Non-liver-related mortality in the DAA era: Insights from post-SVR patients with and without previous HCC history.

BACKGROUND AND AIMS: Mortality after sustained virological response (SVR) with interferon-free direct-acting antiviral (IFN-free DAA) therapy is crucial for optimizing post-SVR patient care, but it remains unclear, especially regarding non-liver-related mortality. METHODS: Consecutive post-SVR patients from 14 institutions were stratified into three cohorts: A (without advanced fibrosis and without prior HCC), B (with advanced fibrosis and without prior HCC), and C (curative HCC treatment). We assessed mortality (per 1000 person-years [/1000PY]) post-SVR. Mortality rates were compared between cohorts A and B and the general population using age- and sex-adjusted standardized mortality ratio (SMR). Comparison of survival between each cohort was performed using propensity-score (PS) matching with sex, age, and comorbidity. RESULTS: In cohort A (n = 762; median age, 65 years), 22 patients died (median follow-up, 36 months); all-cause mortality was 10.0/1000PY, with 86.4% non-liver-related deaths. In cohort B (n = 519; median age, 73 years), 27 patients died (median follow-up, 39 months); all-cause mortality was 16.7/1000PY, with 88.9% non-liver-related deaths. In both cohorts, malignant neoplasm was the most common cause of death; all-cause mortality was comparable to that of the general population (SMR: 0.96 and 0.92). In cohort C (n = 108; median age, 75 years), 15 patients died (median follow-up, 51 months); all-cause mortality was 36.0/1000PY, with 53.3% liver-related deaths. PS matching showed no significant survival differences between cohorts A and B, both of which had better survival than cohort C. CONCLUSIONS: Mortality varies based on HCC history in the DAA era; nevertheless, attention should be paid to non-liver-related deaths in all post-SVR patients.

Analytical and Physical Investigation on Source Resistance in InxGa1-xAs Quantum-Well High-Electron-Mobility Transistors.

We present a fully analytical model and physical investigation on the source resistance (RS) in InxGa1-xAs quantum-well high-electron mobility transistors based on a three-layer TLM system. The RS model in this work was derived by solving the coupled quadratic differential equations for each current component with appropriate boundary conditions, requiring only six physical and geometrical parameters, including ohmic contact resistivity (ρc), barrier tunneling resistivity (ρbarrier), sheet resistances of the cap and channel regions (Rsh_cap and Rsh_ch), side-recessed length (Lside) and gate-to-source length (Lgs). To extract each model parameter, we fabricated two different TLM structures, such as cap-TLM and recessed-TLM. The developed RS model in this work was in excellent agreement with the RS values measured from the two TLM devices and previously reported short-Lg HEMT devices. The findings in this work revealed that barrier tunneling resistivity already played a critical role in reducing the value of RS in state-of-the-art HEMTs. Unless the barrier tunneling resistivity is reduced considerably, innovative engineering on the ohmic contact characteristics and gate-to-source spacing would only marginally improve the device performance.

Explicit Thermal Resistance Model of Self-Heating Effects of AlGaN/GaN HEMTs with Linear and Non-Linear Thermal Conductivity.

We presented an explicit empirical model of the thermal resistance of AlGaN/GaN high-electron-mobility transistors on three distinct substrates, including sapphire, SiC, and Si. This model considered both a linear and non-linear thermal resistance model of AlGaN/GaN HEMT, the thickness of the host substrate layers, and the gate length and width. The non-linear nature of channel temperature-visible at the high-power dissipation stage-along with linear dependency, was constructed within a single equation. Comparisons with the channel temperature measurement procedure (DC) and charge-control-based device modeling were performed to verify the model's validity, and the results were in favorable agreement with the observed model data, with only a 1.5% error rate compared to the measurement data. An agile expression for the channel temperature is also important for designing power devices and monolithic microwave integrated circuits. The suggested approach provides several techniques for investigation that could otherwise be impractical or unattainable when utilizing time-consuming numerical simulations.

A quantitative approach for trap analysis between Al0.25Ga0.75N and GaN in high electron mobility transistors.

The characteristics of traps between the Al0.25Ga0.75N barrier and the GaN channel layer in a high-electron-mobility-transistors (HEMTs) were investigated. The interface traps at the Al0.25Ga0.75N/GaN interface as well as the border traps were experimentally analyzed because the Al0.25Ga0.75N barrier layer functions as a dielectric owing to its high dielectric constant. The interface trap density Dit and border trap density Nbt were extracted from a long-channel field-effect transistor (FET), conventionally known as a FATFET structure, via frequency-dependent capacitance-voltage (C-V) and conductance-voltage (G-V) measurements. The minimum Dit value extracted by the conventional conductance method was 2.5 × 1012 cm-2·eV-1, which agreed well with the actual transistor subthreshold swing of around 142 mV·dec-1. The border trap density Nbt was also extracted from the frequency-dependent C-V characteristics using the distributed circuit model, and the extracted value was 1.5 × 1019 cm-3·eV-1. Low-frequency (1/f) noise measurement provided a clearer picture of the trapping-detrapping phenomena in the Al0.25Ga0.75N layer. The value of the border trap density extracted using the carrier-number-fluctuation (CNF) model was 1.3 × 1019 cm-3·eV-1, which is of a similar level to the extracted value from the distributed circuit model.

Low Infection of Phelipanche aegyptiaca in Micro-Tom Mutants Deficient in CAROTENOIDCLEAVAGE DIOXYGENASE 8.

Strigolactones (SLs), a group of plant hormones, induce germination of root-parasitic plants and inhibit shoot branching in many plants. Shoot branching is an important trait that affects the number and quality of flowers and fruits. Root-parasitic plants, such as Phelipanche spp., infect tomato roots and cause economic damage in Europe and North Africa-hence why resistant tomato cultivars are needed. In this study, we found carotenoid cleavage dioxygenase 8-defective mutants of Micro-Tom tomato (slccd8) by the "targeting induced local lesions in genomes" (TILLING) method. The mutants showed excess branching, which was suppressed by exogenously applied SL. Grafting shoot scions of the slccd8 mutants onto wild-type (WT) rootstocks restored normal branching in the scions. The levels of endogenous orobanchol and solanacol in WT were enough detectable, whereas that in the slccd8 mutants were below the detection limit of quantification analysis. Accordingly, root exudates of the slccd8 mutants hardly stimulated seed germination of root parasitic plants. In addition, SL deficiency did not critically affect the fruit traits of Micro-Tom. Using a rhizotron system, we also found that Phelipanche aegyptiaca infection was lower in the slccd8 mutants than in wild-type Micro-Tom because of the low germination. We propose that the slccd8 mutants might be useful as new tomato lines resistant to P. aegyptiaca.

Frequency of elevated biomarkers in patients with cryptogenic hepatocellular carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) continues to increase in Japan, but the clinical characteristics of Japanese patients with HCC have not been well described. The aim of this study was to determine the frequencies and utilities of elevated a-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) levels as biomarkers in cryptogenic HCC. MATERIAL/METHODS: A total of 2638 patients with HCC diagnosed between 1999 and 2010 in the Nagasaki Association Study of Liver (NASLD) were recruited for this study. The cause of HCC was categorized into 4 groups; HCC-B, HCC-C, HCC-BC, and HCC-nonBC. The significance of factors was examined for HCC-nonBC using logistic regression analysis in all patients. RESULTS: Multivariate analysis identified age, sex, BMI, alcohol consumption, platelet count, AST, ALT, AFP, DCP, and TNM stage as independent and significant risk factors for HCC-nonBC. According to TNM stage, the median AFP levels in HCC-nonBC with TNM stages I, II, and III were significantly lower than in either HCC-B or HCC-C. In TNM stage IV, the median AFP level in HCC-nonBC was significantly lower than in either HCC-B or HCC-BC. The median DCP levels in HCC-nonBC with TNM stages I and II were significantly higher than those in either HCC-B or HCC-C. In TNM stage III, the median DCP level in HCC-nonBC was significantly higher than that in HCC-C. CONCLUSIONS: DCP was more sensitive than AFP for the diagnosis of early stage cryptogenic HCC. DCP should be used as the main serum test for cryptogenic HCC detection.

Relationship of α-fetoprotein levels and development of hepatocellular carcinoma in hepatitis C patients with liver cirrhosis.

α-fetoprotein (AFP) is a tumor marker of hepatocellular carcinoma (HCC) and has also been reported to reflect the effectiveness of long-term low-dose interferon (IFN) therapy in hepatitis C virus (HCV)-infected patients with chronic liver disease. The correlation between AFP levels and the incidence of HCC has been discussed over a long period. We investigated whether high levels of AFP at the time of diagnosis were associated with an increased incidence of HCC in patients with HCV. A total of 107 HCV patients with liver cirrhosis without other risks were evaluated for the predictive value of non-invasive risk factors for HCC, including age, gender, alcohol intake, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count and AFP levels at study entry, as well as the IFN therapy received. During the follow-up period, HCC developed in 68 (63.6%) patients. Kaplan-Meier estimates were made to assess the cumulative risk of HCC. The 10-year cumulative incidence rate of HCC was 80%. Cox regression analysis was performed on several variables, including age, gender, alcohol consumption, experience of IFN therapy and biochemical parameters. The following factors were identified as exhibiting an increased risk of HCC by univariate analysis: aspartate transaminase (AST) ≥71 IU/l, alanine transaminase (ALT) ≥60 IU/l, AFP ≥6 ng/ml and IFN therapy. Multivariate analysis identified that the AFP level [6-19 ng/ml: hazard ratio (HR), 2.22; P=0.006 and ≥20 ng/ml: HR, 2.09; P=0.003] was an independent and significant risk factor for the development of HCC. A slightly elevated (6-19 ng/ml) AFP level may be a risk factor for HCC in certain cases. By contrast, AFP levels <6 ng/ml indicate a low risk of HCC development in HCV patients with liver cirrhosis.

Baseline serum cholesterol is associated with a response to pegylated interferon alfa-2b and ribavirin therapy for chronic hepatitis C genotype 2.

Background. HCV infection is associated with lipid disorders because this virus utilizes the host lipid metabolism to sustain its life cycle. Several studies have indicated that higher concentrations of serum cholesterol and LDL before treatment are important predictors of higher rates of sustained virological response (SVR). However, most of these studies involved patients infected with HCV genotype 1. Thus, we performed a multi-institutional clinical study to evaluate the impact of lipid profiles on SVR rates in patients with HCV genotype 2. Methods. A total of 100 chronic hepatitis C patients with HCV genotype 2 who received peg-IFN alfa-2b and ribavirin therapy were consecutively enrolled. The significance of age, sex, BMI, AST level, ALT level, WBC, hemoglobin, platelet count, gamma-glutamyltransferase, total cholesterol level (TC), LDL level, HCV RNA, and histological evaluation was examined for SVR using logistic regression analysis. Results. The 100 patients infected with HCV genotype 2 were divided into 2 groups, an SVR group and a non-SVR group. Characteristics of each group were subsequently compared. There was no significant difference in the level of HCV RNA, BMI, platelet, TG, or stage of fibrosis between the groups. However, there were significant differences in the levels of TC and LDL-C. In multivariate logistic regression analysis using baseline characteristics, high TC level was an independent and significant risk factor (relative risk 18.59, P = 0.015) for SVR. Conclusion. Baseline serum total cholesterol levels should be considered when assessing the likelihood of sustained treatment response following the course of peg-IFN and ribavirin therapy in patients with chronic HCV genotype 2 infection.

[Successful management of liver metastasis from gastric adenosquamous carcinoma with adjuvant chemotherapy and radiofrequency ablation].

A 70-year-old man was given a diagnosis of advanced type 3 gastric cancer and underwent surgery. In addition to total gastrectomy and D2 lymph node resection, partial liver resection was performed due to detection of a solitary liver metastasis which was initially overlooked on preoperative CT. Histopathologically, the tumor was diagnosed as gastric adenosquamous carcinoma (Int, INFß, pT2 (ss), H1, ly1, v2 (mp), EVG, n (-), pPM (-), pDM (-)). Three metastasic lesions appeared in the liver on abdominal CT scan performed 3 months after the operation. The patient underwent adjuvant chemotherapy with S-1. Since enlargement of the liver metastases was observed following 2 courses of treatment, the patient received combination chemotherapy of irinotecan and cisplatin. Of 3 metastatic lesions, 1 disappeared and 2 decreased to less than 2 cm in diameter after 8 courses of 2nd line treatment. Radiofrequency ablation (RFA) was successfully performed to treat the remaining liver metastases. The patient has been free of recurrence for 41 months.

A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma.

BACKGROUND: SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We conducted a multicenter phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355, using a Zinostatin stimalamer suspension in iodized oil as a reference. METHODS: Patients with unresectable HCC were randomized 2:1 to receive administration of the SM-11355 or Zinostatin stimalamer suspension into the hepatic artery. A second injection was given 4-12 weeks later. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I, where TE V was defined as disappearance or 100% necrosis of all treated tumors. RESULTS: A total of 122 patients were evaluated for efficacy and toxicity (SM-11355, n = 83; Zinostatin stimalamer, n = 39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and Zinostatin stimalamer groups, respectively. In the SM-11355 group,the most frequent drug-related adverse events (AEs) of ≥ grade 3 were elevated AST, elevated ALT, thrombocytopenia, and hyperbilirubinemia. The AEs with the largest difference between the two groups (SM-11355 vs. Zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year and 3-year survival rates were 75.9% vs. 70.3% and 58.4% vs. 48.7%, respectively. CONCLUSIONS: The results suggest that SM-11355 in iodized oil has similar efficacy to Zinostatin stimalamer and that repeated dosing of SM-11355 is possible without hepatic vascular injury in cases of relapse.