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.

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.

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.

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.

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.

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.

APOBEC3G exerts tumor suppressive effects in human hepatocellular carcinoma.

In this study, we collected 44 hepatitis B virus surface antigen positivity HBsAg (+) tumor and nontumor hepatocellular tissues from hepatocellular carcinoma (HCC) patients during hepatectomy, and quantified the APOBEC3G (A3G) mRNA by using a real-time PCR. Our results showed higher expression of A3G mRNA in the nontumor tissues than in the tumor tissues of the HBsAg (+) HCC patients. To further investigate this phenomenon, we constructed a pLV-A3G vector and transfected it into the human HCC cell line, Hep 3B. The results of an immunofluorescence analysis showed the overexpression of A3G in the cytoplasm. We then evaluated A3G cytotoxicity by using a cell viability assay (MTS assay), the results of which showed that Hep 3B cell viability was 88 and 58% after the transfection of pLV and pLV-A3G, respectively, indicating the growth inhibitory effects of A3G on Hep 3B cells. To further evaluate the tumor suppressive effects of A3G, we used a plastic pipette tip to scratch Hep 3B cells grown on a culture dish (to 70-80% confluence) after transfection with pLV-A3G. Our data indicated a ratio of wound closure of 100% in the control cells and in the pLV-expressing cells, compared with 43% in the pLV-A3G-overexpressing cells, 72 h after the wound scratch, as observed using phase-contrast microscopy. These results indicated that A3G inhibits wound healing in Hep 3B cells. Overall, our results suggest that A3G inhibits the growth of human hepatoma cells.

Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis.

BACKGROUND & AIMS: Taiwan has a high prevalence of hepatitis B viral (HBV) infection and hepatocellular carcinoma (HCC) with increasing consumption of alcohol. We investigated the impact of heavy alcohol consumption and HBV infection on HCC in cirrhotic patients. METHODS: 966 cirrhotic patients (132 with HBV infection and alcoholism, 632 with HBV infection, and 202 patients with alcoholism) were enrolled between 2000 and 2009 and followed until 2011. The primary end point was newly developed HCC. RESULTS: Within the three patient groups (cirrhotic patients with HBV infection and alcoholism, HBV infection alone, and alcoholism alone) 38 (28.8%), 100 (15.8%), and 21 (10.4%) showed newly developed HCC, respectively. The 10-year cumulative (52.8% vs. 39.8% vs. 25.6%, p <0.001) and annual incidences (9.9%, 4.1%, and 2.1%) of HCC were significantly higher in cirrhotic patients with HBV infection and alcoholism than those in patients with HBV infection or alcoholism alone. For patients with HBV infection and alcoholism, baseline serum HBV DNA (OR=16.8, p=0.025), antiviral nucleos(t)ides analogues (NUCs) therapy (OR=0.01, p=0.035), and serum α-fetoprotein (OR=1.18, p=0.045) were risk predictors of HCC by multivariate logistic regression models. The cumulative incidence of HCC was higher in patients with higher baseline serum HBV DNA. Antiviral NUCs therapy reduced the incidence of HCC. CONCLUSIONS: Heavy alcohol consumption significantly increased the risk of HCC in HBV-related cirrhotic patients. Elevated baseline serum HBV DNA was a strong risk predictor of HCC and antiviral NUCs therapy reduced the incidence of HCC in cirrhotic patients with HBV infection and alcoholism.

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.

Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection.

OBJECTIVE: To investigate the clinical efficacy of adjuvant interferon alfa-2b (IFNα-2b) therapy on recurrence-free survival (RFS) of patients with postoperative viral hepatitis-related hepatocellular carcinoma (HCC). BACKGROUND: Despite most individual trials have failed to meet their primary endpoint, recent pooled-data meta-analyses suggest that adjuvant IFN therapy may significantly reduce the incidence of recurrence in curatively ablated HCC. METHODS: Patients with curative resection of viral hepatitis-related HCC were eligible, and were stratified by underlying viral etiology and randomly allocated to receive either 53 weeks of adjuvant IFNα-2b treatment or observation alone. The primary endpoint of this study was RFS. RESULTS: A total of 268 patients were enrolled with 133 in the IFNα-2b arm and 135 in the control arm. Eighty percent of them were hepatitis B surface antigen seropositive. At a median follow-up of 63.8 months, 154 (57.5%) patients had tumor recurrence and 84 (31.3%) were deceased. The cumulative 5-year recurrence-free and overall survival rates of intent-to-treat cohort were 44.2% and 73.9%, respectively. The median RFS in the IFNα-2b and control arms were 42.2 (95% confidence interval [CI], 28.1-87.1) and 48.6 (95% CI, 25.5 to infinity) months, respectively (P = 0.828, log-rank test). Adjuvant IFNα-2b treatment was associated with a significantly higher incidence of leucopenia and thrombocytopenia. Thirty-four (24.8%) of treated patients required dose reduction, and 5 (3.8%) of these patients subsequently withdrew from therapy because of excessive toxicity. Adjuvant IFNα-2b only temporarily suppressed viral replication during treatment period. CONCLUSIONS: In this study, adjuvant IFNα-2b did not reduce the postoperative recurrence of viral hepatitis-related HCC. More potent antiviral therapy deserves to be explored for this patient population. This study is registered at ClinicalTrials.gov and carries the identifier NCT00149565.

Expression of aquaporins in rat liver regeneration.

OBJECTIVE: The remarkable ability of liver to regenerate after insults has been harnessed by surgeons when designing techniques for liver resection or transplantation. However, the underlying mechanisms of liver regeneration are not fully clarified. On the other hand, aquaporins (AQPs) are small transmembrane proteins with unexpected physiological roles in addition to water transport. For example, they play pivotal roles in cell migration, angiogenesis, and cell proliferation, events that are also occurred during liver regeneration. We thus examined the possible involvement of AQPs in this regenerative process. MATERIAL AND METHODS: A two-thirds partial hepatectomy (PH) rat model was employed. The temporal expression of various AQPs in the liver following PH was determined by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. The localization of AQPs was evaluated by immunohistochemistry. RESULTS: As anticipated, AQP0, 8, 9, and 11 were detected mainly in hepatocytes; unexpectedly, Kupffer cells were observed to express AQP8 during a specific period of time in the regenerative process. AQP9 protein was shown to be expressed in a progressively enhanced pattern at early time points after PH. A transient expression of AQP11 in the nucleus of hepatocytes was observed. CONCLUSION: These findings suggest the possibility that AQP might be involved in the PH-induced liver regeneration.

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.

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.

Specialty differences in the association between health care climate and patient trust.

CONTEXT: Previous studies have suggested that there is a positive correlation between doctors' emotional intelligence (EI) and patients' trust in their attending physicians; however, there is only limited evidence of specialty differences between internists and surgeons for such an association. OBJECTIVES: This study examined the association of nursing director assessments of doctors' EI, outside observer assessments of doctors' health care climate (HCC) in the examining room and patient-rated trust in internists and surgeons. Health care climate refers to a key component in communication and reflects the extent to which patients perceive their health care providers as supporting patient autonomy rather than controlling the provision of treatment. METHODS: In this observational study, 2702 patients seen by 110 internists and 2642 patients seen by 101 surgeons were surveyed in face-to-face interviews by trained nurses in two teaching hospitals in Taiwan. Using hierarchical linear modelling, we examined the association between EI and HCC as well as patient trust in doctors working in the specialties of internal medicine and surgery. RESULTS: We found a significantly positive correlation between doctor EI and patient trust for all patients (p<0.01). In addition, although HCC was positively associated with patient trust for internists (p<0.01), it was not so for surgeons. CONCLUSIONS: We conclude that doctors might benefit from training programmes aimed at improving EI and that differences in patient expectations might be considered when hospitals attempt to evaluate doctors in different specialties.

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.

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.

Esophagogastric varices predict mortality in hospitalized patients with alcoholic liver disease in Taiwan.

BACKGROUND/AIMS: Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in Western countries. The present study investigated the status and the risk factors for predicting mortality of ALD in Taiwan. METHODOLOGY: We retrospective studied 100 consecutive in patients with ALD between 1992 and 2000. All patients had a history of alcohol consumption exceeding 80 g per day for at least 5 years. RESULTS: The study comprised 93 men and 7 women with a mean age of 45.4 years. The ALD included fatty liver (21%), alcoholic hepatitis (15%), alcoholic hepatitis superimposed on alcoholic cirrhosis (24%), and alcoholic cirrhosis (40%). Forty-four percent of patients had esophagogastric varices. Thirty-three percent of patients were mortality. The presence of esophagogastric varices was the only parameter identified by univariate and multivariate analyses and had a statistically significant association with increased mortality (OR: 8.603; 95% CI: 2.009-36.864; p = 0.004). The cumulative survival for ALD patients with varices was significantly lower than for patients without varices. CONCLUSIONS: The presence of esophagogastric varices had a statistically significant relationship with increased mortality. This study strongly implicates esophagogastric varices were a valuable poor prognostic factor with mortality. Upper gastrointestinal endoscopy is a simple clinical available tool for the assessment of the occurrence of varices to predict the disease severity and mortality in hospitalized patients with ALD.

Retromammary approach for endoscopic resection of benign breast lesions.

BACKGROUND: One of the merits of endoscopic surgery is that it can be performed through small remote incisions made in inconspicuous areas. To improve cosmetic outcomes of surgical treatment of benign breast lesions, we performed endoscopic surgery through minimally sized axillary incisions with the goal of achieving scar-free breasts. METHODS: From August 2007 to August 2008, 18 patients with 20 benign breast lesions underwent endoscopic breast excision in our institution. Endoscopic resection of benign breast lesions was performed via the retromammary route with video assistance. Cosmetic results were evaluated using the five-item, four-step ABNSW scoring system, assessing breast asymmetry, breast shape, nipple shape, skin condition, and wound scars. RESULTS: The median age of the patients was 27 years (IQR 23.0, 29.0). Median resected lesion size was 3.3 cm (IQR 2.9, 3.9). Median operative time was 85.0 min (IQR 70.0, 100.0). A marginally significant difference in operative times was noted between fibroadenoma and/or juvenile fibroadenoma cases and mastopathy or benign phyllodes cases (80.0 vs. 100.0; p < 0.06). Median total ABNSW score was 14 points. Postoperatively, 5 patients had mild local subcutaneous emphysema, and one had transient brachial palsy. No breast ecchymosis or deformity was noted. No major complications developed in any patient, and 89% of patients had good or excellent results. CONCLUSIONS: Video-assisted endoscopic breast surgery has changed routine breast surgery, manifesting cosmetic effects that cannot be achieved by previous routine surgical techniques. Patients with multiple or large benign tumors who desire excellent cosmetic results are good candidates for this approach.

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.