Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.
In this open-label, international, phase 3 trial, we ...randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 PD-1) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.
The median overall survival in the total population was 10.3 months (95% confidence interval CI, 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).
Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).
Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of ...pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.
Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab 200mg every 3weeks (Q3W) or investigator’s choice of paclitaxel (175mg/m2 Q3W), docetaxel (75mg/m2 Q3W), or vinflunine (320mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.
A total of 542 patients were enrolled (pembrolizumab, n=270; chemotherapy, n=272). Median follow-up as of 26 October 2017 was 27.7months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.
Long-term results (>2 years’ follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.
ClinicalTrials.gov: NCT02256436.
We present the fifth portion of an unbiased survey of the Galactic plane, |b| ≤ 2°, for 6668-MHz methanol masers. This section of the survey completes the Galactic longitude range visible to the ...Parkes radio telescope, incorporating the longitude range 20°–60°. Within this section of the survey we find 265 methanol masers, 64 new to the survey, bringing the total number of methanol masers detected across the full longitude coverage (186°, through 0°, to 60°) to 972 sources.
Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6–12 months of treatment. Long-term results in a ...large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3–4 years after surgery. The primary outcome measure was the change in the ‘off’ medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3–4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the ‘off’ medication UPDRS-III score at 3–4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the ‘on’ time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3–4 years showed a significant worsening in the ‘on’ medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3–4 years in a large cohort of patients with severe Parkinson's disease.
Magnetic reconnection is the underlying process that releases impulsively an enormous amount of magnetic energy in solar flares , flares on strongly magnetized neutron stars and substorms in the ...Earth's magnetosphere. Studies of energy release during solar flares, in particular, indicate that up to 50% of the released energy is carried by accelerated 20-100 keV suprathermal electrons. How so many electrons can gain so much energy during reconnection has been a long-standing question. A recent theoretical study suggests that volume-filling contracting magnetic islands formed during reconnection can produce a large number of energetic electrons. Here we report the first evidence of the link between energetic electrons and magnetic islands during reconnection in the Earth's magnetosphere. The results indicate that energetic electron fluxes peak at sites of compressed density within islands, which imposes a new constraint on theories of electron acceleration.
We have identified a spatially extended electron current sheet (ECS) and its adjacent magnetic island during a magnetotail reconnection event with no appreciable guide field. This finding is based on ...data from the four Cluster spacecraft and is enabled by detailed maps of electron distribution functions and DC electric fields within the diffusion region. The maps are developed using two‐dimensional particle‐in‐cell simulations with a mass ratio mi/me = 800. One spacecraft crossed the ECS earthward of the reconnection null and, together with the other three spacecraft, registered the following properties: (1) The ECS is colocated with a layer of bipolar electric fields normal to the ECS, pointing toward the ECS, and with a half width less than 8 electron skin depths. (2) In the inflow region up to the ECS and separatrices, electrons have a temperature anisotropy (Te∥/Te⊥ > 1), and the anisotropy increases toward the ECS. (3) Within about 1 ion skin depth (di) above and below the ECS, the electron density decreases toward the ECS by a factor of 3–4, reaching a minimum at edges of the ECS, and has a local distinct maximum at the ECS center. (4) A di‐scale magnetic island is attached to the ECS, separating it from another reconnection layer. Our simulations established that the electric field normal to the ECS is due to charge imbalance and is of the ECS scale, and ions exhibit electron‐scale structures in response to this electric field.
We found that exposure of mice and rats to male but not female experimenters produces pain inhibition. Male-related stimuli induced a robust physiological stress response that results in ...stress-induced analgesia. This effect could be replicated with T-shirts worn by men, bedding material from gonadally intact and unfamiliar male mammals, and presentation of compounds secreted from the human axilla. Experimenter sex can thus affect apparent baseline responses in behavioral testing.
We present the results of the first complete unbaised survey of the Galactic plane for 6035-MHz excited-state hydroxyl (ex-OH) masers undertaken as part of the methanol multibeam (MMB) survey. These ...observations cover the Galactic longitude ranges 186... < l < 60... including the Galactic Centre. We report the detection of 127 ex-OH masers within the survey region, 47 being new sources. The positions of new detections were determined from interferometric observations with the Australia Telescope Compact Array. We discuss the association of 6035-MHz masers in our survey with the 6668-MHz masers from the MMB Survey, finding 37 likely CH sub( 3)OH-ex-OH maser pairs with physical separations of less than or equal to 0.03 pc and 55 pairings separated by less than or equal to 0.1 pc. Using these we calculate for the first time an ex-OH maser lifetime of between 3.3 x 10 super( 3) and 8.3 x 10 super( 3) yr. We also discuss the variability of the 6035-MHz masers and detection rates of counterpart 6030-MHz ex-OH masers (28 per cent of our sample having detection at both frequencies). (ProQuest: ... denotes formulae/symbols omitted.)
This is the fourth and final instalment of a series of catalogues presenting 12.2-GHz methanol maser observations made towards each of the 6.7-GHz methanol masers detected in the Methanol Multibeam ...(MMB) survey. This final portion of the survey covers the 20...-60... longitude range, increasing the 12.2-GHz follow-up range to the full MMB coverage of 186... ≥ l ≤ 60... and |b| ≤ 2... Towards a total of 260 6.7-GHz MMB methanol masers (we were unable to observe five of the MMB sources in this longitude range) we detect 116 12.2-GHz masers counterparts, 64 of which were discovered in this survey. Including data from the literature, we find that there are 12.2-GHz methanol masers towards 47.1 per cent of the 6.7-GHz methanol masers in this portion of the Galaxy. Across the entire MMB survey range, we find a detection rate of 45.3 per cent. We find that the detection rate of 12.2-GHz methanol masers as a function of Galactic longitude is not uniform and there is an excess of masers with broad velocity ranges at longitudes near 30... and 330... Comparing the occurrence of 12.2-GHz methanol masers with MMB-targeted CO observations has shown that those outflows associated with a 12.2-GHz source have a larger average dynamical time-scale than those associated with only 6.7-GHz methanol masers, supporting the notion that the 12.2-GHz masers are associated with a later phase of high-mass star formation. (ProQuest: ... denotes formulae/symbols omitted.)
NASA's Solar Probe Plus (SPP) mission will make the first in situ measurements of the solar corona and the birthplace of the solar wind. The FIELDS instrument suite on SPP will make direct ...measurements of electric and magnetic fields, the properties of in situ plasma waves, electron density and temperature profiles, and interplanetary radio emissions, amongst other things. Here, we describe the scientific objectives targeted by the SPP/FIELDS instrument, the instrument design itself, and the instrument concept of operations and planned data products.
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