Search

Hepatocellular carcinoma (HCC) is one of the most common cancers and is responsible for the second cancer‐related death globally. Many treatment regimens have been developed to cure the disease; however, life expectancy is still low. Therefore, there is an urgent need to explore new selective, specific, and robust diagnosis markers for efficient early recognition of the ailment. Along with the diagnosis, the treatment's effectiveness can be determined by prognostic markers, and miRNAs are excellent tools for the diagnosis and prognosis of HCC. In addition, the altered expression profile of a few miRNAs promotes HCC cell migration and invasion, and selective up‐ or downregulation of these responsible genes may help mitigate the disorder. On one hand, few of the miRNAs have been found to enhance angiogenesis, a crucial step of tumor growth; on the other hand, upregulation of specific miRNAs is reported to suppress angiogenesis and resulting tumor growth of HCC cells. Exosomal miRNAs have significant implications in promoting angiogenesis, increased endothelial cell permeability, tube formation, and metastasis to hepatic and pulmonary tissues. miRNA also attributes to drug resistance toward chemotherapy and the prevention of autophagy also. Identifying novel miRNA and determining their differential expression in HCC tissue may serve as a potential tool for diagnosis, prognosis, and therapy to enhance the life expectancy and quality of life of HCC patients. In the present review, we have summarized the recent advances in HCC‐related research. [ABSTRACT FROM AUTHOR]

Preoperative α-fetoprotein (AFP) level levels may help select patients with hepatocellular carcinoma (HCC) for surgery. The objective of the current study was to assess an AFP model to predict tumor recurrence and patient survival after curative resection for HCC. Patients undergoing curative-intent resection for HCC between 2000 and 2017 were identified from a multi-institutional database. AFP score was calculated based on the last evaluation before surgery. Probabilities of tumor recurrence and overall survival (OS) were compared according to an AFP model. A total of 825 patients were included. An optimal cut-off AFP score of 2 was identified with an AFP score ≥3 versus ≤2 independently predicting tumor recurrence and OS. Net reclassification improvements indicated the AFP model was superior to the Barcelona Clinic Liver Cancer (BCLC) system to predict recurrence (p < 0.001). Among patients with BCLC B–C, AFP score ≤2 identified a subgroup of patients with AFP levels of ≤100 ng/mL with a low 5-year recurrence risk (≤2 45.2% vs. ≥3 61.8%, p = 0.046) and favorable 5-year OS (≤2 54.5% vs. ≥3 39.4%, p = 0.035). In contrast, among patients within BCLC 0-A, AFP score ≥3 identified a subgroup of patients with AFP values > 1000 ng/mL with a high 5-year recurrence (≥3 47.9% vs. ≤2% 38.4%, p = 0.046) and worse 5-year OS (≥3 47.8% vs. ≤2 65.9%, p < 0.001). In addition, the AFP score independently correlated with vascular invasion, tumor differentiation and capsule invasion. The AFP model was more accurate than the BCLC system to identify which HCC patients may benefit the most from surgical resection. • The AFP score ≥3 versus ≤2 independently predicted tumor recurrence and overall survival (OS). • A high AFP model score ≥3 was strongly correlated with adverse tumor features and behavior, and, in turn, was able to discriminated patients with low versus high risk of recurrence and death. • The AFP model performed better than the BCLC staging as use of the model was able to differentiate patients with BCLC stage 0-A who did poorly after surgery, as well as identify a subgroup of patients with BCLC B–C who actually fared well after resection. [ABSTRACT FROM AUTHOR]

The prognosis of patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) is a research hotspot. This study aimed to incorporate important factors obtained from SEER database to construct and validate a nomogram for predicting the cancer-specific survival (CSS) of patients with HCC and ICC. We obtained patient data from SEER database. The nomogram was constructed base on six prognostic factors for predicting CSS rates in HCC patients. The nomogram was validated by concordance index (C-index), the receiver operating characteristic (ROC) curve and calibration curves. A total of 3227 patients diagnosed with HCC (3038) and ICC (189) between 2010 and 2015 were included in this study. The C-index of the nomogram for HCC patients was 0.790 in the training cohort and 0.806 in the validation cohort. The 3- and 5-year AUCs were 0.811 and 0.793 in the training cohort. The calibration plots indicated that there was good agreement between the actual observations and predictions. In conclusion, we constructed and validated a nomogram for predicting the 3- and 5-year CSS in HCC patients. We have confirmed the precise calibration and excellent discrimination power of our nomogram. [ABSTRACT FROM AUTHOR]

Background. Hepatectomy remains one of the most effective treatments for patients with hepatocellular carcinoma (HCC); however, it can lead to serious complications. Irisin, a key regulator of energy metabolism, is secreted into the circulation by shedding of the extracellular portion of the fibronectin type III domain-containing 5 (FNDC5). We have shown that irisin administration alleviates liver ischemia-reperfusion injury in mice. However, the role of preoperative irisin levels in HCC patients who underwent hepatectomy remained unknown. The purpose of this study was to determine how irisin expression changes in HCC and to explore the relationship between preoperative serum irisin levels and complications after hepatectomy. Methods. FNDC5/irisin expression data in HCC were extracted from The Cancer Genome Atlas (TCGA) dataset. A total of 219 participants, including 102 healthy controls and 117 HCC patients, were recruited in this study. All HCC patients underwent hepatectomy at the First Affiliated Hospital of the Xi'an Jiaotong University. Preoperative serum irisin levels were measured by ELISA. Postoperative complications were assessed using the comprehensive complication index (CCI) score. The Pearson rank correlation coefficient was computed to assess the correlation between preoperative serum irisin levels and postoperative CCI scores. Results. In TCGA dataset, FNDC5/irisin expression was downregulated in HCC tissues (P < 0.001). Similarly, serum irisin levels were decreased in HCC patients (P < 0.001). Low preoperative serum irisin levels were significantly correlated with high CCI scores after hepatectomy. Conclusions. Irisin may be a novel serum biomarker in the diagnosis of HCC and a predictor of complications after hepatectomy. [ABSTRACT FROM AUTHOR]

Background: Despite the identification of autophagy-related protein 5 (ATG5) as a molecule involved in the activated autophagy machinery during hepatitis B virus (HBV) infection and hepatocarcinogenesis, the consequences of ATG5 mutation carriage for patients with chronic HBV infection remain unclear. This study examined the association of ATG5 polymorphisms with HBV-related diseases including hepatocellular carcinoma (HCC). Patients and Methods: Two functionally relevant polymorphisms ATG5 rs573775 and rs510432 were genotyped by ligase detection reaction-polymerase chain reaction in 403 patients with chronic HBV infection (171 chronic hepatitis, 119 cirrhosis and 113 HCC) and 196 healthy controls. Univariate and multivariate logistic regression was performed to evaluate factors associated with HCC. Results: The rs573775 genotype and allele frequencies had no significant differences between patients with different clinical diseases. However, HCC patients had significantly higher frequency of rs510432 genotype AA (odds ratio [OR] 2.185, 95% confidence interval [CI] 1.042–4.581, P = 0.037, P value by Bonferroni correction [Pc] = 0.074) and allele A (OR 1.435, 95% CI 1.023–2.013, Pc = 0.036) than chronic hepatitis patients. In multivariate analyses, rs510432 allele A-containing genotypes (AA+GA) were independently associated with cirrhosis in comparison to chronic hepatitis (OR 1.927, 95%CI 1.011–3.017, P = 0.032). The rs510432 genotypes AA+GA were also independently associated with HCC in comparison to chronic hepatitis (OR 2.583, 95% CI 1.025–3.911, P = 0.006) or chronic HBV infection without HCC (OR 2.632, 95% CI 1.067–3.482, P = 0.032). Conclusion: These results indicate that rs510432 genotypes AA+GA are associated with disease progression and HCC risk in chronic HBV infection, providing novel evidence for a role of ATG5 in the pathogenesis of HBV-related HCC. Abbreviations: HBV: hepatitis B virus; HCC hepatocellular carcinoma; TNFSF10: tumor necrosis factor superfamily member 10; ATG5: autophagy-related protein 5; DNA: deoxyribonucleic acid; LDR-PCR: ligase detection reactions-polymerase chain reaction; PCR: polymerase chain reaction; SLE: systemic lupus erythematosus; BD: Behçet's disease; IL-10: interlukin-10; LPS: lipopolysaccharide; PBMC: peripheral blood mononuclear cells; CWP: coal workers' pneumoconiosis; TNF-α: tumor necrosis factor-α [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common and malignant cancers and has no effective therapeutic approaches. Chemotherapeutic drug doxorubicin (DOX) is widely used for HCC therapy, but its application is limited by the clinical toxicity. In the present study, an Fe3O4-ZIF-8 magnetic nano-composite was fabricated and used for DOX delivery for HCC therapy. The morphology, structure and property of Fe3O4-ZIF-8 nano-composites were evaluated by scanning electron microscopy, transmission electron microscopy and N2 adsorption-desorption isotherms studies. The drug release from DOX@Fe3O4-ZIF-8 was measured in pH 7.4 phosphate-buffered saline. The cellular uptake ability of DOX@Fe3O4-ZIF-8 into hepatocarcinoma cell line (MHCC97H) was visualized with a confocal laser scanning microscope. The effects of Fe3O4-ZIF-8, DOX and DOX@Fe3O4-ZIF-8 against MHCC97H cells were evaluated by CCK-8 assay and flow cytometry assay. Fe3O4-ZIF-8 nano-composites were synthesized and used as a nano-carrier for the delivery of DOX. Because of high drug loading property of ZIF-8, 1 mg Fe3O4-ZIF-8 nano-composites loaded 120 μg DOX when DOX@Fe3O4-ZIF-8 was synthesized in 30 mg/mL DOX solution. The cumulative DOX release curve showed a slow and sustained release pattern over time. The results of CCK-8 assay showed that Fe3O4-ZIF-8 was nontoxic to MHCC97H cells, and DOX@Fe3O4-ZIF-8 presented effective inhibiting effect on cell viability of MHCC97H cells. Cellular uptake assay showed that DOX@Fe3O4-ZIF-8 accumulated in both cytoplasm and nuclei. Moreover, because of valid drug accumulation, DOX@Fe3O4-ZIF-8 exhibited a good inducing effect on cell apoptosis of MHCC97H cells. In conclusion, based on the nontoxic and high drug loading capability of Fe3O4-ZIF-8, DOX@Fe3O4-ZIF-8 presented enhanced effects on HCC cells compared to free DOX, indicating its potential for the chemotherapy of HCC. [ABSTRACT FROM AUTHOR]

Highlights • A transcriptional factor Hes-1 in Notch signaling pathway and an inverted-CCAAT box binding protein ICBP90 are highly expressed in HCC. • The blocking of Notch pathway by a specific inhibitor DAPT prevents HCC cells at the G0/G1 to enter S and G2/M phases through attenuating ICBP90. • Hes-1 gene knockdown suppresses the HCC cell growth through the reduction of ICBP90, potentially applied as a target to treatment of HCC. Abstract The Notch signaling pathway plays a key role in cell proliferation and development that is closely related to an inverted CCAAT box binding protein (ICBP90), but little is known about whether there is a correlation between Notch signaling and ICBP90. The aim of the current study was to elucidate this. MTT assay and flow cytometry were used to determine the proliferation, cell cycle and apoptosis of HepG2 or Hepa1-6 cells treated by N -[ N -(3,5-difluorophenacetyl)- L -alanyl]- S -phenylglycine t-butyl ester (DAPT), a specific inhibitor of the Notch pathway. RT-PCR, Western Blot and in situ immunofluorescence staining were employed to examine expression of ICBP90 in the cells. DAPT caused inhibition of the activation of the Notch signaling pathway, followed by preventing the cells at the G0/G1 phases to enter S and G2/M phases. ICBP90 and Hes-1 proteins were highly expressed in the untreated cells. The reduced levels of Notch intracellular domain (NICD) protein were observed in the DAPT-treated cells, thereby bringing about the down-regulation of ICBP90 with the increment of the DAPT dose. Consistent with this, knockdown of the Hes-1 gene, which encodes a critical transcriptional factor in the Notch pathway, also led to the attenuation of ICBP90. On the contrary, Jagged-1, a Notch ligand, facilitated ICBP90 production. Adriamycin could result in the reduction of ICBP90, which was not accompanied with the alteration of Hes-1. ICBP90 was almost fully distributed within the nuclei, but Hes-1 was visible within both the cytoplasm and nuclei. Our novel findings strongly indicate that inactivation of the Notch signaling pathway impedes hepatocellular carcinoma progress via reduction of ICBP90. [ABSTRACT FROM AUTHOR]

Background/Aims: Patient selection is critically important in improving the outcomes of liver transplantation for hepatocellular carcinoma. The aim of the current study was to identify biochemical measures that could affect patient prognosis after liver transplantation. Methods: A total of 119 patients receiving liver transplantation for hepatocellular carcinoma were used to construct a model for predicting recurrence. The results were validated using an independent sample of 109 patients from independent hospitals. All subjects in both cohorts met the Hangzhou criteria. Results: Analysis of the discovery cohort revealed an association of recurrence with preoperative fibrinogen and AFP levels. A mathematical model was developed for predicting probability of recurrence within 5 years: Y = logit(P) = -4.595 + 0.824 ×fibrinogen concentration (g/L) + 0.641 × AFP score (1 for AFP<=20ng/ml, 2 for 20 400ng/ml). At a cutoff score of -0.85, the area under the curve (AUC) was 0.819 in predicting recurrence (vs. 0.655 when using the Milan criteria). In the validation cohort, this model had reasonable performance in predicting 5-year overall survival (68.8% vs. 28.1% in using the -0.85 cutoff, p< 0.001) and disease-free survival (65.7% vs. 25.9%, p< 0.001). The sensitivity and specificity were 77.0% and 62.5%, respectively. The AUC of this newly developed model was similar to that with the Milan criteria (0.698 vs. 0.678). Surprisingly, the DFS in patients with score <= -0.85 under this model but not meeting the Milan criteria was similar to that in patients meeting the Milan criteria (53.8% vs. 60.0%, p=0.380). Conclusions: Preoperative AFP and fibrinogen are useful in predicting recurrence of hepatocellular carcinoma after liver transplantation. [ABSTRACT FROM AUTHOR]

The neutrophil to lymphocyte ratio (NLR), a simple marker of inflammation, has recently been showed to predict tumor recurrence in hepatocellular carcinoma (HCC) patients after hepatic resection or liver transplantation. However, whether it can be used to predict HCC development in cirrhotic patients remained unknown. The aim of this study was to evaluate the predictive value of the preoperative NLR for the development of HCC in cirrhotic patients who underwent splenectomy. A total of 230 HBV-associated cirrhotic patients who underwent splenectomy in our hospital from January 2000 to December 2012 were included in this study. Detailed clinical data included patients’ general characteristics, laboratory tests and imaging studies, surgical procedures and complications. Information on patients’ follow-up data was also obtained. We found that 38 (16.52%) patients developed HCC after splenectomy during the follow-up period. An elevated preoperative NLR was associated with increased risk of developing HCC in cirrhotic patients after splenectomy. The optimal cutoff value of NLR for HCC development was 2.27. In patients who developed HCC during the follow-up period, NLR scores showed no predictive value in overall survival after splenectomy. However, NLR scores appeared to have a much better predictive value in overall survival in patients who did not develop HCC. In conclusion, cirrhotic patients who underwent splenectomy remain at a relatively high risk of developing HCC, and an elevated preoperative NLR is associated with HCC development in cirrhotic patients who underwent splenectomy for hypersplenism. [ABSTRACT FROM AUTHOR]

Objectives: Surgical resection remains a controversial treatment for hepatocellular carcinoma (HCC) within different Barcelona Clinic Liver Cancer (BCLC) stages. The objective of this study was to evaluate the long-term outcome of patients undergoing surgical resection (SR) compared to non-surgical treatments across different BCLC stages. Patients and methods: One thousand four hundred forty-three HCC patients within BCLC 0, A, B and C stages were identified. Overall survival was compared by log-rank test among patients within different BCLC stages and among patients receiving different treatments (SR vs locoregional therapy [LRT] vs best supportive care). Propensity score matching analysis was introduced to mitigate the confounding biases between the groups. Results: The median survival time of the patients diminished from early, intermediate to advanced BCLC stages (BCLC 0-A 43 [range 0-100] months vs BCLC B 32 [range 0-100] months vs BCLC C 27 [range 0-90] months, all p<0.05). Patients undergoing SR presented with better liver function and more favorable tumor status and, consequently, displayed significant better overall survival than patients receiving LRT or best supportive care at different BCLC stages. In adjusted cohort after propensity score matching, patients who were surgically treated consistently had more favorable outcome than those who were non-curatively treated across different BCLC stages (median survival [range]: BCLC stage B: resection 45 [0-100] months vs LRT 36 [0-81] months, p=0.002; BCLC stage C: resection 39 [3-77] months vs LRT 27 [0-54] months, p=0.003). Conclusion: Surgical resection should be considered as a radical treatment for selected HCC patients regardless of the BCLC stages when appropriate. [ABSTRACT FROM AUTHOR]

Background/Aims: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death. Critical roles for long non-coding RNAs (lncRNAs) have recently been demonstrated for a variety of cancers, including hepatocellular carcinoma. However, the effect and mechanism of lncRNAs in HCC tumorigenesis and chemoresistance have not been extensively characterized. Methods: In the current study, we have identified a HCC-expressed lncRNA termed as HANR (HCC associated long non-coding RNA). We identified HANR by microarray analysis and validated its up-regulated expression by quantitative PCR. RNA pull-down and pathway analyses were conducted to evaluate physical and functional interactions with HANR. In vivo experiments were performed to assess tumorigenesis and increase of chemoresistance. In addition, the HANR expression in HCC specimens was detected by FISH. Xenograft and orthotopic mice model was constructed to observe the effect of HANR on tumorigenesis and chemoresistance in vivo. Results: HANR was demonstrated to be up-regulated in HCC patients and HCC cell lines. Increased HANR expression in HCC predicted short survival of patients. Knock-down of HANR markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin, while overexpression of HANR showed the opposite effects. It was found that HANR bind to GSKIP for regulating the phosphorylation of GSK3ß in HCC. Conclusion: Our results demonstrate that HANR contributes to the development of HCC and is a promising therapeutic target for chemosensitization of HCC cells to doxorubicin, which may represent a promising therapeutic target in the future. [ABSTRACT FROM AUTHOR]

The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. The present study aims to evaluate the role of age on treatments and outcome of HCC patients. 1530 patients firstly diagnosed with HCC were retrospectively included and classified as older (≥65 years, n = 318, 21%) and younger patients (<65 years, n = 1212, 79%). The two groups were compared with clinical characteristics, tumor burden, Barcelona Clinics Liver Cancer (BCLC) stage, treatments and long-term prognosis. Elderly patients were more HCV infected, had more diabetes, poorer performance status, and were less aggressively treated. The proportion of HCC within BCLC stage 0-A, B or C was similar between the two groups, but elderly patients were more presented with BCLC stage D. The overall survival of older patients was poorer compared to younger patients before and after propensity score matching. However, elderly patients were less often effectively treated with surgery and loco-regional therapies across different BCLC stages. After stratified by BCLC stages or treatments, older patients showed comparable long-term outcome to younger patients. Performance status, BCLC stages and effective treatments, rather than age, was independent factors determining prognosis in the whole cohort and only elderly patients by multivariate analysis. In conclusion, older could have comparable survival to younger patients within the same tumor stage or after similar treatments. Thus, equally active treatments should be encouraged to elderly patients. [ABSTRACT FROM AUTHOR]

Background: Clinical data regarding the influence of diabetes mellitus (DM) on the outcomes of patients undergoing hepatectomy are conflicting. To determine the impact of DM on the clinical outcomes of patients undergoing hepatectomy, we systematically reviewed published studies and carried out a meta-analysis. Methods: A systematic literature search of Pubmed, Sciencedirect, Web of Science, and Chinese Biomedical Database was conducted from their inception through February 2, 2016. The combined relative risk (RR) or hazard ratio (HR) with 95% confidence intervals (95% CI) was calculated. Results: A total of 16 observational studies with 15710 subjects were eligible for meta-analysis. The pooled results showed that DM significantly increased the risk of overall postoperative complications (RR 1.34; 95% CI 1.19–1.51; P<0.001), DM-associated complications (RR 1.8; 95% CI 1.29–2.53; P<0.001), liver failure (RR 2.21; 95% CI 1.3–3.76; P = 0.028) and post-operative infections (RR 1.59; 95% CI 1.01–2.5; P = 0.045). In addition, DM was also found to be significantly associated with unfavorable overall survival and disease free survival after liver resection. The pooled HR was 1.63 (95% CI 1.33–1.99; P<0.001) for overall survival and 1.55 (95% CI 1.07–2.25; P = 0.019) for disease free survival. Conclusion: DM is associated with poor outcomes in patients undergoing hepatectomy. DM should be taken into account cautiously in the management of patients undergoing hepatectomy. Further prospective studies are warranted to explore effective interventions to improve the poor outcomes of diabetic patients undergoing hepatectomy. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection is a major cause of chronic liver diseases including hepatocellular carcinoma (HCC). CD14 and its soluble form sCD14 play important roles in immunity and are involved in the translocation of bacteria and their products which is related to the pathogenesis in chronic HBV infection. This study investigated serum sCD14 levels in HBV chronically infected patients with various clinical diseases. Serum sCD14 levels in HBV patients were significantly elevated compared with those of healthy controls. HCC patients had significantly highest levels of serum sCD14 across all the HBV-related diseases. Serum sCD14 levels significantly discriminated HCC from other HBV-related non-HCC diseases. The area under the receiver operating characteristic curve (AUC) of sCD14 levels for HCC was significantly higher in comparison with other HBV-related non-HCC diseases. The AUC of sCD14 for HCC (0.868, 95 % CI 0.791-0.946, P < 0.001) was higher than that of alpha-fetoprotein (0.660, 95 % CI 0.508-0.811, P = 0.039). Serum level of sCD14 was associated with the overall survival (OS) of HCC patients, with sCD14 levels >20 ng/mL being significantly related to poorer OS ( P = 0.017). Multivariate regression showed that serum sCD14 level was an independent factor associated with the OS rates of HBV-related HCC patients (HR 2.544, 95 % CI 1.169-5.538, P = 0.019). HCC resection resulted in a significant decrease of sCD14 levels ( P < 0.001). These findings suggest the potential role of sCD14 in the pathogenesis of chronic HBV infection, especially the development of HCC, and the potential usefulness of sCD14 as a biomarker for discriminating clinical diseases and predicting survival of HCC patients in chronic HBV infection. [ABSTRACT FROM AUTHOR]

Background: Profound organ shortages worldwide have led to the increased utilization of marginal organs from older individuals. However, the effectiveness of liver transplantation (LT) with organs from elderly donors for patients with hepatocellular carcinoma (HCC) remains controversial. The objective of the current study was to assess the overall survival (OS) and disease-free survival (DFS) of patients with HCC following LT using grafts from deceased donors over 60 years old.Material and Methods: Patients with HCC who underwent LT between 2015 and 2018 were identified in the China Liver Transplant Registry database. The overall survival and disease-free survival of older liver donors (OLDs) were compared with those of younger liver donors (YLDs) after propensity score matching.Results: From January 2015 to December 2018, a total of 4971 HCC patients were enrolled in the study according to the screening criteria. The absolute and relative utilization of liver grafts from elderly patients over 60 years for HCC patients increased every year, from 65 (9.3%) in 2015 to 268 (14.5%) in 2018. Disease-free survival (DFS) was significantly lower in HCC patients with elderly donors (both P < 0.05) after propensity score matching. The OLD group had worse DFS than YLD group if patients had tumors beyond the Milan criteria (P < 0.05).Conclusions: The use of older donors for LT has been growing quickly in the last few years in China. Grafts from older donors can be safely used in HCC recipients with similar OS and comparable perioperative complications. However, further investigation into whether older donor has an impact on recurrence is warranted, especially among those with tumors beyond the Milan criteria. [ABSTRACT FROM AUTHOR]

Background: Serum lens culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3%) has been widely used for HCC diagnosis and follow-up surveillance as tumor serologic marker. However, the prognostic value of high pre-treatment serum AFP-L3% in patients with hepatocellular carcinoma (HCC) remains controversial. We therefore conduct a meta-analysis to assess the relationship between high pre-treatment serum AFP-L3% and clinical outcome of HCC. Methods: Eligible studies were identified through systematic literature searches. A meta-analysis of fifteen studies (4,465 patients) was carried out to evaluate the association between high pre-treatment serum AFP-L3% and overall survival (OS) and disease-free survival (DFS) in HCC patients. Sensitivity and subgroup analyses were also conducted in this meta-analysis. Results: Our analysis results showed that high pre-treatment serum AFP-L3% implied poor OS (HR: 1.65, 95%CI: 1.45–1.89 p<0.00001) and DFS (HR: 1.80, 95% CI: 1.49–2.17 p<0.00001) of HCC. Subgroup analysis revealed that there was association between pre-treatment serum AFP-L3% and endpoint (OS and DFS) in low AFP concentration HCC patients (HR: 1.96, 95% CI: 1.24–3.10, p = 0.004; HR: 2.53, 95% CI: 1.09–5.89, p = 0.03, respectively). Conclusion: The current evidence suggests that high pre-treatment serum AFP-L3% levels indicated a poor prognosis for patients with HCC and AFP-L3% may have significant prognostic value in HCC patients with low AFP concentration. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cigarette smoking is a potential risk factor for hepatocellular carcinoma (HCC) initiation, partially through interaction with hepatitis B virus (HBV). We examined the hypothesis that cigarette smoking might be associated with HBV-related HCC recurrence and patient survival after curative surgery. Patients and Methods: Data of 302 patients with HBV infection who had undergone curative resection for HCC were prospectively collected from 2008 to 2011. Smoking status and smoking quantity (pack-years, PY) were asked at admission. Factors affecting recurrence-free survival (RFS) were examined. RFS and liver-specific mortality (LSM) stratified by risk factors were compared with log-rank test. Results: 109 were current smokers. Current smokers were not different from non-smokers in tumor burden and surgical procedure. Univariate and multivariate analysis identified that heavy smoking (PY ≥20) was the most significant factor associated with HBV-related HCC recurrence after curative surgical resection (p = 0.001), followed by anti-HBV treatment (p<0.01), current smoking (p = 0.028), surgical margin <1 cm (p = 0.048) and blood transfusion >600 ml (p = 0.028). The median RFS in non-smokers, ex-smokers and current smokers was 34 months, 24 months and 26 months, respectively (p = 0.033). Current smokers had significantly worse RFS rate and increased 5-year cumulative LSM than non-smokers (p = 0.024, and p<0.001, respectively). Heavy smokers had significantly worse RFS than non- and light smokers (0

Immune checkpoint blockade is considered a breakthrough in cancer treatment. However, with the low response rates and therapeutic resistance of patients with hepatocellular carcinoma (HCC), the challenges facing the application of this treatment are tremendous. Liver fibrosis is a key driver of tumor immune escape, the underlying mechanism has never been clarified. This study sought to explore the role of liver fibrosis in regulating tumor-infiltrating lymphocytes (TILs) and inducing tumor immunosuppression. Ninety-nine fixed HCC tissue samples were used to analyze the association between liver fibrosis and immune escape using immunohistochemistry. In HCC patients, low FIB-4 values and high CD8+ T cell infiltration were correlated with prolonged survival. Elevated expression of immune checkpoints and attenuated antitumor immunity were observed in CCl4-induced mice liver fibrosis models and human fibrotic livers compared to control group. GOLM1 levels were increased in livers of patients with fibrosis and mice in response to CCl4-induced liver fibrosis. CD8+ T cell infiltrations were significantly decreased and PD-L1 expression was significantly increased in tumor tissues from hepatocyte-specific GOLM1 transgenic mice (Alb/GOLM1 mice) inducing chemical carcinogenesis compared to their corresponding control WT mice. GOLM1 induced PD-L1 expression via EGFR pathway activation. EGFR inhibitors, especially together with anti-PD-L1 therapy, improved the efficacy of immunotherapy in HCC. These findings illustrate the importance of liver fibrosis-induced immunosuppression as a tumor-promoting mechanism. GOLM1, which is highly upregulated in the fibrotic liver, regulates tumor microenvironmental immune escape via the EGFR/PD-L1 signaling pathway. EGFR blockade may bolster the efficacy of immune checkpoint inhibitors for HCC treatment. [ABSTRACT FROM AUTHOR]

• PRDM1 plays a crucial role in T cell exhaustion implicated in HBV infection. • PRDM1 rs1010273 and rs2185379 polymorphisms were genotyped in patients HBV-related liver diseases. • PRDM1 rs1010273 polymorphism was independently associated with survival of patients with HBV-related HCC. T cell exhaustion is involved in the pathogenesis of chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). B lymphocyte-induced maturation protein 1 (BLIMP-1), encoded by the PRDM1 gene, plays a crucial role in T cell exhaustion. This study investigated PRDM1 rs1010273 and rs2185379 polymorphisms in 403 patients with chronic HBV infection (171 chronic hepatitis, 119 liver cirrhosis and 113 HCC), 70 spontaneous HBV infection resolvers and 196 healthy controls. The results showed that the rs1010273 and rs2185379 polymorphisms had no significant differences between patients with chronic HBV infection and healthy controls or between patients with different clinical diseases. However, PRDM1 rs1010273 polymorphism was shown to be significantly associated with the overall survival of patients with HBV-related HCC. The 1-, 3-, and 5-year survival rates of HCC patients were 70.5%, 34.6%, and 11.5%, respectively, in genotype GG carriers and 91.4%, 51.4% and 31.4%, respectively, in genotypes AA + GA carriers (p = 0.008). Multivariate analysis showed that PRDM1 rs1010273 polymorphism was an independent factor associated with the overall survival of patients with HCC (odds ratio, 0.529; 95% confidence interval, 0.126-0.862; p = 0.002). These results provide novel evidence for a role of PRDM1 rs1010273 in the pathogenesis of HBV-related HCC. Additional studies are needed to replicate and extend the findings of this study and to elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

PR domain zinc finger protein 1 (PRDM1)/B lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor involved in B and T cell responses which are implicated in chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study investigated the association of PRDM1 with clinical diseases of chronic HBV infection and prognosis of HBV -related HCC patients. Serum PRDM1 levels were determined in 403 patients with chronic HBV infection (171 chronic hepatitis, 119 cirrhosis and 113 HCC), 70 HBV infection resolvers and 96 healthy control individuals. The PRDM1 levels were analyzed with regard to clinical diseases and overall survival of HCC patients. Serum PRDM1 concentrations in patients with chronic HBV infection were significantly elevated compared with infection resolvers and healthy controls. HBV-related HCC patients had the most significantly elevated PRDM1 levels. PRDM1 levels could considerably differentiate HCC from chronic hepatitis [area under receiver operating characteristic curve (AUC) 0.889, p < 0.001] or cirrhosis (AUC 0.910, p < 0.001). HCC patients with high PRDM1 levels had a poor prognosis (>300 pg/mL vs. ≤300 pg/mL, p = 0.001). High PRDM1 levels were independently associated with increased mortality in HCC patients (hazard ratio 2.997, 95% confidence interval 1.103–4.722, p = 0.003). Overall, this study demonstrated that PRDM1 levels are associated with the clinical diseases of chronic HBV infection. Highly elevated PRDM1 levels are discriminative of HCC from other clinical diseases and indicative of a poor prognosis of HCC patients. The potential association of PRDM1 levels with disease progression and treatment response warrants further investigation. • Serum PRDM1 levels were determined in chronic hepatitis B patients with various diseases. • Hepatocellular carcinoma (HCC) patients had the highest PRDM1 levels. • PRDM1 levels significantly identify HCC from other disease conditions. • High PRDM1 levels significantly identify HCC patients with a poor prognosis. [ABSTRACT FROM AUTHOR]

Abstract Background There is a strong correlation between liver fibrosis and postoperative morbidity after hepatectomy in hepatocellular carcinoma (HCC) patients. The aim of this study was to evaluate which noninvasive fibrosis index (gamma-glutamyl transpeptidase to platelet ratio [GPR], aspartate aminotransferase to platelet ratio index, fibrosis-4 index, or Forns index) was best able to predict complications in patients undergoing hepatectomy for HCC. Materials and methods This retrospective analysis included 275 patients who underwent hepatectomy for HCC from January 2008 to December 2012. Postoperative mortality was defined as death within 90 d after surgery. Complications were grouped into seven grades on the basis of the modified Clavien classification, and major postoperative complications were defined as grade 3 or above. The influence of noninvasive fibrosis indices on postoperative outcomes was assessed by receiver operating characteristic analysis. The primary outcomes were overall complications and major complications, estimated by univariate and multivariate analysis. Results Patients with HCC undergoing anatomical liver resection in the authors' department were evaluated for this study. Finally, 275 patients who underwent minor liver resection (≤2 liver segments) were included. Of these, 231 (84%) were male. The multivariate analysis indicated that the GPR index was not only independently associated with overall complications (hazard ratio, 2.692; 95% confidence interval [CI], 1.626-4.250; P < 0.001) but also independently predictive of major complications (hazard ratio, 1.143; 95% CI, 1.046-1.249; P = 0.03). The areas under the receiver operating characteristic curve for predicting overall complications and major complications for the GPR index were 0.704 (95% CI, 0.643-0.765; P < 0.001) and 0.752 (95% CI, 0.638-0.865; P < 0.001), respectively. Conclusions The data suggested that the GPR index could be a promising predictor of overall postoperative complications and major complications after minor hepatectomy for HCC. [ABSTRACT FROM AUTHOR]

Autophagy plays a dual role in many types of cancer, such as hepatocellular carcinoma (HCC). Autophagy seems to be inhibited and functions as a tumor-suppression mechanism in the "inflammation-carcinogenesis" pathway of the liver, including hepatitis B virus and hepatitis C virus, alcoholic steatohepatitis and non-alcoholic steatohepatitis related HCC. However, in established tumors, autophagy plays a tumor-promoting role. Because of the varied function of autophagy in HCC, we hypothesized p62 as a marker to evaluate the autophagic level. Moreover, autophagy is critical in antigen presentation and homeostasis of immune cells and tumor microenvironment. Understanding the intricate relationships of autophagy, inflammation, and immunity provides us with new insights into HCC immunotherapy. [ABSTRACT FROM AUTHOR]

Sex affects the risk, treatment responses and outcome of many types of cancers. The mechanism of gender disparity in development of hepatocellular carcinoma (HCC) remains obscure. Sex-determining region on Y chromosome (SRY) was overexpressed in approximate 84% male patient HCC. Moreover, we are the first to generate a liver-specific transgenic (TG) murine model with overexpression of the male specific gene SRY. Subject to a single intraperitoneal injection N-nitrosodiethylamine (DEN) at day 14, TG and wildtype (WT) mice of both genders were sacrificed at different time points (6-13.5 months). Overexpression of SRY in male TG and ectopic expression of SRY in female TG livers promoted DEN-induced hepatocarcinogenesis compared to age- and sex-matched WT. This accelerated tumorigenesis in TG of both genders was a consequence of increased injury and inflammation, fibrosis, and compensatory enhancement in hepatocytes proliferation secondary to activation of downstream targets Sox9 and platelet-derived growth factor receptor α (PDGFRα)/phosphoinositide 3-kinase (PI3K)/Akt and c-myc/CyclinD1. In conclusion, activation of SRY and its downstream Sox9 and PDGFRα pathways are commonly involved in male hepatocarcinogenesis, which provides novel insights into gender disparity and sex-specific therapeutic strategies of HCC. [ABSTRACT FROM AUTHOR]

Lymphotoxin-β receptor (LTβR) signaling is involved in hepatitis B virus (HBV) infection, hepatitis and liver carcinogenesis. However, the potential association between LTBR polymorphisms and HBV infection remains unclear. This study investigated the associations between LTBR polymorphisms and chronic HBV infection and HBV-related hepatocellular carcinoma (HCC). The study included 409 patients with chronic HBV infection, 73 HBV infection resolvers, and 197 healthy controls. Two polymorphisms rs12354 and rs3759333 were selected and genotyped by polymerase chain reaction-ligase detection reaction method. The frequencies of rs12354 genotype GT and allele T in HBV infection resolvers were significantly higher than those in patients with chronic HBV infection and healthy controls (genotype GT: 38.4% vs. 22.2% and 38.4% vs. 20.8%, P = 0.004 and P = 0.004, respectively; allele T: 20.5% vs. 13.1% and 20.5% vs. 12.9%, P = 0.017 and P = 0.028, respectively). The frequencies of rs3759333 genotypes and alleles between HBV patients, HBV infection resolvers and healthy controls had no statistical difference. The genotype and allele frequencies of rs12354 and rs3759333 had no statistical differences between chronic hepatitis B and HBV-related HCC patients. The serum LTβR levels and the overall survival rate between HBV-related HCC patients carrying different rs12354 and rs3759333 genotypes had no statistical differences. These results suggest that the LTBR rs12354 polymorphism might be associated with the spontaneous resolution of HBV infection. Additional studies with large sample size are needed to confirm and extend these findings. [ABSTRACT FROM AUTHOR]

• CTLA-4 levels and CTLA4 SNPs vs. disease progression in HBV infection was analyzed. • CTLA-4 levels and CTLA4 rs231775 associated with disease condition, especially HCC. • CTLA-4 levels and CTLA4 rs231775 associated with progression from cirrhosis to HCC. • CTLA-4 level and CTLA4 rs231775 associated with HCC and HCC patients survival. • CTLA-4 levels and CTLA4 SNPs may be potential biomarkers for disease progression. CTLA-4 is involved in the immune dysfunction of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study analyzed the association of circulating CTLA-4 levels and CTLA4 polymorphisms with disease condition and progression in chronic HBV infection. Serum CTLA-4 levels and CTLA4 rs231775 and rs5742909 polymorphisms were determined in patients with various HBV-related diseases [53 asymptomatic HBV carrier status (ASC), 147 chronic hepatitis, 130 cirrhosis and 102 HCC] and nearly a 10-year follow-up. Serum CTLA-4 levels were stepwisely increased from ASC, chronic hepatitis, cirrhosis to HCC and independently associated with HCC (OR 2.628, P < 0.001). HCC patients had lower frequencies of rs231775 genotype GA, genotype AA and allele A than ASC, chronic hepatitis and cirrhosis patients. Rs231775 genotype GG was independently associated with HCC (OR 2.324, P = 0.010) and higher CTLA-4 levels in patients with HBV infection. In the follow-up, higher baseline CTLA-4 levels and CTLA4 rs231775 genotype GG significantly associated with disease progression from chronic hepatitis to cirrhosis (OR 2.561, P = 0.011 and OR 2.799, P = 0.015, respectively) or from cirrhosis to HCC (OR 2.673, P = 0.008 and OR 2.097, P = 0.023, respectively) and with a shorter overall survival in HCC patients (HR 0.317, P = 0.018 and HR 0.682, P = 0.026, respectively). Rs5742909 had no significant association with CTLA-4 levels and disease progression. CTLA-4 levels and CTLA4 rs231775 polymorphism associate with the disease condition and progression and HCC development in chronic HBV infection and their determination may be used for monitoring disease progression and predicting patient prognosis. [ABSTRACT FROM AUTHOR]

Blocking the PD-L1/PD-1 pathway to prevent the immune evasion of tumor cells is a powerful approach for treating multiple cancers, including hepatocellular carcinoma (HCC). Previous studies have shown that baicalein and baicalin are directly cytotoxic to some tumors, here we demonstrate that in addition to direct cytotoxicity, these two flavonoids stimulate the T cell mediated immune response against tumors through reduction of PD-L1 expression in cancer cells. Interestingly, more significant tumor regression was observed in BALB/c mice than in BALB/c-nu/nu mice after baicalein and baicalin treatment. PD-L1 upregulation induced by interferon-γ (IFN-γ) was significantly inhibited by these two flavonoids in vitro. Both baicalein and baicalin enhanced the cytotoxicity of T cells to eliminate tumor cells, which was abrogated after HCC cells were transfected with a PD-L1 overexpression plasmid or after T cells were pretreated with an anti-PD-1 blocking antibody. Further mechanistic research indicated that the IFN-γ-induced expression and promoter activity of PD-L1 were suppressed by these two flavonoids, and these effects were mediated by STAT3 activity inhibition. Therefore, baicalein and baicalin decreased STAT3 activity, further downregulated IFN-γ-induced PD-L1 expression and subsequently restored T cell sensitivity to kill tumor cells. Our findings provide novel insight into the anticancer effects of baicalein and baicalin through which tumor growth is inhibited by PD-L1 expression downregulation and suggest that these flavonoids have great potential for clinical treatment. Unlabelled Image • Baicalein and baicalin inhibit tumor growth and immunosuppression in vivo. • Baicalein and baicalin inhibit IFN-γ-induced PD-L1 expression in HCC cells. • Baicalein and baicalin enhance T cell-mediated cancer cell death. • Baicalein- and baicalin-downregulated PD-L1 expression is mediated by STAT3. [ABSTRACT FROM AUTHOR]