Dynamic changes of gut microbiota in mouse models of metabolic dysfunction-associated steatohepatitis and its transition to hepatocellular carcinoma.

Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.

Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy.

BACKGROUND: The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. METHODS: Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification-mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. RESULTS: We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). CONCLUSIONS: Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.

Latest insights into the epidemiology, characteristics, and therapeutic strategies of chronic hepatitis B patients in indeterminate phase.

As a hepatotropic virus, hepatitis B virus (HBV) can establish a persistent chronic infection in the liver, termed, chronic hepatitis B (CHB), which causes a series of liver-related complications, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCC with HBV infection has a significantly increased morbidity and mortality, whereas it could be preventable. The current goal of antiviral therapy for HBV infection is to decrease CHB-related morbidity and mortality, and achieve sustained suppression of virus replication, which is known as a functional or immunological cure. The natural history of chronic HBV infection includes four immune phases: the immune-tolerant phase, immune-active phase, inactive phase, and reactivation phase. However, many CHB patients do not fit into any of these defined phases and are regarded as indeterminate. A large proportion of indeterminate patients are only treated with dynamic monitoring rather than recommended antiviral therapy, mainly due to the lack of definite guidelines. However, many of these patients may gradually have significant liver histopathological changes during disease progression. Recent studies have focused on the prevalence, progression, and carcinogenicity of indeterminate CHB, and more attention has been given to the prevention, detection, and treatment for these patients. Herein, we discuss the latest understanding of the epidemiology, clinical characteristics, and therapeutic strategies of indeterminate CHB, to provide avenues for the management of these patients.

Lower Risks of New-Onset Hepatocellular Carcinoma in Patients With Type 2 Diabetes Mellitus Treated With SGLT2 Inhibitors Versus DPP4 Inhibitors.

BACKGROUND: Type 2 diabetes mellitus (T2DM) may be a risk factor for development of hepatocellular carcinoma (HCC). The association between risk of developing HCC and treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) is currently unknown. This study aimed to compare the risk of new-onset HCC in patients treated with SGLT2i versus DPP4i. METHODS: This was a retrospective cohort study of patients with T2DM in Hong Kong receiving either SGLT2i or DPP4i between January 1, 2015, and December 31, 2020. Patients with concurrent DPP4i and SGLT2i use were excluded. Propensity score matching (1:1 ratio) was performed by using the nearest neighbor search. Multivariable Cox regression was applied to identify significant predictors. RESULTS: A total of 62,699 patients were included (SGLT2i, n=22,154; DPP4i, n=40,545). After matching (n=44,308), 166 patients (0.37%) developed HCC: 36 in the SGLT2i group and 130 in the DPP4i group over 240,269 person-years. Overall, SGLT2i use was associated with lower risks of HCC (hazard ratio [HR], 0.42; 95% CI, 0.28-0.79) compared with DPP4i after adjustments. The association between SGLT2i and HCC development remained significant in patients with cirrhosis or advanced fibrosis (HR, 0.12; 95% CI, 0.04-0.41), hepatitis B virus (HBV) infection (HR, 0.32; 95% CI, 0.17-0.59), or hepatitis C virus (HCV) infection (HR, 0.41; 95% CI, 0.22-0.80). The results were consistent in different risk models, propensity score approaches, and sensitivity analyses. CONCLUSIONS: SGLT2i use was associated with a lower risk of HCC compared with DPP4i use after adjustments, and in the context of cirrhosis, advanced fibrosis, HBV infection, and HCV infection.

Causal associations between platelet count, alcohol consumption, and the risk of liver hepatocellular carcinoma based on a Mendelian randomization study.

Background and aims: Liver hepatocellular carcinoma (LIHC) exhibits a multifactorial etiology, insidious onset, and a significantly low 5-year survival rate. We aimed to evaluate the causal impact of exposure factors (Alzheimer's disease, platelet count, ambidextrousness, cigarettes smoked per day, alcohol consumption, and endocarditis) on the risk of LIHC using a two-sample Mendelian randomization (MR) study. Methods: Independent single nucleotide polymorphisms (SNPs) strongly associated with Alzheimer's disease, platelet count, ambidextrousness, daily cigarette consumption, alcohol intake, and endocarditis were selected as instrumental variables (IVs) from the corresponding genome-wide association studies (GWAS). Genetic summary statistics for LIHC came from a GWAS that included 168 cases and 372,016 controls of European individuals. Multivariable MR analyses were performed to find the causal association between 6 exposure factors and LIHC risk. The inverse-variance weighted (IVW)-MR was employed as the primary analysis, and the MR-Egger regression, LASSO regression, and weighted Median approaches were performed as complementary analyses. Results: Multivariable MR analysis showed causal association between Alzheimer's disease [Odds ratio (OR) = 0.9999, 95% confidence intervals (CI) = 0.9998-0.9999, p = 0.0010], platelet count (OR = 0.9997, 95% CI = 0.9995-0.9999, p = 0.0066), alcohol consumption (OR = 0.9994, 95% CI = 0.9990-0.9999, p = 0.0098) and the LIHC outcome. After IVW-MR, MR-Egger and LASSO tests, the results are still significant. Next, we used different MR Methods to analyze platelet count, alcohol consumption, and Alzheimer's disease separately. Moreover, both funnel plots and MR-Egger intercepts provided compelling evidence to refute the presence of directional pleiotropy in the association between platelet count, alcohol consumption, Alzheimer's disease and the risk of LIHC. The IVW-MR analysis revealed a significant causal association between an elevated platelet count and a reduced risk of LIHC (OR = 0.9996, 95% CI= 0.9995-0.9998, p = 0.0005). Similarly, the analysis of weighted median revealed a negative correlation between platelet count and the risk of LIHC (OR = 0.9995, 95% CI = 0.9993-0.9999; p = 0.0160). Conversely, we observed a positive causal effect of alcohol consumption on the incidence of LIHC (OR = 1.0004, 95% CI = 0.9999-1.0009). However, no significant causal relationship was found between alcohol assumption, Alzheimer's disease, and LIHC susceptibility. Conclusions: A significant causal relationship exists between platelet count, alcohol consumption, Alzheimer's disease, and an increased risk of LIHC. The study presents compelling evidence for a genetically predicted decreased susceptibility to LIHC based on platelet count. The research implies that elevated platelet count may serve as a protective mechanism against LIHC. These findings may inform clinical strategies for LIHC prevention.

Cardiometabolic risk factors in MASLD patients with HCC: the other side of the coin.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) constitutes the commonest cause of chronic liver disorder worldwide, whereby affecting around one third of the global population. This clinical condition may evolve into Metabolic Dysfunction-Associated Steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC), in a predisposed subgroup of patients. The complex pathogenesis of MASLD is severely entangled with obesity, dyslipidemia and type 2 diabetes (T2D), so far so nutritional and lifestyle recommendations may be crucial in influencing the risk of HCC and modifying its prognosis. However, the causative association between HCC onset and the presence of metabolic comorbidities is not completely clarified. Therefore, the present review aimed to summarize the main literature findings that correlate the presence of inherited or acquired hyperlipidemia and metabolic risk factors with the increased predisposition towards liver cancer in MASLD patients. Here, we gathered the evidence underlining the relationship between circulating/hepatic lipids, cardiovascular events, metabolic comorbidities and hepatocarcinogenesis. In addition, we reported previous studies supporting the impact of triglyceride and/or cholesterol accumulation in generating aberrancies in the intracellular membranes of organelles, oxidative stress, ATP depletion and hepatocyte degeneration, influencing the risk of HCC and its response to therapeutic approaches. Finally, our pursuit was to emphasize the link between HCC and the presence of cardiometabolic abnormalities in our large cohort of histologically-characterized patients affected by MASLD (n=1538), of whom 86 had MASLD-HCC by including unpublished data.

Machine learning-based model for predicting tumor recurrence after interventional therapy in HBV-related hepatocellular carcinoma patients with low preoperative platelet-albumin-bilirubin score.

Introduction: This study aimed to develop a prognostic nomogram for predicting the recurrence-free survival (RFS) of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients with low preoperative platelet-albumin-bilirubin (PALBI) scores after transarterial chemoembolization (TACE) combined with local ablation treatment. Methods: We gathered clinical data from 632 HBV-related HCC patients who received the combination treatment at Beijing You'an Hospital, affiliated with Capital Medical University, from January 2014 to January 2020. The patients were divided into two groups based on their PALBI scores: low PALBI group (n=247) and high PALBI group (n=385). The low PALBI group was then divided into two cohorts: training cohort (n=172) and validation cohort (n=75). We utilized eXtreme Gradient Boosting (XGBoost), random survival forest (RSF), and multivariate Cox analysis to pinpoint the risk factors for RFS. Then, we developed a nomogram based on the screened factors and assessed its risk stratification capabilities and predictive performance. Results: The study finally identified age, aspartate aminotransferase (AST), and prothrombin time activity (PTA) as key predictors. The three variables were included to develop the nomogram for predicting the 1-, 3-, and 5-year RFS of HCC patients. We confirmed the nomogram's ability to effectively discern high and low risk patients, as evidenced by Kaplan-Meier curves. We further corroborated the excellent discrimination, consistency, and clinical utility of the nomogram through assessments using the C-index, area under the curve (AUC), calibration curve, and decision curve analysis (DCA). Conclusion: Our study successfully constructed a robust nomogram, effectively predicting 1-, 3-, and 5-year RFS for HBV-related HCC patients with low preoperative PALBI scores after TACE combined with local ablation therapy.

Evaluation of the risk of developing hepatocellular carcinoma in chronic Hepatitis C patients receiving antiviral treatment.

INTRODUCTION: Chronic HC leads to the development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The treatment of chronic HC with DAAs reduces mortality from LC and HCC. The study aimed to investigate the serological markers specific to HCC (PIVKA-II and AFP) in patients with chronic HC before and after DAA treatment. METHODOLOGY: The study involved 35 HCV patients (mean age: 56.23 ± 1.45) divided into two groups. Group 1 included 15 HCV + HCC patients and Group 2 included 20 HCV non-HCC patients. RESULTS: At the end of treatment all the patients were HCV RNA negative. Three months after the end of antiviral treatment, HCV RNA was undetectable in all patients, while a complete biochemical and virological response was observed in 66.7% of HCV + HCC patients and 85.0% of HCV non-HCC patients. PIVKA-II levels before the initiation of antiviral treatment were high in all patients. At the end of the treatment, in the HCV non-HCC group, normalization of PIVKA-II levels was observed only in 20.0% cases, and in 60.0% of cases 3 months after the treatment. Meanwhile, in patients with HCC and chronic HCV, PIVKA-II levels were within the normal range 3 months after treatment in only 13.3% of patients. CONCLUSIONS: It is necessary to monitor HCV patients with cirrhosis (F4) and severe fibrosis (F3) without HCC, who have high PIVKA-II and AFP levels and/or ALT activity despite obtaining sustained virologic response 3 months after treatment with DAAs.

Treatment with Antihistamines and the Risk of Liver Cancer in Patients with Viral Hepatitis: A Multi-Center Cohort Study.

Background: The effects of antihistamines on cancer risk and prognosis have been inconsistent across cancers. The aim of this multi-center cohort study was to investigate the association between antihistamine use and the risk of liver cancer in individuals with viral hepatitis. Methods: This multi-center cohort study included individuals diagnosed with hepatitis B or hepatitis C between January 2008 and March 2022. For antihistamine-treated patients, the index date was the date of antihistamine prescription, and for non-users, it was the date of hepatitis diagnosis. Participants were followed for five years, with the primary outcome of interest being new-onset liver cancer. The incidence rate and the adjusted hazard ratio (aHR) along with its 95% confidence interval (CI) of the outcome were calculated. Subgroup analyses were conducted, stratified by types of viral hepatitis including hepatitis C and hepatitis B. An additional validation study was performed. Results: The study included a total of 7748 patients with viral hepatitis. The incidence rate was 12.58 per 1000 person-years in patients with viral hepatitis on antihistamines, compared to 3.88 per 1000 person-years in those without antihistamine use. After adjusting for factors including age, sex, body mass index (BMI), comorbidities, laboratory data of liver function tests, comedications, and the use of antiviral therapies, the risk of new-onset liver cancer was significantly higher in patients on antihistamines (aHR = 1.83, 95% CI, 1.28-2.60). In patients with hepatitis C, the incidence rate in the antihistamine group was 15.73 per 1000 person-years, while non-users had a rate of 4.79 per 1000 person-years. Patients with hepatitis C on antihistamines had a significantly higher risk of developing liver cancer (aHR = 3.24, 95% CI, 2.16-4.86). Conclusions: This multi-center cohort study reported an increased risk of liver cancer in patients with hepatitis B or hepatitis C treated with antihistamines. Long-term follow-up studies are warranted to validate the findings.

Substitutions of saturated fat intakes with other macronutrients and foods and risk of NAFLD cirrhosis and all-cause hepatocellular carcinoma: a prospective cohort study.

BACKGROUND: Short-term trials have shown a reduction in liver fat when saturated fatty acids (SFAs) are substituted with polyunsaturated fatty acids (PUFA), or with low-glycemic carbohydrates. However, few cohort studies have been conducted to investigate the associations of replacing SFA and SFA-rich foods with different macronutrients and foods in more severe stages of liver disease; nonalcoholic fatty liver disease (NAFLD) cirrhosis and hepatocellular carcinoma (HCC). OBJECTIVES: To investigate associations between the substitution of SFA and SFA-rich foods with other macronutrients and foods and NAFLD cirrhosis and HCC in a middle-aged to elderly Swedish population of n = 77,059 males and females. METHODS: Time-to-event analyses were performed to investigate associations between the food and macronutrient substitutions and NAFLD cirrhosis and HCC. Multivariable Cox regression models were constructed to estimate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Statistical isocaloric and equal-mass substitutions were performed using the leave-one-out method. Prespecified nutrient and food substitutions of interest were SFA with carbohydrates, SFA with fiber, SFA with PUFA, butter with margarine and vegetable oils, unprocessed red meat with fish, and milk with fermented milk. RESULTS: Over a median follow-up of 24 y, 566 cases of NAFLD cirrhosis and 205 cases of HCC were registered. Overall, dietary substitutions showed no clear associations with either NAFLD cirrhosis or HCC. Substituting SFA with carbohydrates showed an HR of 0.87 (95% CI: 0.74, 1.02) for HCC and 1.00 (95% CI: 0.89, 1.11) for NAFLD cirrhosis. Substituting milk with fermented milk showed an HR of 0.93 (95% CI: 0.85, 1.01) for HCC and 0.97 (95% CI: 0.92, 1.03) for NAFLD cirrhosis. CONCLUSIONS: No clear associations were observed between diet and NAFLD cirrhosis or HCC. Although accompanied by low precision, possible lowered risks of HCC by substituting SFA with carbohydrates or milk with fermented milk might be of interest, but needs replication in other cohorts.

Burden of liver cancer attributable to high fasting plasma glucose: a global analysis based on the global burden of disease study 2019.

OBJECTIVE: Liver cancer is the world's sixth most prevalent cancer and the third most frequent cause of cancer-related mortality. Glucose metabolic disorders, indicated by a high fasting plasma glucose (HFPG) concentration, is a contributor to the etiology of liver cancer. With the rising prevalence of glucose metabolic disorders, an assessment of the global burden of liver cancer attributable to HFPG is warranted to inform global liver cancer prevention and control strategies. METHODS AND ANALYSIS: We evaluated the global death and disability-adjusted life years (DALYs) of liver cancer and its subtypes attributable to HFPG at global, regional, and country level. The temporal trend and disparity across geographic regions, social development level, age groups and sex were assessed. RESULTS: In 2019, HFPG-attributable liver cancer was estimated to have caused 4,729.49 deaths and to be responsible for 99,302.25 DALYs. The age-standardized mortality and DALY rate were 0.06 and 1.20 per 100,000 population, and displayed a significantly increasing temporal trend from 1990 to 2019. The age-standardized mortality rate of patients with liver cancer that was attributable to HFPG was higher in men than women. Sex-based disparity narrowed after the women reached menopause, but increased between 1990 and 2019. CONCLUSION: The burden of liver cancer that are attributable to HFPG has been influenced by longitudinal changes in lifestyle, the etiology of liver disease, age demographics, and hormonal status in women. These findings suggest that comprehensive strategies could be implemented, especially for patients with NASH and hyperglycemia, to prevent liver cancer.

Etiologically Significant microRNAs in Hepatitis B Virus-Induced Hepatocellular Carcinoma.

Hepatitis B virus (HBV) infection has been causally linked to hepatocellular carcinoma (HCC) in more than 50% cases. MicroRNAs (miRNAs) play cross-cutting mechanistic roles in the complex interplay between viral pathogenesis, host survival, and clinical outcomes. The present study set out to identify etiologically significant human miRNAs associated with HBV infection in liver-related pathologies leading to HCC. In diverse tissue types, we assembled 573 miRNAs differentially expressed in HBV-associated liver pathologies, HBV infection, fibrosis, cirrhosis, acute on chronic liver failure, and HCC. Importantly, 43 human differentially expressed miRNAs (hDEmiRs) were regulated in serum/plasma and liver tissue of patients with HBV-positive conditions. However, only two hDEmiRs, hsa-miR-21-5p and hsa-miR-143-3p, were regulated across all disease conditions. To shortlist the functional miRNAs in HBV-induced HCC pathogenesis, a reverse bioinformatics analysis was performed using eight GEO datasets and the TCGA database containing the list of differentially regulated mRNAs in HCC. A comparative study using these data with the identified targets of hDEmiRs, a set of unidirectionally regulated hDEmiRs with the potential to modulate mRNAs in HCC, were found. Moreover, our study identified five miRNAs; hsa-miR-98-5p, hsa-miR-193b-3p, hsa-miR-142-5p, hsa-miR-522-5p, and hsa-miR-370-3p targeting PIGC, KNTC1, CSTF2, SLC41A2, and RAB17, respectively, in HCC. These hDEmiRs and their targets could be pivotal in HBV infection and subsequent liver pathologies modulating HCC clinical progression. HBV infection is the largest contributor to HCC, and the present study comprises the first of its kind compendium of hDEmiRs related to HBV-related pathologies.

Serum ApoB/ApoA1 ratio in patients with CHB and the occurrence of HBV related cirrhosis and HBV related hepatocellular carcinoma.

Clinical research has suggested that chronic HBV infection exerts a certain effect on the occurrence of cardiovascular disease by regulating cholesterol metabolism in liver cells. High serum apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio plays a certain role in the above regulation, and it serves as a risk factor for cardiovascular disease. However, whether the ApoB/ApoA1 ratio is correlated with chronic HBV infection and its disease progression remains unclear. In accordance with the inclusion and exclusion criteria, all 378 participants administrated at Renmin Hospital of Wuhan University from March 2021 to March 2022, fell into Healthy Control (HC) group (50 participants), Hepatocellular carcinoma (HCC) group (107 patients), liver cirrhosis (LC) group (64 patients), chronic hepatitis B (CHB) group (62 patients), chronic hepatitis C (CHC) group (46 patients) and Hepatitis E Virus (HEV) group (49 patients). Serum ApoA1 and ApoB concentrations were measured at admission, and the ApoB/ApoA1 ratio was determined. The levels of laboratory parameters in the respective group were compared and ApoB/ApoA1 ratios in HCC patients and LC patients with different severity were further analyzed. ROC curves were plotted to analyze the early diagnostic ability of ApoB/ApoA1 ratio for HBV-associated HCC. Logistic regression and restricted cubic spline analysis were used to explore the correlation between ApoB/ApoA1 ratio and LC and HCC risk. A comparison was drawn in terms of ApoB/ApoA1 ratio between the groups, and the result was expressed in descending sequence: HEV group > CHB group > LC group > HCC group > CHC group > HC group, early-stage HCC < middle-stage HCC < advanced-stage HCC, Class A LC < Class B LC < Class C LC. Serum ApoB/ApoA1 ratio combined diagnosis with AFP exhibited the capability of increasing the detection efficacy and specificity of AFP for HCC and AFP-negative HCC. The incidence of LC and HCC in the respective logistic regression model showed a negative correlation with the serum ApoB/ApoA1 ratio in CHB patients (P < 0.05). After all confounding factors covered in this study were regulated, the result of the restricted cubic spline analysis suggested that in a certain range, serum ApoB/ApoA1 ratio showed an inverse correlation with the prevalence of LC or HCC in CHB patients. Serum ApoB/ApoA1 ratio in CHB patients may be conducive to identifying high-risk patients for HCC or LC, such that LC and HCC can be early diagnosed and treated.

Association between diabetes and subsequent malignancy risk among older breast cancer survivors.

Type II diabetes is associated with cancer risk in the general population but has not been well studied as a risk factor for subsequent malignancies among cancer survivors. We investigated the association between diabetes and subsequent cancer risk among older (66-84 years), 1-year breast cancer survivors within the linked Surveillance Epidemiology and End Results (SEER)-Medicare database using Cox regression analyses to quantify hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). Among 133 324 women, 29.3% were diagnosed with diabetes before or concurrent with their breast cancer diagnosis, and 10 452 women developed subsequent malignancies over a median follow-up of 4.3 years. Diabetes was statistically significantly associated with liver (HR = 2.35, 95% CI = 1.48 to 3.74), brain (HR = 1.94, 95% CI = 1.26 to 2.96), and thyroid cancer risks (HR = 1.38, 95% CI = 1.01 to 1.89). Future studies are needed to better understand the spectrum of subsequent cancers associated with diabetes and the role of diabetes medications in modifying subsequent cancer risk, alone or in combination with cancer treatments.

Reduction of the Risk of Hepatocellular Carcinoma over Time Using Direct-Acting Antivirals: A Propensity Score Analysis of a Real-Life Cohort (PITER HCV).

The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis achieving HCV eradication through DAA treatment and compared it with untreated participants in the multicenter prospective Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. Propensity matching with inverse probability weighting was used to compare DAA-treated and untreated HCV-infected participants with liver cirrhosis. Kaplan-Meier analysis and competing risk regression analysis were performed. Within the first 36 months, 30 de novo HCC cases occurred in the untreated group (n = 307), with a weighted incidence rate of 0.34% (95%CI: 0.23-0.52%), compared to 63 cases among SVR patients (n = 1111), with an incidence rate of 0.20% (95%CI: 0.16-0.26%). The 12-, 24-, and 36-month HCC weighted cumulative incidence rates were 6.7%, 8.4%, and 10.0% in untreated cases and 2.3%, 4.5%, and 7.0% in the SVR group. Considering death or liver transplantation as competing events, the untreated group showed a 64% higher risk of HCC incidence compared to SVR patients (SubHR 1.64, 95%CI: 1.02-2.62). Other variables independently associated with the HCC occurrence were male sex, increasing age, current alcohol use, HCV genotype 3, platelet count ≤ 120,000/µL, and albumin ≤ 3.5 g/dL. In real-life practice, the high efficacy of DAA in achieving SVR is translated into high effectiveness in reducing the HCC incidence risk.

Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells.

BACKGROUND: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. METHODS: The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. RESULTS: HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. CONCLUSIONS: IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.

Nomogram for predicting post-therapy recurrence in BCLC A/B hepatocellular carcinoma with Child-Pugh B cirrhosis.

Introduction: This study conducts a retrospective analysis on patients with BCLC stage A/B hepatocellular carcinoma (HCC) accompanied by Child-Pugh B cirrhosis, who underwent transarterial chemoembolization (TACE) in combination with local ablation therapy. Our goal was to uncover risk factors contributing to post-treatment recurrence and to develop and validate an innovative 1-, 3-, and 5-year recurrence free survival (RFS) nomogram. Methods: Data from 255 BCLC A/B HCC patients with Child-Pugh B cirrhosis treated at Beijing You'an Hospital (January 2014 - January 2020) were analyzed using random survival forest (RSF), LASSO regression, and multivariate Cox regression to identify independent risk factors for RFS. The prognostic nomogram was then constructed and validated, categorizing patients into low, intermediate, and high-risk groups, with RFS assessed using Kaplan-Meier curves. Results: The nomogram, integrating the albumin/globulin ratio, gender, tumor number, and size, showcased robust predictive performance. Harrell's concordance index (C-index) values for the training and validation cohorts were 0.744 (95% CI: 0.703-0.785) and 0.724 (95% CI: 0.644-0.804), respectively. The area under the curve (AUC) values for 1-, 3-, and 5-year RFS in the two cohorts were also promising. Calibration curves highlighted the nomogram's reliability and decision curve analysis (DCA) confirmed its practical clinical benefits. Through meticulous patient stratification, we also revealed the nomogram's efficacy in distinguishing varying recurrence risks. Conclusion: This study advances recurrence prediction in BCLC A/B HCC patients with Child-Pugh B cirrhosis following TACE combined with ablation. The established nomogram accurately predicts 1-, 3-, and 5-year RFS, facilitating timely identification of high-risk populations.

Are we ready for genetic testing in metabolic dysfunction-associated steatotic liver disease?

Metabolic dysfunction-associated steatotic liver disease (MASLD), with its steadily increasing prevalence, represents now a major problem in public health. A proper referral could benefit from tools allowing more precise risk stratification. To this end, in recent decades, several genetic variants that may help predict and refine the risk of development and progression of MASLD have been investigated. In this review, we aim to discuss the role genetics in MASLD plays in everyday clinical practice. We performed a comprehensive literature search of PubMed for relevant publications. Available evidence highlights the emergence of genetic-based noninvasive algorithms for diagnosing fatty liver, metabolic dysfunction-associated steatohepatitis, fibrosis progression and occurrence of liver-related outcomes including hepatocellular carcinoma. Nevertheless, their accuracy is not optimal and application in everyday clinical practice remains challenging. Furthermore, susceptible genetic markers have recently become subjects of great scientific interest as therapeutic targets in precision medicine. In conclusion, decisional algorithms based on genetic testing in MASLD to facilitate the clinician decisions on management and treatment are under growing investigation and could benefit from artificial intelligence methodology.

Shear-wave elastography to predict hepatocellular carcinoma after hepatitis C virus eradication: A systematic review and meta-analysis.

BACKGROUND: Direct-acting antiviral agents (DAAs) are highly effective treatment for chronic hepatitis C (CHC) with a significant rate of sustained virologic response (SVR). The achievement of SVR is crucial to prevent additional liver damage and slow down fibrosis progression. The assessment of fibrosis degree can be performed with transient elastography, magnetic resonance elastography or shear-wave elastography (SWE). Liver elastography could function as a predictor for hepatocellular carcinoma (HCC) in CHC patients treated with DAAs. AIM: To explore the predictive value of SWE for HCC development after complete clearance of hepatitis C virus (HCV). METHODS: A comprehensive literature search of clinical studies was performed to identify the ability of SWE to predict HCC occurrence after HCV clearance. In accordance with the study protocol, a qualitative and quantitative analysis of the evidence was planned. RESULTS: At baseline and after 12 wk of follow-up, a trend was shown towards greater liver stiffness (LS) in those who go on to develop HCC compared to those who do not [baseline LS standardized mean difference (SMD): 1.15, 95% confidence interval (95%CI): 020-2.50; LS SMD after 12 wk: 0.83, 95%CI: 0.33-1.98]. The absence of a statistically significant difference between the mean LS in those who developed HCC or not may be related to the inability to correct for confounding factors and the absence of raw source data. There was a statistically significant LS SMD at 24 wk of follow-up between patients who developed HCC vs not (0.64; 95%CI: 0.04-1.24). CONCLUSION: SWE could be a promising tool for prediction of HCC occurrence in patients treated with DAAs. Further studies with larger cohorts and standardized timing of elastographic evaluation are needed to confirm these data.

Stress-induced epinephrine promotes hepatocellular carcinoma progression via the USP10-PLAGL2 signaling loop.

Hepatocellular carcinoma (HCC) is associated with a poor prognosis. Our previous study demonstrated that Pleomorphic adenoma gene like-2 (PLAGL2) was a potential therapeutic target in HCC. However, the mechanisms that lead to the upregulation of PLAGL2 in HCC remain unclear. The present study revealed that stress-induced epinephrine increased the expression of PLAGL2, thereby promoting the progression of HCC. Furthermore, PLAGL2 knockdown inhibited epinephrine-induced HCC development. Mechanistically, epinephrine upregulated ubiquitin-specific protease 10 (USP10) to stabilize PLAGL2 via the adrenergic ß-receptor-2-c-Myc (ADRB2-c-Myc) axis. Furthermore, PLAGL2 acted as a transcriptional regulator of USP10, forming a signaling loop. Taken together, these results reveal that stress-induced epinephrine activates the PLAGL2-USP10 signaling loop to enhance HCC progression. Furthermore, PLAGL2 plays a crucial role in psychological stress-mediated promotion of HCC progression.