Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib.

Dasatinib, a potent inhibitor of BCR-ABL in vitro, is effective for patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib. To provide a more definitive assessment of dasatinib in chronic-phase (CP)-CML, we report extended follow-up of a phase II trial, presenting data for the entire patient cohort (N=387). Dasatinib (70 mg) twice daily was administered to patients with imatinib-resistant or -intolerant CP-CML. With median follow-up of 15.2 months (treatment duration, <1-18.4 months), a complete hematologic response was attained or maintained in 91% of patients. A major cytogenetic response (MCyR) was attained or maintained by 59% (52% imatinib resistant and 80% imatinib intolerant); this was complete in 49% of patients (40% imatinib resistant and 75% imatinib intolerant). Of 230 patients achieving an MCyR, 7 experienced disease progression. Fifteen-month progression-free survival was 90% while overall survival was 96%. Grade 3/4 thrombocytopenia and neutropenia were reported in 48 and 49% of patients, respectively. Non-hematologic toxicity (any grade) consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), dyspnea (30%) and pleural effusion (27%). Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML.

Relation of the leukocyte count to recurrent cardiac events in stable patients after acute myocardial infarction.

Increasing evidence implicates inflammation as a risk factor for coronary artery disease. We determined whether an elevated leukocyte count is associated with an increased risk of death or reinfarction in stable patients with a past acute myocardial infarction (AMI). The current analysis is a substudy of the Multicenter Diltiazem Postinfarction Trial, which investigated the effect of diltiazem on mortality and reinfarction in 2,466 patients hospitalized for AMI. We included 1,294 patients in whom a leukocyte count was obtained 6 months after the index AMI. The composite end point of reinfarction or death was used as the primary end point of the study and reinfarction or cardiac death was used as a secondary end point. The study population was divided into 4 quartiles (Q1, Q2, Q3, and Q4) based on the leukocyte count. During a mean follow-up period of 25 months, 163 patients reached the primary end point: 8.7%, 10.9%, 14.0%, and 16.7%, in Q1, Q2, Q3, and, Q4 respectively (p = 0.01). After adjusting for potential covariates, Cox proportional-hazards analysis revealed that an increased leukocyte count was associated with an increased risk of both the primary end point (hazard ratio/1 quartile increase in leukocyte count, 1.26; p = 0.003; 95% confidence interval 1.08 to 1.47) and secondary end point (hazard ratio, 1.18/1-quartile increase; p = 0.05; 95% confidence interval 1.00 to 1.40). In conclusion, an increased leukocyte count measured in the stable post-AMI period is associated with an increased risk of cardiac events. These findings indicate that the leukocyte count may be another marker of an atherosclerotic inflammatory process that contributes to cardiac events in postinfarction patients.

Adhesion Probability of Colloidal Particles with Repulsive Soft Interaction.

Computer simulations of the irreversible adhesion of charged colloidal particles at a solid/liquid interface are performed to determine whether the distribution of particles in the vicinity of a preadsorbed (also charged) one follows the Boltzmann law applied to an a priori uniform adhesion probability, as first assumed by Adamczyk et al. (J. Colloid Interface Sci. 140, 123 (1990)). If true, this would indicate that the whole information on the deposition process is contained in the potential energy distribution on the adsorbing surface. In general, diffusion in a field of force and the irreversibility of the process induce significant deviations from the Boltzmann-weighted uniform adhesion density. Nevertheless, it is shown that for particles characterized by a small gravitational energy this procedure leads to a reasonable first approximation of the distribution of the particles over the adsorbing surface. This observation thus demonstrates the validity of Adamczyk's assumption and extends its range of applicability to the case of a weak gravitational field. Copyright 1999 Academic Press.

Influence of diffusion and gravity on the adhesion of a two-component mixture of hard spheres on a flat surface.

The adhesion of hard spheres, modeling particles of biological interest (proteins, bacteria, cells), on flat surfaces is investigated by means of Monte Carlo simulations. These computations include the Brownian diffusion of the particles in the bulk fluid, as well as the systematic displacement due to the gravitational field. The size of the particles influences directly both diffusion coefficient and net weight, with the consequence that the coverage at the jamming limit depends on this parameter. Results obtained in a former paper based on a lattice model are confirmed by the present continuous space model. In order to gain a better understanding of the adsorption competition of two types of particles, the proposed model is applied to the case of binary mixtures of spheres. For polydispersed suspensions, various parameters determine the final coverage, as well as the distribution of the small and large particles on the surface: the radii of the particles and the respective proportions of them in the infinitely large reservoir from which they are randomly selected. In this way, it is shown that the chronology of the adhesion of the small and large particles strongly influences the final number of each type of spheres fixed on the surface. Qualitatively, the present results resemble those obtained with disks placed by means of a classical random sequential adsorption mechanisms. Quantitatively, however, the number densities and coverage values determined in this way are significantly different due to the inclusion of the gravity and of the diffusion in the model.