CTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor ...(EGFR).
Patients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m2) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data.
From February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40–0.75, P < 0.001 as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38–0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49–1.04, P = 0.077). Quality-of-life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43–2.08, P = 0.877).
CTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients.
NCT00891579.
Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the ...purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P<0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P=0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression.
CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.
Adenosquamous carcinoma (ASC) of the lung is a heterogeneous disease that is composed of both adenocarcinoma components (ACC) and squamous cell carcinoma components (SCCC). Their genomic profile, ...genetic origin, and clinical management remain controversial.
Resected ASC and metastatic tumor in regional lymph nodes (LNs) were collected. The ACC and SCCC were separated by microdissection of primary tumor. The 1021 cancer-related genes were evaluated by next-generation sequencing independently in ACC and SCCC and LNs. Shared and private alterations in the two components were investigated. In addition, genomic profiles of independent cohorts of adenocarcinomas and squamous cell carcinomas were examined for comparison. We have also carried out a retrospective study of ASCs with known EGFR mutation status from 11 hospitals in China for their clinical outcomes.
The most frequent alterations in 28 surgically resected ASCs include EGFR (79%), TP53 (68%), MAP3K1 (14%) mutations, EGFR amplifications (32%), and MDM2 amplifications (18%). Twenty-seven patients (96%) had shared variations between ACC and SCCC, and pure SCCC metastases were not found in metastatic LNs among these patients. Only one patient with geographically separated ACC and SCCC had no shared mutations. Inter-component heterogeneity was a common genetic event of ACC and SCCC. The genomic profile of ASC was similar to that of 170 adenocarcinomas, but different from that of 62 squamous cell carcinomas. The incidence of EGFR mutations in the retrospective analysis of 517 ASCs was 51.8%. Among the 129 EGFR-positive patients who received EGFR-TKIs, the objective response rate was 56.6% and the median progression-free survival was 10.1 months (95% confidence interval: 9.0–11.2).
The ACC and SCCC share a monoclonal origin, a majority with genetically inter-component heterogeneity. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR TKI.
•The adenocarcinoma component and squamous cell carcinoma component of adenosquamous carcinoma share a common clonal origin.•High incidence of trunk EGFR and TP53 mutation were noted in adenosqumous cell carcinoma, while the overall genomic profile of adenosqumous cell carcinoma is more similar to adenocarcinoma than squmous cell carcinoma.•EGFR-TKIs should be the standard first-line therapy for advanced stage adenosquamous carcinoma with EGFR mutation.
Background
Acupuncture is used to treat chronic functional constipation (CFC) in China, despite limited evidence. We aim to assess the effectiveness and safety of acupuncture in managing CFC.
Methods
...A multicenter randomized controlled trial was performed involving 684 patients with CFC; the patients were randomly allocated to receive He acupuncture (n = 172), Shu‐mu acupuncture (n = 171), He‐shu‐mu acupuncture (n = 171), or oral administration of mosapride (n = 170). Sixteen sessions of acupuncture were given in the treatment duration of 4 weeks. The primary outcome was the change in spontaneous bowel movements (SBMs) at week 4 (at the end of treatment) compared to baseline. The secondary outcomes included stool consistency (Bristol scale), the degree of straining during defecation, and adverse events.
Key Results
The SBMs increased in all the four groups at week 4, and the magnitude of increase was equivalent in the four groups (He acupuncture, 2.7 95% CI, 2.3‐3.1; Shu‐mu acupuncture, 2.7 95% CI, 2.3‐3.0; He‐shu‐mu acupuncture, 2.2 95% CI, 1.9‐2.5; and mosapride, 2.4 95% CI, 2.0‐2.9; P = .226). However, the change in SBMs at week 8 was significantly smaller in mosapride group (1.4 95% CI, 1.0‐1.8) than the three acupuncture groups (2.4 95% CI, 2.1‐2.7, 2.3 95% CI, 1.9‐2.7, 2.1 95% CI, 1.7‐2.5 in He, Shu‐mu, and He‐shu‐mu group, respectively, P = .005).
Conclusions & Interferences
The three acupuncture treatments were as effective as mosapride in improving stool frequency and stool consistency in CFC, but the magnitude of the treatment effect is unknown due to the lack of sham acupuncture control.
The effectiveness of acupuncture in the treatment of chronic functional constipation is unknown. Our study result showed that acupuncture treatments are as effective as mosapride in improving stool frequency and stool consistency.
Large-scale CuO nanowires were in situ grown on Cu substrate by a very simple catalyst-free thermal oxidation process in atmosphere. The structure characterization revealed that these nanowires are ...monoclinic structured single crystallites with mean diameters of 60–200
nm. The effects of growth time and temperature on the morphology of the nanowires were investigated. It is found that the growth time has an important effect on the length and density of the nanowires, whereas the growth temperature has a distinct influence on the nanowire diameter. Different from the vapor–solid (V–S) mechanism, the growth of nanowires is found to be based on the Cu ion diffusion. The ethanol-sensing properties of these CuO nanowires were also studied based on a self-designed prototype and the results indicated that these large-scale nanowires are indeed a good candidate for gas-sensing applications.
•LaFe11.6Si1.4/Pr2Co7 composites were fabricated by SPS followed by annealing.•10 wt% Pr2Co7 addition and medium LaFe11.6Si1.4 powders were conducive to 1:13 phase formation.•The diffusion of Pr/Co ...into the 1:13 phase improves the TC of these composites.•The composites exhibit excellent (σbc)max of 930–1405 MPa and λ of 14–20.90 W/m∙K.•These composites are promising candidates for near RT cooling applications.
A series of LaFe11.6Si1.4/xwt%Pr2Co7 (x = 0, 5, 10) composites, with a range of particle size of LaFe11.6Si1.4 powders, were successfully fabricated by spark plasma sintering (SPS), followed by annealing. The influence of the particle size of the LaFe11.6Si1.4 powders and the Pr2Co7 binder content on the phase constitution, microstructure, thermal, mechanical, magnetic and magnetocaloric properties were studied. The Pr2Co7 binder content (10 wt%) and the particle size of LaFe11.6Si1.4 powders (100–200 µm) were chosen to be conducive to the formation of the desired 1:13 phase. The magnetic and magnetocaloric properties were influenced by the synergistic effects of Pr and Co atomic diffusion as well by the particle size of the LaFe11.6Si1.4 majority phase powders. The values of TC, (ΔSM)max and RC for the sample could be tuned in the range of 230–297 K, 1.90–3.70 J/kg·K and 84–149 J/kg (ΔH=2 T), respectively, by tuning the Pr2Co7 content and the particle size of the LaFe11.6Si1.4 powders. Significantly, this TC range covers a wide variety of near room temperature cooling applications. The excellent values of thermal conductivity, maximum compressive strength and strain were in the range of 14–20.90 W/m·K, 930–1405 MPa and 5.9–7.9%, respectively. These features make these materials very promising candidates for near room temperature magnetic cooling applications.
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•High density La-Fe-Si based composites were fabricated by short time SPS followed by annealing.•The magnetocaloric and mechanical properties could be tuned by changing the SPS ...temperature.•The optimum process was SPS@1273 K/5min followed by annealing@1323 K/24 h.•Excellent (σbc)max ∼ 1GPa, λ ∼ 17.68 W/m∙K and large (−ΔSM)max ∼ 2.3 J/kg‧K@2T were obtained.
La(Fe,Si)13 based magnetocaloric composites were prepared by spark plasma sintering (SPS), followed by annealing. The microstructure, mechanical and magnetocaloric properties were investigated. With increasing SPS temperature (TSPS) below 1373 K, the content of (La,Pr)(Fe,Co,Si)13 majority phase increased, while the content of minority phase α-Fe decreased. The increase of TSPS from 973 K to 1373 K greatly improved the composite density, and the density sharply increased from ∼ 68 % to 98 %. After SPS at 1273 K/5 min followed by 1323 K/24 h annealing, high content of 89.35 wt% of the desired (La,Pr)(Fe,Co,Si)13 phase was obtained in LaFe11.6Si1.4/10wt%Pr2Co7 composites. A large increase of Curie temperature (TC) from 196 K to 297 K was observed. The maximum magnetic entropy change (−ΔSM)max reached 2.3 J/(kg‧K) under 2 T magnetic field. ∼ 97 % of full density, excellent compressive strength of ∼ 1GPa and high thermal conductivity of 17.68 W/m∙K were exhibited. Thus, a route to produce high density La-Fe-Si based magnetocaloric composites with excellent mechanical properties and thermal conductivity, good (−ΔSM)max and adjustable TC by short time spark plasma sintering followed by annealing was demonstrated.
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•Magnetron sputtering was used to fabricate Al films.•High coercivity and excellent corrosion resistance were obtained.•A weak ferromagnetic phase within intergranular phase was ...investigated.
Al film, which was coated in sintered Nd-Fe-B magnets prepared by magnetron sputtering, was employed for grain boundary diffusion source. Effects of the grain boundary diffusion processes (GBDP) on the microstructure evolution and properties were investigated in detail. Through grain boundary diffusion processes, the highest coercivity of 1184 kA/m and maximum energy product of 238 kJ/m3 could be obtained, increasing by 21.8% and 3.9%, respectively, compared with the initial magnet. Meanwhile, our results showed that fine, uniform and continuous intergranular phase induced by Al diffusion, was the main reason for properties improvement, while a weak ferromagnetic phase and the vague interface between main phase and RE-rich phase should be responsible to the deterioration of coercivity when the diffused temperature exceed 600 °C. Besides, the corrosion resistance of Al-diffused magnets was also greatly improved, owing to the fact that the Al element could promote the electrochemical potential of RE-rich phase and the more thin, continuous intergranular phase would also narrow the corrosion channel.
This article discusses the recent developments in modelling and simulations for analyses of airspace structures and traffic flows. The topics discussed are new models/methods proposed by researchers ...in the world for optimal flight paths/routes, optimal route structures, sectorization and so on and also new developments in the Association of Southeast Asian Nations region. An Association of Southeast Asian Nations modelling and simulation function has been established, so as to perform analyses of airspace structures and traffic flows throughout the Association of Southeast Asian Nations and produce solutions for capacity and efficiency enhancements. The challenges for such research in the Association of Southeast Asian Nations region are also discussed. This review has helped to identify the research gap. The research on air traffic management in the Association of Southeast Asian Nations region is still lacking. Much more efforts should be made in order to meet the demands of this most dynamic and fast growing aviation market in the world. Research on optimal flight paths/routes, more efficient airspace structures and sectorization is expected to be more intensively conducted especially in the Association of Southeast Asian Nations region.
•Anisotropic grain boundary diffusion of NdFeB magnet is studied by micromagnetism.•Anisotropic diffusion is due to anisotropic distribution of demagnetizing field.•Diffusion parallel to easy axis is ...the most effective way to improve coercivity.•To enhance coercivity only a limited diffusion depth along easy axis is needed.
A systematic investigation on the anisotropic grain boundary diffusion in sintered Nd-Fe-B magnets is carried out by micromagnetic simulation. The results indicate that the critical reason for the anisotropic diffusion effect is not the difference in the amount of Dy diffused along different directions but the macroscopic demagnetizing field. The diffusion parallel to the easy axis from both pole surfaces of the magnet can increase the nucleation fields in the two major regions with large macroscopic demagnetizing fields, where the reverse domains can nucleate easily. As a consequence, the grain boundary diffusion along the directions parallel to the easy axis from two pole surfaces is more effective to improve the coercivity of the magnets than that along other directions. It is also found that, to enhance the coercivity, only a limited diffusion depth is required. The present result is in good agreement with the recent experimental findings.
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