An experiment to search for light sterile neutrinos is conducted at a reactor with a thermal power of 2.8 GW located at the Hanbit nuclear power complex. The search is done with a detector consisting ...of a ton of Gd-loaded liquid scintillator in a tendon gallery approximately 24 m from the reactor core. The measured antineutrino event rate is 1976 per day with a signal to background ratio of about 22. The shape of the antineutrino energy spectrum obtained from the eight-month data-taking period is compared with a hypothesis of oscillations due to active-sterile antineutrino mixing. No strong evidence of 3+1 neutrino oscillation is found. An excess around the 5 MeV prompt energy range is observed as seen in existing longer-baseline experiments. The mixing parameter sin^{2}2θ_{14} is limited up to less than 0.1 for Δm_{41}^{2} ranging from 0.2 to 2.3 eV^{2} with a 90% confidence level.
There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have ...failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.
Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10mg/kg by intravenous infusion every 2weeks or physician’s choice of chemotherapy (paclitaxel 80mg/m2 on days 1, 8, and 15 or irinotecan 150mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0months; hazard ratio (HR)=1.1 95% confidence interval (CI) 0.9–1.4; P=0.81} or the secondary end points of PFS median, 1.4 versus 2.7months; HR=1.73 (95% CI 1.4–2.2); P>0.99 or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.
Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.
ClinicalTrials.gov: NCT02625623.
BACKGROUND AND PURPOSE
Ginsenosides are the main constituents for the pharmacological effects of Panax ginseng. Such effects of ginsenosides including cardioprotective and anti‐platelet activities ...have shown stability and bioavailability limitations. However, information on the anti‐platelet activity of ginsenoside‐Rp1 (G‐Rp1), a stable derivative of ginsenoside‐Rg3, is scarce. We examined the ability of G‐Rp1 to modulate agonist‐induced platelet activation.
EXPERIMENTAL APPROACH
G‐Rp1 in vitro and ex vivo effects on agonist‐induced platelet‐aggregation, granule‐secretion, Ca2+i mobilization, integrin‐αIIbβ3 activation were examined. Vasodilator‐stimulated phosphoprotein (VASP) and MAPK expressions and levels of tyrosine phosphorylation of the glycoprotein VI (GPVI) signalling pathway components were also studied. G‐Rp1 effects on arteriovenous shunt thrombus formation in rats or tail bleeding time and ex vivo coagulation time in mice were determined.
KEY RESULT
G‐Rp1 markedly inhibited platelet aggregation induced by collagen, thrombin or ADP. While G‐Rp1 elevated cAMP levels, it dose‐dependently suppressed collagen‐induced ATP‐release, thromboxane secretion, p‐selectin expression, Ca2+i mobilization and αIIbβ3 activation and attenuated p38MAPK and ERK2 activation. Furthermore, G‐Rp1 inhibited tyrosine phosphorylation of multiple components (Fyn, Lyn, Syk, LAT, PI3K and PLCγ2) of the GPVI signalling pathway. G‐Rp1 inhibited in vivo thrombus formation and ex vivo platelet aggregation and ATP secretion without affecting tail bleeding time and coagulation time, respectively.
CONCLUSION AND IMPLICATIONS
G‐Rp1 inhibits collagen‐induced platelet activation and thrombus formation through modulation of early GPVI signalling events, and this effect involves VASP stimulation, and ERK2 and p38‐MAPK inhibition. These data suggest that G‐Rp1 may have therapeutic potential for the treatment of cardiovascular diseases involving aberrant platelet activation.
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.
Primary cosmic-ray elemental spectra have been measured with the balloon-borne Cosmic Ray Energetics And Mass (CREAM) experiment since 2004. The third CREAM payload (CREAM-III) flew for 29 days ...during the 2007-2008 Antarctic season. Energies of incident particles above 1 TeV are measured with a calorimeter. Individual elements are clearly separated with a charge resolution of ∼0.12 e (in charge units) and ∼0.14 e for protons and helium nuclei, respectively, using two layers of silicon charge detectors. The measured proton and helium energy spectra at the top of the atmosphere are harder than other existing measurements at a few tens of GeV. The relative abundance of protons to helium nuclei is 9.53 0.03 for the range of 1 TeV/n to 63 TeV/n. This ratio is considerably smaller than other measurements at a few tens of GeV/n. The spectra become softer above ∼20 TeV. However, our statistical uncertainties are large at these energies and more data are needed.
We present new constraints on the dark matter-induced annual modulation signal using 1.7 years of COSINE-100 data with a total exposure of 97.7 kg yr. The COSINE-100 experiment, consisting of 106 kg ...of NaI(Tl) target material, is designed to carry out a model-independent test of DAMA/LIBRA's claim of WIMP discovery by searching for the same annual modulation signal using the same NaI(Tl) target. The crystal data show a 2.7 cpd/kg/keV background rate on average in the 2-6 keV energy region of interest. Using a χ-squared minimization method we observe best fit values for modulation amplitude and phase of 0.0092±0.0067 cpd/kg/keV and 127.2±45.9 d, respectively.
Up to 40% of patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease ...progression in the central nervous system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80 mg), a third-generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of osimertinib 160 mg in BM or LM is unclear.
This prospective, single-arm, two cohort study evaluated the efficacy of osimertinib 160 mg in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary end points were objective response rate (ORR) (H1 = 30%) for the BM cohort and overall survival (OS) (H1 = 5 months) for the LM cohort.
The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate were 55.0% and 77.5%, respectively. The median progression-free survival (PFS) was 7.6 months 95% confidence interval (CI) 5.0–16.6; the median OS was 16.9 months 95% CI 7.9–not reached (NR). In the LM cohort, intracranial disease control rate was 92.5% and complete response rate was 12.5%. The median OS was 13.3 months (95% CI 9.1–NR); the median PFS was 8.0 months (95% CI 7.2–NR). Subgroup analyses based on previous exposure to T790M-targeting agents, including osimertinib 80 mg or other third-generation EGFR TKIs, showed no difference in PFS in both the BM (n = 18, P = 0.39) and LM (n = 17, P = 0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P = 0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1–2.
Thus, osimertinib 160 mg demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.
•Osimertinib 160 mg exhibited promising ORR and survival benefit in EGFR T790M-positive NSCLC patients with CNS metastasis.•As it caused only grade 1–2 adverse events, osimertinib 160 mg also showed a tolerable safety profile.•It is suitable for BM or LM patients after EGFR TKI treatment and those treated with EGFR T790M-targeting agents or radiotherapy.
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