Network meta-analysis of the prognosis of curative treatment strategies for recurrent hepatocellular carcinoma after hepatectomy.

BACKGROUND: Recurrent hepatocellular carcinoma (rHCC) is a common outcome after curative treatment. Retreatment for rHCC is recommended, but no guidelines exist. AIM: To compare curative treatments such as repeated hepatectomy (RH), radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and liver transplantation (LT) for patients with rHCC after primary hepatectomy by conducting a network meta-analysis (NMA). METHODS: From 2011 to 2021, 30 articles involving patients with rHCC after primary liver resection were retrieved for this NMA. The Q test was used to assess heterogeneity among studies, and Egger's test was used to assess publication bias. The efficacy of rHCC treatment was assessed using disease-free survival (DFS) and overall survival (OS). RESULTS: From 30 articles, a total of 17, 11, 8, and 12 arms of RH, RFA, TACE, and LT subgroups were collected for analysis. Forest plot analysis revealed that the LT subgroup had a better cumulative DFS and 1-year OS than the RH subgroup, with an odds ratio (OR) of 0.96 (95%CI: 0.31-2.96). However, the RH subgroup had a better 3-year and 5-year OS compared to the LT, RFA, and TACE subgroups. Hierarchic step diagram of different subgroups measured by the Wald test yielded the same results as the forest plot analysis. LT had a better 1-year OS (OR: 1.04, 95%CI: 0.34-03.20), and LT was inferior to RH in 3-year OS (OR: 10.61, 95%CI: 0.21-1.73) and 5-year OS (OR: 0.95, 95%CI: 0.39-2.34). According to the predictive P score evaluation, the LT subgroup had a better DFS, and RH had the best OS. However, meta-regression analysis revealed that LT had a better DFS (P < 0.001) as well as 3-year OS (P = 0.881) and 5-year OS (P = 0.188). The differences in superiority between DFS and OS were due to the different testing methods used. CONCLUSION: According to this NMA, RH and LT had better DFS and OS for rHCC than RFA and TACE. However, treatment strategies should be determined by the recurrent tumor characteristics, the patient's general health status, and the care program at each institution.

Clinical prognosis of surgical resection versus transarterial chemoembolization for single large hepatocellular carcinoma (≥5 cm): A propensity score matching analysis.

Favorable prognostic factors and therapeutic strategies are important for patients with single large hepatocellular carcinoma (HCC). This retrospective study aimed to investigate the prognostic factors in patients with single large (≥5 cm) HCC with Child-Pugh (CP) class A patients and to recommend therapeutic strategies. Overall, 298 HCC patients with single and large (≥5 cm) tumors with CP class A, but without distant metastasis and macrovascular invasion were included, and their clinicopathological data, overall survival (OS), and progression-free survival (PFS) were recorded. OS and PFS was analyzed by the Kaplan-Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. The 298 HCC patients were 79.2% male and median age of 64 years. For the initial treatment, surgical resection (SR) and transarterial chemoembolization (TACE) was 50.8% and 49.2%, respectively. The OS and PFS were significantly higher in patients receiving SR than those receiving TACE before and after PSM. Furthermore, in multivariate analysis, cirrhosis (Hazard ratio [HR]: 2.04; 95% confidence interval [CI]: 1.35-3.03, p < 0.001, CP class A5/6 [HR: 4.01; 95% CI: 2.43-6.66, p < 0.001], and initial treatment [SR vs. TACE HR = 3.23; 95% CI: 2.13-5.01, p < 0.001]) remained significantly associated with mortality. Moreover, in multivariate analysis, CP class A5/6 (HR: 3.23; 95% CI: 1.89-5.88, p < 0.001), and initial treatment (Resection vs. TACE; HR = 4.17; 95% CI: 1.64-8.33, p = 0.039) remained significantly associated with recurrence. In conclusion, SR was associated with significantly higher OS and PFS rates than TACE before and after PSM for single large HCC patients.

NPRL2 down-regulation facilitates the growth of hepatocellular carcinoma via the mTOR pathway and autophagy suppression.

Hepatocellular carcinoma (HCC) is a highly invasive malignancy. Recently, GATOR1 (Gap Activity TOward Rags 1) complexes have been shown to play an important role in regulating tumor growth. NPRL2 is a critical component of the GATOR1 complex. Therefore, this study used NPRL2 knockdown to investigate how GATORC1 regulates the prognosis and development of HCC via the mammalian target of rapamycin (mTOR) and autophagy signaling pathways. We established HepG2 cells with NPRL2 knockdown using small interfering RNA (siRNA) and short hairpin RNA (shRNA) systems. The siRNA-mediated and shRNA-mediated NPRL2 down-regulation significantly reduced the expression of NPRL2 and two other GATPOR1 complex components, NPRL3 and DEPDC5, in HepG2 cells; furthermore, the efficient down-regulation of NPRL2 protein expression by both the shRNA and siRNA systems enhanced the proliferation, migration, and colony formation in vitro. Additionally, the NPRL2 down-regulation significantly increased HCC growth in the subcutaneous and orthotopic xenograft mouse models. The NPRL2 down-regulation increased the Rag GTPases and mTOR activation and inhibited autophagy in vitro and in vivo. Moreover, the NPRL2 level in the tumors was significantly associated with mortality, recurrence, the serum alpha fetoprotein level, the tumor size, the American Joint Committee on Cancer stage, and the Barcelona Clinic Liver Cancer stage. Low NPRL2, NPRL3, DEPDC5, and LC3, and high p62 and mTOR protein expression in the tumors was significantly associated with disease-free survival and overall survival in 300 patients with HCC after surgical resection. Conclusion: The efficient down-regulation of NPRL2 significantly increased HCC proliferation, migration, and colony formation in vitro, and increased HCC growth in vivo. Low NPRL2 protein expression in the tumors was closely correlated with poorer clinical outcomes in patients with HCC. These results provide a mechanistic understanding of HCC and aid the development of treatments for HCC.

Association of Heavy Alcohol Intake and ALDH2 rs671 Polymorphism With Hepatocellular Carcinoma and Mortality in Patients With Hepatitis B Virus-Related Cirrhosis.

Importance: The role of heavy alcohol intake, aldehyde dehydrogenase 2 gene (ALDH2) rs671 polymorphism, and hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) development and mortality remains uncertain. Objective: To investigate the association of heavy alcohol intake, ALDH2 rs671 polymorphism, and HBV infection with HCC development and mortality in patients with cirrhosis. Design, Setting, and Participants: This retrospective cohort study enrolled patients with cirrhosis with heavy alcoholism or/and HBV infection from January 2005 to December 2020. Patients were followed up through June 30, 2021. The current data analysis was performed from August 2021 to April 2022. Patients from 3 tertiary hospitals in Taiwan were enrolled. Exposures: Heavy alcohol intake was defined as consuming more than 80 g of ethanol each day for at least 5 years. Main Outcomes and Measures: The primary end point was newly developed HCC. The secondary end point was overall mortality. Results: Of 1515 patients with cirrhosis (342 with concomitant heavy alcoholism and HBV infection, 796 with HBV infection alone, and 377 with heavy alcoholism alone), 1277 (84.3%) were men, and their mean (SD) age was 49.5 (10.2) years; 746 patients had blood samples collected for ALDH2 rs671 polymorphism analysis. The 10-year cumulative incidences of HCC and mortality were significantly higher in patients with cirrhosis with concomitant HBV infection and alcoholism than in those with HBV infection alone or alcoholism alone. Heavy alcohol intake and the ALDH2 rs671 genotype (GA/AA) were associated with significantly increased risk of HCC and mortality in patients with HBV-related cirrhosis. In patients with cirrhosis with concomitant HBV infection and alcoholism, factors associated with risk of HCC were baseline serum HBV DNA (adjusted hazard ratio [aHR], 3.24; 95% CI, 1.43-7.31), antiviral therapy (aHR, 0.15; 95% CI, 0.05-0.39), alcohol intake (aHR, 1.78; 95% CI, 1.02-3.12), abstinence (aHR, 0.32; 95% CI, 0.18-0.59), and ALDH2 rs671 polymorphism (aHR, 5.61; 95% CI, 2.42-12.90). Factors associated with increased risk of mortality were abstinence (aHR, 0.25; 95% CI, 0.16-0.32), ALDH2 rs671 polymorphism (aHR, 1.58; 95% CI, 1.09-2.26), Child-Pugh class B vs A (aHR, 1.43; 95% CI, 1.13-2.25) and class C vs A (aHR, 1.98; 95% CI, 1.18-3.31), serum albumin (aHR, 0.61; 95% CI, 0.43-0.86), and HCC development (aHR, 1.68; 95% CI, 1.12-2.89). Conclusions and Relevance: These findings suggest that heavy alcohol intake and ALDH2 rs671 polymorphism are associated with significantly increased risk of HCC development and mortality in patients with HBV-related cirrhosis. Patients with these risk factors should be monitored closely for HCC.

Clinical outcomes of surgical resection versus radiofrequency ablation in very-early-stage hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND: The detection rate of Barcelona Clinic Liver Cancer (BCLC) very-early-stage hepatocellular carcinoma (HCC) is increasing because of advances in surveillance and improved imaging technologies for high-risk populations. Surgical resection (SR) and radiofrequency ablation (RFA) are both first-line treatments for very-early-stage HCC, but the differences in clinical outcomes between patients treated with SR and RFA remain unclear. This study investigated the prognosis of SR and RFA for very-early-stage HCC patients with long-term follow-up. METHODS: This study was retrospectively collected data on the clinicopathological characteristics, overall survival (OS), and disease-free survival (DFS) of 188 very-early-stage HCC patients (≤ 2 cm single HCC). OS and DFS were analyzed using the Kaplan-Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. RESULTS: Of the 188 HCC patients, 103 received SR and 85 received RFA. The median follow-up time was 56 months. The SR group had significantly higher OS than the RFA group (10-year cumulative OS: 55.2% and 31.3% in the SR and RFA groups, respectively). No statistically significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 45.9% and 32.6% in the SR and RFA groups, respectively). After PSM, the OS in the SR group remained significantly higher than that in the RFA group (10-year cumulative OS: 54.7% and 42.2% in the SR and RFA groups, respectively). No significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 43.0% and 35.4% in the SR and RFA groups, respectively). Furthermore, in the multivariate Cox regression analysis, treatment type (hazard ratio (HR): 0.54, 95% confidence interval (CI): 0.31-0.95; P = 0.032) and total bilirubin (HR: 1.92; 95% CI: 1.09-3.41; P = 0.025) were highly associated with OS. In addition, age (HR: 2.14, 95% CI: 1.36-3.36; P = 0.001) and cirrhosis (HR: 1.79; 95% CI: 1.11-2.89; P = 0.018) were strongly associated with DFS. CONCLUSION: For patients with very-early-stage HCC, SR was associated with significantly higher OS rates than RFA. However, no significant difference was observed in DFS between the SR and RFA groups.

A Novel Combination of Bevacizumab with Chemotherapy Improves Therapeutic Effects for Advanced Biliary Tract Cancer: A Retrospective, Observational Study.

BACKGROUND: Biliary tract cancer (BTC) is a heterogenous collection of biliary tract cancer at different primary sites, and the prognosis of advanced BTC is dismal. Systemic chemotherapy with gemcitabine and cisplatin (GC) has been the reference regimen since 2010. How to improve therapeutic effects of GC regimen is an urgent mission at present. METHODS: Bevacizumab with a reduced dosage and modified schedule (10 mg/Kg/triweekly, 1 day before GS at the first 2 cycles) was combined with standard GC for patients with advanced BTC. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 every 2 months. Kaplan-Meier curves were estimated for time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS). RESULT: A total of thirty cases of advanced BTC accepted this treatment, and the overall response rate (ORR) was 50.0%, and the disease control rate was 80.0% for all patients. The median TTF was 5.8 months, the median PFS was 8.4 months, and the median OS was 13.6 months. Most responses were noted at the first evaluation. Adverse effects (AEs) were mostly tolerable. CONCLUSIONS: After modifying the schedule, adding bevacizumab to a traditional GC regimen could increase the ORR with a shorter time-to-response, a better PFS and OS than GC alone but without the addition of AE. This regimen can be applied to patients with advanced BTC, especially those who are with a big tumor burden and who need a rapid response.

Role of autophagy-related protein in the prognosis of combined hepatocellular carcinoma and cholangiocarcinoma after surgical resection.

BACKGROUND: Autophagy-related proteins may predict postresection overall survival (OS) and disease-free survival (DFS) in patients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC). METHODS: We prospectively investigated how these proteins affect clinical prognosis in 40 patients who underwent hepatectomy for cHCC-CC from 2011 to 2019 at a Taiwanese hospital. Levels of autophagy-related proteins, namely LC3, Beclin-1, and p62, were immunohistochemically assessed in patient tumor and non-tumor tissues. RESULTS: We noted that LC3 expression was significantly correlated with mild clinicopathological characteristics, including macrovascular invasion, lymph node metastasis, American Joint Committee on Cancer and Barcelona Clinic Liver Cancer stages, recurrence, and mortality. Ten patient showed tumor recurrence, and 15 patients died. Postresection 5-year OS and DFS rates were 43.7 and 57.4%, respectively. Cox regression analysis showed that high intratumoral LC3 expression was significantly associated with improved OS [hazard ratio (HR; 95% confidence interval (CI)): (1.68-26.9), p = 0.007], but multiple tumors and microvascular invasion was significantly correlated with poor OS [HR (95% CI): 0.03 (0.01-0.34), p = 0.004, and 0.07 (0.01-0.46), p = 0.006, respectively]. Furthermore, high LC3 expression and cirrhosis had improved DFS [HR (95% CI): 51.3 (2.85-922), p = 0.008, and 17.9 (1.05-306), p = 0.046, respectively]. The 5-year OS and DFS rates were respectively 61.2 and 74.6% in high LC3 expression patients and 0 and 0% in those with low LC3 expression. CONCLUSION: High LC3 expression in tumors is significantly associated with mild clinicopathological characteristics and favorable clinical prognosis in patients with cHCC-CC after resection.

Resubclassification and clinical management for Barcelona Clinic Liver Cancer Stage C hepatocellular carcinoma.

BACKGROUND: Patients with Barcelona Clinic Liver Cancer Stage C (BCLC-C) hepatocellular carcinoma (HCC) can be markedly heterogeneous with varying prognosis. This study aims to establish a new subclassification system for BCLC-C HCC to better predict overall survival (OS) and to tailor therapy. METHODS: We retrospectively studied 1856 BCLC-C HCC patients between 2006 and 2017 from E-Da Hospital, Taiwan (n = 622, training cohort), Kaohsiung Medical University Hospital, Taiwan (n = 774, Taiwan validation cohort), and Stanford University Medical Center and Mayo Clinic (United States), Hanyang University Hospital (South Korea), and Ogaki Municipal Hospital (Japan) to make up the international validation cohort (n = 460). RESULTS: In the training cohort, significant factors associated with OS were largest tumor size ≥ 10 cm, extrahepatic spread, macrovascular invasion, and Child-Pugh class, which provided the basis, together with aged ≥ 75 years, for the substaging, through C0 to C4, of BCLC-C HCC patients. The median OS for substages C0, C1, C2, C3, and C4 were 43.8 months (95% confidence interval [CI] 32.2-53.7), 20.6 months (CI 14.1-25.9), 11.5 months (CI 8.02-14.1), 5.7 months (CI 4.02-5.98), and 3.2 months (CI 2.41-3.59), respectively, (p < 0.05). OS remained distinct among the proposed substages in the Taiwan validation cohort as well as the international validation cohort. The distinction between the substages persisted in subgroup analysis by substage combined with treatment modality. In substage C0-C3, patients receiving HCC curative therapy had a significantly better median OS than those receiving sorafenib or palliative therapy. CONCLUSION: Our new substaging system provides more precise prognosis to better tailor therapy for BCLC-C HCC patients.

Surgical resection significantly promotes the overall survival of patients with hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND: The benefits of surgical resection (SR) for various Barcelona Clinic Liver Cancer (BCLC) stages of hepatocellular carcinoma (HCC) remain unclear. We investigated the risk factors of overall survival (OS) and survival benefits of SR over nonsurgical treatments in patients with HCC of various BCLC stages. METHODS: Overall, 2316 HCC patients were included, and their clinicopathological data and OS were recorded. OS was analyzed by the Kaplan-Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. RESULTS: In total, 66 (2.8%), 865 (37.4%), 575 (24.8%) and 870 (35.0%) patients had BCLC stage 0, A, B, and C disease, respectively. Furthermore, 1302 (56.2%) of all patients, and 37 (56.9%), 472 (54.6%), 313 (54.4%) and 480 (59.3%) of patients with BCLC stage 0, A, B, and C disease, respectively, died. The median follow-up duration time was 20 (range 0-96) months for the total cohort and was subdivided into 52 (8-96), 32 (1-96), 19 (0-84), and 12 (0-79) months for BCLC stages 0, A, B, and C cohorts, respectively. The risk factors for OS were (1) SR and cirrhosis; (2) SR, cirrhosis, and Child-Pugh (C-P) class; (3) SR, hepatitis B virus (HBV) infection, and C-P class; and (4) SR, HBV infection, and C-P class for the BCLC stage 0, A, B, and C cohorts, respectively. Compared to non-SR treatment, SR resulted in significantly higher survival rates in all cohorts. The 5-year OS rates for SR vs. non-SR were 44.0% versus 28.7%, 72.2% versus 42.6%, 42.6% versus 36.2, 44.6% versus 23.5%, and 41.4% versus 15.3% (all P values < 0.05) in the total and BCLC stage 0, A, B, and C cohorts, respectively. After PSM, SR resulted in significantly higher survival rates compared to non-SR treatment in various BCLC stages. CONCLUSIONS: SR conferred significant survival benefits to patients with HCC of various BCLC stages and should be considered a recommended treatment for select HCC patients, especially patients with BCLC stage B and C disease.

Clinical features and outcomes of combined hepatocellular carcinoma and cholangiocarcinoma versus hepatocellular carcinoma versus cholangiocarcinoma after surgical resection: a propensity score matching analysis.

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an infrequent type of primary liver cancer that comprises hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). This study investigated the clinicopathological features and prognosis among cHCC-CC, HCC, and CC groups. METHODS: We prospectively collected the data of 608 patients who underwent surgical resection for liver cancer between 2011 and 2018 at E-Da Hospital, I-Shou University, Kaohsiung, Taiwan. Overall, 505 patients with cHCC-CC, HCC, and CC were included, and their clinicopathological features, overall survival (OS), and recurrence were recorded. OS and recurrence rates were analyzed using the Kaplan-Meier analysis. RESULTS: In the entire cohort, the median age was 61 years and 80% were men. Thirty-five (7.0%) had cHCC-CC, 419 (82.9%) had HCC, and 51 (10.1%) had CC. The clinicopathological features of the cHCC-CC group were more identical to those of the HCC group than the CC group. OS was significantly lower in the cHCC-CC group than in the HCC group but was not significantly higher in the cHCC-CC group than in the CC group. The median OS of cHCC-CC, HCC, and CC groups was 50.1 months [95% confidence interval (CI): 38.7-61.2], 62.3 months (CI: 42.1-72.9), and 36.2 months (CI: 15.4-56.5), respectively. Cumulative OS rates at 1, 3, and 5 years in cHCC-CC, HCC, and CC groups were 88.5%, 62.2%, and 44.0%; 91.2%, 76.1%, and 68.0%; and 72.0%, 48.1%, and 34.5%, respectively. After propensity score matching (PSM), OS in the cHCC-CC group was not significantly different from that in the HCC or CC group. However, OS was significantly higher in the HCC group than in the CC group before and after PSM. Furthermore, the disease-free survival was not significantly different among cHCC-CC, HCC, and CC groups before and after PSM. CONCLUSION: The clinicopathological features of the cHCC-CC group were more identical to those of the HCC group than the CC group. The OS rate was significantly lower in the cHCC-CC group than the HCC group. However, after PSM, OS and disease-free survival in the cHCC-CC group were not significantly different from those in the HCC or CC group.

Comparison of overall survival on surgical resection versus transarterial chemoembolization with or without radiofrequency ablation in intermediate stage hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND: Patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) are recommended to undergo transcatheter arterial chemoembolization (TACE). However, TACE in combination with radiofrequency ablation (RFA) is not inferior to surgical resection (SR), and the benefits of surgical resection (SR) for BCLC stage B HCC remain unclear. Hence, this study aims to compare the impact of SR, TACE+RFA, and TACE on analyzing overall survival (OS) in BCLC stage B HCC. METHODS: Overall, 428 HCC patients were included in BCLC stage B, and their clinical data and OS were recorded. OS was analyzed by the Kaplan-Meier method and Cox regression analysis. RESULTS: One hundred forty (32.7%) patients received SR, 57 (13.3%) received TACE+RFA, and 231 (53.9%) received TACE. The OS was significantly higher in the SR group than that in the TACE+RFA group [hazard ratio (HR): 1.78; 95% confidence incidence (CI): 1.15-2.75, p = 0.009]. The OS was significantly higher in the SR group than that in the TACE group (HR: 3.17; 95% CI: 2.31-4.36, p < 0.0001). Moreover, the OS was significantly higher in the TACE+RFA group than that in the TACE group (HR: 1.82; 95% CI: 1.21-2.74, p = 0.004). The cumulative OS rates at 1, 3 and 5 years in the SR, TACE+RFA, and TACE groups were 89.2, 69.4 and 61.2%, 86.0, 57.9 and 38.2%, and 69.5, 37.0 and 15.2%, respectively. After propensity score matching, the SR group still had a higher OS than those of the TACE+RFA and TACE groups. The TACE+RFA group had a higher OS than that of the TACE group. CONCLUSION: The SR group had higher OS than the TACE+RFA and TACE groups in BCLC stage B HCC. Furthermore, the TACE+RFA group had higher OS than the TACE group.

Sorafenib with concurrent multiple-line therapies improves overall survival in advanced stage hepatocellular carcinoma.

The efficacy of sorafenib in combination with transarterial chemoembolization (TACE) or multiple-line therapies in patients with advanced hepatocellular carcinoma (HCC) remains unclear. This study aimed to investigate the overall survival (OS) of patients with advanced HCC in response to different combination therapies.We analyzed the treatment and OS of 401 patients with Barcelona clinic liver cancer stage C HCC between 2012 and 2017. Mortality was analyzed using multivariate Cox regression, and OS was analyzed by the Kaplan-Meier method.The mean age was 59 years and males were predominant. During a median follow-up time of 8.6 months (range, 1-80 months), 346 (86.2%) patients died. In the multivariate Cox regression analysis, primary tumor size ≥5 cm, serum alpha-fetoprotein ≥200, and serum albumin ≥3.5 were significantly associated with mortality. In addition, compared with sorafenib alone, multiple-line treatments with sorafenib and multiple-line treatments without sorafenib yielded significantly decreased mortality. In the Kaplan-Meier analysis, sorafenib with TACE, multiple-line treatments with sorafenib, third-line treatments with sorafenib, and multiple-line treatments without sorafenib yielded a significantly better median OS than sorafenib alone.Sorafenib with concurrent multiple-line therapies significantly improved OS. These combination therapies will provide important information for immunotherapy combination with locoregional therapies in advanced HCC.

Axl and autophagy LC3 expression in tumors is strongly associated with clinical prognosis of hepatocellular carcinoma patients after curative resection.

BACKGROUND: The role of Axl and LC3 as predictors of tumor recurrence and overall survival (OS) after hepatocellular carcinoma (HCC) resection remains unclear. METHODS: We retrospectively included 535 HCC patients who underwent hepatectomy from 2010 to 2014 in this study. Axl and the autophagy-related marker LC3 were immunohistochemically assessed in tumors. RESULTS: Axl expression was significantly associated with advanced clinicopathological features, including cirrhosis, microvascular invasion, macrovascular invasion, tumor size, BCLC stage, recurrence, and mortality. HCC recurrence occurred in 245 patients, and 219 patients died. The 5-year cumulative incidences of HCC recurrence and OS rate after HCC resection were 53.3% and 58.8%, respectively. In the Cox proportional analyses, high Axl expression and high LC3 expression were significantly associated with HCC recurrence (hazard ratio [HR]: 3.85, 95% confidence interval [CI]: 2.95-5.02, P < 0.001; and HR: 0.38, 95% CI: 0.26-0.55, P < 0.001, respectively). In addition, HCC recurrence (HR: 2.87, 95% CI: 2.01-4.01, P < 0.0001), microvascular invasion (HR: 1.85, 95% CI: 1.08-3.19, P = 0.026), hepatitis B virus-related HCC (HR: 1.77, 95% CI: 1. 21-2.56, P = 0.003), high Axl expression (HR: 1.66, 95% CI: 1.41-1.97, P < 0.0001), antiviral therapy (HR: 0.54, CI: 0.38-0.76, P < 0.001) and LC3 expression (HR: 0.41, 95% CI: 0.28-0.58, P < 0.001) were significantly associated with mortality. Furthermore, patients with a combination of high Axl and low LC3 expression had the highest risk of HCC recurrence (HR: 6.53, 95% CI: 4.11-10.4, P < 0.001) and mortality (HR: 6.66, 95% CI: 4.07-10.9, P < 0.001). In patients with high Axl, low LC3, and combined high Axl and low LC3 expression, the 5-year cumulative incidences of HCC recurrence and OS rate were 77.9%, 73.3%, and 90.0% and 28.8%, 26.7%, and 16.8%, respectively. CONCLUSION: High Axl expression in tumors is associated with aggressive tumor behavior and worse clinical outcomes. Furthermore, the combination of high Axl and low LC3 expression significantly predicts poorer prognosis for HCC patients who underwent hepatectomy.

Significant predictors of overall survival in patients with hepatocellular carcinoma after surgical resection.

BACKGROUND: The predictive factors of overall survival after hepatectomy for HCC remain controversial and need to be investigated. METHODS: In total, 535 consecutive HCC patients undergoing resection were included and their clinicopathological data and overall survival were recorded. Both the tumor and adjacent non-tumor (ANT) tissues were subjected to immunohistochemistry analysis for the expression of autophagy-related markers. RESULTS: Death was observed for 219 patients, and the cumulative overall survival rates at 1, 3, 5 and 7 years were 91.0%, 72.3%, 58.8%, and 27.7%, respectively. In the multivariate analysis, mortality was significantly associated with the following: diminished LC3 expression in both the tumor and ANT tissues, in the HCC tissues alone and in the ANT tissues alone (hazard ratio/95% confidence interval: 6.74/2.052-22.19, 6.70/1.321-33.98 and 2.58/1.499-4.915, respectively); recurrent HCC (5.11/3.136-8.342); HBV infection (2.75/1.574-4.784); cirrhosis (1.78/1.059-2.974); and antiviral therapy (0.42/0.250-0.697). The 5-year overall survival rates were 70.2%, 57.3%, 49.6% and 10.7% for patients with positive LC3 expression in both tissue types, in the HCC tissues alone, in the ANT tissues alone, and in neither tissue type, respectively. The 5-year overall survival rates were 56.7%, 47.3%, 51.2% and 38.7% for patients with HBV-related HCC, cirrhosis, no antiviral therapy, and recurrent HCC, respectively, and these rates were significantly lower than those in their counterparts. CONCLUSIONS: Patients with recurrent HCC, HBV-related HCC, cirrhosis, and the absence of antiviral therapy showed significantly lower overall survival rates. Furthermore, LC3 expression in both the tumor and liver microenvironments were significantly predictive of overall survival after resection for HCC.

Autophagy-related gene LC3 expression in tumor and liver microenvironments significantly predicts recurrence of hepatocellular carcinoma after surgical resection.

BACKGROUND: The role of autophagy-related markers as the prognostic factor of post-operative hepatocellular carcinoma (HCC) recurrence remained controversial. METHODS: Overall, 535 consecutive HCC patients undergoing curative resection from 2010 to 2014 were followed and classified with early (ER, <2 years) or late recurrence (LR). Autophagy-related markers, LC3, Beclin-1, and p62 expression was immunohistochemically assessed in HCC and adjacent non-tumor (ANT) tissues. RESULTS: HCC recurred in 245 patients: 116 with ER and 129 with LR. The cumulative incidence of recurrence at 1, 3, 5, and 7 years was 9.7%, 33.9%, 53.3%, and 66.3%, respectively. In multivariate analysis, HCC recurrence was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (hazard ratio/95% confidence interval: 6.12/2.473-17.53, 4.18/1.285-13.61, and 1.89/1.299-2.757) and macrovascular invasion (1.63/1.043-2.492) and cirrhosis (1.59/1.088-2.326). ER was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (6.54/2.934-15.81, 3.26/1.034-10.27, and 2.09/1.313-3.321) and macrovascular and microvascular invasion (2.65/1.306-5.343 and 2.55/1.177-5.504). LR was significantly associated with low LC3 expression in tumor and ANT tissues, HCC tissues only and ANT tissues only (5.02/1.372-18.83, 3.19/1.13-12.09, and 1.66/1.051-2.620) and cirrhosis (1.66/1.049-2.631). Patients with low and high LC3 expression in tumor and ANT tissues showed a 5-year cumulative recurrence of 94.3% and 41.7%, respectively (p < 0.001). CONCLUSIONS: The high LC3 expression in the tumor and liver microenvironments is significantly associated with lower HCC recurrence. Furthermore, tumor characteristics and liver microenvironment were also significantly associated with ER and LR, respectively. TRANSLATIONAL IMPACT: The analysis for LC3 expression in both the HCC and ANT tissues could identify patients at risk of HCC recurrence.

The autophagy marker LC3 strongly predicts immediate mortality after surgical resection for hepatocellular carcinoma.

The remnant liver's ability to regenerate may affect post-hepatectomy immediate mortality. The promotion of autophagy post-hepatectomy could enhance liver regeneration and reduce mortality. This study aimed to identify predictive factors of immediate mortality after surgical resection for hepatocellular carcinoma (HCC). A total of 535 consecutive HCC patients who had undergone their first surgical resection in Taiwan were enrolled between 2010 and 2014. Clinicopathological data and immediate mortality, defined as all cause-mortality within three months after surgery, were analyzed. The expression of autophagy proteins (LC3, Beclin-1, and p62) in adjacent non-tumor tissues was scored by immunohistochemical staining. Approximately 5% of patients had immediate mortality after surgery. The absence of LC3, hypoalbuminemia (<3.5 g/dl), high alanine aminotransferase, and major liver surgery were significantly associated with immediate mortality in univariate analyses. Multivariate logistic regression demonstrated that absence of LC3 (hazard ratio/95% confidence interval: 40.8/5.14-325) and hypoalbuminemia (2.88/1.11-7.52) were significantly associated with immediate mortality. The 3-month cumulative incidence of mortality was 12.1%, 13.0%, 21.4% and 0.4%, respectively, among patients with absence of LC3 expression, hypoalbuminemia, both, or neither of the two. In conclusion, the absence of LC3 expression in adjacent non-tumor tissues and hypoalbuminemia were strongly predictive of immediate mortality after resection for HCC.

Inflammatory myofibroblastic tumors of the pancreas in children: A case report and literature review.

INTRODUCTION: Inflammatory myofibroblastic tumors are an uncommon neoplasm, which are very rarely located in the pancreas. Clinically and radiologically, this rare pancreatic tumor presents as an abdominal mass lesion that mimics other pancreatic tumors, and should therefore be considered in the differential diagnosis of pancreatic tumors. CLINICAL FINDINGS AND DIAGNOSIS: The 15-year-old boy complained of abdominal pain over the left upper quadrant with intermittent fever for 7 days. Abdominal sonography revealed one cystic lesion with a hyperechoic component in the left upper quadrant of the abdomen. Surgical excision was performed and postoperative findings indicated a pancreatic tail tumor. The pathology indicated inflammatory myofibroblastic tumors. To our knowledge, this patient is a unique case as the tumor was located in the pancreatic tail only, sparing the body. INTERVENTIONS AND OUTCOMES: The patient underwent tumor resection and segmental resection of the transverse colon with simple closure. The patient had no evidence of disease recurrence at 3 years follow-up. CONCLUSION: Inflammatory myofibroblastic tumors of the pancreas in children are extremely rare. Surgical excision is the standard treatment, and corticosteroids use in children need more large-scale studies.

Amiodarone as an autophagy promoter reduces liver injury and enhances liver regeneration and survival in mice after partial hepatectomy.

The deregulation of autophagy is involved in liver regeneration. Here, we investigated the role of autophagy in the regulation of liver regeneration after partial hepatectomy (PHx) and the development of pharmacological interventions for improved liver regeneration after PHx. We show that autophagy was activated in the early stages of liver regeneration following 70% PHx in vivo. Moreover, amiodarone was associated with a significant enhancement of autophagy, liver growth, and hepatocyte proliferation, along with reduced liver injury and the termination of liver regeneration due to decreased transforming growth factor-ß1 expression after 70% PHx. The promotion of autophagy appeared to selectively increase the removal of damaged mitochondria. We also found that Atg7 knockdown or pretreatment with chloroquine aggravated the liver injury associated with 70% PHx and reduced liver growth and hepatocyte proliferation. Finally, amiodarone improved liver regeneration, survival, and liver injury after 90% PHx. In conclusion, our results indicate that autophagy plays an important role in mouse liver regeneration and that modulating autophagy with amiodarone may be an effective method of improving liver regeneration, increasing survival, and ameliorating liver injury following PHx.

APOBEC3B: a potential factor suppressing growth of human hepatocellular carcinoma cells.

BACKGROUND: To realize the role of apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3B (APOBEC3B) in hepatocellular carcinoma (HCC) occurrence, mRNAs of APOBEC3B from tumor and non-tumor tissues of patients with hepatectomy were isolated and in vitro studies were designed. MATERIALS AND METHODS: Seventy-two tumor and non-tumor tissue samples, as well as clinical data, were collected from HCC patients during hepatectomy. The mRNA of APOBEC3B was assessed by real-time polymerase chain reaction. The viability of pLV-APOBEC3B-transfected Hep 3B cells was then determined. Cell growth of pLV-APOBEC3B-transfected Hep 3B cells was evaluated by in vitro migration assay. RESULTS: The real-time polymerase chain reaction results indicated a higher expression of APOBEC3B mRNA in tumor tissues than in non-tumor tissues of patients with HBsAg+ HCC. The expression of APOBEC3B in tumor or non-tumor tissue was not found to be a risk factor of recurrence in patients with HCC. The cell viability assay results indicated the growth-inhibitory effects of APOBEC3B on Hep 3B cells. The cell migration results indicated that APOBEC3B inhibits wound healing in Hep 3B cells. CONCLUSION: Based on these observations, we infer that APOBEC3B is a potential factor contributing to suppression of tumor growth in HCC.

Changing hepatitis D virus epidemiology in a hepatitis B virus endemic area with a national vaccination program.

UNLABELLED: The emergence of hepatitis D virus (HDV) infection in the era of widespread HBV vaccination has not been described before. We aimed to investigate the changing epidemiology of HDV infection among high- and low-risk populations after an outbreak of human immunodeficiency virus (HIV) infection among injection drug users (IDUs) in Taiwan. A prospective, multicenter, cohort study of 2,562 hepatitis B surface antigen (HBsAg)-positive individuals was conducted to determine the prevalence, genotype, and risk factors of HDV infection from 2001 through 2012. The prevalence rates of HDV infection were 74.9%, 43.9%, 11.4%, 11.1%, and 4.4% among HIV-infected IDUs, HIV-uninfected IDUs, HIV-infected men who have sex with men, HIV-infected heterosexuals, and the general population of HBsAg-positive subjects, respectively. A significant increase in the trend of HDV prevalence from 38.5% to 89.8% was observed in HIV-infected IDUs (odds ratio = 3.06; 95% confidence interval: 1.68-5.56; P = 0.0002). In multivariate analysis, injection drug use, hepatitis C virus infection, HIV infection, serum HBsAg level ≧250 IU/mL, duration of drug use, and older age were significant factors associated with HDV infection. HDV genotype IV (72.2%) was the prevalent genotype circulating among IDUs, whereas genotype II was predominant in the non-IDU populations (73.3%). In the HIV cohort born after 1987 who were HBsAg negative, over half (52.9%) had antibody to hepatitis B surface antigen antibody levels of <10 mIU/mL and there was a significantly higher HBsAg seroprevalence in the HIV cohort, compared to the control group (8.1% vs. 0.0%; P = 0.02). CONCLUSION: In the era of HBV vaccination, IDUs and HIV-infected individuals have emerged as high-risk groups and a reservoir for HDV infection. Effective strategies are needed to curb the reemerging epidemic of HDV infection in these high-risk groups.