Time-domain hybrid method for simulating large amplitude motions of ships advancing in waves

Shukui Liu,Apostolos D. Papanikolaou 대한조선학회 2011 International Journal of Naval Architecture and Oc Vol.3 No.1

Typical results obtained by a newly developed, nonlinear time domain hybrid method for simulating large amplitude motions of ships advancing with constant forward speed in waves are presented. The method is hybrid in the way of combining a time-domain transient Green function method and a Rankine source method. The present approach employs a simple double integration algorithm with respect to time to simulate the free-surface boundary condition. During the simulation, the diffraction and radiation forces are computed by pressure integration over the mean wetted surface, whereas the incident wave and hydrostatic restoring forces/moments are calculated on the instantaneously wetted surface of the hull. Typical numerical results of application of the method to the seakeeping performance of a standard containership, namely the ITTC S175, are herein presented. Comparisons have been made between the results from the present method, the frequency domain 3D panel method (NEWDRIFT) of NTUA-SDL and available experimental data and good agreement has been observed for all studied cases between the results of the present method and comparable other data.

Time-domain hybrid method for simulating large amplitude motions of ships advancing in waves

Liu, Shukui,Papanikolaou, Apostolos D. The Society of Naval Architects of Korea 2011 International Journal of Naval Architecture and Oc Vol.3 No.1

Typical results obtained by a newly developed, nonlinear time domain hybrid method for simulating large amplitude motions of ships advancing with constant forward speed in waves are presented. The method is hybrid in the way of combining a time-domain transient Green function method and a Rankine source method. The present approach employs a simple double integration algorithm with respect to time to simulate the free-surface boundary condition. During the simulation, the diffraction and radiation forces are computed by pressure integration over the mean wetted surface, whereas the incident wave and hydrostatic restoring forces/moments are calculated on the instantaneously wetted surface of the hull. Typical numerical results of application of the method to the seakeeping performance of a standard containership, namely the ITTC S175, are herein presented. Comparisons have been made between the results from the present method, the frequency domain 3D panel method (NEWDRIFT) of NTUA-SDL and available experimental data and good agreement has been observed for all studied cases between the results of the present method and comparable other data.

Multivariate Probabilistic Seismic Demand Model for the Bridge Multidimensional Fragility Analysis

Qi’ang Wang,Ziyan Wu,Shukui Liu 대한토목학회 2018 KSCE Journal of Civil Engineering Vol.22 No.9

Seismic fragility analysis for bridges is an essential issue for risk assessment of transportation networks exposed to seismic hazards. Considering multiple Performance Limit States (PLSs) and seismic demand parameters, the study proposes a multidimensional fragility evaluation methodology for engineering structures, and the objective of the paper is to show that the uncertainty and dependence between seismic demand parameters should be considered for fragility analysis. Thus, a new Probabilistic Seismic Demand Model (PSDM) following multivariate logarithmic normal distribution is addressed. Taking PLS correlation into consideration, multidimensional PLS formula is constructed to identify the structural failure domain. A RC bridge is studied to show the proposed theory. To consider bridge column plastic deformation and bearing nonlinear characteristic, nonlinear dynamic analyses are carried out. The bridge multidimensional fragility curves are derived and compared with fragility curves for an individual component. Results indicate that uncertainty and dependence of demand parameters can be properly dealt with by the multivariate PSDM. The multidimensional fragility is higher than fragility of any individual component, and the bridge as a system is more fragile. The ignorance of multiple components contribution to the system will generate an overestimation for the whole structural performance, which is adverse to engineering structural safety.

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

Kudo, Masatoshi,Finn, Richard S,Qin, Shukui,Han, Kwang-Hyub,Ikeda, Kenji,Piscaglia, Fabio,Baron, Ari,Park, Joong-Won,Han, Guohong,Jassem, Jacek,Blanc, Jean Frederic,Vogel, Arndt,Komov, Dmitry,Evans, T Elsevier 2018 The Lancet Vol.391 No.10126

<P><B>Summary</B></P> <P><B>Background</B></P> <P>In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.</P> <P><B>Methods</B></P> <P>This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice–web response system—with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors—to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266.</P> <P><B>Findings</B></P> <P>Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1–14·9) was non-inferior to sorafenib (12·3 months, 10·4–13·9; hazard ratio 0·92, 95% CI 0·79–1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib.</P> <P><B>Interpretation</B></P> <P>Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed.</P> <P><B>Funding</B></P> <P>Eisai Inc.</P>

Regional Differences in Efficacy, Safety, and Biomarkers for Second-Line Axitinib in Patients with Advanced Hepatocellular Carcinoma: From a Randomized Phase II Study

Kudo, Masatoshi,Kang, Yoon-Koo,Park, Joong-Won,Qin, Shukui,Inaba, Yoshitaka,Assenat, Eric,Umeyama, Yoshiko,Lechuga, Maria José,Valota, Olga,Fujii, Yosuke,Martini, Jean-Francois,Williams, J. Andr S. Karger AG 2018 Liver cancer Vol.7 No.2

<P><B><I>Background:</I></B> An unmet need exists for treatment of patients with advanced hepatocellular carcinoma (HCC) who progress on or are intolerant to sorafenib. A global randomized phase II trial (ClinicalTrial.gov No. NCT01210495) of axitinib, a vascular endothelial growth factor receptor 1-3 inhibitor, in combination with best supportive care (BSC) did not prolong overall survival (OS) over placebo/BSC, but showed improved progression-free survival in some patients. Subgroup analyses were conducted to identify potential predictive/prognostic factors. <B><I>Methods:</I></B> The data from this phase II study were analyzed for the efficacy and safety of axitinib/BSC in patients from Asia versus non-Asia versus Asian subgroups (Japan, Korea, or mainland China/Hong Kong/Taiwan) and predictive/prognostic values of baseline microRNAs and serum soluble proteins, using the Cox proportional hazards model. <B><I>Results:</I></B> Of 202 patients, 78 were from non-Asia and 124 from Asia (37 Japanese, 36 Korean, and 51 Chinese). No significant differences in OS were found between axitinib/BSC and placebo/BSC in non-Asians, Asians, or Asian subgroups. However, in an exploratory analysis, axitinib/BSC showed favorable OS in Asians, especially Japanese, when patients intolerant to prior antiangiogenic therapy were excluded from the data set. Axitinib/BSC was well tolerated by non-Asians and Asians alike. The presence of 4 circulating microRNAs, including miR-5684 and miR-1224-5p, or a level lower than or equal to the median protein level of stromal cell-derived factor 1 at baseline was significantly associated with longer OS in axitinib/BSC-treated Asians or non-Asians. <B><I>Conclusions:</I></B> Axitinib/BSC did not prolong survival over placebo/BSC in non-Asians, Asians, or Asian subgroups, but favorable OS with axitinib/BSC was observed in a subset of Japanese patients. A patient population that excludes sorafenib-intolerant patients might potentially be more suitable for clinical trials of new agents in advanced HCC. Since these results are very preliminary, further investigation is warranted. The potential predictive/prognostic value of several baseline microRNAs and soluble proteins identified in this study would require validation in prospective studies on a large cohort of patients.</P>

Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: Results of a Randomized Phase III Trial

Cheng, Ann-Lii,Kang, Yoon-Koo,Lin, Deng-Yn,Park, Joong-Won,Kudo, Masatoshi,Qin, Shukui,Chung, Hyun-Cheol,Song, Xiangqun,Xu, Jianming,Poggi, Guido,Omata, Masao,Pitman Lowenthal, Susan,Lanzalone, Silvan American Society for Clinical Oncology 2013 Journal of clinical oncology Vol.31 No.32

<P><B>Purpose</B></P><P>Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer.</P><P><B>Patients and Methods</B></P><P>Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS).</P><P><B>Results</B></P><P>Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided <I>P</I> = .9990; two-sided <I>P</I> = .0014); median progression-free survival (PFS; 3.6 <I>v</I> 3.0 months; HR, 1.13; one-sided <I>P</I> = .8785; two-sided <I>P</I> = .2286) and time to progression (TTP; 4.1 <I>v</I> 3.8 months; HR, 1.13; one-sided <I>P</I> = .8312; two-sided <I>P</I> = .3082) were comparable. Median OS was similar among Asian (7.7 <I>v</I> 8.8 months; HR, 1.21; one-sided <I>P</I> = .9829) and hepatitis B–infected patients (7.6 <I>v</I> 8.0 months; HR, 1.10; one-sided <I>P</I> = .8286), but was shorter with sunitinib in hepatitis C–infected patients (9.2 <I>v</I> 17.6 months; HR, 1.52; one-sided <I>P</I> = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%).</P><P><B>Conclusion</B></P><P>OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B–infected patients. OS was superior in hepatitis C–infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.</P>

Phase II study of sunitinib as second-line treatment for advanced gastric cancer

Bang, Yung-Jue,Kang, Yoon-Koo,Kang, Won K.,Boku, Narikazu,Chung, Hyun C.,Chen, Jen-Shi,Doi, Toshihiko,Sun, Yan,Shen, Lin,Qin, Shukui,Ng, Wai-Tong,Tursi, Jennifer M.,Lechuga, Maria J.,Lu, Dongrui Ray,R Springer US 2011 Investigational new drugs Vol.29 No.6

<P><B>Summary</B></P><P><I>Purpose.</I> This phase II, open-label, multicenter study assessed the oral, multitargeted, tyrosine kinase inhibitor sunitinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma who had received prior chemotherapy. <I>Experimental design</I>. Patients received sunitinib 50 mg/day on Schedule 4/2 (4 weeks on treatment, followed by 2 weeks off treatment). The primary endpoint was objective response rate; secondary endpoints included clinical benefit rate, duration of response, progression-free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics, safety and tolerability, and quality of life. <I>Results</I>. Of 78 patients enrolled, most had gastric adenocarcinoma (93.6%) and metastatic disease (93.6%). All were evaluable for safety and efficacy. Two patients (2.6%) had partial responses and 25 patients (32.1%) had a best response of stable disease for ≥6 weeks. Median PFS was 2.3 months (95% confidence interval [CI], 1.6–2.6 months) and median OS was 6.8 months (95% CI, 4.4–9.6 months). Grade ≥3 thrombocytopenia and neutropenia were reported in 34.6% and 29.4% of patients, respectively, and the most common non-hematologic adverse events were fatigue, anorexia, nausea, diarrhea, and stomatitis. Pharmacokinetics of sunitinib and its active metabolite were consistent with previous reports. There were no marked associations between baseline soluble protein levels, or changes from baseline, and measures of clinical outcome. <I>Conclusions</I>. The progression-delaying effect and manageable toxicity observed with sunitinib in this study suggest that although single-agent sunitinib has insufficient clinical value as second-line treatment for advanced gastric cancer, its role in combination with chemotherapy merits further study.</P>