Huge decreases in the risk of breast cancer relapse over the last three decades

Introduction The aim of this study was to evaluate local and systemic breast cancer control by comparing the risk of relapse in breast cancer patients in 2003–2004 with that in 1972–1979 and in 1980–1986. Methods About 8,570 women diagnosed with invasive breast cancer in 2003–2004 were selected from the population-based Netherlands Cancer Registry and compared with 133 patients treated in 1972–1979 and 174 in 1980–1986. Five-year risk of relapse was calculated by the Kaplan–Meier method. Cox-proportional hazard models were applied to adjust for tumour size, nodal status and age at diagnosis. Results Patients diagnosed in 2003–2004 had smaller tumours and a less advanced nodal stage than patients diagnosed in 1972–1986. In 1972–1979, 1980–1986 and 2003–2004, treatment included mastectomy in 94%, 72% and 47%; postmastectomy radiotherapy in 75%, 70% and 30%; chemotherapy in 9%, 14% and 37% and hormonal therapy in 3%, 3% and 42% of patients, respectively. Five-year risk of locoregional and distant recurrence decreased from 37% and 34% to 15%, respectively. The 5-year risk of second primary breast cancer did not differ and was 1%, 4% and 2%, respectively. The improved relapse-free survival in patients diagnosed in 2003–2004 as compared with 1972–1979 hardly changed after adjustment (HR = 0.38, 95% CI = 0.28–0.52). Conclusion Over the last decades, local breast cancer therapies have become less rigorous, whereas systemic therapy use has increased. Simultaneously, the risk of breast cancer relapse has tremendously decreased. Future novel therapies may lead to such small additional decreases in relapse rates, while the long-term side effects in breast cancer survivors will increas

Enhanced sensitivity of postsynaptic serotonin-1A receptors in rats and mice with high trait aggression

Individual differences in aggressive behaviour have been linked to variability in central serotonergic activity, both in humans and animals. A previous experiment in mice, selectively bred for high or low levels of aggression, showed an up-regulation of postsynaptic serotonin-1A (5-HT1A) receptors, both in receptor binding and in mRNA levels, in the aggressive line. The aim of this experiment was to study whether similar differences in 5-HT1A receptors exist in individuals from a random-bred rat strain, varying in aggressiveness. In addition, because little is known about the functional consequences of these receptor differences, a response mediated via postsynaptic 5-HT1A receptors (i.e., hypothermia) was studied both in the selection lines of mice and in the randomly bred rats. The difference in receptor binding, as demonstrated in mice previously, could not be shown in rats. However, both in rats and mice, the hypothermic response to the 5-HT1A agonist alnespirone was larger in aggressive individuals. So, in the rat strain as well as in the mouse lines, there is, to a greater or lesser extent, an enhanced sensitivity of postsynaptic 5-HT1A receptors in aggressive individuals. This could be a compensatory up-regulation induced by a lower basal 5-HT neurotransmission, which is in agreement with the serotonin deficiency hypothesis of aggression.

A combination of high concentrations of serum triglyceride and non-high-density-lipoprotein-cholesterol is a risk factor for cardiovascular disease in subjects with abnormal glucose metabolism - The Hoorn Study

Aims/hypothesis. Type 2 diabetes is not only associated with hyperglycaemia, but also with disorders of lipid metabolism. The aim of this study was to investigate the association of triglyceride and non-HDL-cholesterol concentrations with cardiovascular disease in subjects with normal and abnormal glucose metabolism. Methods. Subjects were 869 men and 948 women aged 50 to 75 who participated in the Hoorn Study, a population-based cohort study that started in 1989. Glucose metabolism was determined by a 75 g OGTT. High fasting triglyceride and non-HDL-cholesterol concentrations were defined as above the median of the study population. Results. After 10 years of follow-up, the age- and sex-adjusted hazard ratios for cardiovascular disease were 1.35 (1.11-1.64) and 1.71 (1.40-2.08) for high triglycerides and high non-HDL-cholesterol, respectively, after mutual adjustment. After stratification for glucose metabolism status, the hazard ratios for cardiovascular disease for non-HDL-cholesterol were 1.70 (1.31-2.21) in normal glucose metabolism and 1.56 (1.12-2.18) in abnormal glucose metabolism. Triglycerides were not a risk factor in subjects with normal glucose metabolism, with a hazard ratio of 0.94 (0.73-1.22), but in subjects with abnormal glucose metabolism, the hazard ratio for cardiovascular disease was 1.54 (1.07-2.22). In subjects with abnormal glucose metabolism, the hazard ratio for the combined presence of high triglycerides and non-HDL-cholesterol was 2.12 (1.35-3.34). Conclusion. Our data suggest that in people with abnormal glucose metabolism, but not in those with normal glucose metabolism, high triglyceride concentration could be associated with the risk of cardiovascular disease, particularly in people with high non-HDL-cholesterol

Astrometric Positions and Proper Motions of 19 Radio Stars

We have used the Very Large Array, linked with the Pie Town Very Long Baseline Array antenna, to determine astrometric positions of 19 radio stars in the International Celestial Reference Frame (ICRF). The positions of these stars were directly linked to the positions of distant quasars through phase referencing observations. The positions of the ICRF quasars are known to 0.25 mas, thus providing an absolute reference at the angular resolution of our radio observations. Average values for the errors in our derived positions for all sources were 13 mas and 16 mas in R.A. and declination respectively, with accuracies approaching 1-2 mas for some of the stars observed. Differences between the ICRF positions of the 38 quasars, and those measured from our observations showed no systematic offsets, with mean values of -0.3 mas in R.A. and -1.0 mas in declination. Standard deviations of the quasar position differences of 17 mas and 11 mas in R.A. and declination respectively, are consistent with the mean position errors determined for the stars. Our measured positions were combined with previous Very Large Array measurements taken from 1978-1995 to determine the proper motions of 15 of the stars in our list. With mean errors of approximately 1.6 mas/yr, the accuracies of our proper motions approach those derived from Hipparcos, and for a few of the stars in our program, are better than the Hipparcos values. Comparing the positions of our radio stars with the Hipparcos catalog, we find that at the epoch of our observations, the two frames are aligned to within formal errors of approximately 3 mas. This result confirms that the Hipparcos frame is inertial at the expected level.Comment: 20 pages, 9 figures Accepted by the Astronomical Journal, 2003 March 1

Cardiovascular events in type 2 diabetes: comparison with nondiabetic individuals without and with prior cardiovascular disease - 10-year follow-up of the Hoorn Study

Aims: We questioned whether prior cardiovascular disease has the same impact on risk of cardiovascular events as type 2 diabetes, and whether this differed between men and women. Methods and results: To address these issues we compared the 10-year risk of cardiovascular events among 208 Caucasian individuals with diabetes to that of 2253 Caucasian individuals without diabetes, in a population-based cohort study. Gender significantly modified the association between type 2 diabetes and cardiovascular events (p=0.01). The hazard ratio of cardiovascular events associated with the presence of diabetes was higher in women (adjusted hazard ratio, 1.8; 95% CI, 1.2 to 2.7) than in men (adjusted hazard ratio, 1.3; 0.9 to 2). As compared to men without diabetes but with prior cardiovascular disease, risk of cardiovascular events was significantly lower in men with diabetes but without prior cardiovascular disease (adjusted hazard ratio, 0.5; 0.3 to 0.9). In contrast, this risk was equal in women with diabetes but without prior cardiovascular disease and women without diabetes but with prior cardiovascular disease (adjusted hazard ratio, 1.0; 0.6 to 1.7; P for interaction between gender and diabetes=0.05). Conclusions: Women with diabetes but without prior cardiovascular disease have a risk of cardiovascular events that is similar to that of women without diabetes but with prior cardiovascular disease, whereas in men the presence of prior cardiovascular disease conferred a higher risk. These data emphasise the necessity of aggressive treatment of cardiovascular risk factors in women with type 2 diabetes. © 2003 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved

Relation of impaired fasting and postload glucose with incident type 2 diabetes in a Dutch population - The Hoorn study

Item does not contain fulltextCONTEXT: Persons with impaired glucose tolerance (IGT) are known to have an elevated risk of developing diabetes mellitus. Less is known about diabetes risk among persons with impaired fasting glucose (IFG) or with normal glucose levels. OBJECTIVE: To determine the incidence of diabetes in relation to baseline fasting and postload glucose levels and other risk factors. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study conducted from October 1989 to February 1992 among 1342 nondiabetic white residents of Hoorn, the Netherlands, aged 50 to 75 years at baseline, in whom fasting plasma glucose (FPG) levels and glucose levels 2 hours after a 75-g oral glucose tolerance test were measured at baseline and at follow-up in 1996-1998. MAIN OUTCOME MEASURES: Cumulative incidence of diabetes, defined according to the diagnostic criteria of the World Health Organization (WHO-1985 and WHO-1999) and the American Diabetes Association (ADA-1997), during a mean follow-up of 6.4 years, compared among participants with IFG, IGT, and normal glucose levels at baseline. RESULTS: The cumulative incidence of diabetes was 6.1%, 8.3%, and 9.9% according to the WHO-1985, ADA, and WHO-1999 criteria, respectively. The cumulative incidence of diabetes (WHO-1999 criteria) for participants with both IFG and IGT was 64.5% compared with 4.5% for those with normal glucose levels at baseline. The odds ratios for diabetes (WHO-1999 criteria), adjusted for age, sex, and follow-up duration, were 10.0 (95% confidence interval [CI], 6.1-16.5), 10.9 (95% CI, 6.0-19.9), and 39.5 (95% CI, 17.0-92.1), respectively, for those having isolated IFG, isolated IGT, and both IFG and IGT. In addition to FPG and 2-hour postload glucose levels (P<.001 for both), the waist-hip ratio also was an important risk factor for developing diabetes (P =.002). CONCLUSION: In this study, the cumulative incidence of diabetes was strongly related to both IFG and IGT at baseline and, in particular, to the combined presence of IFG and IGT

Surfactant effect in heteroepitaxial growth. The Pb - Co/Cu(111) case

A MonteCarlo simulations study has been performed in order to study the effect of Pb as surfactant on the initial growth stage of Co/Cu(111). The main characteristics of Co growing over Cu(111) face, i.e. the decorated double layer steps, the multiple layer islands and the pools of vacancies, disappear with the pre-evaporation of a Pb monolayer. Through MC simulations, a full picture of these complex processes is obtained. Co quickly diffuses through the Pb monolayer exchanging place with Cu atoms at the substrate. The exchange process diffusion inhibits the formation of pure Co islands, reducing the surface stress and then the formation of multilayer islands and the pools of vacancies. On the other hand, the random exchange also suppress the nucleation preferential sites generated by Co atoms at Cu steps, responsible of the step decoration.Comment: 4 pages, latex, 2 figures embedded in the tex

Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice

Contains fulltext : 98302.pdf (publisher's version ) (Closed access)PURPOSE: Radiolabelled peptides used for peptide receptor radionuclide therapy are excreted mainly via the kidneys and are partly reabsorbed and retained in the proximal tubular cells. The resulting high renal radiation dose can cause nephrotoxicity, limiting the maximum activity dose and the effectiveness of peptide receptor radionuclide therapy. The mechanisms of kidney reabsorption of these peptides are incompletely understood, but the scavenger receptor megalin has been shown to play a role in the reabsorption of (111)In-octreotide. In this study, the role of megalin in the renal reabsorption of various relevant radiolabelled peptides was investigated. METHODS: Groups of kidney-specific megalin-deficient mice and wild-type mice were injected with (111)In-labelled somatostatin, exendin, neurotensin or minigastrin analogues. Single photon emission computed tomographic (SPECT) images of the kidneys were acquired and analysed quantitatively, or the animals were killed 3 h after injection and the activity concentration in the kidneys was measured. RESULTS: Megalin-deficient mice showed significantly lower uptake of all studied radiolabelled peptides in the kidneys, ranging from 22% ((111)In-octreotide) to 65% ((111)In-exendin) of uptake in wild-type kidneys. Quantitative analysis of renal uptake by SPECT and ex vivo measurements showed a very good correlation. CONCLUSION: Megalin is involved in the renal reabsorption of radiolabelled octreotide, octreotate, exendin, neurotensin and minigastrin. This knowledge may help in the design of strategies to reduce this reabsorption and the resulting nephrotoxicity in peptide receptor radionuclide therapy, enabling more effective therapy. Small-animal SPECT is an accurate tool, allowing in vivo quantification of renal uptake and serial measurements in individual mice

Biological tumor markers associated with local control after primary radiotherapy in laryngeal cancer:A systematic review

Background The choice of treatment in laryngeal cancer is mainly based on tumor stage, post-treatment morbidity and quality of life. Biological tumor markers might also be of potential clinical relevance. Objective of the review The aim was to systematically review the value of published biological tumor markers to predict local control in laryngeal cancer patients treated with definitive radiotherapy. Type of Review Systematic review. Search strategy PubMed, Embase, Cochrane Library. Evaluation Method A literature search was performed using multiple terms for laryngeal cancer, radiotherapy, biological markers, detection methods and local control or survival. Studies regarding the relation between biological tumor markers and local control or survival in laryngeal cancer patients primarily treated with radiotherapy were included. Markers were clustered on biological function. Quality of all studies was assessed. Study selection, data extraction and quality assessment was performed by two independent reviewers. Results A total of 52 studies out of 618 manuscripts, concerning 118 markers, were included. EGFR and P53 showed consistent evidence for not being predictive of local control after primary radiotherapy, whereas proliferation markers (ie high Ki-67 expression) showed some, but no consistent, evidence for being predictive of better local control. Other clusters of markers (markers involved in angiogenesis and hypoxia, apoptosis markers, cell cycle, COX-2 and DNA characteristics) showed no consistent evidence towards being predictors of local control after primary radiotherapy. Conclusions Cell proliferation could be of potential interest for predicting local control after primary radiotherapy in laryngeal cancer patients, whereas EGFR and p53 are not predictive in contrast to some previous analyses. Large diversity in research methods is found between studies, which results in contradictory outcomes. Future studies need to be more standardised and well described according to the REMARK criteria in order to have better insight into which biomarkers can be used as predictors of local control after primary radiotherapy