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

X-ray view of four high-luminosity Swift/BAT AGN: Unveiling obscuration and reflection with Suzaku

The Swift/BAT nine-month survey observed 153 AGN, all with ultra-hard X-ray BAT fluxes in excess of 10^-11 erg cm^-2 s^-1 and an average redshift of 0.03. Among them, four of the most luminous BAT AGN (44.73 < Log L(BAT) < 45.31) were selected as targets of Suzaku follow-up observations: J2246.0+3941 (3C 452), J0407.4+0339 (3C 105), J0318.7+6828, and J0918.5+0425. The column density, scattered/reflected emission, the properties of the Fe K line, and a possible variability are fully analyzed. For the latter, the spectral properties from Chandra, XMM-Newton and Swift/XRT public observations were compared with the present Suzaku analysis. Of our sample, 3C 452 is the only certain Compton-thick AGN candidate because of i) the high absorption and strong Compton reflection; ii) the lack of variability; iii) the "buried" nature, i.e. the low scattering fraction (<0.5%) and the extremely low relative [OIII] luminosity. In contrast 3C 105 is not reflection-dominated, despite the comparable column density, X-ray luminosity and radio morphology, but shows a strong long-term variability in flux and scattering fraction, consistent with the soft emission being scattered from a distant region (e.g., the narrow emission line region). The sample presents high (>100) X-to-[OIII] luminosity ratios, confirming the [OIII] luminosity to be affected by residual extinction in presence of mild absorption, especially for "buried" AGN such as 3C 452. Three of our targets are powerful FRII radio galaxies, making them the most luminous and absorbed AGN of the BAT Seyfert survey despite the inversely proportional N_H - L_X relation.Comment: A&A paper in press, 17 page

Activity of eribulin mesylate in brain metastasis from breast cancer. a stone in a pond?

Background: Brain metastases develop in approximately 10-25% of patients with metastatic breast cancer (MBC) and are associated with a very poor prognosis. Case Report: We report the case of a 40-year-old woman with MBC and associated lung, bone, liver, and brain metastases, who experienced a time to progression of several months with eribulin after whole-brain radiotherapy (WBRT), 2 lines of chemotherapy, and 1 line of hormonal therapy, maintaining a good toxicity profile. Discussion: Eribulin, in association with local treatment such as WBRT, can be well tolerated and effective in achieving a long progression-free survival and a good control of brain metastases in patients with MBC who have received multiple lines of treatment. The vascular remodeling properties of eribulin, combined with brain radiotherapy, might facilitate the passage of eribulin across the blood brain barrier, improving brain response. Conclusion: Our anecdotal experience suggests that eribulin may have a potentially beneficial effect on brain metastases while maintaining a good systemic control of the disease in patients with MBC

GRB Observed by IBIS/PICsIT in the MeV Energy Range

We present the preliminary results of a systematic search for GRB and other transients in the publicly available data for the IBIS/PICsIT (0.2-10 MeV) detector on board INTEGRAL. Lightcurves in 2-8 energy bands with time resolution from 1 to 62.5 ms have been collected and an analysis of spectral and temporal characteristics has been performed. This is the nucleus of a forthcoming first catalog of GRB observed by PICsIT.Comment: 6 pages, 3 figures. Poster presented at COSPAR 2008. Advaces in Space Research, accepted for publicatio

Casting Light on the Hidden Bilevel Combinatorial Structure of the Capacitated Vertex Separator Problem

Given an undirected graph, we study the capacitated vertex separator problem that asks to find a subset of vertices of minimum cardinality, the removal of which induces a graph having a bounded number of pairwise disconnected shores (subsets of vertices) of limited cardinality. The problem is of great importance in the analysis and protection of communication or social networks against possible viral attacks and for matrix decomposition algorithms. In this article, we provide a new bilevel interpretation of the problem and model it as a two-player Stackelberg game in which the leader interdicts the vertices (i.e., decides on the subset of vertices to remove), and the follower solves a combinatorial optimization problem on the resulting graph. This approach allows us to develop a computational framework based on an integer programming formulation in the natural space of the variables. Thanks to this bilevel interpretation, we derive three different families of strengthening inequalities and show that they can be separated in polynomial time. We also show how to extend these results to a min-max version of the problem. Our extensive computational study conducted on available benchmark instances from the literature reveals that our new exact method is competitive against the state-of-the-art algorithms for the capacitated vertex separator problem and is able to improve the best-known results for several difficult classes of instances. The ideas exploited in our framework can also be extended to other vertex/edge deletion/ insertion problems or graph partitioning problems by modeling them as two-player Stackel- berg games and solving them through bilevel optimization

IBIS/PICsIT in-flight performances

PICsIT (Pixellated Imaging CaeSium Iodide Telescope) is the high energy detector of the IBIS telescope on-board the INTEGRAL satellite. PICsIT operates in the gamma-ray energy range between 175 keV and 10 MeV, with a typical energy resolution of 10% at 1 MeV, and an angular resolution of 12 arcmin within a \~100 square degree field of view, with the possibility to locate intense point sources in the MeV region at the few arcmin level. PICsIT is based upon a modular array of 4096 independent CsI(Tl) pixels, ~0.70 cm^2 in cross-section and 3 cm thick. In this work, the PICsIT on-board data handling and science operative modes are described. This work presents the in-flight performances in terms of background count spectra, sensitivity limit, and imaging capabilities.Comment: 8 pages, 4 figures. Accepted for publication on A&A, special issue on First Science with INTEGRA

Force Sensor by Driving Hydraulic Cylinders: Identification of Inertial Parameters and Tests

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