The glass-forming ability of Zr–Cu-based metallic glass with high entropy is investigated. Samples are prepared by adding elements, such as Ag, Hf, and Ni, to ternary Zr48Al7Cu45 to systematically ...evaluate the multicomponent effect. The glass structures are fabricated by tilt casting. In quaternary and senary alloys with increased glass-forming ability, new competitive liquid crystalline phases are generated with the addition of elements. Compared with the quaternary alloy, the quinary alloy does not form a new crystalline phase, and the added Hf is highly soluble in the base crystalline phase. The driving force for crystallization, which is evaluated based on specific heat measurements, is the largest for the quinary alloys. This suggests that stabilization of the competitive phase by the high-entropy effect leads to a decrease in the glass-forming ability. From the kinetics point of view, the relationship between the liquid-phase fragility and glass-forming ability is clarified, and the addition of Ag and Ni, which strengthens the liquid properties, is found to improve the glass-forming ability. Based on the high-entropy strategy, a new high-entropy metallic glass Zr35Hf13Al11Ag8Ni8Cu25, with a maximum vitrification diameter of 20 mm, is fabricated.
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•The glass-forming ability of metallic glasses did not increase monotonically with increase configuration entropy.•When the high-entropy effect occurs in the crystalline phase, the glass-forming ability is reduced.•The driving force of the crystallization and the fragility index of alloys were correlated with the glass-forming ability.•The largest Be-free high-entropy bulk metallic glass with a maximum vitrification diameter of 20 mm, was newly fabricated.
Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit ...of adjuvant chemotherapy in these patients remains unclear.
We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival.
The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval CI, 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group.
After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).
Background: To compare the efficacy and toxicity of three platinum-based combination regimens against cisplatin plus irinotecan (IP) in patients with untreated advanced non-small-cell lung cancer ...(NSCLC) by a non-inferiority design.
Patients and methods: A total of 602 patients were randomly assigned to one of four regimens: cisplatin 80 mg/m2 on day 1 plus irinotecan 60 mg/m2 on days 1, 8, 15 every 4 weeks (IP) carboplatin AUC 6.0 min × mg/mL (area under the concentration–time curve) on day 1 plus paclitaxel 200 mg/m2 on day 1 every 3 weeks (TC); cisplatin 80 mg/m2 on day 1 plus gemcitabine 1000 mg/m2 on days 1, 8 every 3 weeks (GP); and cisplatin 80 mg/m2 on day 1 plus vinorelbine 25 mg/m2 on days 1, 8 every 3 weeks (NP).
Results: The response rate, median survival time, and 1-year survival rate were 31.0%, 13.9 months, 59.2%, respectively, in IP; 32.4%, 12.3 months, 51.0% in TC; 30.1%, 14.0 months, 59.6% in GP; and 33.1%, 11.4 months, 48.3% in NP. No statistically significant differences were found in response rate or overall survival, but the non-inferiority of none of the experimental regimens could be confirmed. All the four regimens were well tolerated.
Conclusion: The four regimens have similar efficacy and different toxicity profiles, and they can be used to treat advanced NSCLC patients.
Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and ...death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality.
We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs).
Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14·4 months and median follow-up was 10·7 years (IQR 9·5 to 11·9). The risks of breast cancer recurrence (RR 0·66, 95% CI 0·62 to 0·71; p<0·0001) and death from breast cancer (0·67, 0·61 to 0·73; p<0·0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Absolute 10-year recurrence risk was reduced by 9·0% (95% CI 7·4 to 10·7; p<0·0001) and 10-year breast cancer mortality was reduced by 6·4% (4·9 to 7·8; p<0·0001), with a 6·5% reduction (5·0 to 8·0; p<0·0001) in all-cause mortality, and no increase in death without recurrence (0·4%, –0·3 to 1·1; p=0·35). The proportional reduction in recurrence was largest in years 0–1 after randomisation (0·53, 99% CI 0·46 to 0·61), with benefits persisting through years 2–4 (0·73, 0·62 to 0·85) and 5–9 (0·80, 0·64 to 1·01), and little follow-up beyond year 10. Proportional recurrence reductions were similar irrespective of recorded patient and tumour characteristics, including ER status. The more high risk the tumour, the larger the absolute reductions in 5-year recurrence (eg, 5·7% 95% CI 3·1 to 8·3, 6·8% 4·7 to 9·0, and 10·7% 7·7 to 13·6 in N0, N1–3, and N4+ disease).
Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics.
Cancer Research UK, UK Medical Research Council.
Hepatocyte growth factor (HGF) is a potent angiogenic factor. The efficacy and safety of intramuscular injection of a naked plasmid encoding human HGF gene (beperminogene perplasmid, Collategene) was ...investigated in patients with critical limb ischemia (CLI) in a multicenter, randomized, double-blind, placebo-controlled trial. The randomization ratio for plasmid to placebo was 2:1. Injection sites were selected in each patient limb based on angiographic findings. Placebo or plasmid was injected on days 0 and 28. Evaluation of efficacy was carried out after 12 weeks. The primary end point was the improvement of rest pain in patients without ulcers (Rutherford 4) or the reduction of ulcer size in patients with ulcer(s) (Rutherford 5). Secondary end points were ankle-brachial pressure index, amputation, and quality of life (QOL). Forty-four patients were treated, and we performed interim analysis of efficacy in 40 patients. The overall improvement rate of the primary end point was 70.4% (19/27) in HGF group and 30.8% (4/13) in placebo group, showing a significant difference (P=0.014). In Rutherford 5 patients, HGF achieved a significantly higher improvement rate (100% 11/11) than placebo (40% 2/5; P=0.018). HGF plasmid also improved QOL. There were no major safety problems. HGF gene therapy is safe and effective for CLI.
Summary Background Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. Methods ...We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44 000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18 000); and polychemotherapy versus no chemotherapy (n=32 000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. Findings In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance 2p=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities. Interpretation 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both. Funding Cancer Research UK; British Heart Foundation; UK Medical Research Council.
The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, ...as the current standard sequence for metastatic colorectal cancer patients.
Patients with KRAS exon 2 wild-type metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence cetuximab ± irinotecan followed by regorafenib (C-R arm). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. Exploratory end points included serial biomarker analyses, including oncogenic alterations from circulating tumor DNA or multiple serum or plasma proteins.
One-hundred one patients were randomized and eligible for efficacy analysis. Sequential treatment was successful in 86% patients in both arms. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (P = 0.0293), with a hazard ratio (HR) of 0.61 for OS 95% confidence interval (CI) 0.39–0.96. The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI 0.61–1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI 0.17–0.50). No unexpected safety signals were observed. The quality of life scores during the entire treatment period was not significantly different between the two arms. Circulating biomarker analyses showed emerging oncogenic alterations in RAS, BRAF, EGFR, HER2, and MET, which were more commonly detected after cetuximab than after regorafenib.
The therapeutic sequence of regorafenib followed by cetuximab suggests a longer OS than the current standard sequence.
Web-based treatment programs are attractive in primary care because of their ability to reach numerous individuals at low cost. Our aim of this meta-analysis is to systematically review the weight ...loss or maintenance effect of the Internet component in obesity treatment programs.
MEDLINE and EMBASE literature searches were conducted to identify studies investigating the effect of Web-based individualized advice on lifestyle modification on weight loss. Randomized controlled trials that consisted of a Web-user experimental and non-Web user control group were included. Weight changes in the experimental group in comparison with the control group were pooled with a random-effects model.
A total of 23 studies comprising 8697 participants were included. Overall, using the Internet had a modest but significant additional weight-loss effect compared with non-Web user control groups (-0.68 kg, P=0.03). In comparison with the control group, stratified analysis indicated that using the Internet as an adjunct to obesity care was effective (-1.00 kg, P<0.001), but that using it as a substitute for face-to-face support was unfavorable (+1.27 kg, P=0.01). An additional effect on weight control was observed when the aim of using the Internet was initial weight loss (-1.01 kg; P=0.03), but was not observed when the aim was weight maintenance (+0.68 kg; P=0.26). The relative effect was diminished with longer educational periods (P-trend=0.04) and was insignificant (-0.20 kg; P=0.75) in studies with educational periods of 12 months or more.
The current meta-analysis indicates that the Internet component in obesity treatment programs has a modest effect on weight control. However, the effect was inconsistent, largely depending on the type of usage of the Internet or the period of its use.
We study a non-equilibrium unitary Fermi gas, being coupled with two baths with different values of chemical potential. Extending a
T
-matrix approximation developed in equilibrium Fermi gases to the ...non-equilibrium steady state by using the Keldysh Green’s function technique, we examine the superfluid phase transition out of equilibrium. We also clarify non-equilibrium effects on the pseudogap phenomenon by strong pairing fluctuations.
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