Long-term Survival Of Hepatocellular Carcinoma Patients Research Articles

Bivalent Role of LncRNA-LRAHC during Liver Regeneration and Hepatocellular Carcinoma

Background: For hepatocellular carcinoma (HCC) patients, surgical resection is the main treatment modality that offers an opportunity for prolonged survival. Tumor recurrence or metastasis after liver resection limits the long-term survival of HCC patients. However, the mechanism of liver regeneration-induced metastasis and augmented growth of residual HCC following liver resection remains obscure. Methods: HCC tissues and matched non-tumor tissues were collected from 75 patients (for mRNA analysis) at the Eastern Hepatobiliary Surgery Hospital from 2008 to 2013. We evaluated the functions of lncRNA-LRAHC through knockdown and overexpression of this lncRNA using lentivirus infection system in vitro and in vivo. Results: In this study, we identified a long noncoding RNA associated with liver regeneration and hepatocellular carcinoma, termed lncRNA-LRAHC, via a liver regeneration microarray (GSE43687). We discovered that lncRNA-LRAHC accelerated hepatocyte proliferation and inhibited HCC cell migration in vitro and in vivo. Mechanistically, we found that lncRNA-LRAHC interacts with RNA-binding protein HuR and enhances XBP1 to promote proliferation during liver regeneration; it combines with protein CDH2 and represses its expression, further altering normal cytoskeleton structure to suppress HCC metastasis. We also found a human ortholog of lncRNA-hLRAHC and determined it was down-regulated in HCC tissues and correlated with poor survival in HCC patients. Conclusions: These data support a crucial function of lncRNA-LRAHC in promoting liver regeneration and tumor suppression in HCC. This indicates a novel therapeutic approach using lncRNA-LRAHC to enhance liver regeneration in HCC patients who undergo liver resection without the risk of cancer recurrence or metastasis. Funding Statement: This work was supported by Grant 81402325, 81874151 from the National Natural Science Foundation of China, Grant 20184Y0241 from Shanghai Municipal Commission of Health and Family Planning. Grant 2016KJ077 from Young Talents Training Moving Program of Tongji University School. Declaration of Interests: The authors have no conflicts to disclose. Ethics Approval Statement: Animal studies were approved by the institutional animal care and use committee of the Fudan University, Shanghai, China.

Exosomal neutral sphingomyelinase 1 suppresses hepatocellular carcinoma via decreasing the ratio of sphingomyelin/ceramide.

Neutral sphingomyelinase 1 (NSMase1) mediates caspase-3 activation and apoptosis. However, the role of NSMase1, especially exosome-borne NSMase1 in hepatocellular carcinoma (HCC), remains unclear. We report that NSMase1, which converts sphingomyelin (SM) to ceramide, was significantly downregulated in HCC tissues. Low NSMase1 expression predicted poor long-term survival of HCC patients. NSMase1 downregulation in HCC resulted in increased SM and reduced ceramide (Cer) that led to an increased SM/Cer ratio. Interestingly, NSMase1 and NSMase activity were also decreased in exosomes isolated from HCC tissues and cell lines. Furthermore, NSMase activity increased in exosomes isolated from the culture medium of L02 cells transfected with pEGFP-C3-NSMase1 (NSMase1-Exo). NSMase1-Exo suppressed HCC cell growth and induced apoptosis via reduction of the SM/Cer ratio. Thus, NSMase1 in exosomes inhibits HCC growth by decreasing the SM/Cer ratio.

Abstract 1334: Withaferin A induces cytoprotective autophagy in hepatocellular cancer cells and concomitant autophagic inhibition augments the efficacy of Withaferin A in hepatocellular carcinoma

Abstract Background and Aim: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related deaths. While multiple chemotherapeutic and targeted agents have been developed for other cancers, Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced HCC. Clearly, it is imperative to develop novel effective therapeutic strategies for HCC to improve long-term survival of HCC patients. We found Withaferin A (WFA), a bioactive alkaloid derived from Withania somnifera, as an effective agent for HCC inhibition. Interestingly, we observed that WFA also induces autophagy in HCC cells. Autophagy can be cancer inducing or cancer inhibiting at the functional level. We aim to systemically investigate the anti-HCC efficacy of WFA, investigate the functional impact of autophagy and explore the efficacy of combined regimens of WFA and autophagic inhibitors. Methods: Using in vitro and in vivo models, we established that WFA inhibits liver tumorigenesis. tfLC3B, LC3B-GFP/Lysotracker and LC3B/Rab7 were used to examine the fusion of autophagosomes with lysosomes. Cathepsin-D activation and DQ-BSA assays were conducted to analyze the protein degradation activity in lysosomes. Multiple cell based assays and Chou-Talalay synergy quantification assays were conducted to analyze the synergistic effect of WFA with autophagic inhibitors. IHC staining was used to study autophagic markers in vivo. Results: WFA inhibited anchorage dependent cell growth in vitro and reduced the HCC tumor burden in vivo. In addition to inducing apoptotic cell death, WFA induced cleavage of Light Chain 3B (LC3B) and increased the expression of autophagic proteins (ATG5, ATG7 and Beclin1) both in vitro and in vivo. The redistribution of LC3B-GFP from cytosol to autophagosome demonstrated enhanced autophagosome formation in WFA treated cells. The fusion of autophagosome with lysosome was observed in WFA-treated HCC cells indicating autolysosome formation. WFA treated HCC cells exhibited elevated lysosomal degradation activity. Inhibiting autophagy either by blocking autophagosome formation or elevating lysosomal pH (CQ and BAF) enhanced WFA-induced growth inhibition and apoptosis indicating the presence of cytoprotective autophagy. Combination index analysis of WFA and CQ showed synergism and increased efficacy as compared to either monotherapy. These in vitro findings were corroborated with in vivo experiments. Conclusion: Our results reveal that WFA inhibits hepatocellular carcinoma by apoptotic induction but the efficacy of WFA is somewhat abrogated by the concomitant induction of cytoprotective autophagy. Our preclinical findings present evidence to support WFA and chloroquine as an effective combination treatment regimen for HCC. Citation Format: Sumit Siddharth, Nethaji Muniraj, Neeraj K. Saxena, Dipali Sharma. Withaferin A induces cytoprotective autophagy in hepatocellular cancer cells and concomitant autophagic inhibition augments the efficacy of Withaferin A in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1334.

Crosstalk between circular RNAs and microRNAs in tumorigenesis

Liver cancer is the fifth most common cancer worldwide and the second leading cause of cancer-related mortality, resulting in approximately 750,000 deaths annually (1). Hepatocellular carcinoma (HCC) accounts for 70–90% of all cases of liver cancer (2). Although significant advances have been made toward understanding its causal mechanisms, the 5-year risk of HCC recurrence still exceeds 70% (3). The low survival rate of HCC patients is widely attributed to postsurgical recurrence and metastases of primary tumours (1). Furthermore, the progression and development of HCC involve multiple genes and pathways that are induced by cellular conditions such as oxidative stress and a tumour microenvironment (4). In addition, hypoxia and inflammation act in concert with various molecular events. There is an urgent need for effective strategies to screen for and detect early-stage HCC, thereby improving the long-term survival of HCC patients.

Vitamin K and hepatocellular carcinoma: The basic and clinic.

Vitamin K (VK), which was originally identified as a cofactor involved in the production of functional coagulation factors in the liver, has been shown to be involved in various aspects of physiological and pathological events, including bone metabolism, cardiovascular diseases and tumor biology. The mechanisms and roles of VK are gradually becoming clear. Several novel enzymes involved in the VK cycle were identified and have been shown to be linked to tumorigenesis. The VKs have been shown to suppress liver cancer cell growth through multiple signaling pathways via the transcription factors and protein kinases. A VK2 analog was applied to the chemoprevention of hepatocellular carcinoma (HCC) recurrence after curative therapy and was shown to have beneficial effects, both in the suppression of HCC recurrence and in patient survival. Although a large scale randomized control study failed to demonstrate the suppression of HCC recurrence, a meta-analysis suggested a beneficial effect on the long-term survival of HCC patients. However, the beneficial effects of VK administration alone were not sufficient to prevent or treat HCC in clinical settings. Thus its combination with other anti-cancer reagents and the development of more potent novel VK derivatives are the focus of ongoing research which seeks to achieve satisfactory therapeutic effects against HCC.

Impact of renal insufficiency on patients with hepatocellular carcinoma undergoing radiofrequency ablation.

Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). We aimed to investigate the impact of RI on the long-term survival of HCC patients undergoing radiofrequency ablation (RFA) and to determine the optimal staging strategy for these patients. RI was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) . A total of 123 and 344 patients with and without RI undergoing RFA, respectively, were enrolled. A one-to-one propensity score matching analysis with preset caliper width was performed. The prognostic ability of four currently used staging systems was compared by the Akaike information criterion (AIC). HCC patients with RI undergoing RFA were older (P < 0.001) and had significantly different baseline characteristics. Of all patients, RI was significantly associated with a decreased long-term survival (P = 0.03). After matching in the propensity model, the baseline characteristics were similar between patients with (n = 92) and without (n = 92) RI. In the propensity model, RI was not significantly associated with a shortened survival (P = 0.273). In the Cox multivariate analysis, Child-Turcotte-Pugh class B or C was identified as the only independent predictor of poor prognosis. Among patients with RI undergoing RFA, the Taipei Integrated Scoring (TIS) system provided the highest homogeneity and lowest AIC value among the currently used staging systems. The long-term survival of HCC patients undergoing RFA is not affected by RI. The TIS staging system may provide a better prognostic prediction for HCC patients with RI undergoing RFA.

Criteria-specific long-term survival prediction model for hepatocellular carcinoma patients after liver transplantation.

To establish a model to predict long-term survival of hepatocellular carcinoma (HCC) patients after liver transplantation (MHCAT). Two hundred and twenty-three patients with HCC were followed for at least six years to identify independent risk factors for long-term survival after liver transplantation (LT). The criteria for HCC liver transplantation included the Milan, University of California San Francisco, Hangzhou and Shanghai Fudan criteria. The Cox regression model was used to build MHCAT specifying these criteria. A survival analysis was carried out for patients with high or low risk. The one-, three- and five-year cumulative survival of HCC patients after LT was 78.9%, 53.2% and 46.4%, respectively. Of the HCC patients, the proportion meeting the Hangzhou and Fudan criteria was significantly higher than the proportion meeting the Milan criteria (64.6% vs 39.5%, 52.0% vs 39.5%, P < 0.05). Moreover, the proportion meeting the Hangzhou criteria was also significantly higher than the proportion meeting other criteria (P < 0.01). Pre-operative alfa-fetoprotein level, intraoperative blood loss and retransplantation were common significant predictors of long-term survival in HCC patients with reference to the Milan, University of California San Francisco and Fudan criteria, whereas in MHCAT based on the Hangzhou criteria, total bilirubin, intraoperative blood loss and retransplantation were independent predictors. The c-statistic for MHCAT was 0.773-0.824, with no statistical difference among these four criteria. According to the MHCAT scoring system, patients with low risk showed a higher five-year survival than those with high risk (P < 0.001). MHCAT can effectively predict long-term survival for HCC patients, but needs to be verified by multi-center retrospective or randomized controlled trials.

Increased Long-term Survival Among Patients With Hepatocellular Carcinoma After Implementation of Model for End-stage Liver Disease Score

Assignment of Model for End-stage Liver Disease (MELD) exception points to patients with hepatocellular carcinoma (HCC) who fall within Milan criteria, which began in 2003, increases their priority on liver transplantation waitlists. However, little is known about how this change affected survival of all patients with HCC (transplant eligible and ineligible). We compared long-term survival of HCC patients before and after this change. We performed a large population-based cohort study by using the Surveillance, Epidemiology, and End Results cancer registry to investigate survival times of patients with HCC before those who met the Milan criteria were given MELD exception points (1998-2003) and afterward (2004-2010) by using Kaplan-Meier methods. Multivariate Cox proportional hazards models evaluated independent predictors of survival. During 2004-2010, a significantly higher percentage of patients with HCC survived for 5 years compared with 1998-2003 (21.9% vs 13.0%, P < .001). This difference remained significant among all treatment groups (no therapy: 15.2% vs 10.2%, P < .001; local tumor destruction: 37.6% vs 22.1%, P < .001; resection: 55.5% vs 39.2%, P < .001; transplantation: 77.2% vs 73.1%, P= .12). Multivariate Cox proportional hazards models, inclusive of sex, age, ethnicity, Milan criteria, number and stage of tumor, and time period, showed increased survival of patients during 2004-2010 (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.83-0.91; P< .001). Compared with non-Hispanic whites, Asians (HR, 0.81; 95% CI, 0.77-0.86; P < .001) and Hispanics (HR, 0.89; 95% CI, 0.84-0.95; P < .001) had longer survival times, whereas blacks had a trend toward shorter survival times (HR, 1.05; 95% CI, 0.98-1.13; P= .16). Patients with HCC who met Milan criteria had significantly longer survival times after implementation of the MELD exception points, regardless of sex or ethnicity. Blacks continued to have the lowest rates of 5-year survival.

Hepatocellular carcinoma: Clinical study of long-term survival and choice of treatment modalities

To analyze the prognostic factors of 5-year survival and 10-year survival in hepatocellular carcinoma (HCC) patients, and to explore the reasons for long-term survival and provide choice of treatment modalities for HCC patients. From January 1990 to October 2012, 8450 HCC patients were included in a prospective database compiled by the Information Center after hospital admission. Long-term surviving patients were included in a 10-year survival group (520 patients) and a 5-year survival group (1516 patients) for analysis.The long-term survival of HCC patients was defined as the survival of 5 years or longer. Clinical and biologic variables were assessed using univariate and multivariate analyses. The survival of patients was evaluated by follow-up data. The long-term survival of HCC patients was associated with the number of lesions, liver cirrhosis and Child-Pugh classification. It was not found to be associated with tumor diameter, histological stage, and pretreatment level of serum α-fetoprotein. The differences in clinical factors between the 5-year survival and the 10-year survival were found to be the number of lesions, liver cirrhosis, Child-Pugh classification, and time elapsed until first recurrence or metastasis. The survival period of different treatment modalities in the patients who survived for 5 years and 10 years showed significant differences: (in order of significance) surgery alone > surgery-transcatheter arterial chemoembolization (TACE) > TACE-radiofrequency ablation (RFA) > TACE alone > surgery-TACE-RFA. The 10-year survival of HCC patients was not associated with the choice of treatment modality. This retrospective study elucidated survival outcomes, prognostic factors affecting survival and treatment modalities in HCC patients.

Performance status in patients with hepatocellular carcinoma: Determinants, prognostic impact, and ability to improve the Barcelona Clinic Liver Cancer system

Performance status is included in the Barcelona Clinic Liver Cancer (BCLC) system for hepatocellular carcinoma (HCC). Few studies specifically evaluated the role of performance status in patients with HCC. This study investigated its distribution, determinants, and prognostic impact, aiming to improve the performance of the BCLC system. A total of 2,381 HCC patients were enrolled. Performance status was determined according to the Eastern Cooperative Oncology Group scale. The prognostic ability of the original and three modified BCLC systems in HCC patients was compared by the Akaike information criterion (AIC). There were 60, 17, 11, 8, and 4% of patients who were classified as performance status 0, 1, 2, 3, and 4, respectively. A worse performance status significantly correlated with age, alcoholism, hypoalbuminemia, hyperbilirubinemia, renal insufficiency, hyponatremia, and prothrombin time prolongation (all P < 0.001). Larger tumor burden, poorer residual liver function, more frequent vascular invasion, and diabetes mellitus were also observed in patients with worse performance status (all P < 0.001). Patients with poorer performance status more often received best supportive care (P < 0.001). In the Cox proportional hazards model, performance status was an independent prognostic predictor and the long-term survival tended to be worse in patients with progressively poor performance status (all P < 0.05). Reassigning patients with performance status 0 or 1 to stage B provided the lowest AIC among the four BCLC-based staging systems. Performance status is strongly associated with both tumoral and cirrhotic factors and accurately predicts long-term survival in HCC patients. Modification of the BCLC system based on performance status may further enhance its prognostic ability in patients with early to advanced cancer stage.

Which Response Criteria Best Help Predict Survival of Patients with Hepatocellular Carcinoma Following Chemoembolization? A Validation Study of Old and New Models

To identify differences in radiologic assessment methods and determine optimal imaging criteria for response evaluation in hepatocellular carcinoma (HCC) patients treated with chemoembolization. Institutional review board approval was obtained, and patient informed consent was waived. The present study included 332 patients with intermediate stage HCC and Child-Pugh A cirrhosis who underwent serial chemoembolization. All measurable target lesions of 1 cm or larger in diameter were uni- and bidimensionally measured both at baseline and during follow-up. Intermodel agreement among the guidelines of the World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), the European Association for the Study of the Liver (EASL), and modified RECIST (mRECIST) were examined. The most reliable model was selected on the basis of the correlation with survival prediction. The κ values of comparisons among WHO, RECIST, and mRECIST guidelines were less than 0.20, whereas the κ value for the comparison of EASL and mRECIST guidelines was 0.94. In patients with a partial response (PR), stable disease (SD), or progressive disease (PD), compared with patients with a complete response (CR), hazard ratios (HRs) for survival were 2.99 (95% confidence interval [CI]: 2.14, 4.17), 3.49 (95% CI: 1.71, 7.10), and 15.63 (95% CI: 9.51, 25.69), respectively, for EASL criteria. In patients with a PR, SD, or PD, compared with patients with a CR, the HRs were 2.75 (95% CI: 1.96, 3.87), 6.32 (95% CI: 3.67, 10.90), and 16.06 (95% CI: 9.76, 26.43), respectively, for mRECIST guidelines (P<.001). The C index for the multivariate model was 0.76 (95% CI: 0.72, 0.79) for both EASL and mRECIST guidelines, thus exhibiting satisfactory capability to help predict survival. The Cox regression model revealed that both mRECIST and EASL guidelines were independent predictors of overall survival (P<.001 for both). The enhancement models more accurately helped predict long-term survival in HCC patients treated with chemoembolization.

Comparison of radiofrequency ablation and transarterial chemoembolization for hepatocellular carcinoma within the Milan criteria: A propensity score analysis

Radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) are used to treat hepatocellular carcinoma (HCC). This study was designed to compare the long-term survival of HCC patients within the Milan criteria who underwent RFA or TACE. In all, 315 RFA patients and 215 TACE patients with HCC within the Milan criteria were analyzed. Propensity scores were generated to select matched patients. For the propensity model, 101 patients were selected from each arm of the study. Independent prognostic predictors were determined with the Cox proportional hazards model. The long-term survival was significantly better for the RFA group in the univariate survival analysis (P = 0.048). In the Cox model, the following were identified as independent predictors of poor prognosis (TACE was not): age > 69 years (P = 0.026), serum α-fetoprotein level > 20 ng/mL (P = 0.003), ascites (P < 0.001), Eastern Cooperative Oncology Group performance status ≥ 1 (P = 0.004), total tumor volume (TTV) > 8.2 cm³ (P = 0.020), and vascular invasion (P = 0.023). With similar baseline patient characteristics generated in the propensity score model, there was no significant difference in the long-term survival rates of the 2 groups of patients. A subgroup analysis showed that among patients with a TTV < 11 cm³, the RFA group had significantly better long-term survival than the TACE group (P = 0.032). In conclusion, TACE and RFA lead to comparable long-term survival rates for HCC patients within the Milan criteria. Patients with a smaller TTV (<11 cm³) are likely to benefit more from RFA treatment. Further studies are needed to compare RFA and TACE in patients with early-stage cancers.

An Overview of Biomarkers and Molecular Signatures in HCC

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Although most HCCs seem to originate from the accumulation of genetic abnormalities induced by various risk factors, underlying mechanisms of hepatocarcinogenesis remain unclear. Long-term survival of HCC patients is also poor, partly due to HCC recurrence. Although serum alpha-fetoprotein (AFP) level is a useful marker for the detection and monitoring of HCC, AFP levels may remain normal in the patients even with advanced HCC. To identify useful biomarkers for HCC, many studies have been conducted on molecular events such as genetic and epigenetic alterations, and gene expression. This review summarizes recent studies of potential molecular markers for diagnosis and monitoring metastasis or recurrence of HCC.

Predictors and prognostic significance of operative complications in patients with hepatocellular carcinoma who underwent hepatic resection

Aims The morbidity rate of hepatic resection for hepatocellular carcinoma (HCC) remains high. To clarify predictors and the prognostic significance of operative complications in patients with HCC, we conducted a comparative retrospective analysis of 291 patients with HCC who underwent hepatic resection. Methods Operative complications included hyperbilirubinemia, ascites, hemorrhage, respiratory and cardiovascular diseases, bile leakage and abscess formation, renal failure, wound infection, and pleural effusion. Predictors of operative complications and their prognostic value for long-term survival were studied by univariate and multivariate analyses. Results Mortality and morbidity rates were 7.2% and 42.6%. The main operative complications were ascites ( n = 30), intraabdominal abscess ( n = 25), hyperbilirubinemia ( n = 19), wound infection ( n = 16), pleural effusion ( n = 10) and intraabdominal hemorrhage ( n = 9). By a multivariate logistic regression model, Child–Pugh class B and increased operative blood loss (≥1200 ml) were independent predictors of postoperative complications. Among 243 patients without operative death, the 5-year overall survival rate was significantly lower in patients with operative complications (34.3%) than in those without these complications (48.7%). By the multivariate Cox proportional hazards model, the presence of operative complications was an independent predictor of poor overall survival as well as presence of portal invasion. Conclusions Child–Pugh class B and operative blood loss ≥1200 ml were independent predictors of complications after hepatic resection for HCC. Long-term survival is poorer in patients with postoperative complications. Decreasing operative blood loss may result in fewer postoperative complications and better long-term survival of HCC patients.

Changing Paradigm in the Management of Hepatocellular Carcinoma Improves the Survival Benefit of Early Detection by Screening

To evaluate the impact of improved surgical management of hepatocellular carcinoma (HCC) on the survival of patients with screened HCC. It is unclear whether the advent of new treatment modalities such as liver transplantation and radiofrequency ablation (RFA) in recent years have improved the long-term survival in patients with HCC detected by screening. A prospective database of 1366 patients with known chronic hepatitis B or C virus infection diagnosed with HCC either by screening or symptomatic presentation from January 1991 to December 2004 was reviewed. The long-term survival of HCC patients in the screened and symptomatic groups was compared. The management and survival of patients in two 7-year periods (1991-1997 vs. 1998-2004) were further compared. Long-term survival was significantly better in the screened group than in the symptomatic group (median survival 61.9 vs. 11.5 months, P < 0.001). The proportion of patients with curative treatment increased from 50.5% in the first period to 67.8% in the second period in the screened group, but there was no significant change in the symptomatic group. Improved long-term survival was observed in patients with HCC detected by screening and treated in the second period compared with the first period (median survival 68.5 vs. 38.7 months, P = 0.022), but no significant improvement was observed for symptomatic patients. Survival of patients with HCC detected by screening has improved in recent years due to increased chance of curative treatment with the advent of liver transplantation and RFA.