Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and ...safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.
Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.
From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months 95% confidence interval (CI) 1.6-2.9 months with pimitespib versus 1.4 months (0.9-1.8 months) with placebo hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo HR 0.42 (0.21-0.85), one-sided P = 0.007. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.
Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.
•Pimitespib improved PFS compared with placebo in patients with previously treated advanced GIST.•OS was improved with pimitespib compared with placebo using the RPSFT model.•Exploratory pharmacogenomic analysis showed a benefit of pimitespib irrespective of KIT mutation status.•The safety profile of pimitespib was acceptable, and quality of life was not deteriorated by pimitespib compared with placebo.
The electrodeposition process of Li metal in 1.0M LiTFSI–ionic liquid (N-methoxymethyl-N-methylpyrrolidinium) bis(trifluoromethane-sulfonyl) imide was observed in situ by optical microscope. ...Morphological variations of electrodeposited Li dendrite and its growth rate were examined and the ionic mass transfer rate in the vicinity of the electrode surface was discussed. Once the dendrite starts to grow, its length is proportional to the square root of time. This indicates that the Li+ mass transfer rate affects its growth. Dendrite growth process can be classified into two regions depending on its growth rate: the initiation period and the growing period with swinging behavior probably caused by residual stress.
•The effectiveness of bio-based repair materials was presented and highlighted.•The resistance against ingress of water was enhanced by alginate-based healing agents.•Re-deterioration in patch repair ...method was prevented by the use of Bacillus subtilis (natto).•The use of Bacillus subtilis (natto) was proved to work as a cathodic inhibitor.
This study explored the application of bio-based repair materials to concrete for crack repair and patch repair methods. First, the concept of crack repair using Bacillus subtilis (natto) under wet conditions is presented. In addition to the self-healing efficiency, enhancement of corrosion resistance owing to consumption of dissolved oxygen by bacteria which could work as a cathodic inhibitor is theoretically explained by electro-chemical reactions. And then, this study exemplified the application of the bio-based repair material to concrete with respect to crack repair and patch repair methods. First, alginate-based self-healing materials (in-situ encapsulation) are newly developed in this study to improve the resistance against ingress of water in cracked mortar specimens, which is demonstrated by the reduced absorption of water. This is adequately explained by the fact that the calcite precipitation in gel films formed in crack is highly effective in sealing crack in mortar specimen. In addition, the healing agents could reduce the concentration of dissolved oxygen in concrete, which is found to contribute to reduction of the macrocell corrosion current density in which the corrosion rate is determined by the cathodic reactions associated with diffusion of dissolved oxygen. The use of Bacillus subtilis (natto) is highly advantageous in preventing re-deterioration owing to macrocell corrosion taking place between patch repair region and surrounding concrete containing chloride.
The strong correlation between grain size and photoresponsivity in polycrystalline GaAs films on glass was experimentally demonstrated using Ge seed layers with a wide range of grain sizes ...(1‒330 μm). The crystal evaluations using Raman spectroscopy, scanning electron microscopy, electron backscatter diffraction, and transmission electron microscopy revealed that 500-nm-thick GaAs films epitaxially grown from the Ge seed layers at 550 °C inherited the grain boundaries and crystal orientations in Ge. With increasing grain size, the photoresponsivity corresponding to GaAs increased from 0.01 to 3 A W
under a bias voltage of 0.3 V. The maximum value approached that of the GaAs film formed simultaneously on a single-crystal Ge wafer, indicating the high potential of the large-grained GaAs film. Knowledge gained from this study will be essential for designing advanced solar cells based on polycrystalline III-V compound semiconductors using inexpensive substrates.
This paper reviews the history of strained-silicon and the adoption of uniaxial-process-induced strain in nearly all high-performance 90-, 65-, and 45-nm logic technologies to date. A more complete ...data set of n- and p-channel MOSFET piezoresistance and strain-altered gate tunneling is presented along with new insight into the physical mechanisms responsible for hole mobility enhancement. Strained-Si hole mobility data are analyzed using six band k/spl middot/p calculations for stresses of technological importance: uniaxial longitudinal compressive and biaxial stress on 001 and 110 wafers. The calculations and experimental data show that low in-plane and large out-of-plane conductivity effective masses and a high density of states in the top band are all important for large hole mobility enhancement. This work suggests longitudinal compressive stress on 001 or 110 wafers and channel direction offers the most favorable band structure for holes. The maximum Si inversion-layer hole mobility enhancement is estimated to be /spl sim/ 4 times higher for uniaxial stress on (100) wafer and /spl sim/ 2 times higher for biaxial stress on (100) wafer and for uniaxial stress on a 110 wafer.
Objectives
The aim of the present study was to verify the associations between dysphagia as screened by the Eating Assessment Tool-10 (EAT-10) and indicators in the 100-mL water swallowing test (WST) ...or medical history among community-dwelling older people.
Study design
A cross-sectional study.
Setting and Participants
The study participants were 202 community-dwelling older Japanese adults aged ≥65 years.
Measurements
We investigated the participants’ basic attributes, including age, sex, body mass index, medical history (cerebrovascular disease, respiratory disease: chronic obstructive pulmonary disease COPD, and history of pneumonia within the previous year), and number of prescribed medications. Dysphagia assessment was performed using the EAT-10 and the 100-mL WST as subjective and objective examinations, respectively. The 100-mL WST used four indicators (SC: swallowing capacity, VS: volume per swallow, TS: time per swallow, and choking signs). Patients with and without dysphagia according to the EAT-10 were divided into two groups according to a cutoff score of 3, and the two groups were then compared in terms of their characteristics including medical history and 100-mL WST indicators. A multiple logistic regression model was used to determine whether the indicators of the 100-mL WST or medical history were independently associated with dysphagia in the EAT-10.
Results
The multiple logistic regression analysis revealed that dysphagia in the EAT-10 was independently associated with male sex (odds ratio OR = 2.78; 95% confidence interval CI = 0.98–7.90), COPD (OR = 14.68; 95% CI = 3.14–68.85), and VS and TS in the 100-mL WST (OR = 0.85; 95% CI = 0.80–0.90 and OR = 3.03; 95% CI = 1.78–5.16, respectively).
Conclusions
Our results revealed that the EAT-10 was independently associated with the 100-mL WST and respiratory disease. We propose that swallowing rehabilitation incorporating respiratory training could be effective for older people screened using the EAT-10.
Objectives
To evaluate the efficacy, safety, and tolerability of perampanel, a selective, non‐competitive, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, as an ...adjunctive treatment for patients with refractory partial‐onset seizures (POS) from Asia‐Pacific.
Materials & methods
This multicenter, randomized, double‐blind, placebo‐controlled trial (ClinicalTrials.gov identifier: NCT01618695) involved patients aged ≥12 years with refractory POS (receiving 1‐3 antiepileptic drugs). Patients were randomized (1:1:1:1) to receive once‐daily placebo or perampanel 4, 8, or 12 mg over a 6‐week titration and 13‐week maintenance double‐blind period. Enzyme‐inducing antiepileptic drugs were equally stratified between groups. The primary efficacy endpoint was percent change in POS frequency per 28 days (double‐blind phase vs baseline). Other efficacy endpoints included ≥50% responder rate and seizure freedom. Treatment‐emergent adverse events (TEAEs) were also monitored.
Results
Of 710 randomized patients, seizure frequency data were available for 704 patients. Median percent changes in POS frequency per 28 days indicated dose‐proportional reductions in seizure frequency: −10.8% with placebo and −17.3% (P = .2330), −29.0% (P = .0003), and −38.0% (P < .0001) with perampanel 4, 8, and 12 mg, respectively. In total, 108 (15.3%) patients discontinued treatment; 44 (6.2%) due to TEAEs. TEAEs occurring in ≥5% of patients, and reported at least twice as frequently with perampanel vs placebo, included dizziness and irritability.
Conclusions
Adjunctive perampanel (8 and 12 mg/d) significantly improved seizure control in patients with refractory POS. Safety and tolerability were acceptable at daily doses of perampanel 4‐12 mg.
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