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Complementary DNA microarray analysis of human livers cannot exclude the influence of the immunological response. In this study, complementary DNA microarray analysis was performed under immunodeficient conditions with human hepatocyte chimeric mice, and gene expression profiles were analyzed by hepatitis B virus (HBV) infection and/or interferon treatment. The expression levels of 183 of 525 genes upregulated by interferon treatment were significantly suppressed in response to HBV infection. Suppressed genes were statistically significantly associated with the interferon signaling pathway and pattern recognition receptors in the bacteria/virus recognition pathway (P = 1.0 x 10(-8) and P = 1.2 x 10(-8), respectively). HBV infection attenuated virus recognition and interferon response in hepatocytes, which facilitated HBV escape from innate immunity. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the efficacy of radical resection and postoperative adjuvant chemotherapy on the survival benefit in patients with pancreatic ductal adenocarcinoma (PDAC), stratified by age, frailty, and other factors in actual clinical practice., Methods: We retrospectively analyzed the clinicopathological and follow-up data of 414 patients with PDAC who underwent surgical resection at nine institutions under the Yamaguchi Pancreat/Biliary Disease Study Group, between January 1997 and December 2016. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Associations between survival and prognostic factors were evaluated by univariate and multivariate analyses., Results: There were 30.5% of patients with PDAC who were aged < 65 years, 37.9% aged 65-74 years, 17.6% aged 75-79 years, and 14.0% aged ≥ 80 years. Notably, RFS declined with increasing age (median RFS: 12.9, 10.2, 9.4, and 7.4 months, respectively), although the differences were not significant (p = 0.223). OS significantly decreased with age (median OS: 21.6, 21.2, 17.0, and 13.9 months, respectively; p = 0.005). In patients aged < 75 years, independent prognostic factors identified by univariate and multivariate analyses included lymph node metastasis (hazard ratio [HR], 1.598; p = 0.007), tumor size (HR, 1.489; p = 0.043), R status (HR, 1.536; p = 0.011), and serum albumin levels (HR, 1.526; p = 0.031). In patients aged ≥ 75 years, a high modified frailty index (HR, 2.446; p = 0.012) emerged as an independent prognostic factor, along with lymph node metastasis, CA19-9 level (HR, 1.897; p = 0.017), and R status (HR, 2.087; p = 0.007)., Conclusion: The prognosis for older patients with PDAC was shorter than that of younger patients. Frailty may contribute to their poorer prognosis in older age., (© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background & Aims: In the global, phase III HIMALAYA study in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) vs. sorafenib; durvalumab was non-inferior to sorafenib. HBV is the predominant HCC aetiology in most of Asia vs. HCV or non-viral aetiologies in Western countries and Japan. This analysis evaluated safety and efficacy outcomes for STRIDE and durvalumab monotherapy vs. sorafenib, in HIMALAYA participants enrolled in Asia, excluding Japan., Methods: In HIMALAYA, participants were randomised to STRIDE, durvalumab, or sorafenib. The Asian subgroup in this analysis included participants enrolled in Hong Kong, India, South Korea, Taiwan, Thailand, and Vietnam. OS, objective response rate (ORR; per RECIST, version 1.1), and safety were assessed in the Asian subgroup and in an exploratory subgroup of participants in Hong Kong and Taiwan., Results: The Asian subgroup included 479 participants randomised to STRIDE (n = 156), durvalumab (n = 167), or sorafenib (n = 156). OS was improved for STRIDE vs. sorafenib (hazard ratio [HR] 0.68; 95% CI 0.52-0.89). The OS HR for durvalumab vs. sorafenib was 0.83 (95% CI 0.64-1.06). In Hong Kong and Taiwan (n = 141), OS HRs for STRIDE vs. sorafenib and durvalumab vs. sorafenib were 0.44 (95% CI 0.26-0.77) and 0.64 (95% CI 0.37-1.08), respectively. In the Asian subgroup, ORR (including unconfirmed responses) was numerically higher for STRIDE (28.2%) and durvalumab (18.6%) vs. sorafenib (9.0%), and Grade 3/4 treatment-related adverse events were numerically lower for STRIDE (19.9%) and durvalumab (13.3%) vs. sorafenib (30.5%)., Conclusions: STRIDE improved outcomes vs. sorafenib in the Asian subgroup. These results support the benefits of STRIDE for participants with uHCC globally, including in the Asia-Pacific region., Clinical Trial Number: NCT03298451., Impact and Implications: The global, phase III HIMALAYA study found that the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen improved overall survival (OS), including long-term OS vs. sorafenib, and that durvalumab monotherapy was non-inferior to sorafenib in participants with unresectable hepatocellular carcinoma (uHCC). However, there are differences in the aetiology and clinical practices related to HCC in parts of Asia, compared to Western countries and Japan, which could lead to differences in treatment outcomes between these regions. The results of this analysis demonstrate the benefits of STRIDE for participants in the Asia-Pacific region, consistent with the full, global study population. Overall, these findings continue to support the use of STRIDE in a diverse population, reflective of uHCC globally., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A 58-year-old man visited an orthopedic clinic complaining of pain in his right lower back and numbness in his lower limbs for one month. Imaging tests revealed a tumorous lesion from the left side of the second lumbar vertebra to the paraspinal muscles. CT-guided biopsy of the tumor was performed, and immunostaining results diagnosed hepatocellular carcinoma (HCC). Although the liver showed signs of chronic liver damage, no primary tumor was found within the liver or in other organs. Blood tests showed negative hepatitis virus markers for both HBV and HCV. The tumor markers AFP, AFP-L3, and DCP were high. Because he developed spinal cord compression syndrome due to a lumbar tumor, radiation therapy and denosumab administration were performed. Subsequently, systemic therapy with durvalumab plus tremelimumab was started. In the year following the start of treatment, the tumor has shrunk, and no new lesions have been observed. Tumor markers have also decreased. We have experienced a case of HCC in the lumbar spine without a primary tumor in the liver. This is a very rare case, and the combination therapy with durvalumab and tremelimumab resulted in a complete response, which we consider to be a valuable case., Competing Interests: Declarations. Conflict of interest: Tomokazu Kawaoka received honoraria (lecture fees) from Chugai Pharmaceutical Co., Ltd and AstraZeneca PLC. Ethics statement: This study was conducted in accordance with the ethics principles of the Declaration of Helsinki. Informed consent: Informed consent was obtained from patient in this study., (© 2024. The Author(s).)

Purpose: To investigate the utility of intracellular enhancement (ICE) technique which suppresses signals from the extracellular space for the evaluation of hepatic function on gadoxetic acid-enhanced hepatobiliary-phase (HBP) images., Methods: We subjected 67 patients with suspected neoplastic hepatic lesions to gadoxetic acid-enhanced HBP imaging with and without ICE [i-HBP, conventional-HBP (c-HBP)]. A radiologist calculated the liver/spleen contrast (LSC) [LSC = signal intensity (SI) of liver/SI of spleen]. Receiver-operating analysis was used to evaluate the diagnostic value of the LSC on i-HBP- (i-LSC) and c-HBP images (c-LSC) to differentiate between Child-Pugh classes A and B., Results: Of the 67 patients, 57 were in Child-Pugh class A and 10 were in class B. For their differentiation, the area under the curve value of i-LSC was higher than of c-LSC (0.81 vs. 0.68)., Conclusions: ICE technique can improve the accuracy of estimating hepatic function on HBP images., Competing Interests: Declarations. Competing interests: Author Kazuo Awai has received a research grant from FUJIFILM Corporation. Author Takashi Nishihara and Masahiro Takizawa are employees of FUJIFILM Corporation. Author Yoshitaka Bito was an employee of FUJIFILM Corporation. The other authors have no relevant financial or non-financial interests to disclose., (© 2025. The Author(s).)

Background: Hepatitis B virus (HBV) RNA is an important serum biomarker of hepatic covalently closed circular DNA (cccDNA) transcriptional activity; however, its clinical characteristics remain unclear. This study evaluated the clinical utility of HBV RNA levels in patients with chronic hepatitis B (CHB)., Methods: We studied 87 CHB patients with serum HBV DNA levels ≥ 5.0 log IU/mL who initiated entecavir (ETV) treatment between 2000 and 2018. Serum HBV RNA levels were measured at three-time points: before ETV treatment, at 12 weeks, and at 48 weeks after starting ETV treatment. Clinical markers associated with the antiviral effects of ETV treatment were analyzed., Results: Serum HBV RNA levels decreased in both HBeAg-positive and -negative patients during the observation period. In HBeAg-positive patients, multivariable analysis showed that lower HBV RNA levels at 48 weeks of ETV treatment were independently associated with HBeAg seroconversion. Additionally, lower baseline HBV RNA levels significantly predicted virologic response in those patients. In contrast, among HBeAg-negative patients, lower HBV core-related antigen (HBcrAg) levels and the FIB-4 index were independently associated with virologic response. In HBeAg-positive patients, those with higher baseline HBV RNA levels showed a more significant reduction in hepatitis B surface antigen levels., Conclusion: Serum HBV RNA levels predicted HBeAg seroconversion and early HBV DNA reduction in HBeAg-positive patients, while HBcrAg was significantly associated with virologic response in HBeAg-negative patients. These findings highlight the different predictive roles of HBV RNA and HBcrAg based on HBeAg status, which may provide individualized treatment strategies., Competing Interests: Declarations. Conflict of interest: All authors declare that they have no affiliations with or involvement in any organization with any financial or non-financial interests in the subject matter or materials discussed in this manuscript. Ethical approval and informed consent: All the participants provided written informed consent. This study was approved by the Ethics Committee of Hiroshima University, Hiroshima, Japan (Approved ID: E2016-0704). This study was conducted in accordance with the principles of the Declaration of Helsinki. All authors declare that they have no affiliations with or involvement in any organization with any financial or non-financial interests in the subject matter or materials discussed in this manuscript., (© 2025. The Author(s).)

Background: Transarterial chemoembolisation (TACE) is standard care for unresectable, non-metastatic hepatocellular carcinoma. We aimed to evaluate the addition of lenvatinib and pembrolizumab to TACE versus dual placebo plus TACE in patients with unresectable, non-metastatic hepatocellular carcinoma., Methods: In this multicentre, randomised, double-blind, phase 3 study (LEAP-012), patients were recruited from 137 global sites in 33 countries or regions. Eligible patients were age 18 years or older with unresectable, non-metastatic hepatocellular carcinoma not amenable to curative treatment, but with tumours amenable to TACE, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and Child-Pugh class A disease. Eligible participants were randomly assigned (1:1), stratified by study site, α-fetoprotein level, ECOG performance status, albumin-bilirubin grade, and tumour burden, by a central interactive response system, to receive TACE and either oral lenvatinib (bodyweight ≥60 kg: 12 mg; bodyweight <60 kg: 8 mg; once daily) plus intravenous pembrolizumab (400 mg once every 6 weeks for up to 2 years) or matched dual placebo (oral and intravenous). Primary endpoints were progression-free survival (threshold one-sided p=0·025), per Response Evaluation Criteria in Solid Tumours version 1.1 (modified for the current study to allow for up to five target tumours in the liver and requiring new intrahepatic tumours to meet LI-RADS 5 criteria to be considered progressive disease) by blinded independent central review, and overall survival (threshold one-sided p=0·0012) in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Safety was assessed in the as-treated population (ie, all participants who were randomly assigned and received at least one dose of any study treatment). Here, we report results from the first interim analysis (final analysis for progression-free survival). This study is registered with ClinicalTrials.gov, NCT04246177, and is active but not recruiting., Findings: Between May 22, 2020, and Jan 11, 2023, 847 patients were screened, of whom 480 (57%) were enrolled and randomly assigned to receive TACE plus lenvatinib plus pembrolizumab (n=237) or TACE plus dual placebo (n=243; ITT population). Median age was 66 years (IQR 58-73), 82 (17%) of 480 participants were female, 398 (83%) were male, 98 (20%) were White, 347 (72%) were Asian, four (1%) were Black or African American, and five (1%) were American Indian or Alaska Native. Median follow-up as of data cutoff (Jan 30, 2024) was 25·6 months (IQR 19·5-32·4). Median progression-free survival was 14·6 months (95% CI 12·6-16·7; 132 events [20 deaths and 112 progressions]) with lenvatinib plus pembrolizumab and 10·0 months (8·1-12·2; 154 events [eight deaths and 146 progressions]) with placebo (hazard ratio [HR] 0·66 [95% CI 0·51-0·84]; one-sided p=0·0002). 69 (29%) of 237 in the lenvatinib plus pembrolizumab group and 82 (34%) of 243 from the placebo group died, with a 24-month overall survival rate of 75% (95% CI 68-80) in the lenvatinib plus pembrolizumab group and 69% (62-74) in the placebo group (HR 0·80 [95% CI 0·57-1·11]; one-sided p=0·087). Grade 3 or worse treatment-related adverse events occurred in 169 (71%) of 237 participants in the lenvatinib plus pembrolizumab group and in 76 (32%) of 241 in the placebo group, the most common of which were hypertension (57 [24%] vs 18 [7%]) and platelet count decreased (27 [11%] vs 15 [6%]). Deaths due to treatment-related adverse events occurred in four (2%) participants in the lenvatinib plus pembrolizumab group (n=1 each due to hepatic failure, gastrointestinal haemorrhage, myositis, and immune-mediated hepatitis) and one (<1%) in the placebo group (due to brain stem haemorrhage)., Interpretation: TACE plus lenvatinib plus pembrolizumab showed significant, clinically meaningful improvement in progression-free survival in patients with unresectable, non-metastatic hepatocellular carcinoma compared with TACE plus placebo. The numerical improvement in overall survival is encouraging, but longer follow-up is necessary., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and Eisai, Nutley, NJ, USA., Competing Interests: Declaration of interests All authors report funding to their institution from Eisai and Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, to support the conduct of this study. All authors received medical writing and editorial support for the preparation of this manuscript from Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA. MK reports researching funding (paid to his institution) from AbbVie, Chugai Pharmaceutical, Eisai, GE Healthcare Japan Corporation, Otsuka Pharmaceutical, and Taiho Pharmaceutical; consulting fees from AstraZeneca, Chugai Pharmaceutical, Eisai, and F Hoffmann-La Roche; and honoraria from AstraZeneca, Chugai Pharmaceutical, Eisai, Eli Lilly Japan, and Takeda Pharmaceutical. ZR reports consulting fees from and participation on a data safety monitoring board or advisory board for AstraZeneca, MSD, and Roche. SO reports grants from AstraZeneca, Bayer, Chugai Pharma, Eli Lilly, Eisai, and Gilead Sciences; consulting fees from AstraZeneca, Chugai Pharma, and MSD; honoraria from AbbVie, AstraZeneca, Bayer, Chugai Pharma, Eli Lilly, Eisai, Gilead Sciences, and Takeda; and participation on a data safety monitoring board or advisory board for AstraZeneca, Chugai Pharma, and MSD. DCM reports participation on a data safety monitoring board or advisory board with honoraria (paid to himself) for AstraZeneca, Boston Scientific, Eisai, GE Healthcare, Guerbet, MSD, Siemens Healthineers, and Sirtex. RMG reports consulting fees from Sanofi; honoraria from Sanofi; participation on a data safety monitoring board or advisory board for LyGenesis, Sirtex, and Transmedics; leadership or fiduciary role for the International Liver Transplantation Society and American Society of Transplant Surgeons Foundation Board; and stock or stock options for Eli Lilly and Transmedic. TK reports honoraria from AstraZeneca and Chugai Pharmaceutical (Roche). MI reports consulting fees from AbbVie, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly Japan, MSD, and Ono; honoraria from Abbott, AstraZeneca, Bristol Myers Squibb (BMS), Chugai, Eisai, Eli Lilly Japan, MSD, and Takeda; and research funding (paid to his institution) from AbbVie, AstraZeneca, Bayer, BMS, Chugai, Eisai, and MSD. HK reports honoraria from AbbVie, Eisai, Gilead Sciences, and Sumitomo Pharma. ABE-K reports grants (paid to his institution) from AstraZeneca, Astex, Auransa, and Fulgent; consulting fees (paid to himself) from Agenus, Bayer, BMS, Eisai, Elevar, Exelixis, Merck, Qurient, Roche/Genentech, Senti Biosciences, Tallac Therapeutics, and Terumo; support for attending meetings or travel from Affimed; leadership or fiduciary role for HCC-Live; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Agenus, Exelixis, Merck, and Roche/Genentech. AV reports consulting fees (paid to himself) from AbbVie, AstraZeneca, Biologix, BMS, Boehringer Ingelheim, Cogent, Eisai, Elevar, Falk, Incyte, Ipsen, Janssen, Jazz Pharma, Lilly, Medivir, MSD, Roche, Servier, Taiho, Terumo, Tyra, and Zymeworks; honoraria (paid to himself) from AbbVie, AstraZeneca, Biologix, BMS, Boehringer Ingelheim, Cogent, Eisai, Elevar, Falk, Incyte, Ipsen, Janssen, Jazz Pharma, Lilly, Medivir, MSD, Roche, Servier, Taiho, Terumo, Tyra, and Zymeworks; support for attending meetings or travel from Astellas, Merck, and Roche; and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Biologix, BMS, Boehringer Ingelheim, Cogent, Eisai, Elevar, Falk, Ipsen, Incyte, Janssen, Jazz Pharma, Lilly, Medivir, MSD, Roche, Servier, Taiho, Terumo, Tyra, and Zymeworks. XP is an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA. KM and CD are employees of Eisai. LD and ABS are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and hold stock in Merck & Co, Inc, Rahway, NJ, USA. RSF reports grants (paid to his institution) from Adaptimmune, Bayer, BMS, Eli Lilly, Genentech, Novartis, Pfizer, and Roche; consulting fees (paid to himself) from Bayer, BMS, CStone, Eli Lilly, Genentech, Novartis, Pfizer, Roche, and Zai Labs; honoraria (paid to himself) from Genentech; and participation on a data safety monitoring board for AstraZeneca. JML reports research grants (paid to his institution) from Bayer Pharmaceuticals and Eisai; fees (paid to himself) for participation on advisory boards from AbbVie, AstraZeneca, Bayer Pharmaceuticals, Exelixis, Genentech, Glycotest, Moderna, Roche, and Sanofi; fees (paid to himself) for serving as a principal investigator from Eisai and Merck; and fees (paid to himself) for data safety monitoring board participation for BMS. All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

We encountered a family with hereditary renal failure, renal medullary cysts, pancreatic hypoplasia, hypomagnesemia, liver enzyme abnormalities, and diabetes mellitus (DM). We identified a novel heterozygous variant of HNF1B (NM&#95;000458.4:c.791dup, p.L264Ffs*30) using whole-exome sequencing of genomic DNA samples from this family. This variant is located in the DNA-binding domain of the HNF1B protein and produces a truncated protein with a de novo sequence, suggesting that this variant changes HNF1B binding to genomic DNA or causes nonsense-mediated mRNA decay. Based on the phenotypes and identified gene variants, this family suffers from autosomal dominant tubulointerstitial kidney disease caused by this HNF1B variant.

Purpose: We aimed to identify the risk factors for severe neutropenia in the early phase of trifluridine-tipiracil (FTD/TPI) treatment, and their impact on overall survival (OS)., Methods: This single-center retrospective study included patients with unresectable metastatic colorectal cancer who were treated with FTD/TPI. The primary endpoint was OS, and the secondary endpoint was severe neutropenia during the first and second cycles of FTD/TPI. We assessed the association between outcomes and potential confounders using multivariate analysis., Results: Of the 77 total patients, 33 developed severe neutropenia during the first and second treatment cycles. In Cox hazard analysis, the independent factors associated with OS were neutropenia ≥ grade 1 during cycles 1 and 2 (adjusted hazard ratio 0.43; 95% confidence interval (CI) 0.21-0.87), combined treatment with bevacizumab (0.47; 95% CI 0.27-0.83), number of metastatic organs ≥ 3 (2.15; 95% CI 1.22-3.82), and time since diagnosis of metastasis until commencement of FTD/TPI < 18 months (1.94; 95% CI 1.13-3.33). Severe neutropenia during cycles 1 and 2 was not associated with OS (0.75; 0.44-1.27). The risk of severe neutropenia adjusted for initial dose reduction was defined as renal impairment with creatinine clearance (Ccr) of < 60 ml/min (adjusted odds ratio, 4.67; 95% CI, 1.38-15.80) and absolute neutrophil count (per 1000/μl, 0.47; 0.27-0.81)., Conclusion: The neutropenia ≥ grade 1 during cycles 1 and 2 of FTD/TPI is a predictor of favorable outcomes; however, the effect of severe neutropenia on OS was not clear. Renal impairment was also associated with severe neutropenia., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Background: This study aims to identify biomarkers for treatment response of atezolizumab plus bevacizumab (Atezo+Bev) in patients with hepatocellular carcinoma (HCC)., Methods: 96 patients who received Atezo+Bev or lenvatinib as a first-line systemic therapy were enrolled as the training group after propensity score matching (PSM), and 42 patients treated with Atezo+Bev were enrolled as the validation group. 17 serum cytokines were measured by Luminex multiplex assay at the start of treatment. For further assessment of the association between cytokine levels and the tumor microenvironment (TME), immunohistochemistry (IHC) was performed on pre-treatment liver biopsy specimens., Results: In the derivation set, multivariate analysis identified elevated IL-6 as an independent risk factor in the Atezo+Bev group (HR 5.80: p<0.01), but not in the lenvatinib group; in a subset analysis of patients with low IL-6, PFS was longer in the Atezo+Bev training group than in the lenvatinib group (p = 0.02). A validation study also showed a significantly longer prognosis in the low IL-6 group for both PFS (p = 0.0001) and OS (p = 0.03). Serum IL-6 had a positive correlation with tumor IL-6 expression (ρ = 0.56, p < 0.0001) and an inverse correlation with the CD8/CD163-positive cell count ratio (ρ = -0.4, p < 0.01)., Conclusion: Serum IL-6 levels are thought to be involved in the suppression of tumor immunity and are useful in predicting the therapeutic effect of Atezo+Bev treatment., Competing Interests: Declarations. Conflict of interest: Authors declare no conflicts of interest for this article., (© 2024. The Author(s).)

Background: Staging laparoscopy(SL)for patients with pancreatic cancer is used to identify occult abdominal metastasis (OAM). The aim of this study is to analyze the efficacy and safety of SL., Methods: Patients with pancreatic cancer who underwent SL before initial treatment at our hospital were included in this study. The short-term outcomes of the patients and the frequency of OAM detection were retrospectively analyzed., Results: Ten patients with pancreatic cancer were enrolled. The tumors were located in the head of the pancreas in 5 cases, and in the body and/or tail in 5 cases. The tumor diameter was 3 cm or more in 2 cases, and the serum CA19-9 level was 150 U/mL or more in 7 cases. No postoperative complications were observed in any of the patients. SL showed OAM in 2 patients., Conclusions: SL can be performed safely and may be useful in detecting OAM and optimizing treatment strategy for pancreatic cancer patients.

Purpose: Postsustained virologic response (SVR) screening following clinical guidelines does not address individual risk of hepatocellular carcinoma (HCC). Our aim is to provide tailored screening for patients using machine learning to predict HCC incidence after SVR., Methods: Using clinical data from 1,028 SVR patients, we developed an HCC prediction model using a random survival forest (RSF). Model performance was assessed using Harrel's c-index and validated in an independent cohort of 737 SVR patients. Shapley additive explanation (SHAP) facilitated feature quantification, whereas optimal cutoffs were determined using maximally selected rank statistics. We used Kaplan-Meier analysis to compare cumulative HCC incidence between risk groups., Results: We achieved c-index scores and 95% CIs of 0.90 (0.85 to 0.94) and 0.80 (0.74 to 0.85) in the derivation and validation cohorts, respectively, in a model using platelet count, gamma-glutamyl transpeptidase, sex, age, and ALT. Stratification resulted in four risk groups: low, intermediate, high, and very high. The 5-year cumulative HCC incidence rates and 95% CIs for these groups were as follows: derivation: 0% (0 to 0), 3.8% (0.6 to 6.8), 26.2% (17.2 to 34.3), and 54.2% (20.2 to 73.7), respectively, and validation: 0.7% (0 to 1.6), 7.1% (2.7 to 11.3), 5.2% (0 to 10.8), and 28.6% (0 to 55.3), respectively., Conclusion: The integration of RSF and SHAP enabled accurate HCC risk classification after SVR, which may facilitate individualized HCC screening strategies and more cost-effective care.

Aim: Shear wave (SW) elastography is used to evaluate metabolic dysfunction-associated steatotic liver disease (MASLD) pathophysiology. Increased elasticity due to fibrosis and increased viscosity due to necrosis and inflammation affect SW. Assessing fibrosis, the most prognostically relevant pathology, is critical. Viscosity is evaluated using the dispersion slope (DS); however, cut-off values that affect SW values are unclear. We compared the ultrasound imaging parameters (SW for viscoelasticity; DS for viscosity) with pathological findings., Methods: Patients (n = 159) who underwent liver biopsy and SW and DS assessments at our hospital were included. Fibrosis stage and inflammation grade cut-off values were calculated from SW, DS, and liver biopsy results using receiver operating characteristic curves. Cases in which liver biopsy results were inconsistent with SW results were used to determine the effect of viscosity on SW values. DS was examined in the Correct and Incorrect Diagnosis groups, which were categorized based on the concordance between SW and liver biopsy results. Dispersion slope cut-off values between the two groups were calculated., Results: Fibrosis stage cut-off values by SW (m/s) were: ≥F2, 1.62; ≥F3, 1.74; and F4, 1.97. Inflammation grade cut-off values by DS (m/s/kHz) were: ≥A1, 11.6; ≥A2, 14.5; and A3, 16.1. The Correct/Incorrect Diagnosis groups had 25/70 patients. The DS cut-off value for both groups was 13.2 m/s/kHz., Conclusions: Shear wave and DS are useful for evaluating liver fibrosis and inflammation in MASLD. For DS > 13.2 m/s/kHz, SW may be affected by the increased viscosity owing to inflammation. In such patients, caution should be used when determining/interpreting values., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background and Hypothesis: Proteinuria exhibits seasonal fluctuations, decreasing in summer and increasing in winter. It is unknown whether the association between proteinuria and the risk of kidney failure varies by season., Methods: The Osaka Consortium for Kidney Disease Research (OCKR) database contained retrospective data from 15 367 patients with estimated glomerular filtration rates of 10-60 mL/min/1.73m2, who were referred to the Department of Nephrology at five clinical centers in Japan, between 2010 and 2021. Multivariate Cox models were used to examine the associations of urinary protein-to-creatinine ratio (UPCR) in summer (UPCRsummer) and winter (UPCRwinter) with kidney failure defined as initiation of kidney replacement therapy. LASSO was used to compare the strength of the association between UPCRsummer and UPCRwinter with respect to kidney failure. We also assessed whether seasonal fluctuations in UPCR were associated with kidney failure., Results: The median [interquartile range] UPCRwinter was 0.89 [0.22, 2.69] g/gCre, 46% higher than UPCRsummer (0.61 [0.16, 1.87] g/gCre). During a median follow-up of 3.0 years, 1 585 patients developed kidney failure. In time-dependent Cox models, UPCRwinter showed a higher hazard of kidney failure (1.66 per 1-standard deviation [SD] increase; 95% confidence interval [CI], 1.60-1.73) than UPCRsummer (1.45 per 1-SD increase; 95%CI, 1.41-1.48). LASSO identified that UPCRwinter was more strongly associated with kidney failure than UPCRsummer. Furthermore, higher % changes in UPCRwinter relative to UPCRsummer was associated with a higher hazard of kidney failure., Conclusions: Proteinuria in winter exhibited stronger associations with kidney failure than that in summer. Seasonal fluctuations in UPCR should not be overlooked in the management of CKD to make reasonable clinical decisions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Cross-sectional analyses using liver tissue from chronic hepatitis B patients make it difficult to exclude the influence of host immune responses. In this study, we performed next-generation sequencing using the livers of hepatitis B virus (HBV)-infected uPA/SCID mice with humanized livers before and after antiviral therapy (AVT) with entecavir and pegylated interferon, and then performed a comparative transcriptome analysis of gene expression alteration. After HBV infection, the expression of genes involved in multiple pathways was significantly altered in the HBV-infected livers. After AVT, the levels of 37 out of 89 genes downregulated by HBV infection were restored, and 54 of 157 genes upregulated by HBV infection were suppressed. Interestingly, genes associated with hypoxia and KRAS signaling were included among the 54 genes upregulated by HBV infection and downregulated by AVT. Several genes associated with cell growth or carcinogenesis via hypoxia and KRAS signaling were significantly downregulated by AVT, with a potential application for the suppression of hepato-carcinogenesis.

Aim: Autotaxin (ATX) is a newly identified liver fibrosis biomarker; however, its clinical usefulness remains unclear. Therefore, we analyzed the changes in patients with chronic hepatitis B virus infection treated with nucleos(t)ide analogs (NAs) to evaluate its usefulness. We also investigated the predictors of hepatocellular carcinoma development, including ATX, in patients with chronic hepatitis B based on their clinical characteristics., Methods: This retrospective study included 179 patients with hepatitis B virus infection treated with NAs for >2 years. First, we measured the ATX levels before and up to 10 years after initiating entecavir (therapy for 88 patients whose serial ATX levels could be measured before and during entecavir therapy. Subsequently, for 179 patients whose ATX levels could be measured at the commencement of NAs, we examined the factors involved in developing hepatocellular carcinoma, including ATX., Results: The ATX levels showed a gradual and significant decrease during the observation period of up to 10 years. Multivariable analysis showed that a baseline ATX/upper limits of normal ratio ≥1.214, age, and alkaline phosphatase levels were independent risk factors for hepatocellular carcinoma development. The combination of age and ATX/upper limits of normal ratio was used to stratify the high-risk groups for liver carcinogenesis., Conclusions: A decrease in ATX levels up to 10 years after the commencement of therapy suggested that ATX is a helpful biomarker in evaluating fibrosis in patients undergoing long-term NA therapy. Furthermore, this study showed that combining age and the baseline ATX/upper limits of normal ratio may help identify high-risk carcinogenesis groups., (© 2024 Japan Society of Hepatology.)

Background: We have been able to use molecular targeted agents for unresectable hepatocellular carcinoma since 2009, and immune checkpoint inhibitors have been approved in recent years. We assessed the efficacy of systemic therapy in Hiroshima University Hospital by each era., Methods: A total of 357 patients who were treated with sorafenib, lenvatinib, atezolizumab plus bevacizumab combination therapy, or durvalumab plus tremeliumab combination therapy as first-line systemic therapy in our hospital from November 2009 to December 2023 were enrolled in this retrospective cohort study. We divided the years from 2009 to 2023 into the following three periods: cohort I, 2009-2016, the single-molecular targeted agent era; cohort II, 2017-2020, the multi-molecular targeted agent era; and cohort III, 2020-2023, the immuno-oncology era., Results: The median survival time was 9.5 months in cohort I, 15.8 months in cohort II, and 20.2 months in cohort III. The median survival time in cohort III was significantly (p < 0.01) longer than in the other cohorts. The overall response rate by mRECIST was 4.1% in cohort I, 28.7% in cohort II, and 47.2% in cohort III. The disease control rate was 41.6% in cohort I, 61.2% in cohort II, and 73.6% in cohort III. Both overall response rate and disease control rate significantly increased by era., Conclusions: We consider that advancements in systemic therapy, along with changes in treatment strategies, such as sequential therapy after progression, contribute to the prolonged prognosis across different eras., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)