Abstract
Considering the lower risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long‐term potent antiviral therapy, models predicting HCC after 5 years of ...therapy are needed. We conducted a multicenter retrospective cohort study to construct and validate a model predicting HCC after 5 years of entecavir (ETV) or tenofovir (TFV) therapy for CHB. The endpoint was HCC after 5 years of ETV/TFV therapy. Information on age, sex, liver cirrhosis (assessed by diagnosis code and confirmed by clinical findings) and type of antiviral agent was obtained at baseline (initiation of ETV/TFV). Laboratory values were collected at baseline and 5 years. Risk factors for HCC were identified in the training set and the final prediction model was validated using the test set. Among 7542 patients, 345 (4.6%) developed HCC after 5 years of ETV/TFV therapy. HCC risk after 5 years of ETV/TFV therapy was increased by 4‐fold in patients with liver cirrhosis than in those without cirrhosis at baseline. Furthermore,
P
latelet counts and
P
rothrombin time at 5 years,
A
ge at baseline and
S
ex were associated with risk of HCC and were incorporated into a prediction model, PPACS. PPACS showed a good performance with a time‐dependent area under the curve of 0.80 (95% confidence interval, 0.75‐0.85) at 8‐year of ETV/TFV therapy, a Brier score of 0.031 and an integrated Brier score of 0.006 in the test set. In conclusion, the PPACS model provides a reliable assessment of HCC risk after 5 years of ETV/TFV therapy (
https://ppacs.shinyapps.io/shiny_app_up/
).
The RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on ...liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1-/-, and A1cf-/- mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose diet and was independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), and proliferation (Kif20a, Mcm2, Mcm4, Mcm6), and a subset of mRNAs (including Sox4, Sox9, Cdh1) were identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. In conclusion, we show that hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative, and inflammatory pathways leading to HCC.
Background and Aims
Sirtuin 1 (SIRT1) is a complex NAD+‐dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of ...SIRT1‐induced destabilization of primary cilia in cholangiocarcinoma (CCA).
Approach and Results
A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)‐mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD ‐producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1‐overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α‐tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma‐associated oncogene 1, phosphorylated extracellular signal‐regulated kinase, and IL‐6) expression.
Conclusions
In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.
Although previous studies have focused on hepatobiliary and gastrointestinal adverse drug reactions (ADRs) associated with COVID‐19 vaccines, literature on such ADRs with other vaccines is limited, ...particularly on a global scale. Therefore, we aimed to investigate the global burden of vaccine‐associated hepatobiliary and gastrointestinal ADRs and identify the vaccines implicated in these occurrences. This study utilized data from the World Health Organization (WHO) international pharmacovigilance database to extract reports of vaccine‐associated hepatobiliary and gastrointestinal ADRs from 1967 to 2023 (total reports = 131 255 418). Through global reporting counts, reported odds ratios (ROR) with 95% confidence interval (CI), and information components (IC) with IC0.25, the study examined the association between 16 vaccines and the incidence of hepatobiliary and gastrointestinal ADRs across 156 countries. Of the 6 842 303 reports in the vaccine‐associated ADRs, 10 786 reports of liver injury, 927 870 reports of gastrointestinal symptoms, 2978 reports of pancreas and bile duct injury, and 96 reports of intra‐abdominal hemorrhage between 1967 and 2023 were identified. Most hepatobiliary and gastrointestinal ADRs surged after 2020, with the majority of reports attributed to COVID‐19 messenger RNA (mRNA) vaccines. Hepatitis A vaccines exhibited the highest association with liver injury (ROR 95% CI: 10.30 9.65–10.99; IC IC0.25: 3.33 3.22), followed by hepatitis B, typhoid, and rotavirus. Specifically, ischemic hepatitis had a significant association with both Ad5‐vectored and mRNA COVID‐19 vaccines. Gastrointestinal symptoms were associated with all vaccines except for tuberculosis vaccines, particularly with rotavirus (11.62 11.45–11.80; 3.05 3.03) and typhoid (11.02 10.66–11.39; 3.00 2.96). Pancreas and bile duct injury were associated with COVID‐19 mRNA (1.99 1.89–2.09; 0.90 0.83), MMR (measles, mumps, and rubella), and papillomavirus vaccines. For intra‐abdominal hemorrhage, inactivated whole‐virus COVID‐19 vaccines (3.93 1.86–8.27; 1.71 0.41) had the highest association, followed by COVID‐19 mRNA (1.81 1.42–2.29; 0.77 0.39). Most of these ADRs had a short time to onset, within 1 day, and low mortality rate. Through a global scale database, the majority of ADRs occurred within 1 day, emphasizing the importance of healthcare workers' vigilant monitoring and timely management.
The purpose of this study was to demonstrate the prognostic significance of changes in body composition in patients with newly diagnosed hepatocellular carcinoma (HCC).
Patients (n=178) newly ...diagnosed with HCC participated in the study between 2007 and 2012. Areas of skeletal muscle and abdominal fat were directly measured using a three-dimensional workstation. Cox proportional-hazards modes were used to estimate the effect of baseline variables on overall survival. The inverse probability of treatmentweighting (IPTW) method was used to minimize confounding bias.
Cutoff values for sarcopenia, obtained from receiver-operating characteristic curves, were defined as skeletal muscle index at the third lumbar vertebra of ≤ 45.8 cm/m2 for males and ≤ 43.0 cm/m2 for females. Sarcopenia patients were older, more likely to be female, and had lower body mass index. Univariable analysis showed that the presence of sarcopenia and visceral to subcutaneous fat area ratio (VSR) were significantly associatedwith prognosis. The multivariable analyses revealed that VSR was predictive of overall survival. However, in the multivariable Cox model adjusted by IPTW, sarcopenia, not VSR, were associated with overall survival.
The presence of sarcopenia at HCC diagnosis is independently associated with survival.
Genetic and nutritional factors contribute to the development of non-alcoholic fatty liver disease (NAFLD); however, gene–diet interactions in NAFLD development are poorly understood. In this ...case–control study, a large dataset from the Korean Genome and Epidemiology Study cohort (n = 72,299) comprising genomic data, medical records, social history, and dietary data was used. We investigated the interactions between the PNPLA3 rs738409 genotype and nutritional factors and their possible effect on the risk of NAFLD development in 2950 patients with NAFLD and 12,907 controls. In the PNPLA3 risk allele group, high protein, fat, sodium, phosphorus, niacin, and vitamin B6 intakes were associated with a decreased risk of NAFLD. In the non-risk allele group, only high fat intake was associated with a decreased risk of NAFLD. Among these nutrients, high sodium intake had a significant protective interaction with the PNPLA3 genotype against NAFLD (p = 0.002). Among salty foods, only kimchi had a significant protective effect against the PNPLA3 genotype (p = 0.012). Thus, the PNPLA3 genotype is differentially associated with nutritional factors. In particular, it interacts with kimchi, a fermented vegetable dish. Therefore, fermented vegetables may serve as a tailored therapeutic food for people with the PNPLA3 risk allele.
Background/Aims: Atezolizumab plus bevacizumab (ATE+BEV) therapy has become the recommended first-line therapy for patients with unresectable hepatocellular carcinoma (HCC) because of favorable ...treatment responses.
However, there is a lack of data on sequential regimens after ATE+BEV treatment failure. We aimed to investigate the clinical outcomes of patients with advanced HCC who received subsequent systemic therapy for disease progression after ATE+BEV.
Methods: This multicenter, retrospective study included patients who started second-line systemic treatment with sorafenib or lenvatinib after HCC progressed on ATE+BEV between August 2019 and December 2022. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). Clinical features of the two groups were balanced through propensity score (PS) matching.
Results: This study enrolled 126 patients, 40 (31.7%) in the lenvatinib group, and 86 (68.3%) in the sorafenib group. The median age was 63 years, and males were predominant (88.1%). In PS-matched cohorts (36 patients in each group), the objective response rate was similar between the lenvatinib- and sorafenib-treated groups (5.6% vs. 8.3%; P=0.643), but the disease control rate was superior in the lenvatinib group (66.7% vs. 22.2%; P<0.001). Despite the superior progression-free survival (PFS) in the lenvatinib group (3.5 vs. 1.8 months, P=0.001), the overall survival (OS, 10.3 vs. 7.5 months, P=0.353) did not differ between the two PS-matched treatment groups.
Conclusions: In second-line therapy for unresectable HCC after ATE+BEV failure, lenvatinib showed better PFS and comparable OS to sorafenib in a real-world setting. Future studies with larger sample sizes and longer followups are needed to optimize second-line treatment.
Background
Previous studies evaluating association between circulating tumor cells (CTCs) and clinical outcomes in hepatocellular carcinoma (HCC) have shown inconsistent results due to suboptimal ...detection methods and patient heterogeneity.
Methods
Patients undergoing surgery for early-stage HCC were prospectively enrolled. The CTC numbers were determined using a tapered slit platform, which detects CTCs based on the cell size and morphology. Survival and recurrence were evaluated, and Cox proportional hazards models were used to demonstrate the prognostic significance of CTC.
Results
Of 105 patients, 25 had increased CTC numbers after surgery (ΔCTC > 0, defined as positive) and a significantly higher level of recurrence (
p
= 0.042). A positive ΔCTC was seen to be an independent predictor of recurrence (hazard ratio 2.28), along with hepatitis B virus infection, alanine aminotransferase level, and the presence of satellite nodules (all
p
< 0.05). Subgroup analyses showed that a positive ΔCTC was associated with lower survival and higher recurrence among patients with low alpha-fetoprotein levels and cirrhosis (all
p
< 0.05).
Conclusion
Calculation of ΔCTC based on the physical properties of the cells is predictive of recurrence in patients with early HCC undergoing surgery.
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