Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial

Background Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. Methods In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0–2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. Findings Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637–0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83–20·99) in the fulvestrant group versus 13·8 months (11·99–16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Interpretation Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients

Evidence for solar cycles in a late Holocene speleothem record from Dongge Cave, China

The association between solar activity and Asian monsoon (AM) remains unclear. Here we evaluate the possible connection between them based on a precisely-dated, high-resolution speleothem oxygen isotope record from Dongge Cave, southwest China during the past 4.2 thousand years (ka). Without being adjusted chronologically to the solar signal, our record shows a distinct peak-to-peak correlation with cosmogenic nuclide 14C, total solar irradiance (TSI) and sunspot number (SN) at multi-decadal to centennial timescales. Further cross-wavelet analyses between our calcite δ18O and atmospheric 14C show statistically strong coherence at three typical periodicities of ~80, 200 and 340 years, suggesting important roles of solar activities in modulating AM changes at those timescales. Our result has further indicated a better correlation between our calcite δ18O record and atmospheric 14C than between our record and TSI. This better correlation may imply that the Sun–monsoon connection is dominated most likely by cosmic rays and oceanic circulation (both associated to atmospheric 14C), instead of the direct solar heating (TSI)

Understanding extreme sea levels for broad-scale coastal impact and adaptation analysis

One of the main consequences of mean sea level rise (SLR) on human settlements is an increase in flood risk due to an increase in the intensity and frequency of extreme sea levels (ESL). While substantial research efforts are directed towards quantifying projections and uncertainties of future global and regional SLR, corresponding uncertainties in contemporary ESL have not been assessed and projections are limited. Here we quantify, for the first time at global scale, the uncertainties in present-day ESL estimates, which have by default been ignored in broad-scale sea-level rise impact assessments to date. ESL uncertainties exceed those from global SLR projections and, assuming that we meet the Paris agreement goals, the projected SLR itself by the end of the century in many regions. Both uncertainties in SLR projections and ESL estimates need to be understood and combined to fully assess potential impacts and adaptation needs

Extending the fabric from the EGRIPice core in space with geophysicalmethods and modelling

Anisotropic crystal fabrics in ice sheets develop as a consequence of deformation and hence record information of past ice flow. Simultaneously, the fabric affects the present-day bulk mechanical properties of glacier ice because the susceptibility of ice crystals to deformation is highly anisotropic. This is particularly relevant in dynamic areas such as fast-flowing glaciers and ice streams, where the formation of strong fabrics might play a critical role in facilitating ice flow. Anisotropy is ignored in most state-of-the-art ice sheet models, and while its importance has long been recognized, accounting for fabric evolution and its impact on the ice viscosity has only recently become feasible. Both the application of such models to ice streams and their verification through in-situ observations are still rare. Ice cores provide direct and detailed information on the crystal fabric, but the logistical cost, technical challenges, particularly in fast-flowing ice and shear margins, difficulty in reconstructing the absolute orientation of the core, and their limitation of being a point measurement, make ice cores impractical for a spatially extensive evaluation of the fabric type. Indirect geophysical methods applied from or above the ice surface create the link between the small scale of laboratory experiments and ice–core observations to the large-scale coverage required for ice flow models and the complete understanding of ice stream dynamics. Here, we present a comprehensive analysis of the distribution of the ice fabric in the upstream part of the North-East Greenland Ice Stream (NEGIS). Our results are based on a combination of methods applied to extensive airborne and ground-based radar surveys, ice- and firn-core observations, and numerical ice-flow modelling. They show that in the onset region of NEGIS and around the EGRIP ice core drilling site, the fabric is horizontally strongly anisotropic, forming a horizontal girdle perpendicular to the ice flow, while the horizontal anisotropy reduces quickly over distances of less than five ice thicknesses outside of the ice stream’s shear margins. Downstream of the drill site, the fabric develops into a more vertically symmetric configuration on a time scale of around 2 ka, the first observation of this kind. Our study shows how ice-core based fabric observations, geophysical surveys and ice-flow modelling complement each other to obtain a more comprehensive picture of the spatially strongly varying fabric

A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors

<p><b>Purpose:</b> This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies and determined the safety, tolerability, and pharmacokinetic (PK) profile of selumetinib and its active metabolite N-desmethyl-selumetinib in fed and fasted states.</p> <p><b>Methods:</b> A single dose of 75 mg selumetinib was to be taken with food on Day 1 followed by a single dose of 75 mg after fasting for at least 10 h on Day 8, or vice versa, followed by twice daily dosing of 75 mg selumetinib from Day 10. Plasma concentrations and PK parameters were determined on Days 1 and 8. Patients could continue to receive selumetinib for as long as they benefitted from treatment.</p> <p><b>Results:</b> In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of C<sub>max</sub> and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (t<sub>max</sub>) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated.</p> <p><b>Conclusions:</b> The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population.</p&gt

Satellite Observations of Separator Line Geometry of Three-Dimensional Magnetic Reconnection

Detection of a separator line that connects magnetic nulls and the determination of the dynamics and plasma environment of such a structure can improve our understanding of the three-dimensional (3D) magnetic reconnection process. However, this type of field and particle configuration has not been directly observed in space plasmas. Here we report the identification of a pair of nulls, the null-null line that connects them, and associated fans and spines in the magnetotail of Earth using data from the four Cluster spacecraft. With di and de designating the ion and electron inertial lengths, respectively, the separation between the nulls is found to be ~0.7di and an associated oscillation is identified as a lower hybrid wave with wavelength ~ de. This in situ evidence of the full 3D reconnection geometry and associated dynamics provides an important step toward to establishing an observational framework of 3D reconnection.Comment: 10 pages, 3 figures and 1 tabl

Paleoclimate Implications for Human-Made Climate Change

Paleoclimate data help us assess climate sensitivity and potential human-made climate effects. We conclude that Earth in the warmest interglacial periods of the past million years was less than 1{\deg}C warmer than in the Holocene. Polar warmth in these interglacials and in the Pliocene does not imply that a substantial cushion remains between today's climate and dangerous warming, but rather that Earth is poised to experience strong amplifying polar feedbacks in response to moderate global warming. Thus goals to limit human-made warming to 2{\deg}C are not sufficient - they are prescriptions for disaster. Ice sheet disintegration is nonlinear, spurred by amplifying feedbacks. We suggest that ice sheet mass loss, if warming continues unabated, will be characterized better by a doubling time for mass loss rate than by a linear trend. Satellite gravity data, though too brief to be conclusive, are consistent with a doubling time of 10 years or less, implying the possibility of multi-meter sea level rise this century. Observed accelerating ice sheet mass loss supports our conclusion that Earth's temperature now exceeds the mean Holocene value. Rapid reduction of fossil fuel emissions is required for humanity to succeed in preserving a planet resembling the one on which civilization developed.Comment: 32 pages, 9 figures; final version accepted for publication in "Climate Change at the Eve of the Second Decade of the Century: Inferences from Paleoclimate and Regional Aspects: Proceedings of Milutin Milankovitch 130th Anniversary Symposium" (eds. Berger, Mesinger and Sijaci

A comparison of five surface mixed layer models with a year of observations in the North Atlantic

Five upper ocean mixed layer models driven by ERA-Interim surface forcing are compared with a year of hydrographic observations of the upper 1000 m, taken at the Porcupine Abyssal Plain observatory site using profiling gliders. All the models reproduce sea surface temperature (SST) fairly well, with annual mean warm biases of 0.11  ° C (PWP model), 0.24  ° C (GLS), 0.31  ° C (TKE), 0.91  ° C (KPP) and 0.36  ° C (OSMOSIS). The main exception is that the KPP model has summer SSTs which are higher than the observations by nearly 3 ° . Mixed layer salinity (MLS) is not reproduced well by the models and the biases are large enough to produce a non-trivial density bias in the Eastern North Atlantic Central Water which forms in this region in winter. All the models develop mixed layers which are too deep in winter, with average winter mixed layer depth (MLD) biases between 160 and 228 m. The high variability in winter MLD is reproduced more successfully by model estimates of the depth of active mixing and/or boundary layer depth than by model MLD based on water column properties. After the spring restratification event, biases in MLD are small and do not appear to be related to the preceding winter biases. There is a very clear relationship between MLD and local wind stress in all models and in the observations during spring and summer, with increased wind speeds leading to deepening mixed layers, but this relationship is not present during autumn and winter. We hypothesize that the deepening of the MLD in autumn is so strongly driven by the annual cycle in surface heat flux that the winds are less significant in the autumn. The surface heat flux drives a diurnal cycle in MLD and SST from March onwards, though this effect is much more significant in the models than in the observations. We are unable to identify one model as definitely better than the others. The only clear differences between the models are KPP’s inability to accurately reproduce summer SSTs, and the OSMOSIS model’s more accurate reproduction of MLS

Dynamic Changes in Brain Functional Connectivity during Concurrent Dual-Task Performance

This study investigated the spatial, spectral, temporal and functional proprieties of functional brain connections involved in the concurrent execution of unrelated visual perception and working memory tasks. Electroencephalography data was analysed using a novel data-driven approach assessing source coherence at the whole-brain level. Three connections in the beta-band (18–24 Hz) and one in the gamma-band (30–40 Hz) were modulated by dual-task performance. Beta-coherence increased within two dorsofrontal-occipital connections in dual-task conditions compared to the single-task condition, with the highest coherence seen during low working memory load trials. In contrast, beta-coherence in a prefrontal-occipital functional connection and gamma-coherence in an inferior frontal-occipitoparietal connection was not affected by the addition of the second task and only showed elevated coherence under high working memory load. Analysis of coherence as a function of time suggested that the dorsofrontal-occipital beta-connections were relevant to working memory maintenance, while the prefrontal-occipital beta-connection and the inferior frontal-occipitoparietal gamma-connection were involved in top-down control of concurrent visual processing. The fact that increased coherence in the gamma-connection, from low to high working memory load, was negatively correlated with faster reaction time on the perception task supports this interpretation. Together, these results demonstrate that dual-task demands trigger non-linear changes in functional interactions between frontal-executive and occipitoparietal-perceptual cortices

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes

BACKGROUND: Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours. METHODS: Tumour samples from an olaparib maintenance monotherapy trial (Study 19, D0810C00019; NCT00753545) were analysed. Analyses included classification of mutations in genes involved in homologous recombination repair (HRR), BRCA1 promoter methylation status, measurement of BRCA1 protein and Myriad HRD score. RESULTS: Patients with BRCAm tumours gained most benefit from olaparib; a similar treatment benefit was also observed in 21/95 patients whose tumours were BRCAwt but had loss-of-function HRR mutations compared to patients with no detectable HRR mutations (58/95). A higher median Myriad MyChoice® HRD score was observed in BRCAm and BRCAwt tumours with BRCA1 methylation. Patients without BRCAm tumours derived benefit from olaparib treatment vs placebo although to a lesser extent than BRCAm patients.CONCLUSIONS: Ovarian cancer patients with tumours harbouring loss-of-function mutations in HRR genes other than BRCA1/2 may constitute a small, molecularly identifiable and clinically relevant population who derive treatment benefit from olaparib similar to patients with BRCAm