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

Seismic amelioration of existing reinforced concrete buildings. Strategy to optimize the amount of reinforcement for joints

Most of the existing Reinforced Concrete (RC) buildings in Italy were built according to obsolete regulations that were not enough aware of issues related to seismic design so that they need to be upgraded by pursuing either amelioration or full seismic rehabilitation. In doing that, the first step is to figure out what is, based on the results of the initial analysis of the structure in its ante-operam version, the best overall dissipative mechanism that could be ob-tained by a number of suitable and economically convenient local interventions. The choice of the overall dissipative mechanism strongly affects the amount of reinforcement to be adopted for the beam-column joints. For new buildings, the current adopted capacity design philosophy pursues an overall beam-sway mechanism in which plastic hinges first form in beams and at last at the base of the columns. On the contrary,for existing ones, often very irregular and gravity-load-dominated, pursuing such overall mechanism may result either uneconomic or even extremely difficult to implement due to the amount of reinforcement to be inserted in the joints. In such cases, an overall dissipative mechanism allowing, at some extent, columns flex-ural plasticizationshould be accepted and clearly identified in advance. Anyway,such ap-proach needs to be addressed properly in order to avoid the formation of column-sways at one story only that would result very dangerous due to the excessive demand of plastic rotations on the resulting hinges. This paper presents two simple models that may help the designer in deal-ing with the operations above. The formeris a model that allows to understand if, given the existing RC building case-study, either the beam-sway or a hybrid beam-column-sway mecha-nism should be conveniently pursued during the design of the retrofitting intervention. The lat-ter isa model that allows to design a hybrid beam-column-sway overall mechanism involving a suitable number of stories such as to guarantee a uniform and reasonable demand of plastic rotations in the involved columns

Supporting experienced hospital nurses to move into community matron roles

Report of a study to examine the key knowledge and support required by nurses, experienced in the management of patients with long term conditions, to work in primary care contexts in undertaking community matron roles. Commissioned by the Department of Health (England) 200

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