Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study

Immunoterapia; Pembrolizumab; neoplàsies mamàries triple-negativesInmunoterapia; Pembrolizumab; neoplasias mamarias triple-negativasImmunotherapy; Pembrolizumab; triple-negative breast neoplasmsBackground: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, ?1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ?24 weeks), progression-free survival, and overall survival. Results: All enrolled patients (N¼170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ?3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2þ–21.5þ) and in the PD-L1–positive (range, 6.3–21.5þ) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Global Standards in Action: Insights from Anti-Money Laundering Regulation

As organizations have come under the increasing influence of global rules of all sorts, organization scholars have started studying the dynamics of global regulation. The purpose of this article is to identify and evaluate the contribution to this interdisciplinary field by the ‘Stockholm Centre for Organisational Research’. The latter’s key proposition is that while global regulation often consists of voluntary best practice rules it can nevertheless become highly influential under certain conditions. We assess how innovative this approach is using as a benchmark the state of the art in another field of relevance to the study of global regulation, i.e. ‘International Relations’. Our discussion is primarily theoretical but we draw on the case of global anti-money laundering regulation to illustrate our arguments and for inspirations of how to further elaborate the approach

Constraints on dark matter models from a Fermi LAT search for high-energy cosmic-ray electrons from the Sun

During its first year of data taking, the Large Area Telescope (LAT) onboard the Fermi Gamma-Ray Space Telescope has collected a large sample of high-energy cosmic-ray electrons and positrons (CREs). We present the results of a directional analysis of the CRE events, in which we searched for a flux excess correlated with the direction of the Sun. Two different and complementary analysis approaches were implemented, and neither yielded evidence of a significant CRE flux excess from the Sun. We derive upper limits on the CRE flux from the Sun's direction, and use these bounds to constrain two classes of dark matter models which predict a solar CRE flux: (1) models in which dark matter annihilates to CREs via a light intermediate state, and (2) inelastic dark matter models in which dark matter annihilates to CREs.Comment: 18 pages, 8 figures, accepted for publication in Physical Review D - contact authors: Francesco Loparco ([email protected]), M. Nicola Mazziotta ([email protected]) and Jennifer Siegal-Gaskins ([email protected]

Instrumentation-related uncertainty of reflectance and transmittance measurements with a two-channel spectrophotometer

Spectrophotometers are operated in numerous fields of science and industry for a variety of applications. In order to provide confidence for the measured data, analyzing the associated uncertainty is valuable. However, the uncertainty of the measurement results is often unknown or reduced to sample-related contributions. In this paper, we describe our approach for the systematic determination of the measurement uncertainty of the commercially available two-channel spectrophotometer Agilent Cary 5000 in accordance with the Guide to the expression of uncertainty in measurements. We focus on the instrumentation-related uncertainty contributions rather than the specific application and thus outline a general procedure which can be adapted for other instruments. Moreover, we discover a systematic signal deviation due to the inertia of the measurement amplifier and develop and apply a correction procedure. Thereby we increase the usable dynamic range of the instrument by more than one order of magnitude. We present methods for the quantification of the uncertainty contributions and combine them into an uncertainty budget for the device. © 2017 Author(s)

Fermi Large Area Telescope Observations of the Cosmic-Ray Induced gamma-ray Emission of the Earth's Atmosphere

We report on measurements of the cosmic-ray induced gamma-ray emission of Earth's atmosphere by the Large Area Telescope onboard the Fermi Gamma-ray Space Telescope. The LAT has observed the Earth during its commissioning phase and with a dedicated Earth-limb following observation in September 2008. These measurements yielded 6.4 x 10^6 photons with energies >100MeV and ~250hours total livetime for the highest quality data selection. This allows the study of the spatial and spectral distributions of these photons with unprecedented detail. The spectrum of the emission - often referred to as Earth albedo gamma-ray emission - has a power-law shape up to 500 GeV with spectral index Gamma = 2.79+-0.06.Comment: Accepted for publication in PR

The radio/gamma-ray connection in Active Galactic Nuclei in the era of the Fermi Large Area Telescope

We present a detailed statistical analysis of the correlation between radio and gamma-ray emission of the Active Galactic Nuclei (AGN) detected by Fermi during its first year of operation, with the largest datasets ever used for this purpose. We use both archival interferometric 8.4 GHz data (from the VLA and ATCA, for the full sample of 599 sources) and concurrent single-dish 15 GHz measurements from the Owens Valley Radio Observatory (OVRO, for a sub sample of 199 objects). Our unprecedentedly large sample permits us to assess with high accuracy the statistical significance of the correlation, using a surrogate-data method designed to simultaneously account for common-distance bias and the effect of a limited dynamical range in the observed quantities. We find that the statistical significance of a positive correlation between the cm radio and the broad band (E>100 MeV) gamma-ray energy flux is very high for the whole AGN sample, with a probability <1e-7 for the correlation appearing by chance. Using the OVRO data, we find that concurrent data improve the significance of the correlation from 1.6e-6 to 9.0e-8. Our large sample size allows us to study the dependence of correlation strength and significance on specific source types and gamma-ray energy band. We find that the correlation is very significant (chance probability <1e-7) for both FSRQs and BL Lacs separately; a dependence of the correlation strength on the considered gamma-ray energy band is also present, but additional data will be necessary to constrain its significance.Comment: Accepted for publications by ApJ. Contact authors: M. Giroletti, V. Pavlidou, A. Reime

Fermi-LAT Study of Gamma-ray Emission in the Direction of Supernova Remnant W49B

We present an analysis of the gamma-ray data obtained with the Large Area Telescope (LAT) onboard the Fermi Gamma-ray Space Telescope in the direction of SNR W49B (G43.3-0.2). A bright unresolved gamma-ray source detected at a significance of 38 sigma is found to coincide with SNR W49B. The energy spectrum in the 0.2-200 GeV range gradually steepens toward high energies. The luminosity is estimated to be 1.5x10^{36} (D/8 kpc)^2 erg s^-1 in this energy range. There is no indication that the gamma-ray emission comes from a pulsar. Assuming that the SNR shell is the site of gamma-ray production, the observed spectrum can be explained either by the decay of neutral pi mesons produced through the proton-proton collisions or by electron bremsstrahlung. The calculated energy density of relativistic particles responsible for the LAT flux is estimated to be remarkably large, U_{e,p}>10^4 eV cm^-3, for either gamma-ray production mechanism.Comment: 9 pages, 10 figure

Fermi Gamma-ray Space Telescope Observations of the Gamma-ray Outburst from 3C 454.3 in November 2010

The flat-spectrum radio quasar 3C 454.3 underwent an extraordinary 5-day gamma-ray outburst in November 2010 where the daily flux measured with the Fermi Large Area Telescope (LAT) at photon energies E>100 MeV reached (66+/-2) x 10^-6 ph cm^-2 s^-1. This is a factor of 3 higher than its previous maximum flux recorded in December 2009 and ~5 times brighter than the Vela pulsar, which is normally the brightest source in the gamma-ray sky. The 3-hr peak flux was (85+/-5) x 10^-6 ph cm^-2 s^-1, corresponding to an apparent isotropic luminosity of 2.1+/-0.2 10^50 erg s^-1, the highest ever recorded for a blazar. In this paper, we investigate the features of this exceptional event in the gamma-ray band of the Fermi-LAT. In contrast to previous flares of the same source observed with the Fermi-LAT, clear spectral changes are observed during the flare.Comment: Contact authors: Lise Escande, Charles Dermer and Benoit Lott. One new figure. Accepted for publication by ApJ