Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2-negative breast cancer.

BackgroundThe importance of human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive marker in invasive breast cancer is well established. Accurate assessment of HER2 status is essential to determine optimal treatment options.MethodsBreast cancer tumor tissue samples from the VIRGO observational cohort tissue substudy that were locally HER2-negative were retested centrally with both US Food and Drug Administration (FDA)-approved immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, using FDA-approved assay cutoffs; results were compared.ResultsOf the 552 unique patient samples centrally retested with local HER2-negative results recorded, tumor samples from 22 (4.0%) patients were determined to be HER2-positive (95% confidence interval [CI] = 2.5%-5.7%). Of these, 18 had been tested locally by only one testing methodology; 15 of 18 were HER2-positive after the central retesting, based on the testing methodology not performed locally. Compared with the 530 patients with centrally confirmed HER2-negative tumors, the 22 patients with centrally determined HER2-positive tumors were younger (median age 56.5 versus 60.0 years) and more likely to have ER/PR-negative tumors (27.3% versus 22.3%). These patients also had shorter median progression-free survival (6.4 months [95% CI = 3.8-15.9 months] versus 9.1 months [95% CI = 8.3-10.3 months]) and overall survival (25.9 months [95% CI = 13.8-not estimable] versus 27.9 months [95% CI = 25.0-32.9 months]).ConclusionsThis study highlights the limitations of employing just one HER2 testing methodology in current clinical practice. It identifies a cohort of patients who did not receive potentially efficacious therapy because their tumor HER2-positivity was not determined by the test initially used. Because of inherent limitations in testing methodologies, it is inadvisable to rely on a single test to rule out potential benefit from HER2-targeted therapy

The Antidepressant Mirtazapine Inhibits Hepatic Innate Immune Networks to Attenuate Immune-Mediated Liver Injury in Mice

Activation of the innate immune system, including tissue macrophages and associated neutrophil infiltration, is an important driver of subsequent adaptive immune responses in many autoimmune diseases, including autoimmune hepatitis (AIH). The antidepressant mirtazapine has a unique complex pharmacology, altering signaling through a number of serotonin and histamine receptors that can impact macrophage function; an effect potentially influencing AIH outcome. In the mouse model of concanavalin A (Con A) induced liver injury (mimics many aspects of human AIH), in which early innate immune activation (i.e., stimulated hepatic macrophages/monocytes recruit neutrophils and additional monocytes to the liver) critically drives immune-mediated hepatitis induction, mirtazapine strikingly and dose-dependently inhibited Con A-induced liver injury. This inflammation-suppressing effect of mirtazapine was linked to an attenuation of Con A-stimulated early innate immune responses within the liver, including inhibition of hepatic macrophage/monocyte activation, decreased hepatic macrophage/monocyte-derived pro-inflammatory cytokine (e.g., TNFα) and chemokine (e.g., CXCL1 and CXCL2) production, suppression of Con A-induced increases in the hepatic expression of the neutrophil relevant endothelial cell adhesion molecule ICAM-1, with the resultant significant reduction in neutrophil recruitment into the liver. Consistent with our findings in the Con A model, mirtazapine also significantly reduced activation-induced release of cytokine/chemokine mediators from human CD14+ monocytes in vitro.Conclusion: Our data suggest that mirtazapine can attenuate hepatic innate immune responses that critically regulate the subsequent development of autoimmune liver injury. Therefore, given that it is a safe and widely used medication, mirtazapine may represent a novel therapeutic approach to autoimmune liver disease

A ground-based near-infrared emission spectrum of the exoplanet HD 189733b

Detection of molecules using infrared spectroscopy probes the conditions and compositions of exoplanet atmospheres. Water (H2O), methane (CH4), carbon dioxide (CO2), and carbon monoxide (CO) have been detected in two hot Jupiters. These previous results relied on space-based telescopes that do not provide spectroscopic capability in the 2.4 - 5.2 micron spectral region. Here we report ground-based observations of the dayside emission spectrum for HD 189733b between 2.0-2.4 micron and 3.1-4.1 micron, where we find a bright emission feature. Where overlap with space-based instruments exists, our results are in excellent agreement with previous measurements. A feature at ~3.25 micron is unexpected and difficult to explain with models that assume local thermodynamic equilibrium (LTE) conditions at the 1 bar to 1 x 10-6 bar pressures typically sampled by infrared measurements. The most likely explanation for this feature is that it arises from non-LTE emission from CH4, similar to what is seen in the atmospheres of planets in our own Solar System. These results suggest that non-LTE effects may need to be considered when interpreting measurements of strongly irradiated exoplanets.Comment: 12 pages, 2 figures, published in Natur

Direct Multipixel Imaging and Spectroscopy of an Exoplanet with a Solar Gravity Lens Mission

We examined the solar gravitational lens (SGL) as the means to produce direct high-resolution, multipixel images of exoplanets. The properties of the SGL are remarkable: it offers maximum light amplification of ~1e11 and angular resolution of ~1e-10 arcsec. A probe with a 1-m telescope in the SGL focal region can image an exoplanet at 30 pc with 10-kilometer resolution on its surface, sufficient to observe seasonal changes, oceans, continents, surface topography. We reached and exceeded all objectives set for our study: We developed a new wave-optical approach to study the imaging of exoplanets while treating them as extended, resolved, faint sources at large but finite distances. We properly accounted for the solar corona brightness. We developed deconvolution algorithms and demonstrated the feasibility of high-quality image reconstruction under realistic conditions. We have proven that multipixel imaging and spectroscopy of exoplanets with the SGL are feasible. We have developed a new mission concept that delivers an array of optical telescopes to the SGL focal region relying on three innovations: i) a new way to enable direct exoplanet imaging, ii) use of smallsats solar sails fast transit through the solar system and beyond, iii) an open architecture to take advantage of swarm technology. This approach enables entirely new missions, providing a great leap in capabilities for NASA and the greater aerospace community. Our results are encouraging as they lead to a realistic design for a mission that will be able to make direct resolved images of exoplanets in our stellar neighborhood. It could allow exploration of exoplanets relying on the SGL capabilities decades, if not centuries, earlier than possible with other extant technologies. The architecture and mission concepts for a mission to the strong interference region of the SGL are promising and should be explored further

Evidence for H2 Dissociation and Recombination Heat Transport in the Atmosphere of KELT-9b

Phase curve observations provide an opportunity to study the energy budgets of exoplanets by quantifying the amount of heat redistributed from their daysides to their nightsides. Theories of phase curves for hot Jupiters have focused on the balance between radiation and dynamics as the primary parameter controlling heat redistribution. However, recent phase curves have shown deviations from the trends that emerge from this theory, which has led to work on additional processes that may affect hot Jupiter energy budgets. One such process, molecular hydrogen dissociation and recombination, can enhance energy redistribution on ultra-hot Jupiters with temperatures above similar to 2000 K. In order to study the impact of H-2 dissociation on ultra-hot Jupiters, we present a phase curve of KELT-9b observed with the Spitzer Space Telescope at 4.5 mu m. KELT-9b is the hottest known transiting planet, with a 4.5 mu m dayside brightness temperature of 5 sigma confidence. This discrepancy may be due to magnetic effects in the planet's highly ionized atmosphere.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]