First-line therapy in HER2 positive metastatic breast cancer. Is the mosaic fully completed or are we missing additional pieces?

The discovery of human epidermal growth factor receptor 2 (HER2) and its role in the biology of breast cancer and the subsequent development of HER2-targeted therapies, have dramatically improved clinical outcomes for women with early-stage and advanced HER2-positive breast cancer (BC). HER-2 targeted therapies represent a major step forward in achieving the goal of delivering individualized targeted therapy for BC, and trastuzumab was the first anti-HER-2 strategy to be approved for treatment of HER-2 positive BC. This review discusses the treatment of metastatic HER2-positive BC and describes efficacy and safety of novel anti-HER2 target therapies in first-line metastatic settings and the future challenges include refining such treatments, reducing toxicity and simultaneously developing innovative therapies. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described. In the next future will be possible to use an ample armamentarium of combination therapies directed against HER2 and key signaling components integrated in the HER network. This approach will allow clinicians to tailor the management of the individual patient on the basis of tumor- specific biomarker profiles. There is an urgent need for prospective biomarker-driven trials to identify patients for whom targeting is cost-effective

R & D Planning Involving Multicriteria Decision Analytic Methods at the Branch Level

This series of papers are a product of collaborative research coordinated through IIASA's Management and Technology Area. The collaborating institutions are Hungarian State Office of Technical Development (Personnel: Anna Vari, Janos Vecsenyi, Laszlo David); Decision Analysis Unit, Brunel University, England (Personnel: Patrick Humphreys, Lawrence D. Phillips); All-Union Research Institute of Systems Studies, USSR (Personnel: Oleg. I Larichev). The papers report case studies prepared by the personnel from the collaborating institutions based on their own, and their colleagues' work in their own institutions. They worked together as a team in developing the methods for the analysis of these case studies which are described in the first paper in the series. IIASA provided support for this work through its telecenter for communication between the investigations, and provided facilities for short term meetings between the investigations at IIASA for development of case studies and their comparative analysis. Particular MMT staff were Ronald M. Lee, Nora Avedisians, and Miyoko Yamada, who is the editor of this series. A summary of this comparative analysis, based on the first four case studies in this series was presented at the IFIP/IIASA Conference on "Processes and Tools for Decision Support", Laxenburg, Austria, July, 1982. The paper presented at the IFIP/IIASA conference will be published as Humphreys, P.C., O.I. Larichev, A. Vari, and J. Vecsenyi, Comparative analysis of decision support systems in R&D decisions, in H.G. Sol (ed.), "Processes and Tools for Decision Support", Amsterdam: North Holland, 1982. Another study in this series was published separately as L.D. Phillips: Requisite decision modeling: a case study. "Journal of the Operations Research Society, 1982, 33:303-311

Design of Flood-loss Sharing Programs in the Upper Tisza Region, Hungary: A dynamic multi-agent adaptive Monte Carlo approach

Losses from human-made and natural catastrophes are rapidly increasing. The main reason for this is the clustering of people and capital in hazard-prone areas as well as the creation of new hazard-prone areas, a phenomenon that may be aggravated by a lack of knowledge of the risks. This alarming human-induced tendency calls for new integrated approaches to catastrophic risk management. This paper demonstrates how flood catastrophe model and adaptive Monte Carlo optimization can be linked into an integrated Catastrophe Management Model to give insights on the feasibility of a flood management program and to assist in designing a robust program. As a part of integrated flood risk management, the proposed model takes into account the specifics of the catastrophic risk management: highly mutually dependent losses, the lack of information, the need for long-term perspectives and geographically explicit models, the involvement of various agents such as individuals, governments, insurers, reinsurers, and investors. Therefore, the integrated catastrophe management model turns out to be an important mitigation measure in comprehending catastrophes. As a concrete case we consider a pilot region of the Upper Tisza river, Hungary. Specifically, we analyze the demand of the region in a multipillar flood-loss sharing program involving a partial compensation by the central government, a voluntary private property insurance, a voluntary private risk-based insurance GIS-based catastrophe models and specific stochastic optimization methods are used to guide policy analysis with respect to location-specific risk exposures. To analyze the stability of the program, we use economically sound risk indicators

Flood Risk Management Policy in the Upper Tisza Basin: A System Analytical Approach. Simulation and Analysis of Three Flood Management Strategies

This report describes an integrated flood catastrophe model as well as some results of a case study made in the upper Tisza region in northeastern Hungary: the Palad-Csecsei basin (the pilot basin). The background data was provided through the Hungarian Academy of Sciences and complemented by interviews with different stakeholders in the region. Based upon these data, where a large degree of uncertainty is prevailing, we demonstrate how an implementation of a simulation and decision analytical model can provide insights into the effects of imposing different policy options for a flood risk management program in the region. We focus herein primarily on general options for designing a public-private insurance and reinsurance system for Hungary. Obviously, this is a multi-criteria and multi-stakeholder problem and cannot be solved using standard approaches. It should however be emphasized that the main purpose of this report is not to provide any definite recommendations, but rather to explore a set of policy packages that could gain a consensus among the stakeholders

The ATLAS barrel level-1 Muon Trigger Sector-Logic/RX off-detector trigger and acquisition board

The ATLAS experiment uses a system of three concentric layers of Resistive Plate Chambers (RPC) detector for the Level-1 Muon Trigger in the air-core barrel toroid region. The trigger algorithm looks for hit coincidences within different detector layers inside the programmable geometrical road which defines the transverse momentum cut. The on-detector electronics that provides the trigger and detector readout functionalities collects input signals coming from the RPC front-end. Trigger and readout data are then sent via optical fibres to the off-detector electronics. Six or seven optical fibres from one of the 64 trigger sectors go to one Sector-Logic/RX module, that later elaborates the collected trigger and readout data, and sends data respectively to the Read-Out Driver modules and to the Central Level-1 Trigger. We present the functionality and the implementation of the VME Sector-Logic/RX module, and the configuration of the system for the first cosmic ray data collected using this module

Prospective study on nanoparticle albumin-bound paclitaxel in advanced breast cancer. Clinical results and biological observations in taxane-pretreated patients

Background: There is a deep need to improve the care of metastatic breast cancer (MBC) patients, since even today it remains an incurable disease. Taxanes are considered the most effective cytotoxic drugs for the treatment of MBC, both in monotherapy and in combined schedules, but the need for synthetic solvents contributes to the severe toxicities and may have a negative impact on the efficacy. Nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) is a colloidal suspension of paclitaxel and human serum albumin initially developed to avoid the toxicities associated with conventional taxanes. Patients and methods: The aim of this prospective, single-center open-label, noncomparative study was to evaluate the efficacy and safety of nab-paclitaxel in MBC patients pretreated with taxanes. The patients were treated with nab-paclitaxel as a single agent, 260 mg/m2 on day 1 of each 3-week cycle or 125 mg/m2 weekly. The primary endpoint was the overall response rate (ORR). Secondary objectives were duration of response, clinical benefit rate, progression-free survival (PFS), overall survival, and safety. Results: A total of 42 patients (median age 48 years, median Eastern Cooperative Oncology Group performance status 0, triple-negative MBC 19%, all pretreated with a taxane-based therapy, mainly in advanced disease) were enrolled in the study. The ORR was 23.8%, including one complete response (2.4%) and nine partial responses (21.4%); the disease control rate was 50%. The median duration of response was 7.2 months. After a median follow-up of 9 months, the median PFS was 4.6 months. ORR and PFS were similar irrespective of the previous chemotherapy lines, metastatic sites, and biomolecular expression. Nab-paclitaxel was well tolerated, and the most frequent treatment-related toxicities were mild to moderate (grades 1–2). Conclusion: This real-life study shows that nab-paclitaxel has a significant antitumor activity and a manageable safety profile in patients pretreated with taxanes and experiencing a treatment failure after at least one line of chemotherapy