The association between proton-pump inhibitor use and recurrence of hepatocellular carcinoma after hepatectomy.

BACKGROUND AND AIM: The association between long-term proton-pump inhibitors (PPIs) use and malignancies had long been discussed, but it still lacks consensus. Our study investigated the association between PPI use and hepatocellular carcinoma (HCC) recurrence following curative surgery. METHODS: We retrospectively enrolled 6037 patients with HCC who underwent hepatectomy. Patients were divided into four groups according to their PPI usage. (non-users: < 28 cumulative defined daily dose [cDDD]; short-term users: 28-89 cDDD; mid-term users: 90-179 cDDD, and long-term users: ≥ 180 cDDD, respectively). Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazard models. RESULTS: Among the 6037 HCC patients, 2043 (33.84%) were PPI users. PPI users demonstrated better median RFS (3.10 years, interquartile range [IQR] 1.49-5.01) compared with non-users (2.73 years, IQR 1.20-4.74; with an adjusted hazard ratio [aHR] of 0.57, 95% confidence interval [CI] 0.44-0.74, P < 0.001). When considering the cumulative dosage of PPI, only long-term PPI users had significant lower risk of HCC recurrence than non-PPI group (adj-HR: 0.50; 95% CI: 0.35-0.70; P < 0.001). Moreover, the impact of long-term PPIs use on improving RFS was significant in most of the subgroup analysis, except in patients with advanced tumor stages, with non-cirrhosis, or with a history of chronic kidney disease. However, there were no significant differences in median OS between PPI users and non-users (4.23 years, IQR 2.73-5.86 vs 4.04 years, IQR 2.51-5.82, P = 0.369). CONCLUSION: Long-term PPI use (≥ 180 cDDD) may be associated with a better RFS in HCC patients after hepatectomy.

Conventional and machine learning-based risk scores for patients with early-stage hepatocellular carcinoma.

BACKGROUND/AIMS: The performance of machine learning (ML) in predicting the outcomes of patients with hepatocellular carcinoma (HCC) remains uncertain. We aimed to develop risk scores using conventional methods and ML to categorize early-stage HCC patients into distinct prognostic groups. METHODS: The study retrospectively enrolled 1,411 consecutive treatment-naïve patients with the Barcelona Clinic Liver Cancer (BCLC) stage 0 to A HCC from 2012 to 2021. The patients were randomly divided into a training cohort (n=988) and validation cohort (n=423). Two risk scores (CATS-IF and CATS-INF) were developed to predict overall survival (OS) in the training cohort using the conventional methods (Cox proportional hazards model) and ML-based methods (LASSO Cox regression), respectively. They were then validated and compared in the validation cohort. RESULTS: In the training cohort, factors for the CATS-IF score were selected by the conventional method, including age, curative treatment, single large HCC, serum creatinine and alpha-fetoprotein levels, fibrosis-4 score, lymphocyte-tomonocyte ratio, and albumin-bilirubin grade. The CATS-INF score, determined by ML-based methods, included the above factors and two additional ones (aspartate aminotransferase and prognostic nutritional index). In the validation cohort, both CATS-IF score and CATS-INF score outperformed other modern prognostic scores in predicting OS, with the CATSINF score having the lowest Akaike information criterion value. A calibration plot exhibited good correlation between predicted and observed outcomes for both scores. CONCLUSION: Both the conventional Cox-based CATS-IF score and ML-based CATS-INF score effectively stratified patients with early-stage HCC into distinct prognostic groups, with the CATS-INF score showing slightly superior performance.

Prognostic Nutritional Index as a Prognostic Factor for Very Early-Stage Hepatocellular Carcinoma.

INTRODUCTION: Field factors play more important roles in predicting the outcomes of patients compared with tumor factors in early-stage hepatocellular carcinoma (HCC). However, the prognostic ability of noninvasive serum marker scores for hepatic fibrosis and liver functional reserve on very early-stage HCC is still not yet determined. We aimed to investigate the performance of these serum marker scores in predicting the prognoses of patients with very early-stage HCC. METHODS: A total of 446 patients with very early-stage HCC from 2012 to 2022 were retrospectively enrolled. Serum biomarkers and prognostic scores determining overall survival (OS) were analyzed by Cox proportional hazards model. We compared the Akaike information criterion among the prognostic nutritional index (PNI), aspartate aminotransferase-to-platelet ratio index, albumin-bilirubin (ALBI) score, EZ (easy)-ALBI score, modified ALBI score, fibrosis-4 score, and lymphocyte-to-monocyte ratio to determine the predictability on the OS. RESULTS: After a median follow-up of 41.0 months (interquartile range 36.9-45.1 months), 81 patients died, with a 5-year OS rate of 71.0%. Among the noninvasive serum marker scores, PNI had the best performance in predicting the OS with the lowest Akaike information criterion (846.407) compared with other scores. Moreover, we stratified the patients into high-risk (PNI <45) and low-risk (PNI ≥45) groups. It showed that the 5-year OS rates were 83.4% and 60.8% in the low-risk and high-risk PNI groups, respectively ( P < 0.001). DISCUSSION: PNI had the best performance in predicting the OS for patients with very early-stage HCC.

The Bioactive Extract of Pinnigorgia sp. Induces Apoptosis of Hepatic Stellate Cells via ROS-ERK/JNK-Caspase-3 Signaling.

The activation of hepatic stellate cells (HSCs) is a significant phenomenon during the pathogenesis of liver disorders, including liver cirrhosis and fibrosis. Here, we identified that the extract from a gorgonian coral Pinnigorgia sp. (Pin) induced apoptosis of HSC-T6 cells. Pin inhibited the viability of HSC-T6 cells and increased their subG1 population, DNA fragmentation, caspase-3 activation, and reactive oxygen species (ROS) production in a concentration-dependent manner. The Pin-induced ROS generation and apoptotic effects were significantly reversed by a thiol antioxidant, N-acetylcysteine (NAC). Additionally, Pin induced ERK/JNK phosphorylation and pharmacological inhibition of ERK/JNK rescued the Pin-induced cell death. Pin-activated ERK/JNK were significantly reduced after the administration of NAC; however, the inhibition of ERK/JNK failed to change the Pin-induced ROS production. Similarly, pinnigorgiol A, a pure compound isolated from Pin, elicited ROS production and apoptosis in HSC-T6 cells. The pinnigorgiol A-induced apoptosis was retrained by NAC. Together, it appears that Pin leads to apoptosis in HSC-T6 cells through ROS-mediated ERK/JNK signaling and caspase-3 activation. Pinnigorgiol A serves as a bioactive compound of Pin and may exhibit therapeutic potential by clearance of HSCs.