No association found between CYP2D6 genotype and early breast cancer events in tamoxifen-treated patients.

Background. CYP2D6 is considered the key enzyme in tamoxifen metabolism. Several studies have investigated the relationship between the CYP2D6 genotype and tamoxifen treatment outcome, with discrepant results. CYP2D6 inhibitor use, aromatase inhibitor use, and chemotherapy may account for some of the discrepancies. We examined the association between CYP2D6 genotype and early breast cancer events in tamoxifen-treated breast cancer patients, in relation to CYP2D6 inhibitor use, aromatase inhibitor use, and chemotherapy. Material and methods. Pre- and postoperative questionnaires on lifestyle and concomitant medications were completed by 634 primary breast cancer patients between 2002 and 2008, among whom 333 patients had ER-positive tumors and received tamoxifen. CYP2D6*3, *4, *6, *10 and *41 were genotyped. Information on clinical data, breast cancer events, and tumor characteristics was obtained from patients' charts, population registries, the Regional Tumor Registry, and pathology reports. Results. Median follow-up was 4.9 years. Neither poor metabolizers (adjusted HR 0.50; 95% CI 0.07-3.82) nor intermediate metabolizers (adjusted HR 1.00; 95% CI 0.47-2.11) had an increased risk of early breast cancer events when compared with extensive metabolizers. CYP2D6 activity score (taking into account genotype and CYP2D6 inhibitor use) was not associated with early breast cancer events (LogRank, Ptrend = 0.44). Conclusions. CYP2D6 genotype was not associated with tamoxifen treatment outcome, even when CYP2D6 inhibitor use, aromatase inhibitor use, or chemotherapy was taken into account. CYP2D6 genotype may be of minor importance for tamoxifen-treated patients in Scandinavia

Økonomistyrings kobling til Corporate Governance: en ny udvikling?

Økonomistyring er i dag en identifikation, måling, akkumulering, analyse, forberedelse, oversættelse og kommunikation af information, der er finansiel, og operationelt anvendes af ledelsen til at planlægge, styre samt evaluere virksomheden. Dermed søges sikret, at ressourcer opgøres korrekt i regnskabet. Ligeledes er det økonomistyringens opgave at forberede sammenstillingen af finansielle rapporter til ekstern rapportering. Økonomistyring bliver leverandør af information med formål at understøtte formuleringen af virksomhedens strategi. Det giver et indtryk af en intention om en øget forståelse og kobling mellem økonomistyring og strategi. Dermed tager økonomistyring afsæt i information, som er relevant for ”Corporate Governance”, og således bliver ”Corporate Governance” et nyt begreb i økonomistyringsfeltet, der synes at medvirke til diffusion heraf. Begrebet er en tilnærmelse eller fællesbetegnelse for principper, der synes vanskelige at oversætte. Dette forsøges netop gennemført i denne artikel

Given breast cancer, is fat better than thin? Impact of the estrogen receptor beta gene polymorphisms.

The role of estrogen receptor beta (ERβ) in breast cancer has been investigated since its identification in 1996. Studies based on protein expression have indicated that ERβ is a favorable prognostic marker. Further, ERβ expression is lower in obese breast cancer patients. Fewer studies have focused on the prognostic impact of ERβ polymorphisms. Therefore, we analyzed the associations between four previously identified haplotype tagging single nucleotide polymorphisms (htSNPs), associated haplo- and diplotypes, and breast cancer-free survival according to body constitution. The patient cohort included 634 women from the prospective breast cancer and blood study (BC Blood study, Sweden) with a median follow-up of 4.92 years. Four htSNPs (i.e., rs4986938, rs1256049, rs1256031, rs3020450) in the ESR2 gene and the correlating haplo- and diplotypes were analyzed and correlated to selected patient and tumor characteristics and to disease-free survival, including stratification for BMI. Based on the four htSNPs, seven haplotypes and eight diplotypes were identified. The patient and tumor characteristics were well-balanced across all geno- and haplotypes. Disease-free survival differed according to rs4986938 and rs1256031 (Log-Rank P = 0.045 and P = 0.041, respectively) and the number of haplotype copies of the wildtype CCGC and TCAC (Log-Rank P = 0.027 and P = 0.038, respectively). In the survival analyses stratified for BMI, significant survival differences between alleles were observed among overweight women (rs4986938 and rs1256031 with Log-Rank P = 0.001 and P = 0.001, respectively). The BMI-stratified survival analyses based on haplotypes showed shorter disease-free survival for overweight women with null copies of CCGC (Log-Rank P = 0.001) and for overweight women with any TCAC copy (Log-Rank P < 0.0001). Markedly impaired disease-free survival was found for genotypes in two out of four ESR2 htSNPs and for two haplotypes. ESR2 polymorphisms seem to divide patients into good and poor survivors based on BMI, stressing the need of taking host factors into consideration in the evaluation of prognostic markers

Androgen receptor genotypes predict response to endocrine treatment in breast cancer patients.

Background:The androgen receptor (AR) is frequently expressed in breast cancers. The AR genotype may affect disease-free survival and response to endocrine therapy.Methods:In all, 634 women undergoing breast cancer surgery between 2002 and 2008 were followed until 30 June 2010. Six haplotype-tagging single-nucleotide polymorphisms in the AR, and the resulting AR diplotypes, were examined in relation to breast cancer patient characteristics, tumour characteristics, disease-free survival, and response to endocrine treatment.Results:Five common AR diplotypes were found. Seventeen rare variants were combined into a composite group. The resulting six AR diplotype groups were clustered into two subgroups, groups A (n=128) and B (n=499), with three diplotypes in each. Patients in group B had larger total breast volume (P=0.024), higher body mass index (BMI) (P=0.050), more axillary lymph node involvement (P(trend)=0.020), and higher histological grade (P(trend)=0.031). There were 59 breast cancer events in the 569 patients with invasive cancers and no preoperative treatment. Patients in group B also had shorter disease-free survival (P=0.037) than patients in group A. Among patients in group B with oestrogen receptor α positive tumours, tamoxifen (TAM) treatment was associated with longer disease-free survival (P=0.008), while treatment with aromatase inhibitors (AIs) was not (P=0.94). Response to endocrine treatment could not be predicted based on BMI, suggesting that the effect of AR diplotypes went beyond that of a higher BMI.Conclusion:A marker for a group of patients who responded to TAM, but not to AIs, was identified. If this finding is confirmed, AR genotyping may provide useful information for selection of endocrine treatment of breast cancer patients.British Journal of Cancer advance online publication, 27 October 2011; doi:10.1038/bjc.2011.441 www.bjcancer.com

Methacholine challenge – Comparison of an ATS protocol to a new rapid single concentration technique

SummaryBronchial methacholine challenge is well established in asthma diagnostics and research. ATS guidelines propose a five step standard dosimeter (SDM) protocol with incremental concentrations of methacholine to calculate the concentration causing a 20% drop in FEV1 in an individual (PC20FEV1). In contrast, the aerosol provocation system (APS) by Viasys® automatically determines the administered dose of methacholine by measuring the effective nebulisation time and referring it to drug concentration and nebuliser power. Therefore, it offers a feasible and less time-consuming provocation procedure by applying incremental doses (PD20) of methacholine using a single concentration (16mg/mL methacholine, APS-SC). In this study we compared these two methods in 52 young adults (25±5.8 years). Following a screening visit, subjects were randomly assigned to undergo either SDM or APS-SC followed by the other method within 1 week. A close correlation between concentration and dosage causing a 20% fall of FEV1 was found (r=0.69, p<0.001).Using the ATS categorisation of bronchial responsiveness we interpreted the results of the APS-SC method as follows: PD20 methacholine<0.3mg as “moderate to severe BHR”, 0.3 – 0.6mg as “mild BHR”, 0.6 – 1.0mg as “borderline BHR”, and>1.0mg as “normal bronchial response”.We conclude that the five-step APS-SC is a suitable method, providing reliable results. In clinical practice the APS-SC is a timesaving procedure and less prone to errors since only one dilution of methacholine is necessary compared to the SDM

Excessive milk production during breast-feeding prior to breast cancer diagnosis is associated with increased risk for early events

Breast-feeding is a known protective factor against breast cancer. Breast-feeding duration is influenced by hormone levels, milk production, and lifestyle factors. The aims were to investigate how breast-feeding duration and milk production affected tumor characteristics and risk for early breast cancer events in primary breast cancer patients. Between 2002 and 2008, 634 breast cancer patients in Lund, Sweden, took part in an ongoing prospective cohort study. Data were extracted from questionnaires, pathology reports, and patients’ charts from 592 patients without preoperative treatment. Breast-feeding duration ≤12 months of the first child was associated with higher frequency of ER+/PgR+ tumors (P=0.02). Median follow-up time was 4.9 years. Higher risk for early events was observed for breast-feeding duration of first child >12 months (LogRank P=0.001), total breast-feeding duration >12 months (LogRank P=0.008), as well as ‘excessive milk production’ during breast-feeding of the first child (LogRank P=0.001). Patients with ‘almost no milk production’ had no events. In a multivariable model including both ‘excessive milk production’ and breast-feeding duration of the first child >12 months, both were associated with a two-fold risk for early events, adjusted HRs 2.33 (95% CI: 1.25-4.36) and 2.39 (0.97-5.85), respectively, while total breast-feeding duration was not. ‘Excessive milk production’ was associated with a two-fold risk of early distant metastases, adjusted HR 2.59 (1.13-5.94), but not duration. In conclusion, ‘excessive milk production’ during breast-feeding was associated with higher risk for early events independent of tumor characteristics, stressing the need to consider host factors in the evaluation of prognostic markers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2193-1801-2-298) contains supplementary material, which is available to authorized users

Given breast cancer, does breast size matter? Data from a prospective breast cancer cohort.

PURPOSE: Body mass index (BMI), waist-to-hip ratio (WHR), and tumor characteristics affect disease-free survival. Larger breast size may increase breast cancer risk, but its influence on disease-free survival is unclear. The purpose of this study was to elucidate whether breast size independently influenced disease-free survival in breast cancer patients. METHODS: Body measurements were obtained preoperatively from 772 breast cancer patients in a population-based ongoing cohort from southern Sweden. The research nurse measured breast volumes with plastic cups used by plastic surgeons doing breast reductions. Clinical data were obtained from patient charts and pathology reports. RESULTS: Patients with a BMI ≥ 25 kg/m(2) had larger tumors (p 0.85 had larger tumors (p = 0.013), more advanced histological grade (p = 0.0016), and more axillary nodal involvement (p = 0.012). Patients with right + left breast volume ≥ 850 mL were more likely to have larger tumor sizes (p = 0.018), more advanced histological grade (p = 0.031), and more axillary nodal involvement (p = 0.025). There were 62 breast cancer events during the 7-year follow-up. Breast volume ≥ 850 mL was associated with shorter disease-free survival (p = 0.004) and distant metastasis-free survival (p = 0.001) in patients with estrogen receptor (ER)-positive tumors independent of other anthropometric measurements and age. In patients with ER-positive tumors, breast size was an independent predictor of shorter disease-free (HR 3.64; 95 % CI 1.42-9.35) and distant metastasis-free survival (HR 6.33; 95 %CI 1.36-29.43), adjusted for tumor characteristics, BMI, age, and treatment. CONCLUSION: A simple and cheap anthropometric measurement with standardized tools may help identify a subgroup of patients in need of tailored breast cancer therapy

Simulation and experiment of gas diffusion in a granular bed

The diffusion of gas through porous material is important to understand the physical processes underlying cometary activity. We study the diffusion of a rarefied gas (Knudsen regime) through a packed bed of monodisperse spheres via experiments and numerical modelling, providing an absolute value of the diffusion coefficient and compare it to published analytical models. The experiments are designed to be directly comparable to numerical simulations, by using precision steel beads, simple geometries, and a trade-off of the sample size between small boundary effects and efficient computation. For direct comparison, the diffusion coefficient is determined in Direct Simulation Monte Carlo (DSMC) simulations, yielding a good match with experiments. This model is further-on used on a microscopic scale, which cannot be studied in experiments, to determine the mean path of gas molecules and its distribution, and compare it against an analytical model. Scaling with sample properties (particle size, porosity) and gas properties (molecular mass, temperature) is consistent with analytical models. As predicted by these, results are very sensitive on sample porosity and we find that a tortuosity $q(\varepsilon)$ depending linearly on the porosity $\varepsilon$ can well reconcile the analytical model with experiments and simulations. Mean paths of molecules are close to those described in the literature, but their distribution deviates from the expectation for small path lengths. The provided diffusion coefficients and scaling laws are directly applicable to thermophysical models of idealised cometary material.Comment: accepted by MNRA

Tumor-specific expression of HMG-CoA reductase in a population-based cohort of breast cancer patients

The mevalonate pathway synthetizes cholesterol, steroid hormones, and non-steriod isoprenoids necessary for cell survival. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) is the rate-limiting enzyme of the mevalonate pathway and the target for statin treatment. HMGCR expression in breast tumors has recently been proposed to hold prognostic and treatment-predictive information. This study aimed to investigate whether HMGCR expression in breast cancer patients was associated with patient and tumor characteristics and disease-free survival (DFS)

Arctic Ocean Sea Level Record from the Complete Radar Altimetry Era: 1991-2018

In recent years, there has been a large focus on the Arctic due to the rapid changes of the region. Arctic sea level determination is challenging due to the seasonal to permanent sea-ice cover, lack of regional coverage of satellites, satellite instruments ability to measure ice, insufficient geophysical models, residual orbit errors, challenging retracking of satellite altimeter data. We present the European Space Agency (ESA) Climate Change Initiative (CCI) Technical University of Denmark (DTU)/Technischen Universität München (TUM) sea level anomaly (SLA) record based on radar satellite altimetry data in the Arctic Ocean from the European Remote Sensing satellite number 1 (ERS-1) (1991) to CryoSat-2 (2018). We use updated geophysical corrections and a combination of altimeter data: Reprocessing of Altimeter Product for ERS (REAPER) (ERS-1), ALES+ retracker (ERS-2, Envisat), combination of Radar Altimetry Database System (RADS) and DTUs in-house retracker LARS (CryoSat-2). Furthermore, this study focuses on the transition between conventional and Synthetic Aperture Radar (SAR) altimeter data to make a smooth time series regarding the measurement method. We find a sea level rise of 1.54 mm/year from September 1991 to September 2018 with a 95% confidence interval from 1.16 to 1.81 mm/year. ERS-1 data is troublesome and when ignoring this satellite the SLA trend becomes 2.22 mm/year with a 95% confidence interval within 1.67–2.54 mm/year. Evaluating the SLA trends in 5 year intervals show a clear steepening of the SLA trend around 2004. The sea level anomaly record is validated against tide gauges and show good results. Additionally, the time series is split and evaluated in space and time