Impact of age on breast cancer mortality and competing causes of death at 10 years follow-up in the adjuvant TEAM trial.

AIM: Due to increasing life expectancy, patients with breast cancer remain at risk of dying due to breast cancer over a long time. This study aims to assess the impact of age on breast cancer mortality and other cause mortality 10 years after diagnosis. METHODS: Postmenopausal patients with hormone-receptor positive breast cancer were included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. Age at diagnosis was categorised as <65 years (n = 3369), 65-74 years (n = 1896) and ≥75 years (n = 854). Breast cancer mortality was assessed considering other cause mortality as competing event using competing risk analysis. RESULTS: After a median follow-up of 9.8 years (interquartile range 8.0-10.3), cumulative incidence of breast cancer mortality increased with increasing age (age <65 years, 11.7% [95% confidence interval {CI}: 10.2-13.2]; 65-74 years, 12.7% (11.2-14.2) and ≥75 years, 15.6% (13.1-18.0)). Univariate subdistribution hazard ratio (sHR) increased with increasing age (age: 65-74 years, sHR: 1.08, 95% CI: 0.92-1.27 and ≥75 years sHR: 1.30, 95% CI: 1.06-1.58, P = 0.013). Multivariable sHR adjusted for tumour and treatment characteristics increased with age but did not reach significance (age 65-74 years, sHR: 1.11, 95% CI: 0.94-1.31; ≥75 years, sHR: 1.18, 95% CI: 0.94-1.48, P = 0.055). CONCLUSION: Ten years after diagnosis, older age at diagnosis is associated with increasing breast cancer mortality in univariate analysis, but it did not reach significance in multivariable analysis. This is not outweighed by a substantially higher other cause mortality with older age. This underlines the need to improve the balance between undertreatment and overtreatment in older patients with breast cancer. The trial was registered in International Trial Databases (ClinicalTrials.govNCT00279448, NCT00032136, and NCT00036270; the Netherlands Trial Registry NTR267).

Primary Endocrine Therapy in Older Women with Breast Cancer.

PURPOSE OF REVIEW: Breast cancer incidence increases with age. In recent years, primary endocrine therapy has been increasingly used as a treatment option for frail elderly women with breast cancer, although surgery is still the guideline-recommended treatment. In this review, we discuss the evidence for primary endocrine therapy versus surgical treatment in older women with early breast cancer. RECENT FINDINGS: Both randomised controlled trials and recent observational studies showed a favourable progression-free survival but not overall survival for surgery plus adjuvant endocrine therapy versus primary endocrine therapy. Information about quality of life with either treatment strategy is so far lacking. Deciding who is fit for surgery and has sufficiently long life expectation to be at risk of disease progression can be supported by performing an individual geriatric assessment. SUMMARY: This review suggests that primary endocrine therapy is a reasonable alternative to primary surgery in frail older women with breast cancer. Future studies should focus on the long-term effects on quality of life and physical functioning.

Lanthanide-based laser-induced phosphorescence for spray diagnostics.

Laser-induced phosphorescence (LIP) is a relatively recent and versatile development for studying flow dynamics. This work investigates certain lanthanide-based molecular complexes for their use in LIP for high-speed sprays. Lanthanide complexes in solutions have been shown to possess long phosphorescence lifetimes (∼1-2 ms) and to emit light in the visible wavelength range. In particular, europium and terbium complexes are investigated using fluorescence/phosphorescence spectrometry, showing that europium-thenoyltrifluoracetone-trioctylphosphineoxide (Eu-TTA-TOPO) can be easily and efficiently excited using a standard frequency-tripled Nd:YAG laser. The emitted spectrum, with maximum intensity at a wavelength of 614 nm, is shown not to vary strongly with temperature (293-383 K). The decay constant of the phosphorescence, while independent of ambient pressure, decreases by approximately 12 µs/K between 323 and 373 K, with the base level of the decay constant dependent on the used solvent. The complex does not luminesce in the gas or solid state, meaning only the liquid phase is visualized, even in an evaporating spray. By using an internally excited spray containing the phosphorescent complex, the effect of vaporization is shown through the decrease in measured intensity over the length of the spray, together with droplet size measurements using interferometric particle imaging. This study shows that LIP, using the Eu-TTA-TOPO complex, can be used with different solvents, including diesel surrogates. Furthermore, it can be easily handled and used in sprays to investigate spray breakup and evaporation.

Rayleigh-Brillouin Scattering in Binary-Gas Mixtures.

Precise measurements are performed on spectral line shapes of spontaneous Rayleigh-Brillouin scattering in mixtures of the noble gases Ar and Kr, with He. Admixture of a light He atomic fraction results in marked changes of the spectra, although in all experiments He is merely a spectator atom: it affects the relaxation of density fluctuations of the heavy constituent, but its contribution to the scattered light intensity is negligibly small. The results are compared to a theory for the spectral line shape without adjustable parameters, yielding excellent agreement for the case of binary monatomic gases, signifying a step towards modeling and understanding of light scattering in more complex molecular media.

Contralateral breast cancer risk in relation to tumor morphology and age-in which patients is preoperative MRI justified?

Identification of patients who are at increased risk for contralateral breast cancer is essential to determine which patients should be routinely screened for contralateral breast cancer using MRI. The aim of this study was to assess the association of age and tumor morphology with contralateral breast cancer incidence in a large, nationwide population-based study in the Netherlands. All patients with breast cancer stage I-III, diagnosed between 1989 and 2009, were selected from the Netherlands Cancer Registry. The association between contralateral breast cancer risk with tumor morphology and age was assessed using competing-risk regression according to Fine & Gray. Overall, 194,898 patients were included. In multivariable analyses, lobular tumors were significantly associated with an increased risk of contralateral breast cancer within 6 months (cumulative incidence 1.9 %, subdistribution hazard ratio (SHR) 1.17, 95 % confidence interval (CI) 1.06-1.30 compared with 1.3 % in ductal tumors, p = 0.002). Age was also associated with an increased risk of contralateral breast cancer within 6 months (SHR 2.34, 95 % CI 2.08-2.62, p < 0.002 for patients over the age of 75 as compared to patients younger than 50 years). The absolute risk of contralateral breast cancer within 6 months is only slightly increased in patients with a lobular tumor and older patients. In our view, this small increased risk does not justify standard use of preoperative MRI based on tumor morphology or age alone. We propose a more personalized strategy in which additional risk factors (family history, prognosis of primary tumor, and others) may play a role.

Rayleigh-Brillouin scattering of carbon dioxide.

The spectral line shape of spontaneous Rayleigh-Brillouin scattering in CO2 is studied in a range of pressures. The spectrum is influenced by the bulk viscosity η(b), which is a relaxation phenomenon involving the internal degrees of freedom of the molecule. The associated relaxation rates can be compared to the frequency shift of the scattered light, which demands precise measurements of the spectral line shape. We find η(b)=(5.7±0.6)×10(-6) kg m(-1) s(-1) for the range of pressures p=2-4 bar and for room temperature conditions.

Diabetes in relation to breast cancer relapse and all-cause mortality in elderly breast cancer patients: a FOCUS study analysis.

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.

Postoperative complications and survival of elderly breast cancer patients: a FOCUS study analysis.

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.

Molecular tagging velocimetry in turbulence using biacetyl.

We evaluate various molecular tagging velocimetry (MTV) techniques for application in turbulent flows of gases where the smallest length scales must be resolved. We argue that tracer diffusion dictates the use of large complex molecules and discuss a few candidate molecules. The accuracy of MTV is determined by the profile of written lines which widen due to molecular dynamics, including both diffusion and chemical reaction. We evaluate these profiles for tagging with phosphorescing biacetyl molecules, which is a commonly used probe in MTV. For relatively large laser power, these profiles are determined not by molecular diffusion, but by the triplet-triplet annihilation reaction of excited biacetyl molecules. We identify a new reaction pathway, and present a model for the observed line shapes. The rapid widening of tagged lines of biacetyl molecules due to chemical reaction restricts this MTV technique to large-scale turbulent motion in gases of comparable molecular weight.

Adherence to treatment guidelines and survival in patients with early-stage breast cancer by age at diagnosis.

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.

Surgery in metastatic breast cancer: patients with a favorable profile seem to have the most benefit from surgery.

INTRODUCTION: About 3-10% of breast cancer patients have distant metastases (Stage IV) at initial presentation; standard treatment (in the Netherlands) of these patients consists of palliative systemic therapy. However, retrospective studies have shown an improved survival in patients who received surgery for their primary tumor. The aim of this study was to assess characteristics associated with surgical treatment and to determine the impact on survival in women with stage IV breast cancer. METHODS: A cohort of women with a diagnosis of breast cancer and concomitant distant metastases was retrospectively studied. Patient characteristics, treatment and survival distilled from medical files were evaluated using univariate and multivariable analysis. RESULTS: Of 171 patients included in this analysis, 59 underwent surgery. In multivariable analysis lower age, no medication use, lower clinical T-stage and lower grade were associated with receiving surgery. In 21 of the 59 patients (35%) who received surgery it was unknown at the time of surgery that the patient had metastatic disease. Stratified survival analyses showed an association between surgery and improved survival for young patients (HR 0.3; p = 0.02), without comorbidity (HR 0.4; p = 0.002), with no medication use (HR 0.5; p = 0.009), with a small tumor (HR 0.4; p = 0.01), no regional lymph node involvement (HR 0.4; p = 0.01), with positive Estrogen (HR 0.6; p = 0.02) or Progesterone receptor (HR 0.4; p = 0.03) and with only visceral metastases (HR 0.5; p = 0.03). In multivariable analyses, younger patients and patients without comorbidity that received surgery had an increased survival (HR 0.3; p = 0.03 and HR 0.5; p = 0.03, respectively). CONCLUSION: This study showed that patients with the most favorable profile receive local surgery and that a survival gain for operated patients was seen in young patients and in patients without comorbidity.

Surgical treatment of early stage breast cancer in elderly: an international comparison.

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.

Spectral narrowing in coherent Rayleigh-Brillouin scattering.

Coherent Rayleigh-Brillouin scattering is a four-wave mixing technique that provides information on various physical properties of the scattering medium in the spectral domain. Being based on density gratings generated by dipole forces, the method requires two pump beams of sufficient spectral width to span the full response bandwidth of the scattering medium. We provide experimental data on the scattered spectrum as a function of the coherence between the two pump beams and derive the corresponding pump beam spectrum. We argue that all experiments on coherent Rayleigh-Brillouin scattering to date, have, in fact, been performed in the incoherent regime and show that orders of magnitude in scattering efficiency are to be expected when the experiments are performed with bandwidth-limited picosecond laser pulses.

Coherent Rayleigh-Brillouin scattering measurements of bulk viscosity of polar and nonpolar gases, and kinetic theory.

We investigate coherent Rayleigh-Brillouin spectroscopy as an efficient process to measure the bulk viscosity of gases at gigahertz frequencies. Scattered spectral distributions are measured using a Fizeau spectrometer. We discuss the statistical error due to the fluctuating mode structure of the used pump laser. Experiments were done for both polar and nonpolar gases and the bulk viscosity was obtained from the spectra using the Tenti S6 model. Results are compared to simple classical kinetic models of molecules with internal degrees of freedom. At the extremely high (gigahertz) frequencies of our experiment, most internal vibrational modes remain frozen and the bulk viscosity is dominated by the rotational degrees of freedom. Our measurements show that the molecular dipole moments have unexpectedly little influence on the bulk viscosity at room temperature and moderate pressure.

Breast cancer in elderly compared to younger patients in the Netherlands: stage at diagnosis, treatment and survival in 127,805 unselected patients.

Breast cancer is the most common type of cancer in several parts of the world and the number of elderly patients is increasing. The aim of this study was to describe stage at diagnosis, treatment, and relative survival of elderly patients compared to younger patients in the Netherlands. Adult female patients with their first primary breast cancer diagnosed between 1995 and 2005 were selected. Stage, treatment, and relative survival were described for young and elderly (≥ 65 years) patients and within the cohort of elderly patients according to 5-year age groups. Overall, 127,805 patients were included. Elderly breast cancer patients were diagnosed with a higher stage of disease. Moreover, within the elderly differences in stage were observed. Elderly underwent less surgery (99.2-41.2%); elderly received hormonal treatment as monotherapy more frequently (0.8-47.3%); and less adjuvant systemic treatment (79-53%). Elderly breast cancer patients with breast cancer had a decreased relative survival. Although relative survival was lower in the elderly, the percentage of patients who die of their breast cancer less than 50% above age 75. In conclusion, the relative survival for the elderly is lower as compared to their younger counterparts while the percentage of deaths due to other causes increases with age. This could indicate that the patient selection is poor and fit patients could suffer from "under treatment". In the future, specific geriatric screening tools are necessary to identify fit elderly patients who could receive more "aggressive" treatment while best supportive care should be given to frail elderly patients.

Failure of chaos control

We study the control of chaos in an experiment on a parametrically excited pendulum whose excitation mechanism is not perfect. This imperfection leads to a weakly excited degree of freedom with an associated small eigenvalue. Although the state of the pendulum could be characterized well and although the perturbation is weak, we fail to control chaos. From a numerical model we learn that the small eigenvalue cannot be ignored when attempting control. However, the estimate of this eigenvalue from an (experimental) time series is elusive. The reason is that points in an experimental time series are distributed according to the natural measure. It is this extremely uneven distribution of points that thwarts attempts to measure eigenvalues that are very different. Another consequence of the phase-space distribution of points for control is the occurrence of logarithmic-oscillations in the waiting time before control can be attempted. We come to the conclusion that chaos needs to be destroyed before the information needed for its control can be obtained.

Grazing impact oscillations

An impact oscillator is a periodically driven system that hits a wall when its amplitude exceeds a critical value. We study impact oscillations where collisions with the wall are with near-zero velocity (grazing impacts). A characteristic feature of grazing impact dynamics is a geometrically converging series of transitions from a nonimpacting period-1 orbit to period-M orbits that impact once per period with M=1,2,ellipsis. In an experiment we explore the dynamics in the vicinity of these period-adding transitions. The experiment is a mechanical impact oscillator with a precisely controlled driving strength. Although the excitation of many high-order harmonics in the experiment appeared unavoidable, we characterize it with only three parameters. Despite the simplicity of this description, good agreement with numerical simulations of an impacting harmonic oscillator was found. Grazing impact dynamics can be described by mappings that have a square-root singularity. We evaluate several mappings, both for instantaneous impacts and for impacts that involve soft collisions with a yielding wall. As the square-root singularity appears persistent in the reduction of the dynamics to mappings, and because impact dynamics appears insensitive to experimental nonidealities, the characteristic bifurcation scenario should be observed in a wide class of experimental systems.