Comparison of Adjuvant Therapies Using Quality-Of-Life Considerations

The benefit for patients with operable breast cancer treated with adjuvant systemic therapy is small, if reduction of early mortality within the context of randomized control trials is used for treatment comparison. One might consider that the 75%-85% of patients who die despite treatment are overtreated, as are patients who remain alive even without therapy within a given time frame. Larger treatment benefits in terms of avoided or delayed breast cancer relapse have been demonstrated even at early phases of follow-up in the vast majority of adjuvant trials. Exposure of all patients to adjuvant therapy at a time at which no symptoms of disease are present is detrimental in terms of quality of life. Based on our assumption that the quality of life of the patient is typically altered both by subjective toxic effects of adjuvant treatment and by the appearance of relapse, we developed a method of comparing treatment effects in terms of time without symptoms of disease and toxicity of treatment (TWiST). Because the impact of treatment on relapse rates appears earlier than survival effects in all adjuvant therapy trials, and because the value of time without relapse in terms of the quality of life of the patients is as yet poorly defined, we have generalized our method of comparing treatment attitudes to include individual qualitative judgment values. The experience gained from integrating quality-of-life issues into clinical trials for breast cancer might also be applied to other diseases characterized by a chronic course, toxic treatments, and gains in periods of relative or absolute freedom from toxic effects and progressive diseas

Impact of high-energy tails on granular gas properties

The velocity distribution function of granular gases in the homogeneous cooling state as well as some heated granular gases decays for large velocities as $f\propto\exp(- {\rm const.} v)$. That is, its high-energy tail is overpopulated as compared with the Maxwell distribution. At the present time, there is no theory to describe the influence of the tail on the kinetic characteristics of granular gases. We develop an approach to quantify the overpopulated tail and analyze its impact on granular gas properties, in particular on the cooling coefficient. We observe and explain anomalously slow relaxation of the velocity distribution function to its steady state.Comment: 5 pages, 5 figure

Scale separation in granular packings: stress plateaus and fluctuations

It is demonstrated, by numerical simulations of a 2D assembly of polydisperse disks, that there exists a range (plateau) of coarse graining scales for which the stress tensor field in a granular solid is nearly resolution independent, thereby enabling an `objective' definition of this field. Expectedly, it is not the mere size of the the system but the (related) magnitudes of the gradients that determine the widths of the plateaus. Ensemble averaging (even over `small' ensembles) extends the widths of the plateaus to sub-particle scales. The fluctuations within the ensemble are studied as well. Both the response to homogeneous forcing and to an external compressive localized load (and gravity) are studied. Implications to small solid systems and constitutive relations are briefly discussed.Comment: 4 pages, 4 figures, RevTeX 4, Minor corrections to match the published versio

New treatments for breast cancer: Breakthroughs for patient care or just steps in the right direction?

Three areas of clinical research in breast cancer treatment led to news breaking presentations at the American Society of Clinical Oncology (ASCO) meeting, 1998, in Los Angeles. All three subjects represent important advances in cancer medicine. Prevention: Two related drugs, tamoxifen and raloxifene, were found in placebo controlled trials to significantly reduce the incidence of breast cancer for women at increased risk of developing the disease. Patterns of relapse showed that the reduced rate of breast cancer was exclusively observed for tumors expressing estrogen receptors, while the rate of tumors classified as estrogen-receptor negative was similar for the treatment and the control groups. This may indicate that the observed reduction in breast cancer incidence is due to a treatment effect on occult disease rather than its prevention. We certainly have no adequate information on mortality prevention. Adjuvant therapies: Taxol given every three weeks for four courses following an adjuvant treatment with four courses of doxorubicin and cyclophosphamide (AC) combination was found to be superior to not adding treatment after the four courses of AC in a trial involving 3170 patients. At 22 months of median follow-up, the quoted P-values were P = 0.0077 for disease-free survival and P = 0.039 for overall survival, but these did not cross the prospectively defined interim analysis boundaries for statistical significance at the 0.05 level. The difference was observed early during follow-up, and was exclusively seen in the 40% of patients who had ER-negative primaries and, therefore, did not receive tamoxifen following chemotherapy. One may thus argue that the early difference observed was primarily due to differences in the duration of the treatment regimens in the two groups and the early entry into the trial of patients with particularly aggressive neoplasia (e.g., ER-negative primaries) who would have benefited from a longer duration treatment. Treatment of advanced disease: The use of monoclonal antibodies to c-erb-B2 was found to induce responses in metastatic breast cancer. Patients with tumors expressing c-erb-B2 responded to weekly infusions of this biological agent. It was particularly impressive that the response rate for patients receiving infusion of the monoclonal antibodies together with the cytotoxics was superior to that with chemotherapy alone in a randomized trial. It is important to note that only patients with tumors overexpressing c-erbB-2 (the overall incidence is about 20%) were tested. It must still be demonstrated that the effect of these monoclonal antibodies is indeed confined to cells overexpressing c-erbB-2. Treatment related cardiac tox-icity remains a problem, and the effects of treatment in various subsets of patients need to be defined before starting investigations in the adjuvant setting, which is a clear further objective of this specific research. The significant findings from clinical research opened several new questions, which must be answered before allowing them to be employed in routine patient car

Systemic treatments for women with breast cancer: outcome with relation to screening for the disease

Early detection and proper care of breast cancer are currently the best available approaches to the treatment of patients with the disease. In countries with a breast cancer screening programme, there has been a demonstrated reduction in breast cancer-related mortality. Such reduction has also been observed in Switzerland, a country in which no national programme of screening is available. Although there is no doubt that early diagnosis might have had a major role in reducing breast cancer mortality the magnitude of this effect is unknown. Research with tailored approaches on alternative imaging for early detection of breast cancer in high-risk women and on treatments offered according to proper criteria of responsiveness to therapies is warrante

Inherent Rheology of a Granular Fluid in Uniform Shear Flow

In contrast to normal fluids, a granular fluid under shear supports a steady state with uniform temperature and density since the collisional cooling can compensate locally for viscous heating. It is shown that the hydrodynamic description of this steady state is inherently non-Newtonian. As a consequence, the Newtonian shear viscosity cannot be determined from experiments or simulation of uniform shear flow. For a given degree of inelasticity, the complete nonlinear dependence of the shear viscosity on the shear rate requires the analysis of the unsteady hydrodynamic behavior. The relationship to the Chapman-Enskog method to derive hydrodynamics is clarified using an approximate Grad's solution of the Boltzmann kinetic equationComment: 10 pages, 4 figures; substantially enlarged version; to be published in PR

Local Equation of State and Velocity Distributions of a Driven Granular Gas

We present event-driven simulations of a granular gas of inelastic hard disks with incomplete normal restitution in two dimensions between vibrating walls (without gravity). We measure hydrodynamic quantities such as the stress tensor, density and temperature profiles, as well as velocity distributions. Relating the local pressure to the local temperature and local density, we construct a local constitutive equation. For strong inelasticities the local constitutive relation depends on global system parameters, like the volume fraction and the aspect ratio. For moderate inelasticities the constitutive relation is approximately independent of the system parameters and can hence be regarded as a local equation of state, even though the system is highly inhomogeneous with heterogeneous temperature and density profiles arising as a consequence of the energy injection. Concerning the local velocity distributions we find that they do not scale with the square root of the local granular temperature. Moreover the high-velocity tails are different for the distribution of the x- and the y-component of the velocity, and even depend on the position in the sample, the global volume fraction, and the coefficient of restitution.Comment: 14 pages, 14 figures of which Figs. 13a-f and Fig. 14 are archived as separate .gif files due to upload-size limitations. A version of the paper including all figures in better quality can be downloaded at http://www.theorie.physik.uni-goettingen.de/~herbst/download/LocEqSt.ps.gz (3.8 MB, ps.gz) or at http://www.theorie.physik.uni-goettingen.de/~herbst/download/LocEqSt.pdf (4.9 MB, pdf

The dissipative linear Boltzmann equation for hard spheres

We prove the existence and uniqueness of an equilibrium state with unit mass to the dissipative linear Boltzmann equation with hard--spheres collision kernel describing inelastic interactions of a gas particles with a fixed background. The equilibrium state is a universal Maxwellian distribution function with the same velocity as field particles and with a non--zero temperature lower than the background one, which depends on the details of the binary collision. Thanks to the H--theorem we then prove strong convergence of the solution to the Boltzmann equation towards the equilibrium.Comment: 17 pages, submitted to Journal of Statistical Physic

Fluctuation-Dissipation relations in Driven Granular Gases

We study the dynamics of a 2d driven inelastic gas, by means of Direct Simulation Monte Carlo (DSMC) techniques, i.e. under the assumption of Molecular Chaos. Under the effect of a uniform stochastic driving in the form of a white noise plus a friction term, the gas is kept in a non-equilibrium Steady State characterized by fractal density correlations and non-Gaussian distributions of velocities; the mean squared velocity, that is the so-called {\em granular temperature}, is lower than the bath temperature. We observe that a modified form of the Kubo relation, which relates the autocorrelation and the linear response for the dynamics of a system {\em at equilibrium}, still holds for the off-equilibrium, though stationary, dynamics of the systems under investigation. Interestingly, the only needed modification to the equilibrium Kubo relation is the replacement of the equilibrium temperature with an effective temperature, which results equal to the global granular temperature. We present two independent numerical experiment, i.e. two different observables are studied: (a) the staggered density current, whose response to an impulsive shear is proportional to its autocorrelation in the unperturbed system and (b) the response of a tracer to a small constant force, switched on at time $t_w$, which is proportional to the mean-square displacement in the unperturbed system. Both measures confirm the validity of Kubo's formula, provided that the granular temperature is used as the proportionality factor between response and autocorrelation, at least for not too large inelasticities.Comment: 11 pages, 7 figures, submitted for publicatio