Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2.

BackgroundIn the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study.Patients and methodsPatients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations.ResultsThe safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%).ConclusionsMost EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education.Trial registration numberNCT00863655

Predicting the Distribution of Spiral Waves from Cell Properties in a Developmental-Path Model of Dictyostelium Pattern Formation

The slime mold Dictyostelium discoideum is one of the model systems of biological pattern formation. One of the most successful answers to the challenge of establishing a spiral wave pattern in a colony of homogeneously distributed D. discoideum cells has been the suggestion of a developmental path the cells follow (Lauzeral and coworkers). This is a well-defined change in properties each cell undergoes on a longer time scale than the typical dynamics of the cell. Here we show that this concept leads to an inhomogeneous and systematic spatial distribution of spiral waves, which can be predicted from the distribution of cells on the developmental path. We propose specific experiments for checking whether such systematics are also found in data and thus, indirectly, provide evidence of a developmental path

Advantages of Randomization in Coherent Quantum Dynamical Control

Control scenarios have been identified where the use of randomized design may substantially improve the performance of dynamical decoupling methods [L. F. Santos and L. Viola, Phys. Rev. Lett. {\bf 97}, 150501 (2006)]. Here, by focusing on the suppression of internal unwanted interactions in closed quantum systems, we review and further elaborate on the advantages of randomization at long evolution times. By way of illustration, special emphasis is devoted to isolated Heisenberg-coupled chains of spin-1/2 particles. In particular, for nearest-neighbor interactions, two types of decoupling cycles are contrasted: inefficient averaging, whereby the number of control actions increases exponentially with the system size, and efficient averaging associated to a fixed-size control group. The latter allows for analytical and numerical studies of efficient decoupling schemes created by exploiting and merging together randomization and deterministic strategies, such as symmetrization, concatenation, and cyclic permutations. Notably, sequences capable to remove interactions up to third order are explicitly constructed. The consequences of faulty controls are also analyzed.Comment: 27 pages, 7 figure