of depression. We examined the cross-sectional relation of current systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) with different depressive symptom domains among depressed older persons.Methods:In the Netherlands Study of Depression in Older Persons (NESDO), 270 participants aged 60 years and above were diagnosed with depression in the past month. Using the three corresponding subscales of the Inventory of Depressive Symptoms-Self Report (IDS-SR), motivational, mood and somatic symptom domains were assessed. Additionally, symptoms of apathy were determined with the Apathy Scale. Multiple linear regression was used to examine the cross-sectional relationship between current SBP, DBP and MAP with both IDS-SR subscale and Apathy Scale scores. Unstandardized betas were calculated per 10 mmHg increase in blood pressure measures.Results:Mean age of participants was 70.4 years (standard deviation 7.3). Higher SBP (Beta 0.33, t (254) = 2.01, p = 0.045), higher DBP (Beta 0.68, t (254) = 2.15, p = 0.03) and higher MAP (Beta 0.63, t (254) = 2.33, p = 0.02) were associated with higher Apathy Scale scores in the fully adjusted model. Furthermore, a higher SBP was associated with higher IDS-SR mood subscale scores (Beta 0.25, t (254) = 2.13, p = 0.03).Conclusions:Depressed older people with higher blood pressure measures had particularly more symptoms of apathy. To disentangle the relationship of blood pressure with late-life depression, it is important to pay attention to the role of apathy symptoms.

Background Older women are more likely to be diagnosed with primary metastasised breast cancer than their younger counterparts. Evolving treatment strategies of metastasised breast cancer have resulted in improved survival in younger patients, but it remains unclear if this improvement has occurred in older patients as well. The aim of this study was to assess changes in treatment strategies over time in relation to overall and relative survival of older patients compared to younger patients with primary metastasised breast cancer. Methods All patients with a breast cancer diagnosis and distant metastases at first presentation (stage IV), between 1990 and 2012, were selected from the Netherlands Cancer Registry. Changes in treatment over time per age-group (75 years) were assessed using logistic regression. Overall survival over time was calculated using Cox Regression Models and relative survival was assessed using the Ederer II method. Results Overall, 14,310 patients were included. Treatment strategies have strongly changed in the past twenty years; especially the use of chemotherapy has increased (P < 0.001 in all age-groups). Overall survival of patients 75). Similarly, relative survival has improved in patients 75. Conclusion Overall and relative survival of older patients with metastasised breast cancer at first presentation have not improved in recent years in contrast with the survival of younger patients, despite increased treatment with chemotherapy for women of all ages. Future studies should focus on stratification models that can be used to predict which patients may benefit from specific treatment options.

Post-mortem analyses suggest that atherosclerosis more often contributes to late-onset dementia than hitherto expected. We set out to further unravel the relation between atherosclerosis and cognitive impairment. We therefore tested the hypothesis that the number of cardiovascular pathologies is positively associated with cognitive impairment in elderly subjects, and that the smaller number of cardiovascular pathologies in women explains the better cognitive function of elderly women. Within the Leiden 85-plus Study, we assessed the atherosclerotic burden by counting the number of cardiovascular pathologies in the medical histories of a population-based sample of 599 subjects aged 85 years (response 87%). Significantly more men than women had a history of cardiovascular pathologies (67% compared to 59%, P

We tested the hypothesis that an additional effort to increase the response rate would diminish selection bias in a community-based cohort study. In the Leiden 85-plus Study, all subjects of the town of Leiden who had reached their 85th birthday were informed of the study by mail and then asked to participate by telephone. In an additional recruitment stage, those subjects who did not participate directly were visited and personally asked to participate. When these subjects refused, some nonresponse questions were asked. In this way we collected data on the whole source population. Of 691 eligible elderly subjects, 511 subjects (74%) participated directly. Of those who did not participate directly, 88 subjects participated after the additional effort. The response rate increased from 74% to 87%. Compared to the 511 subjects who directly participated, the 88 subjects who entered the study after the additional effort had poorer health and lower survival. The subjects who refused were more healthy and had poorer mood. The direct sample did not differ from the source population with respect to socio-demographics, health, and mortality. In conclusion, we showed that given a moderately high direct response the additional effort was effective in increasing the response rate, but was also selective and was not necessary to prevent selection bias.

Background The C282Y mutation in the gene for haemochromatosis (HFE) has been associated with various diseases at middle age. However, recent studies indicate that penetrance of the C282Y mutation is low. We explored the association between the C282Y mutation, iron metabolism, and morbidity and mortality in participants of the Leiden 85-plus. Study design A cross-sectional comparison and prospective follow-up was conducted in two unselected cohorts of 661 and 552 subjects. All subjects were aged 85 years and over. We determined the prevalence of C282Y homozygous and heterozygous subjects, and the association between the C282Y mutation and iron metabolism, all-cause and specific causes of death.

Long-lived individuals delay aging and age-related diseases like diabetes, hypertension, and cardiovascular disease. The exact underlying mechanisms are largely unknown, but enhanced mitochondrial biogenesis and preservation of mitochondrial function have been suggested to explain healthy ageing. We investigated whether individuals belonging to long-lived families have altered mitochondrial DNA (mtDNA) content, as a biomarker of mitochondrial biogenesis and measured expression of genes regulating mitochondrial biogenesis. mtDNA and nuclear DNA (nDNA) levels were measured in blood samples from 2,734 participants from the Leiden Longevity Study: 704 nonagenarian siblings, 1,388 of their middle-aged offspring and 642 controls. We confirmed a negative correlation of mtDNA content in blood with age and a higher content in females. The middle-aged offspring had, on average, lower levels of mtDNA than controls and the nonagenarian siblings had an even lower mtDNA content (mtDNA/nDNA ratio = 0.744 ± 0.065, 0.767 ± 0.058 and 0.698 ± 0.074, respectively; p controls-offspring = 3.4 × 10(-12), p controls-nonagenarians = 6.5 × 10(-6)), which was independent of the confounding effects of age and gender. Subsequently, we examined in a subset of the study the expression in blood of two genes regulating mitochondrial biogenesis, YY1 and PGC-1α. We found a positive association of YY1 expression and mtDNA content in controls. The observed absence of such an association in the offspring suggests an altered regulation of mitochondrial biogenesis in the members of long-lived families. In conclusion, in this study, we show that mtDNA content decreases with age and that low mtDNA content is associated with familial longevity. Our data suggest that preservation of mitochondrial function rather than enhancing mitochondrial biogenesis is a characteristic of long-lived families.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Researchers have a number of different options for their choice of control or comparison intervention in randomized trials. We surveyed the methodological literature looking for reasons why a researcher might choose to administer a placebo (i.e., a mimic intervention) to control subjects. Two implicit assumptions were that the issue of placebo is pertinent only to drug trials and that the nonplacebo effect of a treatment is the "real" or "true" effect. Explicit reasons given in the literature for the use of placebos were facilitating blinding and controlling for the placebo effect. The importance of the latter was often inadequately argued. Reasons to avoid placebos in controlled trials, other than ethics and feasibility, are that placebos do not inform real decisions, and may interfere with accurate estimation of effect size and with nonspecific aspects of treatment. Placebo-controlled trials have high internal validity but may be difficult to apply to clinical practice; the situation is reversed for trials without placebo control.

Summary The aim of this overview is to discuss the usefulness of two re­ search tools often advocated in complementary medicine: the n = 1 study and case series. These methodologies are defined and their advantages and disadvantages are outlined. It is concluded that both designs have advantages and disadvantages. For testing the ef­ ficacy/effectiveness of complementary therapies neither design will lead to conclusive, generalizable results. Yet both methodologies can be valuable adjuncts to other types of investigation.

Background Older patients with breast cancer are often not treated in accordance with guidelines. With the emergence of endocrine therapy, omission of surgery can be considered in some patients. The aim of this population-based study was to investigate time trends in surgical treatment between 1995 and 2011, and to evaluate the effects of omitting surgery on overall and relative survival in older patients with resectable breast cancer. Methods Patients aged 75 years and older with stage I–III breast cancer diagnosed between 1995 and 2011 were selected from the Netherlands Cancer Registry. Time trends of all treatment modalities were evaluated using linear regression models. Changes in overall survival were calculated by Cox regression. Relative survival was calculated using the Ederer II method. Results Overall, 26 292 patients were included. The proportion of patients receiving surgical treatment decreased significantly, from 90·8 per cent in 1995 to 69·9 per cent in 2011 (P < 0·001). Multivariable analysis showed that overall survival did not change over time (hazard ratio 1·00 (95 per cent confidence interval (c.i.) 0·99 to 1·00) per year); nor did relative survival (relative excess risk 1·00 (0·98 to 1·02) per year). Conclusion Omission of surgery has become more common in older patients with breast cancer during the past 15 years in the Netherlands, but this has not altered overall or relative survival.

Skeletal muscle is important in insulin-stimulated glucose uptake. Sarcopenia is, therefore, a possible risk factor for insulin resistance. Currently, different diagnostic criteria for sarcopenia include low muscle mass, muscle strength, and walking speed. We assessed these muscle characteristics in relation to insulin resistance in nondiabetics. This cross-sectional study included 301 nondiabetics, mean age 65.9 years. Area under curve (AUC) calculations of insulin and glucose from a 2-h oral glucose tolerance test (OGTT) and homeostasis model assessment of insulin resistance (HOMA-IR) were used as measures of insulin resistance. Muscle characteristics were relative muscle mass (total or appendicular lean mass (ALM) as percentage of body mass), absolute muscle mass (ALM/height(2) and total lean mass), handgrip strength, and walking speed. All muscle characteristics were standardized and analyzed in linear regression models, stratified by gender. For both males and females, relative muscle mass was inversely associated with AUC insulin, AUC glucose, and HOMA-IR (ALM percentage all p ≤ 0.004). Absolute muscle mass was positively associated with AUC insulin and HOMA-IR (ALM/height(2) all p < 0.001) but not with AUC glucose. Adjustments for fat mass attenuated aforementioned associations. There were no associations between handgrip strength and insulin resistance. Walking speed was inversely associated with AUC insulin in males (p = 0.032). The association between muscle characteristics and insulin resistance was strongest for relative muscle mass. Diagnostic criteria for sarcopenia relate differently to insulin resistance. The role of muscle tissue as an internal glucose-regulating organ is better reflected by relative muscle mass than by absolute muscle mass, muscle strength, or walking speed.

Background In the aging population cardiovascular disease (CVD) is highly prevalent. Identification of very old persons at high risk of recurrent CVD is difficult, since traditional risk markers loose predictive value with age. Methods In a population-based sample of 282 85-year old participants with established CVD from the Leiden 85-plus Study, we studied predictive values of traditional cardiovascular risk markers, a history of major CVD (myocardial infarction, stroke or arterial surgery), and new cardiovascular biomarkers (estimated glomerular filtration rate (MDRD), C-reactive protein (CRP), homocysteine and N-terminal pro B-type natriuretic peptide (NT-proBNP)) regarding 5-year risk of recurrent cardiovascular events and mortality (composite endpoint). Results During complete 5-year follow-up 157 (56%) participants died. 109 (39%) had a cardiovascular event or died from cardiovascular causes. Individually related to the composite endpoint were: a history of major CVD (HR 1.5 (95%CI 1.03-2.3)), CRP (HR 1.3 (95%CI 1.03-1.5)), homocysteine (HR 1.4 (95%CI 1.2-2.6)) and NT-proBNP (HR 1.7 (95%CI 1.4-2.1)). A prediction model including all traditional risk markers yielded a C-statistic of 0.59 (95%CI 0.52-0.66). Of all five new markers only addition of NT-proBNP improved the C-statistic (0.67 (95%CI 0.61-0.74, p=0.023)). The categoryless net reclassification improvement for NT-proBNP was 39% (p=0.001), for a history of major CVD 27.2% (p=0.03) and for homocysteine 24.7% (p=0.04). Conclusions Among very old subjects with established CVD, NT-proBNP was the strongest risk marker for cardiovascular events and cardiovascular mortality. When estimating risk in secondary prevention in very old age, use of NT-proBNP should be considered.

Background In developed countries, 40% of breast cancer patients are >65 years of age at diagnosis, of whom 16% additionally suffer from diabetes. The aim of this study was to assess the impact of diabetes on relapse-free period (RFP) and overall mortality in elderly breast cancer patients. Patients and Methods Patients were selected from the retrospective FOCUS cohort, which contains detailed information of elderly breast cancer patients. RFP was calculated using Fine and Gray competing risk regression models for patients with diabetes versus patients without diabetes. Overall survival was calculated by Cox regression models, in which patients were divided into four groups: no comorbidity, diabetes only, diabetes and other comorbidity or other comorbidity without diabetes. Results Overall, 3124 patients with non-metastasized breast cancer were included. RFP was better for patients with diabetes compared with patients without diabetes (multivariable HR 0.77, 95% CI 0.59–1.01), irrespective of other comorbidity and most evident in patients aged ≥75 years (HR 0.67, 95% CI 0.45–0.98). The overall survival was similar for patients with diabetes only compared with patients without comorbidity (HR 0.86, 95% CI 0.45-0.98), while patients with diabetes and additional comorbidity had the worst overall survival (HR 1.70, 95% CI 1.44–2.01). Conclusion When taking competing mortality into account, RFP was better in elderly breast cancer patients with diabetes compared with patients without diabetes. Moreover, patients with diabetes without other comorbidity had a similar overall survival as patients without any comorbidity. Possibly, unfavourable effects of (complications of) diabetes on overall survival are counterbalanced by beneficial effects of metformin on the occurrence of breast cancer recurrences.

Old age is associated with comorbidity and decreased functioning which influences treatment decisions in elderly breast cancer patients. The purpose of this study was to identify risk factors for complications after breast cancer surgery in elderly patients, and to assess mortality in patients with postoperative complications. The FOCUS cohort is a detailed retrospective cohort of all breast cancer patients aged 65 years and older who were diagnosed between 1997 and 2004 in the South-West of the Netherlands. Risk factors for postoperative complications were assessed using univariable and multivariable logistic regression models. One-year survival and overall survival were calculated using univariable and multivariable Cox Regression models, and relative survival was calculated according to the Ederer II method. 3179 patients received surgery, of whom 19 % (n = 618) developed 1 or more postoperative complication(s). The odds ratio of having postoperative complications increased with age [OR 1.85 (95 % confidence interval (CI) 1.37–2.50, p = 0.001) in patients >85 years] and number of concomitant diseases [OR 1.71 (95 % CI 1.30–2.24, p ≤ 0.001) for 4 or more concomitant diseases]. One-year overall survival, overall survival, and relative survival were worse in patients with postoperative complications [multivariable HR 1.49 (95 % CI 1.05–2.11), p = 0.025. HR 1.21, (95 % CI 1.07–1.36), p = 0.002 and RER 1.19 (95 % CI 1.05–1.34), p = 0.006 respectively]. Stratified for comorbidity, relative survival was lower in patients without comorbidity only. Increasing number of concomitant disease increased the risk of postoperative complications. Although elderly patients with comorbidity did have a higher risk of postoperative complications, relative mortality was not higher in this group. This suggests that postoperative complications in itself did not lead to higher relative mortality, but that the high relative mortality was most likely due to geriatric parameters such as comorbidity or poor physical function.

Contains fulltext : 117437.pdf (Publisher’s version ) (Open Access) Hepcidin, an important regulator of iron homeostasis, is suggested to be causally related to anemia of inflammation. The aim of this study was to explore the role of plasma hepcidin in anemia among older persons from the general population. The Leiden 85-Plus Study is a population-based study of 85-year olds in Leiden, the Netherlands. Eighty-five-year old inhabitants of Leiden were enrolled between September 1997 and September 1999. At the age of 86, plasma hepcidin was determined with time of flight mass spectrometry in 490 participants [160 (32.7%) male, 114 (23.3%) with anemia]. Anemia was defined according to criteria of the World Health Organization (hemoglobin level

Background Elderly patients with breast cancer are under-represented in clinical studies. It is not known whether treatment guidelines, based on clinical trials, can be extrapolated to this population. The aim of this study was to assess adherence to treatment guidelines by age at diagnosis, and to examine age-specific survival in relation to adherence to guidelines. Methods Patients with early-stage breast cancer aged either less than 65 years, or 75 years or more, diagnosed between 2005 and 2008, were identified from the Netherlands Cancer Registry. Adherence to treatment guidelines for breast and axillary surgery, radiotherapy, chemotherapy and endocrine therapy was determined. Non-adherence to the guidelines was defined as overtreatment or undertreatment. The primary endpoint was overall survival, assessed by means of an instrumental variable, the comprehensive cancer centre region. Results Some 24 959 patients younger than 65 years and 6561 patients aged 75 years or more were included in the analysis. Median follow-up was 2·8 years. Compared with patients younger than 65 years, those aged at least 75 years were less frequently treated in concordance with guidelines: 62·0 per cent (15 487 patients) versus 55·6 per cent (3647 patients) (P < 0·001). In both age groups, most patients received at least three of five treatment modalities in concordance with guidelines: 98·8 per cent (24 652 patients) and 93·8 per cent (6152 patients) respectively. Analysis of survival using the instrumental variable showed that adherence to guidelines was not associated with overall survival in patients younger than 65 years (P = 0·601) or those aged at least 75 years (P = 0·190). Conclusion Adherence to treatment guidelines was affected by age at diagnosis. However, adherence to the guidelines was not associated with overall survival in either age group.

Background: The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients. Methods: Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998–2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure. Results: In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63–0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50–0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46–0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79–1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70–2.20; P

Over 40% of breast cancer patients are diagnosed above the age of 65. Treatment of these elderly patients will probably vary over countries. The aim of this study was to make an international comparison (several European countries and the US) of surgical and radiation treatment for elderly women with early stage breast cancer. Survival comparisons were also made. Data were obtained from national or regional population-based registries in the Netherlands, Switzerland, Ireland, Belgium, Germany, and Portugal. For the US patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Early stage breast cancer patients aged ≥ 65 diagnosed between 1995 and 2005 were included. An international comparison was made for breast and axillary surgery, radiotherapy after breast conserving surgery (BCS), and relative or cause-specific survival. Overall, 204.885 patients were included. The proportion of patients not receiving any surgery increased with age in many countries; however, differences between countries were large. In most countries more than half of all elderly patients received breast conserving surgery (BCS), with the highest percentage in Switzerland. The proportion of elderly patients that received radiotherapy after BCS decreased with age in all countries. Moreover, in all countries the proportion of patients who do not receive axillary surgery increased with age. No large differences in survival between countries were recorded. International comparisons of surgical treatment for elderly women with early stage breast cancer are scarce. This study showed large international differences in treatment of elderly early stage breast cancer patients, with the most striking result the large proportion of elderly who did not undergo surgery at all. Despite large treatment differences, survival does not seem to be affected in a major way.