Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase ½ dose escalation and expansion trial

El-Khoueiry, A.B.,Sangro, B.,Yau, T.,Crocenzi, T.S.,Kudo, M.,Hsu, C.,Kim, T.Y.,Choo, S.P.,Trojan, J.,Welling, T.H.,Meyer, T.,Kang, Y.K.,Yeo, W.,Chopra, A.,Anderson, J.,dela Cruz, C.,Lang, L.,Neely, J. J. Onwhyn ; Elsevier Science Ltd 2017 The Lancet Vol.389 No.10088

Background: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. Methods: We did a phase ½, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. Findings: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade ¾ treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. Interpretation: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. Funding: Bristol-Myers Squibb.

Applying Multi-Oversampling to One-Comparator Counter-Based Sampling to Enhance System Stability

Y. T. Yau,K. I. Hwu,C. W. Wang,Jenn-Jong Shieh 전력전자학회 2019 ICPE(ISPE)논문집 Vol.2019 No.5

This paper presents a novel method to enhance the system stability of a digital controller for a switching power converter under one-comparator counter-based sampling based on higher sampling frequency. However, the sampling rate and the hardware are not changed. The measured results of the proposed strategy are presented to demonstrate this concept.

System Clock Reduction Based on Multiple Sampling for Digital Switching Power Supplies

Y. T. Yau,K. I. Hwu,W. Z. Jiang 전력전자학회 2015 ICPE(ISPE)논문집 Vol.2015 No.6

In this paper, the proposed sampling structure based on one-comparator sampling is presented, which can significantly reduce the system clock frequency from 100MHz to 25MHz, so as to reduce chip area. This method is verified by a synchronously-rectified buck converter with a switching frequency of 200kHz, and the digital controller takes as a control kernel the EP1C3T100 FPGA created by Altera Co., along with the VHDL language to program this controller.

Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma

Kang, Y.-K.,Yau, T.,Park, J.-W.,Lim, H. Y.,Lee, T.-Y.,Obi, S.,Chan, S. L.,Qin, SK.,Kim, R. D.,Casey, M.,Chen, C.,Bhattacharyya, H.,Williams, J. A.,Valota, O.,Chakrabarti, D.,Kudo, M. Oxford University Press 2015 Annals of oncology Vol.26 No.12

<P>Axitinib plus best supportive care failed to meet the primary end point of overall survival in second-line treatment of advanced hepatocellular carcinoma in a randomized phase II study. However, the axitinib arm showed substantially improved progression-free survival, time to tumour progression, and clinical benefit rate compared with the placebo arm, with acceptable safety profile. Background: The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Patients and methods: Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS). Results: The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival. Conclusions: Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC. Trial Registration: ClinicalTrials.gov, NCT01210495.</P>

Fundamental investigation of micro-scale wear characteristics of ultra-fine gold wires under low contact force and long sliding distance

Yau, S.Y.,Kim, T.H.,Yoo, S.S.,Kim, D.E. Elsevier Sequoia [etc.] 2016 Wear: An international journal on the science and Vol.348 No.-

<P>Micro-scale wear characteristics of ultra-fine gold wires with a diameter of 28 pm was investigated under a low contact force over a long sliding distance up to 200 km. The tip of the wire was slid against a silicon wafer under a low normal force of 5 mu N. Wear of the gold wire was quantified from the images of the tip obtained by a 3D laser microscope and a scanning electron microscope before and after the wear test. The dimensionless Archard relationship wear coefficient was in the order of 10(-7) which was extremely low considering that sliding was carried out in dry condition. Such a low wear characteristics was attributed to low contact pressure that could be achieved by formation of a conformal contact due to flattening of the wire tip as sliding wear progressed. Wear behavior of the gold wire could be characterized by formation of thin flakes of wear debris that were generated as a result of adhesive shear stress imparted at the sliding interface. As an effort to reduce the wear coefficient even further, octadecyltrichlorosilane self-assembled monolayer was deposited on the silicon to serve as a nano-lubricant. It was effective in improving the wear resistance by about two-fold. (C) 2015 Elsevier B.V. All rights reserved.</P>

저하중 접촉에서 미세 글라스볼의 마모 특성

수이(S.Y. Yau),유신성(S.S. Yoo),김태형(T. H. Kim),김대은(D. E. Kim) 한국트라이볼로지학회 2014 한국트라이볼로지학회 학술대회 Vol.2014 No.10

Evolution of Diabetes Care in Hong Kong: From the Hong Kong Diabetes Register to JADE-PEARL Program to RAMP and PEP Program

Ivy H.Y. Ng,Kitty K.T. Cheung,Tiffany T.L. Yau,Elaine Chow,Risa Ozaki,Juliana CN Chan 대한내분비학회 2018 Endocrinology and metabolism Vol.33 No.1

The rapid increase in diabetes prevalence globally has contributed to large increases in health care expenditure on diabetic complications,posing a major health burden to countries worldwide. Asians are commonly observed to have poorer β-cell function and greaterinsulin resistance compared to the Caucasian population, which is attributed by their lower lean body mass and central obesity. This “double phenotype” as well as the rising prevalence of young onset diabetes in Asia has placed Asians with diabetes at high riskof cardiovascular and renal complications, with cancer emerging as an important cause of morbidity and mortality. The experiencefrom Hong Kong had demonstrated that a multifaceted approach, involving team-based integrated care, information technologicaladvances, and patient empowerment programs were able to reduce the incidence of diabetic complications, hospitalizations, andmortality. System change and public policies to enhance implementation of such programs may provide solutions to combat the burgeoninghealth problem of diabetes at a societal level.