Interleukin-17A educated hepatic stellate cells promote hepatocellular carcinoma occurrence through fibroblast activation protein expression.

BACKGROUND: Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly influences tumorigenesis. Interleukin-17A (IL-17A), a pivotal pro-inflammatory cytokine predominantly secreted by Th17 cells, is known to play a substantial role in the etiology and progression of liver cancer. However, the precise mechanism by which IL-17A engages with hepatic stellate cells (HSCs) to facilitate the development of hepatocellular carcinoma (HCC) remains to be fully elucidated. This investigation seeks to unravel the interplay between IL-17A and HSCs in the context of HCC. METHODS: An HCC model was established in male Sprague-Dawley rats using diethylnitrosamine to explore the roles of IL-17A and HSCs in HCC pathogenesis. In vivo overexpression of Il17a was achieved using adeno-associated virus. A suite of molecular techniques, including RT-qPCR, enzyme-linked immunosorbent assays, Western blotting, cell counting kit-8 assays and colony formation assays, was employed for in vitro analyses. RESULTS: The study findings indicate that IL-17A is a key mediator in HCC promotion, primarily through the activation of hepatic progenitor cells (HPCs). This pro-tumorigenic influence appears to be mediated by HSCs, rather than through a direct effect on HPCs. Notably, IL-17A-induced expression of fibroblast activation protein (FAP) in HSCs emerged as a critical factor in HCC progression. Silencing Fap in IL-17A-stimulated HSCs was observed to reverse the HCC-promoting effects of HSCs. CONCLUSIONS: The collective evidence from this study implicates the IL-17A/FAP signaling axis within HSCs as a contributor to HCC development by enhancing HPC activation. These findings bolster the potential of IL-17A as a diagnostic and preventative target for HCC, offering new avenues for therapeutic intervention.

Silymarin Synergizes with Antiviral Therapy in Hepatitis B Virus-Related Liver Cirrhosis: A Propensity Score Matching Multi-Institutional Study.

Hepatitis B virus (HBV)-related liver cirrhosis (HBV-LC) presents a substantial mortality and hepatocellular carcinoma (HCC) risk. While antiviral therapy (AVT) is the standard, complete HBV clearance remains elusive and may not reduce the risk of death in patients with decompensated cirrhosis. Silymarin, a centuries-old herbal remedy, has shown promise against HBV infection and as an antifibrosis therapy. This study explores the potential of silymarin combined with AVT to reduce mortality and HCC incidence in patients with HBV-LC. This research, spanning from 2001 to 2019, entailed a multi-institutional retrospective cohort study which included 8447 HBV-LC patients all undergoing AVT. After applying inclusion and exclusion criteria, the study comprised two cohorts: a case cohort receiving silymarin alongside AVT for at least 30 days, and a control cohort on AVT alone. Propensity score matching, based on baseline parameters including HBV-DNA levels, comorbidity, and an important LC medication, namely, non-selective ß-blockers, was employed to ensure balanced groups, resulting in 319 patients in each cohort for subsequent analyses. Overall mortality was the primary outcome, with HCC occurrence as a secondary outcome. Among 319 patients in both cohorts, the case cohort exhibited significant improvements in the international normalized ratio (INR), model for end-stage liver disease (MELD) score and the Charlson comorbidity index (CCI) one year after the index date. A competing risk survival analysis demonstrated superior one-year and two-year mortality outcomes in the case cohort. However, no significant impact on one-year and two-year HCC occurrence was observed in either cohort. The combination of silymarin and AVT in HBV-LC patients demonstrated a synergistic effect, leading to decreased overall mortality and an improved comorbidity index. While the incidence of HCC remained unchanged, our results suggested promising potential for further clinical trials investigating the synergistic role of silymarin in the treatment of HBV-LC.

aMAP score prediction of hepatocellular carcinoma occurrence and incidence-free rate after a sustained virologic response in chronic hepatitis C.

AIMS: Hepatocellular carcinoma (HCC) can still occur in hepatitis C virus (HCV) patients who have achieved a sustained virologic response (SVR), which remains an important clinical issue in the direct-acting antivirals era. The current study investigated the clinical utility of the aMAP score (consisting of age, male, albumin-bilirubin, and platelets) for predicting HCC occurrence in HCV patients achieving an SVR by direct-acting antivirals. METHODS: A total of 1113 HCV patients without HCC history, all of whom achieved an SVR, were enrolled for clinical comparisons. RESULTS: Hepatocellular carcinoma was recorded in 50 patients during a median follow-up period of 3.7 years. The aMAP score was significantly higher in the HCC occurrence group than in the HCC-free group (53 vs. 47, p < 0.001). According to risk stratification based on aMAP score, the cumulative incidence of HCC occurrence for the low-, medium-, and high-risk groups was 0.14%, 4.49%, and 9.89%, respectively, at 1 year and 1.56%, 6.87%, and 16.17%, respectively, at 3 years (low vs. medium, low vs. high, and medium vs. high: all p < 0.01). Cox proportional hazard analysis confirmed aMAP ≥ 50 (hazard ratio [HR]: 2.78, p = 0.014), age≥ 70 years (HR: 2.41, p = 0.028), ALT ≥ 17 U/L (HR: 2.14, p < 0.001), and AFP ≥ 10 ng/mL (HR: 2.89, p = 0.005) as independent risk factors of HCC occurrence. Interestingly, all but one patient (99.5%) with aMAP less than 40 was HCC-free following an SVR. CONCLUSION: The aMAP score could have clinical utility for predicting HCC occurrence in HCV patients achieving an SVR.

Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C.

BACKGROUND AND AIMS: Although treatment for hepatitis C virus has been dramatically improved by the development of direct-acting antiviral agents (DAAs), whether interferon (IFN)-free therapy reduces hepatocarcinogenesis in an equivalent manner to IFN-based therapy remains controversial. The aims of this study were to evaluate the occurrence and recurrence of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients treated with DAAs and to identify biomarkers of HCC development after antiviral treatment. METHODS: A restrospective review of a prospective database of 1,897 CHC patients who were treated with IFN-based (1,145) or IFN-free therapies (752) was carried out. Cumulative HCC occurrence and recurrence rates were compared using propensity score-matched analysis. Predictors of HCC development after viral eradication were identified by multivariate analysis. RESULTS: Propensity score-matched analysis showed no significant difference in HCC occurrence (p=0.49) and recurrence rates (p=0.54) between groups treated with IFN-based or IFN-free therapies. In multivariate analysis, higher levels of post-treatment α-fetoprotein (AFP) or Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+M2BP) were independently associated with HCC occurrence and recurrence after viral eradication. Only post-treatment WFA+M2BP level was significantly associated with HCC occurrence and recurrence among patients without severe fibrosis. The area under the receiver operating characteristic (ROC) curve for WFA+M2BP levels was greater than that for AFP levels in ROC analysis. CONCLUSION: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy. Patients with high WFA+M2BP levels after antiviral treatment, even without severe fibrosis, must be followed up carefully for HCC development. Lay summary: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy.

Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) represents a serious complication of HCV-related cirrhosis. New direct-acting antivirals (DAA) cure HCV infection in over 90% of patients. The aim of this study was to evaluate the early occurrence and recurrence of HCC in cirrhotic patients treated with DAA. METHODS: We analysed 344 consecutive cirrhotic patients, without HCC, who were treated with DAA, and followed for 24weeks. Fifty-nine patients had previous HCC. RESULTS: DAA therapy induced sustained virological response in 91% of patients. During 24-week follow-up, HCC was detected in 26 patients (7.6%, 95% CI: 4.99-10.84): 17 of 59 patients (28.81%, 95% CI: 17.76-42.07) with previous HCC and 9 of 285 patients (3.16%, 95% CI: 1.45-5.90) without previous HCC. Child-Pugh Class B, more severe liver fibrosis, lower platelet count, and previous HCC were significantly associated with HCC development, at univariate analysis. At multivariate analysis, Child-Pugh class (p=0.03, OR: 4.18, 95% CI: 1.17-14.8) and history of HCC (p<0.0001, OR: 12.0, 95% CI: 4.02-35.74) resulted independently associated with HCC development. Among the 59 patients with previous HCC, younger age and more severe liver fibrosis were significantly associated with HCC recurrence, both at univariate and at multivariate analysis. CONCLUSIONS: In patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumour recurrence, in the short term. For these reasons, all cirrhotic patients should be closely monitored and followed during and after antiviral therapy. LAY SUMMARY: New direct-acting antivirals are able to eradicate HCV infection in over 90% of patients with advanced liver disease. Unfortunately, the occurrence of liver cancer is not reduced in effectively treated cirrhotic patients. In addition, patients previously treated for HCC have still a high risk of tumour recurrence in the short term, despite DAA treatment.

Liver Stiffness Values to Predict Occurrence and Recurrence of Hepatocellular Carcinoma.

Globally, liver cancer is the third most frequent etiology of cancer death, with the rates of occurrence of both new cases and mortality estimated to increase. Given the availability of multiple treatments, interdisciplinary management of the patient is crucial. Moreover, the diagnostic assessment of patients with severe liver fibrosis is essential for the staging of HCC and liver cirrhosis and early diagnosis of HCC. In this context, non-invasive evaluation plays a critical role in identifying prognostic factors of clinical application for the surveillance of the occurrence or recurrence of HCC. The new frontiers of transient elastography have become a useful tool to assess the risk of HCC occurrence and recurrence. There has been a major increase in studies investigating the cutoff liver stiffness value that best predicts the need for monitoring for the onset of HCC. Therefore, this review discusses the new advances that have occurred in the last four years on HCC, highlighting the new frontiers of non-invasive evaluation of HCC subjects, with particular attention regarding the clinical application of liver stiffness assessment for de novo HCC and predicting recurrence in patients with chronic HCV achieving sustained virological response after treatment with direct antiviral agents.

Direct-Acting Antiviral Drugs and Occurrence of Hepatocellular Carcinoma: Unjust or Oppressed.

PURPOSE: In interferon-free era, direct-acting antiviral agents (DAAs) have achieved high eradication rates with an excellent safety profile since revolutionized the management of hepatitis c virus (HCV) patients. Published papers have suggested a possible increased incidence of hepatocellular carcinoma (HCC) after successful DAAs treatment. Other papers have been published about the problem but without conclusive results. Because of this debate, we aim to evaluate the effects of antiviral therapy (Sofosbuvir plus Daclatasvir with or without Ribavirin) on the de novo occurrence of HCC in patients with liver cirrhosis (LC). PATIENTS AND METHODS: A prospective cohort study has included 350 patients who have visited our center for HCV treatment. Pretreatment history, examination, complete blood picture, liver function tests, kidney function tests, HA1C for diabetic patients, HCV PCR, HBsAg, alpha-fetoprotein (AFP), and abdominal ultrasound have been done, also Child-Pogh (CP) and Model for End-Stage Liver Disease (MELD) score before treatment. These investigations have been repeated for 3 months after the end of treatment. Abdominal ultrasound (US) has been done for 3 months after treatment and every 4 months for 2 years after the end of treatment to detect HCC occurrence. RESULTS: Patients age (58.11 ± 7.48), 55.4% of patients were males, 30.3% of patients were diabetic, 84.3% of them were treatment naïve and sustained virological response (SVR) occured in 94% of them. HCC occurrence after treatment was 6.7% in patients with SVR and 23.8% in patients with non-SVR (P value=0.016) during follow-up period. There is significant improvement of CP score. No significant changes in MELD score. CONCLUSION: Treatment of HCV-related LC patients with sofosbuvir and daclatasvir with or without ribavirin for 3 or 6 months showed high SVR and significant improvement in CP score, but still at risk of HCC even if treated and should be followed up regularly according to screening programs with special meticulous attention to those with non-SVR.