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

On the Optimal Boundary of a Three-Dimensional Singular Stochastic Control Problem Arising in Irreversible Investment

de Angelis T, Federico S, Ferrari G. On the Optimal Boundary of a Three-Dimensional Singular Stochastic Control Problem Arising in Irreversible Investment. Center for Mathematical Economics Working Papers. Vol 509. Bielefeld: Center for Mathematical Economics; 2014.This paper examines a Markovian model for the optimal irreversible investment problem of a firm aiming at minimizing total expected costs of production. We model market uncertainty and the cost of investment per unit of production capacity as two independent one-dimensional regular diffusions, and we consider a general convex running cost function. The optimization problem is set as a three-dimensional degenerate singular stochastic control problem. We provide the optimal control as the solution of a Skorohod reflection problem at a suitable free-boundary surface. Such boundary arises from the analysis of a family of two-dimensional parameter-dependent optimal stopping problems and it is characterized in terms of the family of unique continuous solutions to parameter-dependent nonlinear integral equations of Fredholm type

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

How Do Police Respond to Stalking? An Examination of the Risk Management Strategies and Tactics Used in a Specialized Anti-Stalking Law Enforcement Unit

How do police respond to and manage complaints of stalking? To answer this question, we conducted a 3-phase study. First, we reviewed the literature to identify risk management tactics used to combat stalking. Second, we asked a group of police officers to review those tactics for completeness and group them into categories reflecting more general risk management strategies. The result was 22 categories of strategies. Finally, we used qualitative methods to evaluate the files of 32 cases referred to the specialized anti-stalking unit of a metropolitan police department. We coded specific risk management tactics and strategies used by police. Results indicated that a median number of 19 specific tactics from 7 general strategies were used to manage risk. Also, the implementation of strategies and tactics reflected specific characteristics of the cases (e.g., perpetrator risk factors, victim vulnerability factors), suggesting that the risk management decisions made by police were indeed strategic in nature. Qualitative analyses indicated that some of the strategies and tactics were more effective than others. We discuss how these findings can be used to understand and use stalking risk management more generally, as well as improve research on the efficacy of risk assessment and management for stalking