Immune checkpoint inhibitors (ICI) have been applied to treat advanced stage hepatocellular carcinoma (HCC) and obtain promising effects. However, tumor response to treatment was unpredictable. A predicting biomarker of objective response or disease-control is an unmet need for patient selection. In this study, 45 advanced HCC patients who failed to sorafenib treatment and received nivolumab, 3 mg/kg bi-weekly, were included. Tumor responses to nivolumab treatment were assessed by the modified response evaluation criteria in solid tumors (mRECIST) criteria. Tumor responses were correlated to clinical characteristics to find out response predictors. In this small series, the prevalence of extrahepatic nodal metastasis, distant metastasis, and portal vein thrombus among the patients were 22.2% (n = 10), 48.9% (n = 22), and 42.2% (n = 19), respectively. The pre-treatment tumor size was 7.2 ± 4.2 cm in maximal diameter, and the calculated total tumor volume was 619.0 ± 831.1 cm³. Among 45 patients, 3 patients had partial response (PR), 11 had stable disease (SD), and the other 31 had progression of disease. By correlating clinical data to the patients with PR and SD, serum neutrophil-to-lymphocyte ratio (NLR) (hazard ratio (HR) = 2.04) and patient-generated subjective global assessment (PG-SGA) score (HR = 2.30) were the independent factors in multivariate analysis. By receiver operating characteristic curve analysis, pre-treatment NLR ≤ 2.5 and PG-SGA score < 4 were the cutoff points to predict tumor response to ICI treatment. In conclusion, biomarkers to predict tumor response for HCC are still lacking in this costly ICI therapy. In this study, NLR ≤ 2.5 and PG-SGA score < 4 indicated disease-control, and can be applied as biomarkers to select the right patients to receive this costly therapy.

Microvascular invasion (MVI) is a significant risk factor for the recurrence of hepatocellular carcinoma, but it is a histological feature that needs to be confirmed after hepatectomy or liver transplantation. The preoperative prediction of MVI can optimize the treatment plan of HCC, but an easy and widely applicable model is still lacking. The aim of our study was to predict the risk of MVI using objective preoperative factors. We retrospectively collected 1153 patients who underwent liver resection for HCC, and MVI was found to be associated with significantly poor disease-free survival. The patients were randomly split in a 3:1 ratio into training (n = 864) and validation (n = 289) datasets. The multivariate analysis of the training dataset found preoperative total tumor volume (TTV) and alpha-fetoprotein (AFP) to be independent risk factors for MVI. We built a risk score model with cutoff points of TTV at 30, 60, and 300 cm³ and AFP at 160 and 2000 ng/mL, and the model stratified the risk of MVI into low risk (14.1%), intermediate risk (36.4%), and high risk (60.5%). The validation of the risk score model with the validation dataset showed moderate performance (the concordance statistic: 0.731). The model comprised simple and objective preoperative factors with good applicability, which can help to guide treatment plans for HCC and future study design.

Background: Patients with hepatocellular carcinoma (HCC) tend to be referred for liver transplantation (LT) at an early stage of cirrhosis, with lower pre-LT Model of End-Stage Liver Disease (MELD) scores. We investigated the impact of high MELD scores on post-LT outcomes in patients with HCC and validated the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR). Patients and Method: This retrospective single-center cohort study enrolled 230 patients with HCC who underwent LDLT from 2004–2019 in our institute. We defined a high MELD score as ≥20. Results: The MELD < 20 and MELD ≥ 20 groups comprised 205 and 25 cases, respectively. Although there was no significant difference in disease-free survival between the two groups (p = 0.629), the incidence of septic shock (p = 0.019) was significantly higher in the high MELD group. The one-, three-, and five-year overall survival rates were not significantly different between the two groups (p = 0.056). In univariate analysis, a high pre-LT NLR was associated with poorer survival in the high MELD group (p = 0.029, hazard ratio [HR]: 1.07, 90% confidence interval [CI]: 1.02–1.13). NLR cut-off values of ≥10.7 and <10.7 were predictive of mortality, with an AUC of 0.705 (90% CI: 0.532–0.879). The one-, three-, and five-year post-LT survival rates were significantly higher among the recipients with an NLR < 10.7 than those with an NLR ≥ 10.7 (p = 0.005). Conclusions: Pre-LT MELD score ≥ 20 was associated with a higher risk of developing post-LT septic shock and mortality. The pre-LT serum NLR is a useful predictive factor for clinical outcomes in patients with HCC with high MELD scores.

Portal vein thrombus (PVT) is a challenge in liver transplantation. How PVT develops in cirrhotic patients who already have coagulopathy is unclear. This study aimed to investigate possible contributing factors to PVT in cirrhotic patients. A total of 349 cirrhotic patients who waited liver transplantation were included in this study and 48 of them had PVT. For all the patients, the mean age was 53.5 ± 9.0 year old, and 75.9% of the patients were male. There were 233 (66.8%) patients who had either hepatitis B or C. The mean Model For End-Stage Liver Disease (MELD) score was 16.4 ± 7.5. Eighteen of 48 patients with PVT and 145 of 301 patients without PVT received liver transplantation. Multivariate analysis showed that low protein S level (hazard ratio = 2.46, p = 0.017) was the only independent risk factor for PVT development. Protein S deficiency also demonstrated prognostic value on short-term survival, not only for cirrhotic patients awaiting liver transplantation (69.9% versus 84.1% at 1 year survival, p = 0.012), but also for the patients having liver transplantation (70.4% versus 84.8% at 1 year survival, p = 0.047). In conclusion, protein S level was an independent risk factor for PVT development in decompensated cirrhotic patients, and protein S deficiency was also a prognostic factor for the patients waiting for liver transplantation.

Human cytomegalovirus (CMV) infection has been reported to compromise liver transplantation (LT) outcomes. Recent studies have shown that CMV has a beneficial oncolytic ability. The aim of this study was to investigate the impact of CMV on tumor recurrence in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). This retrospective study enrolled 280 HCC patients with LT at our institute between January 2005 and January 2016. Their relevant demographic characteristics, pre- and post-LT conditions, and explant histology were collected. A CMV pp65 antigenemia assay was performed weekly following LT to identify CMV infection. A total of 121 patients (43.2%) were CMV antigenemia-positive and 159 patients (56.8%) were negative. A significantly superior five-year recurrence-free survival was observed among CMV antigenemia-positive patients compared with the CMV-negative group (89.2% vs. 79.9%, p = 0.049). There was no significant difference in overall survival between the positive and negative CMV antigenemia groups (70.2% vs. 75.3%, p = 0.255). The major cause of death was HCC recurrence in CMV antigenemia-negative patients (51.3%), whereas more CMV antigenemia-positive patients died due to other bacterial or fungal infections (58.3%). In the multivariate analysis, the independent risk factors for tumor recurrence included positive CMV antigenemia (p = 0.042; odds ratio (OR) = 0.44; 95% confidence interval (CI) = 0.20–0.97), microscopic vascular invasion (p = 0.001; OR = 3.86; 95% confidence interval (CI) = 1.78–8.36), and tumor status beyond the Milan criteria (p = 0.001; OR = 3.69; 95% CI = 1.77–7.71). In conclusion, in addition to the well-known Milan criteria, human CMV is associated with a lower HCC recurrence rate after LT. However, this tumor suppressive property does not lead to prolonged overall survival, especially in severely immunocompromised patients who are vulnerable to other infections.

Background. A combination of antihepatitis B immunoglobulin and antiviral agents is the most common regimen for prophylaxis of hepatitis B recurrence after liver transplantation. However, hepatitis B recurrence still happens. The significance of hepatitis B recurrence is less mentioned. Materials. Forty‐eight of the 313 hepatitis B liver transplant recipients having hepatitis B recurrence were included in this study. The patients were divided into group A, the patients transplanted for hepatitis B‐related liver failure, and group B, the patients transplanted for hepatitis B‐related cirrhosis and HCC. The clinical manifestations after hepatitis B recurrence were recorded. Results. Among the 48 patients with hepatitis B recurrence, 23 patients were in group A and 25 patients in group B. The age was 51.6 ± 9.4 years in group A and 52.8 ± 6.4 in group B (p = 0.869). The MELD score prior to transplantation was 23.1 ± 9.9 in group A patients and 12.9 ± 5.6 in group B patients (p < 0.001). The median (interquartile) interval from transplantation to hepatitis B recurrence was 10 (2‐19) months for group A patients and 13 (8.5‐35) months for group B patients (p = 0.051). After hepatitis B recurrence, the liver function was almost normal in both groups. In group B patients, 10 patients had HCC recurrence with 7 of 10 patients having hepatitis B recurrence earlier than HCC recurrence. The interval between hepatitis B and HCC recurrence was 1 to 15 months. The 1‐, 3‐, and 5‐year survival rates were 82.6%, 73.9%, and 69.0%, respectively, for group A patients and 96%, 76%, and 68%, respectively, for group B patients (p = 0.713). Conclusion. The patients have uneventful liver function under antiviral agent while hepatitis B recurred. For the patients having HCC prior to transplantation, close monitoring of HCC recurrence is necessary if hepatitis B recurs.