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Simple Summary: Systemic chemotherapies have revolutionized therapeutic paradigms for hepatocellular carcinoma (HCC) over the past decade. Various regimens have progressively become standard-of-care in clinical practice. However, there are no reports regarding the impact of multiple sequential therapies including immune-oncologic agents on their outcomes. This study investigated the change, over three time periods, in survival for patients with unresectable HCC, and the effects of sequential treatments on their outcomes. The results showed that the number of patients who received more than two lines steadily increased, and the overall survival significantly improved over time. Surprisingly, the 3-year survival rate increased from 12.1% in the early period to 44.4% for the most recent period. Using less than three lines, the non-objective response of the first line and extrahepatic metastasis were identified as the strongest drivers of a worse prognosis. Sequential treatment post-progression is valuable for prolonging survival. Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009–2013, n = 86; period 2: 2014–2018, n = 132; period 3: 2019–2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1–3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin–bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival. [ABSTRACT FROM AUTHOR]

Aim: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver‐related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. Methods: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti‐hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75‐g oral glucose tolerance test results. Results: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver‐related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. Conclusions: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver‐related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow‐up is required for patients with hepatitis C based on their glucose tolerance status. [ABSTRACT FROM AUTHOR]

The no‐heating deposition of x%YO1.5–(100−x%)(Hf1−yZry)O2 (x = 0−0.09, y = 0, 0.25, 0.50, and 1) is achieved using a radio‐frequency magnetron sputtering method. To investigate the crystal structure and ferroelectric properties, epitaxial films are grown on (111)‐oriented indium tin oxide (ITO)/(111) Y‐stabilized zirconia (YSZ) substrates. The ferroelectric orthorhombic phase is obtained for the 5–7%YO1.5–95–93%HfO2 and 5%YO1.5–95% (Hf0.75Zr0.25)O2 films. The field‐induced phase transition from tetragonal to orthorhombic is confirmed for the 8%YO1.5–92%HfO2 and 5%YO1.5–95%(Hf0.50Zr0.50)O2 films. The remnant polarization (Pr) and coercive field (Ec) are 12–19 μC cm−2 and 2,000–2,500 kV cm−1, respectively. The piezoelectric response of 1 μm thick films is investigated for 6%YO1.5–94% HfO2, 7%YO1.5–93%HfO2, and 5%YO1.5–95%(Hf0.50Zr0.50)O2 films, which have piezoelectric coefficients (d33) of 1.0, 3.3, and 5.0 pm V−1, respectively. These results show no‐heating deposition of x%YO1.5–(100−x%)(Hf1−yZry)O2 films with ferroelectric and piezoelectric properties. [ABSTRACT FROM AUTHOR]

Background: The novel 2‐D shear wave elastography (2D‐SWE) can measure two ultrasound parameters: shear wave dispersion (SWD) and shear wave speed (SWS). We investigated the ability of 2D‐SWE in measuring spleen stiffness using ultrasound multiparametric imaging. Methods: This cross‐sectional study included patients with chronic liver disease who underwent esophagogastroduodenoscopy and ultrasonographic examinations of the spleen between September 2018 and December 2021. In total, 157 patients were enrolled in this study: 81 and 67 patients were included in the pilot set for hepatic venous pressure gradient (HVPG) measurements and validation cohort without HVPG measurements, respectively. To confirm reproducibility between the two examiners, an additional 30 patients were enrolled. Results: The Bland–Altman plots revealed no significant bias in the SWD as measured by two examiners. The splenic SWS (r = 0.752) and SWD (r = 0.444) were correlated with the HVPG. Regarding high‐risk varices, as per the Youden index, the cut‐off value for splenic SWS was 3.30 m/s, with a sensitivity of 85.7%, specificity of 92.5%, positive predictive value of 85.7%, and negative predictive value of 92.4% in the pilot set. In the validation set, good diagnostic performance by the splenic SWS was observed. However, SWD did not perform as well as SWS. Conclusions: The splenic SWS, measured using ultrasound multiparametric imaging, was closely correlated with the HVPG. Thus, SWS is a useful predictive marker for high‐risk varices. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease all over the world. Therapeutic strategies targeting its multidirectional pathways are required. Particularly, fibrosis is closely associated with its prognosis. We previously found that B cell-activating factor (BAFF) is associated with severity of NAFLD. Here, we determined the direct in vivo role of BAFF in the development of liver fibrosis. Histological and biochemical analyses were performed using wild-type and BAFF-deficient mice. We established a murine model of non-alcoholic steatohepatitis (NASH) using carbon tetrachloride injection accompanied by high-fat/high-cholesterol diet feeding. Additionally, in vitro analysis using mouse macrophage-like cell line RAW264.7 and primary hepatic stellate cells was performed. Hepatic steatosis and inflammation, and most importantly, the progression of liver fibrosis, were ameliorated in BAFF-deficient mice compared to those wild-type mice in our model. Additionally, BAFF deficiency reduced the number of CD11c+ M1-type macrophages in the liver. Moreover, BAFF stimulated RAW264.7 cells to secrete nitric oxide and tumor necrosis factor α, which drove the activation of hepatic stellate cells. This indicates that BAFF plays a crucial role in NASH development and may be a promising therapeutic target for NASH. [ABSTRACT FROM AUTHOR]

The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid composition in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) and evaluate the relationship between histological findings and fatty acid composition. Overall, 235 patients (134 women) with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. Multivariate analyses adjusted for age, sex, body mass index, alanine aminotransferase, hemoglobin A1c, creatinine, total cholesterol, triglyceride, and NAFLD Activity Score values showed that lower levels of arachidic, behenic, α-linolenic, eicosatetraenoic, docosapentaenoic, and docosahexaenoic acids and higher levels of mead acid were associated with fibrosis stage 3–4. Furthermore, higher lauric acid, myristic acid, and palmitic acid levels and monounsaturated fatty acids such as palmitoleic acid and oleic acid were significantly associated with high NAS in analyses adjusted for the same factors and fibrosis stage. The plasma fatty acid composition was associated with the histological evidence of NASH. Increased synthesis of fatty acids is associated with NASH; insufficient intake of n-3 essential fatty acids and reduced elongation of fatty acids are associated with fibrosis in NASH. These features may help clinicians to understand and treat advanced NASH cases. [ABSTRACT FROM AUTHOR]

Introduction: Fatty liver disease (FLD) is a surrogate condition for glucose intolerance development. FLD may involve normal or abnormal liver enzyme levels. Whether FLD is a risk factor for glucose intolerance, regardless of liver enzyme levels, remains unknown. We assessed relationships between the development of impaired fasting glucose (IFG) and FLD, liver enzyme abnormalities, and alcohol consumption. Materials and Methods: We retrospectively evaluated 8,664 participants with more than two annual health check‐ups. Participants were classified according to sex, alcohol consumption, alanine aminotransferase (ALT) levels, and fatty liver status. Results: In univariate analyses, IFG onset among men was related to normal or high ALT levels with FLD in the nonalcoholic and alcoholic groups (P‐trend < 0.01). In multivariate analyses, IFG onset among nonalcoholic men was associated with normal or high ALT levels with FLD, independent of potential confounding factors (P‐trend < 0.01). However, IFG onset was non‐independently associated with any condition among alcoholic men. In univariate analyses, IFG onset among women was related to normal or high ALT levels with FLD in the nonalcoholic group (P‐trend < 0.01) and high ALT levels with FLD in the alcoholic group (P‐trend < 0.05). In multivariate analyses, IFG onset was independently associated with only normal ALT levels in nonalcoholic FLD women. Conclusions: Among nonalcoholic men and women, FLD was a risk factor for IFG onset, including normal ALT concentrations. Care is needed for individuals with nonalcoholic FLD, regardless of liver injury, possibly helping reduce glucose intolerance risk. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma has been considered to disseminate through the tumor blood drainage area. To improve curation rates, treatment should cover this area as it may contain satellite lesions. This retrospective study aimed to investigate whether radiofrequency ablation (RFA) completely covering the blood drainage area can improve the overall and disease‐free survival. We enrolled 526 patients who underwent computed tomography during hepatic arteriography following RFA from April 2001 to May 2019. Patients were categorized into a covered group in which the blood drainage area was completely covered by RFA and a noncovered group in which coverage was incomplete. The primary endpoint was the overall survival rate; secondary outcomes included disease‐free survival rate, distant intrahepatic and local recurrence rate, and changes in the Child‐Pugh score. There were no significant differences in baseline characteristics between the two groups. Cumulative overall survival rates were significantly higher in the covered group than in the noncovered group (hazard ratio, 0.63; 95% confidence interval, 0.48‐0.84; P = 0.002). On multivariate Cox proportional hazard model analysis, age <65 years, Child‐Pugh class A, and coverage of the entire drainage area were independent protective factors. Child‐Pugh worsened in 11 (4.2%) patients in the covered group compared to 18 (6.7%) patients in the noncovered group. Conclusion: RFA covering the complete drainage area improved overall survival without decreasing liver function. [ABSTRACT FROM AUTHOR]

Aim: Liver stiffness measured using transient elastography (TE) is affected by tissue viscosity. The role of intrahepatic lymphatic fluid in liver stiffness is unclear. The present study aimed to investigate the effects of lymphatic vessel dilatation on liver stiffness. Methods: Patients with chronic liver disease (n = 116) were enrolled from June 2018 to March 2020. All specimens were acquired by laparoscopic liver biopsy. Biopsy samples were stained with D2‐40 for lymphatic vessel quantification based on a five‐point scale for each specimen. Independent associations of liver stiffness measured by TE, strain elasticity (liver fibrosis index), and controlled attenuation parameter with fibrosis, lymphatic vessels, alanine aminotransferase, bilirubin, and steatosis were evaluated. Results: Fibrosis, splenic stiffness measurement, and splenic volume were significantly correlated with the area of lymphatic vessels. Fibrosis, lymphatic vessels, and alanine aminotransferase were independent factors significantly associated with liver stiffness measurement (LSM; standardized coefficient [β] = 0.375, P < 0.001; β = 0.342, P < 0.001; and β = 0.359, P < 0.001, respectively). Fibrosis was the only independent factor significantly associated with liver fibrosis index (β = 0.360, P < 0.001), whereas the fat deposit area was the only independent factor significantly associated with controlled attenuation parameter (β = 0.455, P < 0.001). The areas under the receiver operating characteristic curves for diagnosing controlled ascites based on LSM, liver fibrosis index, splenic stiffness measurement, collagen proportionate area, and area of lymphatic vessels were 0.94, 0.66, 0.76, 0.64, and 0.79, respectively. Conclusions: Lymphatic vessel dilatation can affect liver stiffness measured using TE. Liver stiffness measurement is a predictive factor for ascites. [ABSTRACT FROM AUTHOR]

Background: Hepatic venous pressure gradient (HVPG) is the gold standard index for evaluating portal hypertension; however, measuring HVPG is invasive. Although transient elastography (TE) is the most common procedure for evaluating organ stiffness, accurate measurement of spleen stiffness (SS) is difficult. We developed a device to demonstrate the diagnostic precision of TE and suggest this technique as a valuable new method to measure SS. Methods: Of 292 consecutive patients enrolled in this single-centre, translational, cross-sectional study from June through September in 2019, 200 underwent SS measurement (SSM) using an M probe (training set, n = 130; inspection set, n = 70). We performed TE with B-mode imaging using an ultrasound-fusion method, printed new devices with a three-dimensional printer, and attached the magnetic position sensor to the convex and M probes. We evaluated the diagnostic precision of TE to evaluate the risk of esophagogastric varices (EGVs). Results: The median spleen volume was 245 mL (range, 64–1,720 mL), and it took 2 minutes to acquire a B-mode image using the ultrasound-fusion method. The median success rates of TE were 83.3% and 57.6% in patients with and without the new device, respectively (p<0.001); it was 76.9% and 35.0% in patients with and without splenomegaly (<100 mL), respectively (p<0.001). In the prediction of EGVs, the areas under the receiver operating characteristic curve were 0.921 and 0.858 in patients with and without the new device, respectively (p = 0.043). When the new device was attached, the positive and negative likelihood ratios were 3.44 and 0.11, respectively. The cut-off value of SSM was 46.0 kPa. Data that were similar between the validation and training sets were obtained. Conclusions: The SS can be precisely measured using this new device with TE and ultrasound-fusion method. Similarly, we can estimate the bleeding risk due to EGV using this method. [ABSTRACT FROM AUTHOR]

Sex differences in the predictors for hepatocellular carcinoma (HCC) development after direct‐acting antiviral (DAA) therapy was investigated. DAA therapy was given to 1438 (663 male, 775 female) patients. Sex differences in the HCC development rate and the factors contributing to HCC development after DAA therapy were investigated. Male patients had a significantly higher cumulative HCC incidence (log‐rank test, P =.007). On multivariate analysis, the fibrosis‐4 index (HR = 1.11; 95%CI, 1.042‐1.202, P =.002) and posttreatment α‐fetoprotein (AFP) (HR = 1.11; 95%CI, 1.046‐1.197, P =.001) were found to be independent factors that contributed to HCC development following DAA therapy in female patients, whereas only posttreatment AFP (HR = 1.090; 95%CI, 1.024‐1.160, P =.007) was an independent factor in male patients. The optimal posttreatment AFP cut‐off values were set based on receiver operating characteristic curve analyses. The optimal posttreatment AFP cut‐off value was much higher in females (6.0 ng/mL) than in male (3.5 ng/mL) patients. In conclusion both in male and female patients, posttreatment AFP was an independent predictor of HCC development after DAA therapy. However, the cut‐off values differed between the sexes. In male patients, HCC could be seen in patients with relatively low posttreatment AFP levels; more careful observation might be needed in such patients. [ABSTRACT FROM AUTHOR]