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

Experiments and computer simulations of the dynamic cavity formed by a particulated shaped-charge jet in sand

Experiments have been carried out to measure the dynamic cavity growth of dry sand during penetration by particulated jets from Viper 65-mm-diameter, Cu-lined conical shaped charges at 1,000-mm standoff. The sand target was instrumented with foil switches, piezoelectric pins, and pressure transducers. Flash radiography at 450-keV was used to characterize the jets before impact and to image the target hole during jet penetration. The authors have developed a dry sand equation of state based on existing Hugoniot data as input to a porous material model incorporated in the 2-D arbitrary Lagrangian-Eulerian hydrocode CALE. They have carried out sand penetration simulations in which the particulated jet is modeled as hot copper rods. By varying parameters in the sand and copper descriptions they identify those features that affect the dynamic cavity formation

Development of intuitive rules: Evaluating the application of the dual-system framework to understanding children's intuitive reasoning

This is an author-created version of this article. The original source of publication is Psychon Bull Rev. 2006 Dec;13(6):935-53 The final publication is available at www.springerlink.com Published version: http://dx.doi.org/10.3758/BF0321390

Gamma-ray flaring activity from the gravitationally lensed blazar PKS 1830-211 observed by Fermi LAT

The Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope routinely detects the highly dust-absorbed, reddened, and MeV-peaked flat spectrum radio quasar PKS 1830-211 (z=2.507). Its apparent isotropic gamma-ray luminosity (E>100 MeV) averaged over $\sim$ 3 years of observations and peaking on 2010 October 14/15 at 2.9 X 10^{50} erg s^{-1}, makes it among the brightest high-redshift Fermi blazars. No published model with a single lens can account for all of the observed characteristics of this complex system. Based on radio observations, one expects time delayed variability to follow about 25 days after a primary flare, with flux about a factor 1.5 less. Two large gamma-ray flares of PKS 1830-211 have been detected by the LAT in the considered period and no substantial evidence for such a delayed activity was found. This allows us to place a lower limit of about 6 on the gamma rays flux ratio between the two lensed images. Swift XRT observations from a dedicated Target of Opportunity program indicate a hard spectrum and with no significant correlation of X-ray flux with the gamma-ray variability. The spectral energy distribution can be modeled with inverse Compton scattering of thermal photons from the dusty torus. The implications of the LAT data in terms of variability, the lack of evident delayed flare events, and different radio and gamma-ray flux ratios are discussed. Microlensing effects, absorption, size and location of the emitting regions, the complex mass distribution of the system, an energy-dependent inner structure of the source, and flux suppression by the lens galaxy for one image path may be considered as hypotheses for understanding our results.Comment: 14 pages, 6 figures, 2 tables. Accepted by the The Astrophysical Journal. Corresponding authors: S. Ciprini (ASI ASDC & INAF OAR, Rome, Italy), S. Buson (INAF Padova & Univ. of Padova, Padova, Italy), J. Finke (NRL, Washington, DC, USA), F. D'Ammando (INAF IRA, Bologna, Italy

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]

Current management of treatment-induced bone loss in women with breast cancer treated in the United Kingdom

New therapeutic options in breast cancer have improved survival but consequently increase the relevance of late complications. Ovarian suppression/ablation and aromatase inhibitors (AI) in the adjuvant setting have improved outcome, but have clinically important adverse effects on bone health. However, investigation and management of cancer treatment-induced bone loss (CTIBL) is poorly defined with no national guidance. In 2004, a questionnaire was sent to over 500 breast surgeons and oncologists who treat breast cancer within the United Kingdom. The questionnaire evaluated access to bone densitometry and specialist expertise as well as attitudes to investigation of CTIBL and anticipated changes in the use of AI for postmenopausal early breast cancer. A total of 354 completed questionnaires were received, 47 from clinicians not currently treating breast cancer. Of the 307 evaluable questionnaires, 164 (53%) were from breast surgeons, 112 (36%) from clinical oncologists and 31 (10%) from medical oncologists. Although most respondents recognised that CTIBL was the responsibility of the treating breast team, investigations for CTIBL are limited even though most had adequate access to bone densitometry; 98 (32%) had not requested a DXA scan in the last 6 months and 224 (73%) had requested fewer than five scans. In all, 235 (76%) were not routinely investigating patients on AI for bone loss. A total of 277 (90%) felt that their practice would benefit from national guidelines to manage these patients, and the majority (59%) had little or no confidence in interpreting DXA results and advising on treatment. This questionnaire has highlighted clear deficiencies in management of CTIBL in early breast cancer. The development of national guidelines for the management of these patients and educational initiatives for breast teams are urgently required

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

Periodic Emission from the Gamma-ray Binary 1FGL J1018.6-5856

Gamma-ray binaries are stellar systems containing a neutron star or black hole with gamma-ray emission produced by an interaction between the components. These systems are rare, even though binary evolution models predict dozens in our Galaxy. A search for gamma-ray binaries with the Fermi Large Area Telescope (LAT) shows that 1FGL J1018.6-5856 exhibits intensity and spectral modulation with a 16.6 day period. We identified a variable X-ray counterpart, which shows a sharp maximum coinciding with maximum gamma-ray emission, as well as an O6V((f)) star optical counterpart and a radio counterpart that is also apparently modulated on the orbital period. 1FGL J1018.6-5856 is thus a gamma-ray binary, and its detection suggests the presence of other fainter binaries in the Galaxy.Comment: Contact authors: R.H.D. Corbet, M. Kerr, C.C. Cheun