Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and ...safety of vandetanib 300 mg daily in this patient population.
This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0–2. The primary endpoint was the objective response rate.
A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35–71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity.
Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.
Development of advanced high energy density lithium ion batteries is important for promoting electromobility. Making electric vehicles attractive and competitive compared to conventional automobiles ...depends on the availability of reliable, safe, high power, and highly energetic batteries whose components are abundant and cost effective. Nickel rich LiNi x Co y Mn 1−x−y O 2 layered cathode materials ( x > 0.5) are of interest because they can provide very high specific capacity without pushing charging potentials to levels that oxidize the electrolyte solutions. However, these cathode materials suffer from stability problems. We discovered that doping these materials with tungsten (1 mol%) remarkably increases their stability due to a partial layered to cubic (rock salt) phase transition. We demonstrate herein highly stable Li ion battery prototypes consisting of tungsten-stabilized Ni rich cathode materials ( x > 0.9) with specific capacities >220 mA h g -1 . This development can increase the energy density of Li ion batteries more than 30% above the state of the art without compromising durability.
Abstract
Effective models focused on pertinent low-energy degrees of freedom have substantially contributed to our qualitative understanding of quantum materials. An iconic example, the Kondo model, ...was key to demonstrating that the rich phase diagrams of correlated metals originate from the interplay of localized and itinerant electrons. Modern electronic structure calculations suggest that to achieve quantitative material-specific models, accurate consideration of the crystal field and spin-orbit interactions is imperative. This poses the question of how local high-energy degrees of freedom become incorporated into a collective electronic state. Here, we use resonant inelastic x-ray scattering (RIXS) on CePd
3
to clarify the fate of all relevant energy scales. We find that even spin-orbit excited states acquire pronounced momentum-dependence at low temperature—the telltale sign of hybridization with the underlying metallic state. Our results demonstrate how localized electronic degrees of freedom endow correlated metals with new properties, which is critical for a microscopic understanding of superconducting, electronic nematic, and topological states.
Reactor experiment for neutrino oscillation (RENO) began data-taking from August 2011. It successfully observed reactor antineutrino disappearance in April 2012 to measure the smallest mixing angle ...of θ13. Two identical detectors, one at near location and the other at far location, are constructed at the Yonggwang nuclear power plant in South Korea, to compare the observed reactor neutrino fluxes. Each RENO detector is filled with 16 mass tons of Gadolinium loaded liquid scintillator (GdLS) in the neutrino target region, and with 28 mass tons of unloaded liquid scintillator (LS) in the γ-catcher region surrounding the target. LS was developed to satisfy chemical, physical, optical properties, and safety requirements. Linear alkyl benzene (LAB) was chosen as a solvent because of its high flash-point, sufficient light yield, and being environmentally friendly. GdLS is carefully developed to keep a long attenuation length and high light yield for a long time period. In this paper, we report the characteristics and mass production of the RENO LS and GdLS.
The retrospective forecast skill of three coupled climate models (NCEP CFS, GFDL CM2.1, and CAWCR POAMA 1.5) and their multi-model ensemble (MME) is evaluated, focusing on the Northern Hemisphere ...(NH) summer upper-tropospheric circulation along with surface temperature and precipitation for the 25-year period of 1981–2005. The seasonal prediction skill for the NH 200-hPa geopotential height basically comes from the coupled models’ ability in predicting the first two empirical orthogonal function (EOF) modes of interannual variability, because the models cannot replicate the residual higher modes. The first two leading EOF modes of the summer 200-hPa circulation account for about 84% (35.4%) of the total variability over the NH tropics (extratropics) and offer a hint of realizable potential predictability. The MME is able to predict both spatial and temporal characteristics of the first EOF mode (EOF1) even at a 5-month lead (January initial condition) with a pattern correlation coefficient (PCC) skill of 0.96 and a temporal correlation coefficient (TCC) skill of 0.62. This long-lead predictability of the EOF1 comes mainly from the prolonged impacts of El Niño-Southern Oscillation (ENSO) as the EOF1 tends to occur during the summer after the mature phase of ENSO. The second EOF mode (EOF2), on the other hand, is related to the developing ENSO and also the interdecadal variability of the sea surface temperature over the North Pacific and North Atlantic Ocean. The MME also captures the EOF2 at a 5-month lead with a PCC skill of 0.87 and a TCC skill of 0.67, but these skills are mainly obtained from the zonally symmetric component of the EOF2, not the prominent wavelike structure, the so-called circumglobal teleconnection (CGT) pattern. In both observation and the 1-month lead MME prediction, the first two leading modes are accompanied by significant rainfall and surface air temperature anomalies in the continental regions of the NH extratropics. The MME’s success in predicting the EOF1 (EOF2) is likely to lead to a better prediction of JJA precipitation anomalies over East Asia and the North Pacific (central and southern Europe and western North America).
Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that ...reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non‐liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti‐HBc+) donors. Organs from anti‐HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non‐liver recipients but is not recommended in immune non‐liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost‐effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.
A multidisciplinary panel of experts from AST reviews the literature regarding the use of organs from donors who test positive for hepatitis B virus, and provides recommendations for their use in liver, kidney, heart, and lung transplant recipients.
Objectives. Hypoxia-inducible factor-1α (HIF-1α) is a master regulator in the cellular response to hypoxic conditions, and rheumatoid synovial tissue is known to exist under hypoxic conditions. ...Therefore, this study was conducted to determine the contribution of HIF-1α to hypoxia-induced MMP and cytokine production in fibroblast-like synoviocytes (FLS). Methods. RA FLS were transfected with either a plasmid that expresses HIF-1α or an empty vector as a control, and then cultured under normoxia (21% O2). Also, FLS were transfected with either HIF-1α small interfering RNA (siRNA) or control siRNA, and cultured under hypoxic conditions (1% O2). Following transfection, the amounts of MMP and cytokine mRNAs and HIF-1α protein were examined using real-time RT–PCR and western blotting, respectively. Results. The expression of HIF-1α, MMP-1, MMP-3, IL-6 and IL-8 was markedly enhanced in FLS that were cultured under hypoxia. We confirmed that transient transfection of HIF-1α overexpressing vector or siRNA had occurred using western blotting, and in vitro studies conducted using FLS transfected with HIF-1α overexpression vector showed that they had significantly increased MMP-1, MMP-3 and IL-8 expression levels. Further, hypoxia-induced MMP-3 expression was significantly attenuated by knock-down of HIF-1α, whereas hypoxia-induced IL-8 or MMP-1 expression was not significantly repressed by HIF-1α siRNA. Conclusions. Hypoxia-induced MMP-3 expression is exclusively regulated by HIF-1α, and hypoxia-induced MMP-1 or IL-8 expression appears to have salvage pathways other than the HIF-1α pathway. Together, these data provide new insight regarding the mechanism by which hypoxia participates in joint inflammation and destruction in RA.
ZnO-nanowire gas sensors were fabricated by a selective growth of nanowires on patterned Au catalysts thus forming nanowire air bridges or ‘
nanobridges’ between two Pt pillar electrodes. The gas ...sensing properties of nanobridge gas sensors were demonstrated using a diluted NO
2. The response, as a function of temperature, was highest at 225
°C and was linearly increased with the concentration of NO
2 in the range of 0.5–3
ppm and then showed a sign of saturation. Our sensor showed higher response compared with different types of sensors including ZnO nanocrystals, Sn- and In-doped ZnO thin film, or ZnO nanowires. The enhanced response was attributed to the additional modulation of the sensor resistance due to potential barrier at nanowire/nanowire junctions as well as the surface depletion region of each nanowire. Also nanobridge structure enabled fast recovery behavior because desorbed gas molecules can be easily swept away from the surface of ZnO nanowire without re-adsorption.
PDF
