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High efficiency video coding (HEVC) is the newest video coding standard of the ITU-T Video Coding Experts Group and the ISO/IEC Moving Picture Experts Group. The introduction of multiple-input multiple-output (MIMO) eigenbeam-space division multiplexing (E-SDM) systems makes it possible to increase data rate by multiplexing different data streams on multiple parallel eigen-channels. In this paper, we propose a MIMO video transmission scheme for scalable high efficiency video coding (SHVC), which is the scalable extension of H.265/HEVC. Simulation results show that our video transmission scheme has more potential to broadcast video streams efficiently than conventional MIMO systems.

Background and aim This study aimed to elucidate whether interferon (IFN)-free direct-acting antiviral (DAA) therapy for hepatitis C after curative treatment of hepatocellular carcinoma (HCC) promotes HCC recurrence in a real-world large-scale cohort. Methods This multicenter study was conducted by the Japanese Red Cross Hospital Liver Study Group. This retrospective study analyzed 516 patients who underwent antiviral treatment for hepatitis C with either IFN (n = 148) or IFN-free DAA (n = 368) after curative HCC treatment; 78 IFN-treated patients and 347 IFN-free DAA-treated patients achieved sustained virological response (SVR). The recurrence rate of HCC was compared between the antiviral therapies. Logistic analysis and Cox proportional hazards analysis identified factors associated with early recurrence of HCC within 24 weeks of antiviral therapy and recurrence throughout the observation period, respectively. Results AFP at the completion of antiviral therapy, clinical stage of HCC, and non-SVR were independent factors associated with early recurrence of HCC. Among patients who had achieved SVR, the clinical stage of HCC and the level of AFP at completion of antiviral therapy were independent factors associated with early recurrence of HCC. For recurrence throughout the observation period in SVR patients, AFP at completion of antiviral therapy, duration between last HCC treatment to antiviral therapy, and the number of treatments were independent factors. There was no significant difference in the rate of early recurrence of HCC or recurrence throughout the observation period between IFN and IFN-free DAA treated patients. Conclusions There were no differences in the early recurrence rate of HCC between patients who underwent IFN and those who underwent IFN-free DAA as antiviral therapies.

Significant associations of HLA-DP alleles with chronic hepatitis B (CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1(*) 05:01 and (*) 09:01, and three protective alleles, DPB1(*) 02:01, (*) 04:01, and (*) 04:02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02:01, *04:01, and *04:02) and the susceptible allele DPB1*05:01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules.

Aim The presence of resistance-associated variants (RAV) may attenuate the efficacy of direct-acting antivirals (DAA) in combination therapy for hepatitis C. The aim of this study was to characterize the NS3 and NS5A regions of hepatitis C virus (HCV) in naturally occurring RAV. Methods The NS3 and NS5A regions of HCV were amplified by nested polymerase chain reaction and their nucleotide sequences were determined by direct sequencing in 493 genotype 1b patients naive to DAA-based therapies. The effect of baseline RAV on response to pegylated interferon and ribavirin therapy was analyzed in 65 patients after stratification by interleukin (IL)-28B genotype. Results The incidence of RAV was 7.9% in NS3 (V36I/L, 1.2%; T54S, 2.8%; Q80K/R, 3.0%; A156S, 0.2%; and D168E/T, 2.4%) and 20.2% in NS5A (L31I/M, 2.2%; and Y93H, 19.0%). The incidence in interferon experienced and naive patients was similar. The incidence of Y93H in NS5A was significantly higher in the IL-28B TT genotype (rs8099917) than non-TT (27.1% vs 9.5%, P

We performed a prospective study to evaluate the ability of L-carnitine, which is involved in the β-oxidation of fatty acids, to reduce muscle cramps in patients with cirrhosis. Consecutive patients with cirrhosis and muscle cramps were given L-carnitine 300 mg, 3 times/day (900 mg/day, n = 19) or 4 times/day (1200 mg/day, n = 23) for 8 weeks. The frequency of muscle cramps was assessed by questionnaires, and the degree of muscle cramping was assessed by using the visual analogue scale (VAS). Muscle cramping was reduced in 88.1% of all subjects at the end of the 8-week study period and disappeared for 28.6% of patients. Overall VAS scores decreased significantly from 69.9 ± 22.5 at baseline to 26.2 ± 29.1 after 8 weeks (P .0001). The dose of L-carnitine was significantly associated with percentages of patients with reduced muscle cramps after 8 weeks (43.5% in the 1200 mg/day group vs 10.5% in the 900 mg/day group, P = .037) and VAS scores at 8 weeks (9.9 ± 13.5 in the 1200 mg/day group vs 39.6 ± 31.9 in the 900 mg/day group, P = .003). No adverse events were reported. Therefore, L-carnitine appears to be safe and effective for reducing liver cramps in patients with cirrhosis.

Background and Objectives The optimal cutoff of each value in configuring selection criteria for pre-transplant assessment of hepatocellular carcinoma (HCC) remains uncertain. Methods To build a predictive model for recurrent HCC, we performed data mining analysis on patients who underwent LT for HCC at University Health Network (n = 246). The model was externally validated using a cohort from the Scientific Registry of Transplant Recipients (SRTR) database (n = 9,769). Results Among 246 patients, 14.6% (n = 36) experienced recurrent HCC within 2.5 years post-LT. The risk prediction model for recurrent HCC identified two subgroups with low-risk (total tumor diameter [TTD] 4 cm and/or AFP >73 ng/ml, n = 111). The reproducibility of the model was validated through the SRTR database; overall patient survival rate was significantly better in low-risk group than high-risk group (P

Aim To investigate, in a large number of cases at multiple institutions, the effects and limitations of antiviral therapy for hepatitis C following treatment of hepatocellular carcinoma (HCC) in clinical practice. Methods Retrospective analysis was performed of 112 patients who had received interferon (IFN) for treating hepatitis C following treatment of HCC and were registered with the Japanese Red Cross Liver Study Group. Factors that may influence recurrence and survival rates were investigated. Results Factors involved in prevention of recurrence were: surgical resection as HCC treatment, platelet and α-fetoprotein (AFP) levels prior to IFN administration, IFN adherence and post-IFN AFP level. Multivariate analysis showed post-IFN AFP level to be an independent factor. Factors involved in prolonging survival were: IFN adherence, IFN response (sustained viral response), pre-IFN alanine aminotransferase and AFP levels, post-IFN AFP level and absence of recurrence. Multivariate analysis showed absence of recurrence to be an independent factor. Although IFN adherence was involved in recurrence and survival, ribavirin adherence was not. IFN was suggested to be involved in preventing recurrence and improving survival due not only to its anti-viral effect, but also its antitumor effect. Conclusion Although complete prevention of HCC recurrence is difficult, the most important factor affecting first recurrence is the AFP level at 6 months after the conclusion of antiviral treatment. The survival rate improves dramatically if the hepatitis C virus is eliminated, but the most important factor for improving survival is absence of recurrence.

Aims Wisteria floribunda agglutinin (WFA)-positive human Mac-2-binding protein (WFA+-M2BP) is a new glycol marker related to liver fibrosis. The aim of the present study was to evaluate WFA+-M2BP as a predictor of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Methods This case–control study included 14 patients with chronic hepatitis C who developed HCC and 52controls, matched for age, gender, and fibrosis stage. WFA+-M2BP was measured at biopsy and follow-up. Time zero was set at the date of liver biopsy. Results WFA+-M2BP increased stepwise with progression of liver fibrosis (p < 0.001). Cumulative incidence of HCC development was significantly higher in patients with WFA+-M2BP ≥4.2 (p < 0.001) or in those with time-course changes in WFA+-M2BP (ΔWFA+-M2BP/year) ≥0.3 (p = 0.03). Multivariate analyses demonstrated that WFA+-M2BP ≥4.2 [hazard ratio (HR): 4.1, 95% confidence interval (CI): 1.1–15, p = 0.04], ΔWFA+-M2BP/year ≥0.3 (HR: 5.5, 95% CI: 1.5–19, p = 0.008), and AFP ≥10 ng/ml (HR: 4.7, 95% CI: 1.1–19, p = 0.03) were independent predictive factors of HCC development. Based on these data, we developed a simple scoring system to predict HCC development using these three factors. Using these scores, patients were classified into four groups; cumulative incidence of HCC development significantly increased with increasing scores (p < 0.001). Conclusions WFA+-M2BP measurements and time-course changes in WFA+-M2BP can be used to identify patients at high risk of HCC development. Real-time monitoring of WFA+-M2BP can be a novel predictor of HCC development.

Cytopenia during interferon-based (IFN-based) therapy for chronic hepatitis C (CHC) often necessitates reduction of doses of drugs and premature withdrawal from therapy resulting in poor response to treatment. To identify genetic variants associated with IFN-induced neutropenia, we conducted a genome-wide association study (GWAS) in 416 Japanese CHC patients receiving IFN-based therapy. Based on the results, we selected 192 candidate single nucleotide polymorphisms (SNPs) to carry out a replication analysis in an independent set of 404 subjects. The SNP rs2305482, located in the intron region of the PSMD3 gene on chromosome 17, showed a strong association when the results of GWAS and the replication stage were combined (OR = 2.18, P = 3.05 × 10(-7) in the allele frequency model). Logistic regression analysis showed that rs2305482 CC and neutrophil count at baseline were independent predictive factors for IFN-induced neutropenia (OR = 2.497, P = 0.0072 and OR = 0.998, P 0.0001, respectively). Furthermore, rs2305482 genotype was associated with the doses of pegylated interferon (PEG-IFN) that could be tolerated in hepatitis C virus genotype 1-infected patients treated with PEG-IFN plus ribavirin, but not with treatment efficacy. Our results suggest that genetic testing for this variant might be useful for establishing personalized drug dosing in order to minimize drug-induced adverse events.

To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV).A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken.The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non-HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and α-fetoprotein. Multivariate analysis revealed that viral load, α-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, α-fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared.For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, α-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome.

In this paper, we propose a positioning system using a time-synchronized wireless network that can achieve high positioning accuracy without being dependent on any global positioning system (GPS) devices with cm-level accuracy as the main goal and objective. The proposed system utilizes time of arrival (ToA) method to estimate the target's position. Based on the results, we can achieve time synchronization with less than 1ns accuracy with the average offset error of 0.05ns and cm-level positioning accuracy with the position error of 1.23cm through our simulation. Furthermore, increasing the number or measuring device in positioning system will increase the accuracy of positioning a target. High accuracy time synchronization is achievable by deploying proposed PTP with a high number of iteration performed inside the synchronization period. In this research, we aim to deploy the proposed system in industrial wireless LAN. It is applicable by embedding the system into customized wireless LAN chip with positioning ability.

Current and next generation WLAN devices have an increasing need for processing power to support new WLAN features that require high computation complexity. In this paper, we present our design for an 802.11ac/ax system with an application specific instruction-set processor (ASIP) to implement multiple disjoint system tasks at much faster speed compared to a general purpose processor. As a proof of concept, we implemented the channel SVD, channel compression/decompression and beam-forming weight computations at the same time in the embedded ASIP core to support the 802.11ac MU-MIMO beamforming feature. In addition, the design was synthesized in the Zynq zc706 evaluation board programmable logic (PL) along with the rest of the PHY. The actual task to be done by the ASIP core at any given time can be programmed via the zc706 processing system (PS) resulting in a very high hardware savings compared to an all hardware implementation.

The new use case of 5G network, such as industrial wireless control system and Machine-to-Machine (M2M) communication system, requires high reliability and real-time communication (ultra low-latency) at the same time. To increase system reliability, re-transmission scheme is one of popular technique, but it introduces a significant communication latency. To address this latency introduced by conventional re-transmission scheme, this paper presents re-transmission diversity through channel selectivity. Adjacent channel selection and random channel selection are the two channel selectivity schemes that are being considered as fast and low-latency channel selection method. The performance comparison of these two schemes are evaluated in an industrial wireless system. Evaluation results show that channel selectivity based on adjacent channel selection gives a better performance as compared with random channel selection. Furthermore, the impact of channel selectivity in different channel models are also presented to evaluate its effectiveness and to provide an insight for final deployment.

Recently, wireless technology experiences a fast growth to meet user demand and push toward the boundary limit of system performance. The simulation and verification framework play important role for accelerating investigation of technology proof of concept, field-trial, and large-scale commercial prototyping. In this paper, we present system-level simulation of heterogeneous model and unified HW/SW framework, particularly for next generation wireless system. The proposed framework includes a unified HW/SW co-evaluation methodology, the flexible HW/SW architecture, and fast HW/SW co-evaluation. The co-evaluation is carried out by employing hardware-in-the loop scheme that covers various abstraction level of simulation, from algorithm-level into physical-level simulation, with respect to system level simulation. The proposed co-verification framework allows a comprehensive system evaluation for a wireless system, involving various system parameters, hardware impairments, different channel conditions and cross-layer evaluations with fast run-time evaluations. Additionally, we also show an application example of multi-user wireless communication system and its experimental evaluations.

Image and video transmission is highly expected to proliferate with the wide spread of Wi-Fi devices and the introduction of multiple-input multiple-output (MIMO) systems. This paper proposes a novel precoder for video transmission in overloaded MIMO systems, which is based on an eigenbeam space division multiplexing (E-SDM) technique. This paper also proposes a low complexity postcoder, which detects some of data symbols by a linear approach and the others by a prevoting vector cancellation (PVC) approach. It is shown from simulation results that the proposed precoder and postcoder achieve 40 dB in peak signal-to-noise ratio while reducing the computational complexity by over 61 compared to the conventional PVC-based detection when received signal-to-noise ratio is higher than 10 dB.

Interleave division multiple access (IDMA) is a potential candidate for the future fifth generation (5G) systems. In this paper, we propose a novel architecture for IDMA system with low latency while maintaining low complexity. In the conventional architecture, the IDMA receiver sequentially processes deinterleaving, despreading, spreading and interleaving for multiuser detection. The proposed architecture, which is called the interleaved domain, can perform multi-user detection directly without deinterleaving the received frame. Because of this, the interleaving is no longer needed in the interference cancellation loop resulting in the decrease of latency by half and the increase of throughput by twice. In VLSI implementation results, the proposed architecture has reduced circuit area and power consumption by 53% and 58% compared to the conventional architecture on the same throughput condition.

Recently, 802.11ax has introduced uplink Orthogonal Frequency Division Multiple Access (UL OFDMA)-based random access transmission to provide uplink multiuser capability to stations (STA) with unknown buffer status. These STAs include those that are waking up from sleep and unassociated STAs trying to establish connection for the first time. Due to the absence of carrier sensing per resource unit, this procedure has a maximum efficiency of only about 37% for high number of STAs. The efficiency will decrease further without properly choosing the random access parameters. In this paper, we first build an analytical model of the performance of UL OFDMA random access transmission and verify it using simulations. In addition, we propose methods to optimize various random access parameters to maintain a system efficiency near the 37% limit. Simulation results show that our optimization methods can increase the throughput of UL OFDMA random access by as much as 39% when compared to randomly chosen parameters.

Intermediate-stage hepatocellular carcinoma varies widely in tumor burden and liver function. This study aimed to clarify the importance of subclassification by the up-to-seven criteria in both clinical course and liver function deterioration in such patients.We retrospectively analyzed 224 patients with Child-Pugh grade A who underwent initial transarterial chemoembolization (TACE) for hepatocellular carcinoma. Tumor downstaging to within the Milan criteria within 1 year and liver function worsening as Child-Pugh grade deterioration from A to B were analyzed.The median survival time was 35.8 months. Forty-five patients had no recurrence within 1 year after initial TACE. Of the 179 patients with at least one recurrence within a year, 44 (25%) achieved tumor downstaging to within the Milan criteria and showed significantly longer survival than non-downstaged ones (P = 0.02). Logistic regression univariate analysis revealed that up-to-seven criteria fulfillment was associated with tumor downstaging to within the Milan criteria (odds ratio 2.6; P = 0.007). The median deterioration time was 26.7 months. Multivariate analysis revealed that beyond the up-to-seven criteria (hazard ratio [HR] 1.9; P = 0.005) was an independent factor associated with Child-Pugh grade deterioration, along with serum albumin (HR 1.54; P = 0.01), serum bilirubin (HR 1.49; P = 0.02), and prothrombin time (HR 1.54; P = 0.04).The up-to-seven criteria had prognostic value and could predict non-critical recurrence and maintenance of Child-Pugh grade in patients who underwent initial conventional TACE.

Background Tolvaptan is vasopressin type 2 receptor antagonist that inhibits water reabsorption. It is used in combination with standard diuretics to treat ascites unresponsive to standard diuretic therapy or hyponatremia because of liver cirrhosis. This study evaluated the effectiveness and safety of tolvaptan in clinical practice and aimed to determine the factors related to its effectiveness. Methods Tolvaptan was administered to 88 consecutive cirrhotic patients with ascites unresponsive to standard diuretic therapy. An effective treatment response was a ≥2% reduction in body weight on day 7. The association of patient pretreatment characteristics with therapeutic effects was analyzed. Results Mean weight reduction on day 7 of tolvaptan therapy was −2.9% ± 3.2%, and treatment was effective in 52% of patients. Multivariate analysis revealed that spot urine Na/K ratio ≥2.5 at baseline was the only factor independently related to therapeutic effect, with an odds ratio of 7.85 (95% confidence interval 2.64–23.40, p = 0.0002). Weight reduction percentage on day 7 was −4.0% ± 2.8% in patients with spot urine Na/K ≥2.5, which was significantly greater than the 0.7% ± 2.7% loss in those with urine Na/K < 2.5 (p < 0.05). A spot urine Na/K ratio ≥2.5 had a sensitivity of 85% and specificity of 60% for predicting effective treatment. No adverse events of treatment led to treatment discontinuation. Conclusions Baseline spot urine Na/K was predictive of an effective response to tolvaptan therapy. It is simple to perform and readily available and might serve as an indicator of optimal timing of tolvaptan administration in patients with inadequate response to conventional Na diuretic therapy.

This paper proposes a fast and low-complexity retransmission scheme for Industrial WLAN system. The proposed scheme exploits the frequency diversity and employs channel selectivity in order to achieve high-reliability and low-latency communication. The channel selectivity is carried out instantly by re-scheduling sub-carrier allocation during OFDM transmission in order to obtain diversity gain. Evaluation results show that the performance of the proposed scheme in terms of system-error rate and achievable transmission throughput rate, are significantly improved from the conventional re-transmission scheme. Furthermore, the proposed method only need a minor modification in both of communication protocol and transceiver design from the existing Industrial WLAN system. Hence, the low-complexity transmission scheme could be realized in current OFDM-based wireless system.

Hepatitis C virus (HCV) infection is common in hemodialysis patients and worsens their prognosis, while antiviral therapy options are limited. Recently, clinical trial and real-world, small-scale studies have reported excellent responses to direct-acting antivirals in patients with advanced chronic kidney diseases. However, real-world, large-scale data were lacking. This large multicenter analysis included HCV-infected hemodialysis patients receiving combination therapy with a nonstructural protein 5A (NS5A) inhibitor, daclatasvir (DCV), and a protease inhibitor, asunaprevir (ASV). Twenty-three centers in Japan participated in this study of 123 hemodialysis patients with genotype 1 HCV infection, who received DCV/ASV combination therapy between November 2014 and March 2016. We collected and analyzed data relating to treatment outcome, baseline clinical information, laboratory measurements (during and after the treatment), and adverse events. Thirty-nine patients (31.7%) had advanced liver fibrosis, 12 (9.8%) had histories of hepatocellular carcinoma (HCC), and 18 (14.6%) had baseline resistance-associated variants (RAVs) of NS5A. The overall sustained virological response (SVR)12 rate was 95.9% (118/123). Notably, all patients with HCC and 94.4% (17/18) of those with NS5A RAVs achieved SVR12. Significant factors associated with non-SVR were advanced fibrosis and the interleukin-28B non-TT genotype at rs8099917. Four patients (3.3%) discontinued therapy because of adverse events including elevated serum alanine transaminase levels (n = 2), rash (n = 1), and HCC (n = 1); all of these achieved SVR12. This real-world, nationwide study revealed that DCV/ASV combination therapy was safe and highly effective for hemodialysis patients with genotype 1 HCV infections. This study was registered at the UMIN Clinical Trials Registry (UMIN000024227).

Multi-mode fast Fourier Transform (FFT) circuits are essential in orthogonal frequency domain (OFDM) based systems which supports multiple bandwidth. Typically, hardware implementation employs a single FFT circuit for the highest supported bandwidth and using oversampling, the same FFT circuit is used to support lower bandwidth. For the new 802.11ax wireless local area network (WLAN) standard whose frame consists of the regular 3.2us length symbol as well as a longer 12.8us symbol, a fast switchable double-mode FFT circuit is required. In addition, the 802.11ax SIG-B symbol contains a maximum of two independent symbol streams that requires two FFT circuits for the 3.2us symbol length. Our proposed FFT architecture is optimized to support the 802.11ax standard with low latency, area and power requirements. FPGA implementation results show that our proposed circuit has efficiency 13.7% lower area compared to conventional architecture.

In this paper, we propose a novel architecture for IDMA system with low latency and high throughput for the uplink multi-user wireless system. The throughput of the proposed IDMA system can be improved to about double compared to the conventional IDMA system while the hardware complexity remains unchanged. To achieve this, the proposed system utilizes the interleaver/de-interleaver-less architecture to minimize the latency of the interference canceller in IDMA receiver. In the conventional architecture, the IDMA receiver sequentially processes the de-interleaving, interleaving, de-spreading and spreading that cause high latency. The proposed architecture can perform these sequential processes at the same time resulting in a reduction of interference cancellation operation cycles in half.

Aim Some patients develop hepatocellular carcinoma (HCC) during nucleoside/nucleotide analog (NA) therapy even if alanine aminotransferase (ALT) or hepatitis B virus (HBV) DNA levels are sufficiently reduced. The aim of this study is to identify the risk factors of development of HCC during NA therapy. Methods Six hundred and two patients were analyzed who were continuously receiving NA for chronic HBV infection. The patients who developed HCC previously or within 1 year of therapy were excluded. In the patients studied, the median duration of therapy was 90 months. A total of 492 patients had chronic hepatitis (CH) and 110 had liver cirrhosis (LC). Results In 602 patients, the rate of normalization of ALT, loss of serum HBV DNA and development of HCC were 90.4%, 55.4%, and 6.1%, respectively. The significant risk factors of development of HCC were LC status and duration of therapy. The annual incidence of HCC in LC patients was 2.53%/year, compared with 0.34%/year in CH patients. When the relation between the incidence of HCC and the response to therapy was evaluated, in patients with normalization of ALT level, loss of HBV DNA by real-time polymerase chain reaction or hepatitis B e-antigen seroconversion, the incidences of HCC was reduced to some extent. However, none of the patients who achieved hepatitis B surface antigen (HBsAg) seroclearance during NA therapy developed HCC. Conclusion LC status was the significant risk factor of development of HCC during NA therapy. However, none of the patients who showed HBsAg seroclearance developed HCC. The ultimate goal of therapy for reduced risk of HCC may be HBsAg seroclearance.

Aim To investigate the relation between systemic complications of non-alcoholic fatty liver disease (NAFLD) and non-invasive fibrosis scores. Methods The NAFLD fibrosis score (NFS) and FIB-4 were measured in 1559 people who underwent a complete medical checkup at our hospital and were followed for more than 3 years. Correlation between these scores and prevalence and new incidence rates of diabetes or cerebral–cardiovascular diseases were analyzed. Results The 1559 cases were classified into two groups using the low cut-off values of NFS and FIB-4: group 1 (≥low cut-off score with fatty liver) and group 2 (the others). In group 1, the prevalence of diabetes and cerebral–cardiovascular diseases at baseline and additional incidences during the observation period was higher compared with group 2. Diabetes at baseline in group 1 versus group 2 were 31.5% versus 3.1% (NFS, P

Aim To investigate whether the patients with hypovascular liver nodules determined on the arterial phase and hypointensity on the hepatocyte phase gadoxetic acid-enhanced magnetic resonance imaging (hypovascular hypointense nodules) are at increased risk of hepatocarcinogenesis, we assessed subsequent typical hepatocellular carcinoma (HCC) development at any sites of the liver with and without such nodules. Methods One hundred and twenty-seven patients with chronic hepatitis B or C and without a history of HCC, including 68 with liver cirrhosis, were divided into those with (non-clean liver group, n = 18) and without (clean liver group, n = 109) hypovascular hypointense nodules. All the patients were followed up for 3 years, and HCC development rates and risk factors were analyzed with the Kaplan–Meier method and the Cox proportional hazard model, respectively. Results A total of 17 patients (10 in the non-clean liver group and seven in the clean liver group) developed typical HCC. Cumulative 3-year rates of HCC development were 55.5% in the non-clean liver group and 6.4% in the clean liver group (P

Objectives: Recent reports indicated that reduced SLC22A7 (a gene-encoding organic anion transporter 2) expression in noncancerous liver tissue predicts hepatocellular carcinoma (HCC) recurrence after curative resection. Our study aimed to elucidate the association between SLC22A7 expression and HCC development in chronic hepatitis C patients. Methods: HCC recurrence after local ablation therapy and SLC22A7 expression in noncancerous liver tissue were analyzed in 20 patients. Subsequently, the association between de novo HCC development and SLC22A7 expression was examined at baseline in 38 hepatitis C patients without HCC who subsequently developed HCC as well as in 76 hepatitis C patients who did not develop HCC and were matched for age, gender and stage of fibrosis. Results: In the patients whose HCC had been cured, reduced SLC22A7 expression in noncancerous liver tissue was significantly associated with a high incidence of multifocal HCC recurrence. In patients without HCC at baseline, cumulative incidence of de novo HCC development was significantly higher with a reduced SLC22A7 expression than with a normal expression (p = 0.01). This difference remained significant among patients without known risk factors for HCC like age and advanced fibrosis. Conclusion: Reduced SLC22A7 expression in the liver indicates a significant risk for HCC development in chronic hepatitis C, independently of other risk factors.

Background The efficacy and safety of lenvatinib (LEN) are unknown in cases that were excluded in the phase III trial (REFLECT trial) of LEN, including those who experienced tyrosine kinase inhibitors (TKI) before LEN. In addition, no evidence has been established for early introduction of molecular targeted therapy in BCLC stage B patients. Therefore, we verified the efficacy and safety in the patients who did not meet the inclusion criteria of REFLECT trial and those who were BCLC Stage B. Methods A total of 203 patients received LEN from March 2018 to January 2019 at 21 sites in Japanese Red Cross Study Liver Group were registered. 128 cases out of REFLECT trial criteria and 74 cases of BCLC Stage B were retrospectively investigated. Tumors assessments in accordance with modified RECIST were done using dynamic CT and/or MRI. Results 128 of 203 (63%) patients did not meet the inclusion criteria of the REFLECT trial. These cases included 69 receiving TKI therapy before LEN. The ORR and DCR in TKI naive were 45% and 84%, respectively, and were 29% and 81% in TKI experienced (p = 0.072, p = 0.671). The OS between TKI naive and experienced patients was not significantly different (p = 0.618), even though baseline albumin level and ALBI score were significantly lower in TKI experienced patients than TKI naive (p = 0.001 and 0.005). 74 cases of BCLC Stage B included 57 with TACE history, 8 without, and 9 cases unknown. Although there was no difference between two groups in the baseline Child-Pugh score, ALBI score and AFP value, patients with TACE less than 6 times (n = 53) before LEN was significantly better in OS than those with TACE of 6 times or more (n = 12) (p = 0.025). Conclusions Also in TKI experienced which was excluded from the REFLECT trial, ORR, DCR and OS did not differ from TKI naive, and LEN may be useful as TKI 2nd line and 3rd line. In BCLC Stage B patients, TACE group less than 6 times has a better prognosis after LEN treatment compared with group more than 6 times, and an early introduction of LEN for multiple TACE cases may contribute to life prognosis improvement is there. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

e15629 Background: Lenvatinib (LEN) has been approved as a single agent for patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. We conducted a nationwide multicenter study and especially focused on the efficacy and safety in the patients who did not meet the inclusion criteria of the phase 3 trial (REFLECT trial). Methods: A total of 202 patients received LEN from March 2018 at 21 sites in Japan was registered. Tumour assessments in accordance with modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Adverse events (AEs) were graded according to the CTCAE ver4.0. Results: In this study, 128 of 202 (63%) patients did not meet the inclusion criteria of the REFLECT trial. For the reasons, 69 patients received TKI therapy before LEN, 37 patients were Child-Pugh B, 6 patients showed main portal vein invasion,13 patients had HCC which occupied ≥ 50% of liver, and 22 patients were with lower platelet ( < 75 × 10⁹ per L) . Median observation time was 4.1 months in all patients, 22 patients died, and median overall survival (OS) was not reached. As the 2nd-line therapy (after sorafenib), 45 patients received LEN and 24 patients did as the 3rd-line (after regorafenib). The OS between TKI naïve and experienced patients was not significantly different, even though baseline albumin level and ALBI score were significantly lower in TKI experienced patients than TKI naïve (p = 0.001 and 0.005). Objective response rate (ORR) and disease control rate (DCR) of TKI naïve patients were 37% and 84%, while those of TKI experienced were 27% and 76%. Child-Pugh B patients (n = 36) had significantly shorter OS than Child-Pugh A (p = 0.01) and median OS in Child-Pugh B patients was 6.1 months. Drug discontinuation due to AEs and elevated aspartate aminotransferase were significantly higher in Child-Pugh B patients (p = 0.005 and 0.001). The OS, treatment duration and drug discontinuation were not significantly different between patients with or without lower platelets. ORR and DCR in patients with lower platelets (n = 22) were 18% and 63%. Conclusions: The response rate of LEN in patients who experienced TKI therapies was similar to that in TKI naïve patients. The median OS in Child-Pugh B patients was 6.1 months and elevated aspartate aminotransferase during LEN was frequently reported in such patients. The OS and treatment duration were not significantly different between patients with or without lower platelets at the cut off of < 75 × 10⁹ per L.

4072 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of advanced/metastatic (a/m) hepatocellular carcinoma (HCC). Avelumab is a human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a tyrosine kinase inhibitor selective for VEGF receptors 1/2/3. VEGF Liver 100 (NCT03289533) is a phase 1b study evaluating safety and efficacy of avelumab + axitinib in treatment-naive patients (pts) with HCC; interim results are reported here. Methods: Eligible pts had confirmed a/m HCC, ≥1 measurable lesion, a fresh or archival tumor specimen, ECOG PS ≤1, and Child-Pugh class A. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and objective response (RECIST v1.1; modified [m] RECIST for HCC). Results: Interim assessment was performed after a minimum follow up of 6 months based on the released study data set (clinical cut-off date: Aug 1, 2018). As of the cut-off date, 22 pts (median age: 68.5 y) were treated with avelumab (median: 20.0 wk) and axitinib (median: 19.9 wk). The most common grade 3 treatment-related adverse events (TRAEs) (≥10% of patients) were hypertension (50.0%) and hand-foot syndrome (22.7%); no grade 4/5 TRAEs were reported. Immune-related AEs (irAEs) (≥10% of pts) were hypothyroidism (31.8%) and hyperthyroidism (13.6%). No grade ≥3 irAEs were reported; no pts discontinued treatment due to TRAEs or irAEs. Based on Waterfall plot calculations, tumor shrinkage was observed in 15 (68.2%) and 16 (72.7%) pts by RECIST and mRECIST, respectively. ORR was 13.6% (95% CI, 2.9%-34.9%) and 31.8% (95% CI, 13.9%-54.9%) by RECIST and mRECIST, respectively. OS data were immature at data cutoff. Conclusions: The preliminary safety of avelumab + axitinib in HCC is manageable and consistent with the known safety profiles of avelumab and axitinib when administered as monotherapies. This study demonstrates antitumor activity of the combination in HCC. Follow-up is ongoing. Clinical trial information: NCT03289533. [Table: see text]

e15639 Background: Tyrosine kinase inhibitors (TKI) are important treatment options for unresectable hepatocellular carcinoma (HCC). The survival benefit of sorafernib was demonstrated not only in advanced stage but also for BCLC-B intermediate stage who are refractory to transcatheter arterial chemoembolization by OPTIMIS study. Skeletal muscle mass depletion (Myopenia) is a poor prognostic factor in HCC treated by resection or loco-reginal ablation, but its effect on survival in TKI treated patients, especially in those within BCLC-B stage remains unclear. The aim of the present study is to elucidate the impact of myopenia on survival among HCC treated with sorafenib, especially in BCLC-B stage. Methods: In 213 patients who started treatment with sorafenib between 2009 and 2016, myopenia at baseline was determined by using skeletal muscle index calculated from CT images of the third lumber vertebra level. The impact of myopenia on survival was analyzed in whole patients, after stratification by BCLC stage, and after matching for backgrounds within BCLC-B patients. Results: The median survival in whole, BCLC-C, and –B was 13.7, 8.7 and 15.2 months, respectively. Myopenia was not a significant prognostic factor in whole patients and in BCLC-C stage. However, among BCLC-B patients (n = 104), survival was significantly better in patients with no myopenia (p = 0.05). Among them, 85 patients who continued sorafenib for more than 8 weeks were extracted and those with or without myopenia were matched for backgrounds by propensity score. Backgrounds including etiology, Child-Pugh score, BMI, AFP and PIVKA-Ⅱwas not different between myopenia (n = 30) and no myopenia group (n = 30) after matching. The overall survival at 6-, 12-, and 24-months was 96%, 74%, and 62% in no myopenia group which was significantly better compared to 89%, 64%, and 28% in myopenia group (p = 0.019). The hazard ratio was 2.12 (95% CI 1.11-4.03). Conclusions: Absence of myopenia predicts favorable outcome in sorafenib treated HCC patients within BCLC-B intermediate stage.

323 Background: Sorafenib, approved in Japan in 2009, is the first systemic therapy demonstrated to significantly improve overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). In Japan, hepatic arterial infusion chemotherapy (HAIC), which directly delivers high concentrations of cytotoxic agents to liver tumors, has been offered to patients with advanced HCC since before sorafenib was approved. HAIC is particularly used in patients without extrahepatic metastases (EHM). This study aimed to compare the outcomes of patients with advanced HCC who received HAIC and sorafenib. Methods: Consecutive patients with advanced HCC who received sorafenib or HAIC as the first-line systemic therapy were enrolled from 10 Japanese centers. The statistical analysis plan included pre-defined propensity score matching method and risk factors. All statistical analyses were performed by an independent biostatistician. Results: Between June 2009 and May 2016, 2006 patients were enrolled (sorafenib: 1465 patients, HAIC: 541 patients). The mean OS of patients with macrovascular invasion (MVI) and without EHM was significant longer in the HAIC group compared with the sorafenib group. After propensity score matching, there were 172 patients in each cohort. The OS was 9.1 months for the sorafenib group and 10.1 months for the HAIC group (hazard ratio [HR]: 0.668 [95% CI: 0.475–0.935], P = 0.018). There was no significant difference in OS between patients without both MVI and EHM. After propensity score matching, there were 76 patients in each cohort. The OS was 15.4 months for the sorafenib group and 12.2 months for the HAIC group (hazard ratio [HR]: 1.227 [95% CI: 0.699–2.155], P = 0.475). Conclusions: HAIC might be a potential initial treatment for patients with advanced HCC with MVI (without EHM). Currently, several new drugs appear clinically beneficial for patients with advanced HCC. Although this study only focused on sorafenib as the chemo-agent, additional studies should be conducted to confirm the benefits associated with HAIC in a limited population of patients with advanced HCC.

364 Background: Lenvatinib(LEN) has been approved as a single agent for patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. A few results from a large sample size cohort of LEN therapy in real world practice has been reported. Therefore, we performed a retrospective nationwide multicenter study. Methods: A total of 116 u-HCC patients received LEN from March 2018 at 14 sites in Japan were registered. Tumour assessments in accordance with RECICT ver1.1 and modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Adverse events (AEs) were graded according to the CTCAE ver4.0. Results: Median age was 72 (46-91)years, 88 (75.9%) patients were male, and median body weight was 60 (30-94) kg. The baseline liver function was Child-Pugh class A in 106 (91.4%) patients. Seventy-three (62.9%) patients were BCLC stage C. As the 2nd-line therapy (after sorafenib), 28 (24.1%) patients received LEN and 17 (14.7%) patients did as the 3rd-line (after regorafenib). Median observation time was 2.5 months and one patient died from HCC progression. The imaging findings of 49 (42.2%) patients were evaluated at 4-8weeks. Based on mRECIST, CR was shown in 3 (6.1%), PR in 14 (28.6%), SD in 23 (46.9%), and PD in 6 (12.2%). In the 3 patients, target lesions of liver showed PR, however bone metastases had progressed. [overall response rate (ORR) 34.7%, disease control rate (DCR) 81.6%]. ORR and DCR of tyrosine kinase inhibitor (TKI) naïve patients (n = 26) were 34.6% and 80.8%, while those of TKI experienced (n = 23) were 34.8% and 82.6%. The most common any-grade AEs were hypertension (52.0%), diarrhoea (32.1%), decreased appetite (63.5%) and fatigue (49.4%). Hand-food skin reaction (HFSR) was observed in 28% of patients. Conclusions: The efficacy of LEN therapy in real world practice in Japan was similar to the phase 3 clinical trial, even though elderly patients with lower body weight were included in this study. The incidence of HFSR during LEN in real world practice was lower than that of the sorafenib group in the phase 3 trial of LEN. Decrease appetite and fatigue must be carefully monitored and managed during LEN therapy.

The proportion of patients who progress to chronicity following acute hepatitis B (AHB) varies widely worldwide. Moreover, the association between viral persistence after AHB and hepatitis B virus (HBV) genotypes in adults remains unclear. A nationwide multicenter study was conducted throughout Japan to evaluate the influence of clinical and virological factors on chronic outcomes in patients with AHB. For comparing factors between AHB patients with viral persistence and those with self-limited infection, 212 AHB patients without human immunodeficiency virus (HIV) coinfection were observed in 38 liver centers until serum hepatitis B surface antigen (HBsAg) disappeared or a minimum of 6 months in cases where HBsAg persisted. The time to disappearance of HBsAg was significantly longer for genotype A patients than that of patients infected with non-A genotypes. When chronicity was defined as the persistence of HBsAg positivity for more than 6 or 12 months, the rate of progression to chronicity was higher in patients with genotype A, although many cases caused by genotype A were prolonged cases of AHB, rather than chronic infection. Multivariate logistic regression analysis revealed only genotype A was independently associated with viral persistence following AHB. A higher peak level of HBV DNA and a lower peak of alanine aminotransferase (ALT) levels were characteristics of AHB caused by genotype A. Treatment with nucleotide analogs (NAs) did not prevent progression to chronic infection following AHB overall. Subanalysis suggested early NA initiation may enhance the viral clearance. Conclusion: Genotype A was an independent risk factor for progression to chronic infection following AHB. Our data will be useful in elucidating the association between viral persistence after AHB, host genetic factors, and treatment with NAs in future studies. (Hepatology 2014;58:89–97)