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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this largest phase II trial with advanced thymic carcinoma (TC), carboplatin and paclitaxel (CbP) showed promising efficacy in advanced TC when compared with anthracycline-based chemotherapy, ...which is the current standard treatment of TC. Our results established that CbP, one of the standard treatments for non-small-cell lung cancer, might be an option as a chemotherapy regimen for TC.
Thymic carcinoma (TC) is an exceptionally rare tumor, which has a very poor prognosis differing from thymoma. Till date, there has been no report of any results of clinical trials focusing on TC. The role of non-anthracycline-based chemotherapy has not been elucidated since the previous studies included a relatively small number of TC patients. This single-arm study evaluated carboplatin and paclitaxel (CbP) in chemotherapy-naive patients with advanced TC.
The study treatment consisted of carboplatin (area under the curve 6) and paclitaxel (200 mg/m2) every 3 weeks for a maximum of six cycles. The primary end point was objective response rate (ORR) by independent review. The secondary end points included overall survival (OS), progression-free survival (PFS), and safety. Based on the SWOG 2-stage design, the planned sample size of 40 patients was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05.
Forty patients from 21 centers were enrolled for this study from May 2008 to November 2010. Of the 39 patients evaluable for analysis, 36 were pathologically diagnosed by independent review, and 97% patients were eventually TC. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval 21%–53%; P = 0.031). The median PFS was 7.5 (6.2–12.3) months, while OS did not reach the median value. Major adverse event was grade 3–4 neutropenia in 34 patients (87%). There was no treatment-related death.
In this largest trial with TC, CbP showed promising efficacy in advanced TC when compared with anthracycline-based chemotherapy, which is the current standard treatment of thymic neoplasm. Our results established that CbP, one of the standard treatments for non-small-cell lung cancer, might be an option as a chemotherapy regimen for TC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous ...non-small-cell lung cancer (NSCLC).
Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC).
Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively.
The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.
•Nivolumab with carboplatin, paclitaxel, and bevacizumab was evaluated as first-line therapy for nonsquamous NSCLC.•The nivolumab combination therapy provided superior PFS across all patients with any PD-L1 expression levels.•The median PFS of 12.1 months is the longest among all phase III studies for nonsquamous NSCLC without driver mutations.•No new safety signals were observed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates ...energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumour types. We investigated the roles and mechanisms of RTK heterodimerisation in lung cancer with MET amplification.
With ...the use of an RTK array, we identified phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays.
We identified epidermal growth factor receptor (EGFR), human EGFR (HER)2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signalling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signalling.
Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET have differential roles in tumour development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerisation partners of MET in lung cancer with MET amplification.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor ...(EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data.
Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan–Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model.
OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 95% confidence interval (CI): 0.883–1.775, P = 0.2070. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312–0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively.
G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.
This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
We investigated the location of radical in various sesame seeds using continuous-wave (CW) electron paramagnetic resonance (EPR) and 9-GHz EPR imaging. CW EPR detected persistent radicals ...(single line) for various sesame seeds. The EPR linewidth of black sesame seeds was narrower than that of the irradiated white sesame seeds. A very small signal was detected for the white sesame seeds. Two-dimensional (2D) imaging using a 9-GHz EPR imager showed that radical locations vary for various sesame seeds. The paramagnetic species in black sesame seeds were located on the seed coat (skin) and in the hilum region. The signal with the highest intensity was obtained from the hilum part. A very low-intensity image was observed for the white sesame seeds. In addition, the 2D imaging of the irradiated white sesame seeds showed that free radicals were located throughout the entire seed. For the first time, CW EPR and 9-GHz EPR imaging showed the exact location of radical species in various sesame seeds.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Maintaining oral function in older individuals with missing teeth is important for leading a healthy and independent life. This study aimed to evaluate whether simple isometric exercises can maintain ...and improve the oral function maximum occlusal force (MOF) and masticatory ability (MA) and the masticatory muscle properties masseter muscle thickness (MMT) and echo intensity (MMEI) in older adults during the maintenance phase of removable prosthetic treatment. Participants were randomly categorized into the intervention and control groups. The mouthpieces were distributed, and participants were instructed to use them for exercising. The intervention group was instructed to perform maximum clenching for 10 s, whereas the control group was instructed to tap the teeth at an arbitrary speed for 10 s. Both were repeated five times at an interval of 5 s between each activity and twice daily for 4 weeks. The outcomes were measured after a month of exercise. The intervention group showed a significant improvement in the MOF, MMT during contraction, MMT at rest and MMEI during contraction. There were no significant differences in the MA and MMEI at rest. In the control group, no improvement was observed in any of the parameters. When the isometric exercises were performed using a mouthpiece, there was an improvement in the oral function and masseter muscle properties in older individuals with Eichner B status who used dentures.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Structural and electrical properties of a Ge(111) layer directly grown on a Si(111) substrate are studied. Via optimized two-step growth manner, we form a high-quality relaxed Ge layer, where ...strain-relieving dislocations are confined close to a Ge/Si interface. Consequently, a density of holes, which unintentionally come from crystal defects, is highly suppressed below 4×1016cm−3, which leads to significantly high hole Hall mobility exceeding 1500cm2/Vs at room temperature. By layer transfer of the grown Ge layer, we also fabricate a Ge(111)-on-Insulator, which is a promising template for high-performance Ge-based electronic and photonic devices.
•A high-quality Ge layer is epitaxially grown on a Si(111) by two-step growth manner.•Growth conditions, such as growth temperatures, are optimized.•Very high hole mobility is obtained from Ge(111) grown on Si(111).•High-quality thin Ge-on-Insulator with (111) orientation is obtained.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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