不同方案治疗直径小于10cm肝细胞癌合并门静脉癌栓患者影响生存率的观察

目的：探讨两种不同方案治疗直径小于10cm肝细胞癌合并门静脉癌栓患者影响生存率。方法：将我院100例直径小于10cm肝细胞癌合并门静脉癌栓患者按照抽签法随机地均分为A、B两组,A组行单纯肝动脉插管化疗栓撒（TACE）治疗,B组肝癌手术切除联合癌栓切除＋TACE术,比较两组患者治疗前后DLIA蛋白与VEGF蛋白阳性表达率、五年生存率以及影响患者生存率的因素。结果：（1）A组治疗前后DLL4蛋白与VEGF蛋白阳性表达率差异无统计学意义（P〉0．05）,B组治疗前后上述蛋白阳性表达率差异具有统计学意义（P〈0．05,P〈0．01）;（2）根据Kaplan—Meir计算方法,B组五年生存率均明显大于A组（P〈0．001）;（3）经Pearson单因素与COX多因素分析,影响患者预后的危险独立因素为肿瘤大小与手术方式。结论：综合治疗方案用于治疗直径小于10cm肝细胞癌合并门静脉癌栓患者之中,疗效显著,患者五年生存率明显提高。     

Comparison of Long-Term Survival of Patients with BCLC Stage B Hepatocellular Carcinoma after Liver Resection or Transarterial Chemoembolization

Background and Aims

Treatment of patients with Barcelona Clinic Liver Cancer Stage B hepatocellular carcinoma (BCLC-B HCC) is controversial. This study compared the long-term survival of patients with BCLC-B HCC who received liver resection (LR) or transarterial chemoembolization (TACE).

Methods

A total of 257 and 135 BCLC-B HCC patients undergoing LR and TACE, respectively, were retrospectively evaluated. Kaplan–Meier method was used for long-term survival analysis. Independent prognostic predictors were determined by the Cox proportional hazards model.

Results

The hospital mortality rate was similar between groups (3.1% vs. 3.7%; P = 0.76). However, the LR group showed a significantly higher postoperative complication rate than the TACE group (28 vs. 18.5%; P = 0.04). At the same time, the LR group showed significantly higher overall survival rates (1 year, 84 vs. 69%; 3 years, 59 vs. 29%; 5 years, 37 vs. 14%; P<0.001). Moreover, similar results were observed in the propensity score model. Three independent prognostic factors were associated with worse overall survival: serum AFP level (≥400 ng/ml), serum ALT level, and TACE.

Conclusions

LR appears to be as safe as TACE for patients with BCLC-B HCC, and it provides better long-term overall survival. However, prospective studies are needed to disclose if LR may be regarded as the preferred treatment for these patients as long as liver function is preserved.     

不同方式治疗原发性肝癌合并门静脉癌栓的治疗效果比较

目的:对不同方式治疗原发性肝癌(HCC)合并门静脉癌栓(PVTT)的治疗效果进行比较。方法:收取我院2010年2月至2013年3月收治的HCC合并PVTT患者83例进行回顾性分析,按照治疗方法的不同分为A组(手术+经导管动脉化疗栓塞TACE)26例、B组(手术+门静脉化疗PVC)25例以及C组(手术+TACE+PVC)32例。对三组患者不良反应发生情况、生存率、生存质量进行考察与比较,并对可能影响生存率的因素进行分析。结果:三组患者均行手术切除,切除率为100%。三组患者化疗后不良反应发生率方面比较差异无统计学意义(P0.05)。C组患者生存质量提高总有效率及改善率分别为78.13%和50.00%,均显著高于其他两组,差异有统计学意义(P0.05)。C组患者中位生存时间及半年、1年、2年、3年生存率均显著高于A组和B组,差异具有统计学意义(P0.05)。影响HCC合并PVTT患者的主要因素包括肿瘤大小、肿瘤数目、病理分级及癌栓类型(P0.05)。结论:HCC合并PVTT患者术后使用TACE+PVC联合治疗可有效提高患者生存率,改善生活质量。     

Positive Lymph Node Metastasis Has a Marked Impact on the Long-Term Survival of Patients with Hepatocellular Carcinoma with Extrahepatic Metastasis

Background

The prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastasis is extremely poor. However, what is the main risk factor for survival remains unclear for these patients. We aimed to find out the relative frequency, incidence and locations of extrahepatic metastases and the risk factors of long-term survival of the patients.

Methods

132 HCC patients with extrahepatic metastasis diagnosed by ¹⁸F-FDG PET/CT and conventional workup were enrolled into this study. The incidence and locations of extrahepatic metastases were summarized, and the related risk factors of overall survival were analyzed.

Results

The most frequent extrahepatic metastatic sites were lymph nodes in 72 (54.5%), bone in 33 (25.0%) and lung in 28 (21.2%) patients. On univariate analysis, prothrombin time, Child-Pugh grade, portal/hepatic vein invasion and lymph node metastasis were independent risk factors of overall survival. On multivariate analysis, lymph node metastasis was the only independent risk factor of overall survival. The cumulative survival rates at 1- and 3-years after diagnosis of extrahepatic metastasis of HCC were 34.4% and 9.3%, respectively. The median survival time was 7 months (range 1 ∼38 months). The median survival time for patients with or without lymph node metastasis were 5 months (range 1∼38 months) and 12 months (range 1∼30 months), respectively (P = 0.036).

Conclusions

This study showed lymph nodes to be the most frequent site of extrahepatic metastases for primary HCC. Lymph node metastasis was the main risk factor of overall survival in patients with HCC with extrahepatic metastasis.     

The Diagnostic Value of Tumor Biomarkers for Detecting Hepatocellular Carcinoma Accompanied by Portal Vein Tumor Thrombosis

Tumor biomarkers commonly used for the detection of hepatocellular carcinoma (HCC) complicated with portal vein tumor thrombosis (PVTT) do not show satisfactory sensitivity and specificity. This study assesses the diagnostic value of the tumor biomarkers for the diagnosis of HCC with PVTT. A retrospective study was conducted on 475 patients diagnosed as HCC with PVTT and 977 patients diagnosed with HCC by imaging and requiring surgery at our hospital from January 1993 to January 2011. Serum alpha-fetoprotein AFP, carcinoembryonic antigen, and cancer antigen 125 (Ca125) of the patients were studied. No significant differences were observed in the patients’ general characteristics. The receiver operating characteristic (ROC) analysis showed that the cut-off of AFP and Ca125 was 32.91 ng/ml and 113.65 U/ml, respectively (AUC = 0.814 and 0.783). The parallel testing with AFP and Ca125 has a sensitivity of 0.909 and a specificity of 0.410; the serial testing has a sensitivity of 0.520 and a specificity of 0.97. The condition of AFP ≥ 20,000 ng/ml can detect HCC with PVTT with a sensitivity of 0.24, a specificity of 0.96, and an accuracy of 0.73 and positive screening of 0.76. The standard of both AFP > 32.91 ng/ml and Ca125 > 113.65 U/ml or AFP ≥ 20,000 ng/ml can detect HCC with PVTT with a specificity of 0.97 and 0.96, respectively, providing important guidance for clinical practice.     

不同临床分期肝癌患者抗AFPTh1和Tc1应答反应研究

目的:研究CD4(Th1)和CD8(Tc1)T细胞对肝癌患者的AFP的应答反应及其与临床特征的相关性,为其早期诊断与预防提供新策略。方法:研究对象为62例HCC患者,30例肝硬化患者及30例健康志愿者;重点分析CD4 T细胞和CD8 T细胞对HCC患者的AFP-衍生肽的反应;用胞内细胞因子检测法对IFN-γ进行检测。结果:抗AFP的Tc1反应检测阳性结果在对照组为28.5%,在OkudaⅠ期的肝癌患者中为25.0%,在Ⅱ或Ⅲ期的HCC患者中为31.6%。抗AFP Th1阳性反应仅在HCC患者中检测到。抗AFP Th1阳性反应在44.4%的Child-Pugh A级的HCC患者中检测到,但是在Child-Pugh B或C级中仅15.4%。Tc1型反应在Child-Pugh A级肝功的患者中为16.7%,在Child-Pugh B或C级患者中为46.2%。结论:抗AFP Th1应答更多出现在早期肝硬化的HCC的患者中,而抗AFP Tc1应答更可能出现在晚期肝硬化患者中,这些结论为抗肝癌疫苗药物设计提供了理论基础。     

The Survival Benefit of Liver Transplantation for Hepatocellular Carcinoma Patients with Hepatitis B Virus Infection and Cirrhosis

Background

A precise predictive survival model of liver transplantation (LT) with antiviral prophylaxis for hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and cirrhosis has not been established. The aim of our study was to identify predictors of outcome after LT in these patients based on tumor staging systems, antitumor therapy pre-LT, and antiviral prophylaxis in patients considered to be unfit by Milan or UCSF criteria.

Methods

From 2002 to 2008, 917 LTs with antiviral prophylaxis were performed on patients with HBV-cirrhosis, and 313 had concurrent HCC.

Results

Stratified univariate and multivariate analyses demonstrated that independent predictors for poor survival were tumor size >7.5 cm (P = 0.001), tumor number >1 (P = 0.005), vascular invasion (P = 0.001), pre-LT serum alpha-fetoprotein (AFP) level ≥1000 ng/ml (P = 0.009), and pre-LT aspartate aminotransferase (AST) level ≥120 IU/L (P = 0.044). Pre-LT therapy for HCC was an independent predictor of better survival (P = 0.028). Based on CLIP and TNM tumor staging systems, HCC patients with HBV-cirrhosis who met the following criteria: solitary tumor ≤7.5 cm, or ≤4 multifocal nodules, the largest lesion ≤5 cm and total tumor diameter ≤10 cm, or more nodules with the largest lesion ≤3 cm, and pre-LT serum AFP level <1000 µg/L and AST level <120 IU/L without vascular invasion and lymph node metastasis who were unfit for UCSF, had survival rates of 89% at 5 years. There was a 47% 5-year survival rate for patients with HCC exceeding the revised criteria.

Conclusions

The current criteria for LT based on tumor size, number and levels of AFP and AST may be modestly expanded while still preserving excellent survival after LT. The expanded criteria combined with antiviral prophylaxis and pre-LT adjuvant therapy for HCC may be a rational strategy to prolong survival after LT for HCC patients with HBV-associated cirrhosis.     

Establishment and Validation of SSCLIP Scoring System to Estimate Survival in Hepatocellular Carcinoma Patients Who Received Curative Liver Resection

Background and Aims

There is no prognostic model that is reliable and practical for patients who have received curative liver resection (CLR) for hepatocellular carcinoma (HCC). This study aimed to establish and validate a Surgery-Specific Cancer of the Liver Italian Program (SSCLIP) scoring system for those patients.

Methods

668 eligible patients who underwent CLR for HCC from five separate tertiary hospitals were selected. The SSCLIP was constructed from a training cohort by adding independent predictors that were identified by Cox proportional hazards regression analyses to the original Cancer of the Liver Italian Program (CLIP). The prognostic performance of the SSCLIP at 12 and 36-months was compared with data from existing models. The patient survival distributions at different risk levels of the SSCLIP were also assessed.

Results

Four independent predictors were added to construct the SSCLIP, including age (HR = 1.075, 95%CI: 1.019–1.135, P = 0.009), albumin (HR = 0.804, 95%CI: 0.681–0.950, P = 0.011), prothrombin time activity (HR = 0.856, 95%CI: 0.751–0.975, P = 0.020) and microvascular invasion (HR = 19.852, 95%CI: 2.203–178.917, P = 0.008). In both training and validation cohorts, 12-month and 36-month prognostic performance of the SSCLIP were significantly better than those of the original CLIP, model of end-stage liver disease-based CLIP, Okuda and Child-Turcotte-Pugh score (all P < 0.05). The stratification of risk levels of the SSCLIP showed an enhanced ability to differentiate patients with different outcomes.

Conclusions

A novel SSCLIP to predict survival of HCC patients who received CLR based on objective parameters may provide a refined, useful prognosis algorithm.     

Comparison of Long-Term Survival of Patients with Solitary Large Hepatocellular Carcinoma of BCLC Stage A after Liver Resection or Transarterial Chemoembolization: A Propensity Score Analysis

Background

The aim of this study was to compare the long-term outcome of patients with a solitary large (>5 cm) hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage A who received liver resection (LR) or transarterial chemoembolization (TACE).

Methods

Our study examined 128 patients treated by LR and 90 treated by TACE. To reduce bias in patient selection, we conducted propensity score analysis in the present study and 54 pairs of patients after propensity score matching were generated, their long-term survival was compared using the Kaplan–Meier method. Independent predictors of survival were identified by multivariate analysis.

Results

Long-term survival was significantly better for the LR group by log-rank test (P<0.001). In multivariate analysis, tumor size, serum ALT level and TACE independently predicted survival. Despite similar baseline characteristics after propensity score matching, LR group still had significantly better survival (1 year, 68.5 vs. 55.0%; 3 years, 47.6 vs. 21.2%; 5 years, 41.3 vs. 18.5%; P = 0.007) than TACE group. The LR and TACE groups had comparable 30- and 90-day post-treatment mortality. Multivariate analysis showed that serum ALT level, serum AFP level and TACE independently predicted survival by multivariate analysis after propensity score matching.

Conclusion

Our propensity-score-matched study suggested that LR provided significantly better long-term survival than TACE for a solitary large HCC of the BCLC stage A, regardless of tumor size.     

TACE 联合其他介入手段治疗肝癌伴门静脉癌栓

肝癌是世界范围内恶性程度最高的恶性肿瘤之一。门静脉癌栓的出现加速了肝功衰竭以及门静脉高压的发生概率,严重影响了肝癌患者的预后,临床上对于肝癌合并门静脉癌栓的诊疗尤为棘手。传统的治疗手段对于肝癌合并门静脉癌栓的疗效欠佳,且创伤大、住院时间长、并发症多。介入治疗因其创伤小、住院时间短、并发症少,疗效确切等优势逐渐被人们认可。以往单独应用经导管肝动脉化疗栓塞术(Transcatheter Arterial Chemoembolization,TACE)治疗肝癌取得了可喜的成果,随着介入治疗的发展,TACE联合其他介入手段治疗肝癌伴门静脉癌栓引起了越来越多的学者重视。本文回顾了近几年来国内外的相关文献,对TACE联合其他介入手段治疗肝癌合并门静脉癌栓的方式及疗效做一综述,以期对肝癌的临床诊疗工作提供一些帮助。     

肝细胞肝癌E-Cadherin 蛋白的表达及其对判断肝癌肝移植 疗效的意义

目的:探讨E-Cadherin蛋白在肝细胞肝癌组织中的表达及其对判断肝癌肝移植患者预后的价值。方法:选择肝细胞肝癌行全肝移植患者68例,应用免疫组化方法检测其切除的肝癌组织和癌旁正常肝组织中E-Cadherin蛋白的表达情况,并对患者进行移植术后随访,分析E-Cadherin蛋白表达与肝癌肝移植患者预后的关系。结果:肝癌组织中E-Cadherin蛋白阳性表达率明显低于癌旁组织(P<0.01)。经Logrank检验分析显示,E-Cadherin蛋白低表达组移植后的无瘤生存率明显低于E-Cadherin蛋白高表达组(P<0.01)。多因素Cox回归分析显示,E-Cadherin蛋白表达是影响肝细胞肝癌患者肝移植术后肝癌复发的独立预后因素之一。结论:E-Cadherin蛋白表达是一个预测肝细胞肝癌患者肝移植预后的重要因子。     

肝细胞肝癌E-Cadherin蛋白的表达及其对判断肝癌肝移植疗效的意义

目的：探讨E-Cadherin蛋白在肝细胞肝癌组织中的表达及其对判断肝癌肝移植患者预后的价值。方法：选择肝细胞肝癌行全肝移植患者68例,应用免疫组化方法检测其切除的肝癌组织和癌旁正常肝组织中E-Cadherin蛋白的表达情况,并对患者进行移植术后随访,分析E-Cadherin蛋白表达与肝癌肝移植患者预后的关系。结果：肝癌组织中E-Cadherin蛋白阳性表达率明显低于癌旁组织（P〈0.01）。经Logrank检验分析显示,E-Cadherin蛋白低表达组移植后的无瘤生存率明显低于E-Cadherin蛋白高表达组（P〈0.01）。多因素Cox回归分析显示,E-Cadherin蛋白表达是影响肝细胞肝癌患者肝移植术后肝癌复发的独立预后因素之一。结论：E-Cadherin蛋白表达是一个预测肝细胞肝癌患者肝移植预后的重要因子。     

Comparison of Steroid-Free Immunosuppression and Standard Immunosuppression for Liver Transplant Patients with Hepatocellular Carcinoma

Immunosuppression therapy following liver transplantation often includes steroids. However, extended corticosteroid therapy is associated with numerous complications. This study evaluated the efficacy and safety of using basiliximab in place of a corticosteroid for immunosuppression following liver transplantation for hepatocellular carcinoma (HCC) in Chinese patients. The records of 178 patients with HCC who underwent orthotopic liver transplantation from January 2003 to December 2009 were retrospectively reviewed. All patients received immunosuppression therapy that contained either basiliximab (n = 78) or steroids (n = 100) in addition to tacrolimus and mycophenolate mofetil. Assessments included complications related to liver transplantation, occurrence of steroid side effects, recurrence of HCC, and patient and graft survival. A smaller proportion of patients receiving basiliximab compared with steroids experienced de novo diabetes (38.7% vs. 91.0%, respectively) or long-term de novo diabetes mellitus (7.7% vs. 38.0%, respectively) (both, P<0.0001). The median overall and disease free survival was similar between basiliximab (50.8 months and 19.6 months, respectively) and steroid treated patients (64.2 months and 23.8 months, respectively). The 5-year overall survival and disease free survival rates was also similar between the basiliximab (42.5% and 38.9%, respectively) and steroid (50.5% and 39.2%) groups (all, P>0.730). However, in patients who met the Milan criteria basiliximab was associated with greater 5-year overall survival rate as compared with steroid therapy (88.9% vs. 57.4%, respectively, P = 0.022). These findings provide further evidence of the negative impact of steroids as a part of immunosuppression therapy following liver transplantation for HCC.     

Linkage Specific Fucosylation of Alpha-1-Antitrypsin in Liver Cirrhosis and Cancer Patients: Implications for a Biomarker of Hepatocellular Carcinoma

Background

We previously reported increased levels of protein-linked fucosylation with the development of liver cancer and identified many of the proteins containing the altered glycan structures. One such protein is alpha-1-antitrypsin (A1AT). To advance these studies, we performed N-linked glycan analysis on the five major isoforms of A1AT and completed a comprehensive study of the glycosylation of A1AT found in healthy controls, patients with hepatitis C- (HCV) induced liver cirrhosis, and in patients infected with HCV with a diagnosis of hepatocellular carcinoma (HCC).

Methodology/Principal Findings

Patients with liver cirrhosis and liver cancer had increased levels of triantennary glycan-containing outer arm (α-1,3) fucosylation. Increases in core (α-1,6) fucosylation were observed only on A1AT from patients with cancer. We performed a lectin fluorophore-linked immunosorbent assay using Aleuria Aurantia lectin (AAL), specific for core and outer arm fucosylation in over 400 patients with liver disease. AAL-reactive A1AT was able to detect HCC with a sensitivity of 70% and a specificity of 86%, which was greater than that observed with the current marker of HCC, alpha-fetoprotein. Glycosylation analysis of the false positives was performed; results indicated that these patients had increases in outer arm fucosylation but not in core fucosylation, suggesting that core fucosylation is cancer specific.

Conclusions/Significance

This report details the stepwise change in the glycosylation of A1AT with the progression from liver cirrhosis to cancer and identifies core fucosylation on A1AT as an HCC specific modification.     

Silencing of DLGAP5 by siRNA Significantly Inhibits the Proliferation and Invasion of Hepatocellular Carcinoma Cells

Background

The dysregulation of oncogenes and tumor suppressor genes plays an important role in many cancers, including hepatocellular carcinoma (HCC), which is one of the most common cancers in the world. In a previous microarray experiment, we found that DLGAP5 is overexpressed in HCCs. However, whether the up-regulation of DLGAP5 contributes to hepatocarcinogenesis remains unclear.

Methodology/Principal Findings

In this study, we showed that DLGAP5 was significantly up-regulated in 76.4% (168 of 220) of the analyzed HCC specimens when compared with adjacent liver tissue. DLGAP5 overexpression was evident in 25% (22 of 88) of the HCC specimens without AFP expression, suggesting that DLGAP5 may be a novel biomarker for HCC pathogenesis. The silencing of DLGAP5 gene expression by RNA interference significantly suppressed cell growth, migration and colony formation in vitro. The expression level of DLGAP5 was also found to be related to the methylation level of its promoter in the HCC specimens.

Conclusions/Significance

Taken together, these data suggest that the expression of DLGAP5 is regulated by methylation and that the up-regulation of DLGAP5 contributes to HCC tumorigenesis by promoting cell proliferation.     

Genetic Variants in the EPCAM Gene Is Associated with the Prognosis of Transarterial Chemoembolization Treated Hepatocellular Carcinoma with Portal Vein Tumor Thrombus

The epithelial cell adhesion molecule (EPCAM) is involved in the tumorigenesis and progression of many malignancies, including hepatocellular carcinoma (HCC). Single nucleotide polymorphisms (SNPs) of EPCAM have been reported to be with the risk and prognosis of several malignancies. However, the association of SNPs in EPCAM gene with the prognosis of HCC patients has never been investigated. In this study, two functional SNPs (rs1126497 and rs1421) in the EPCAM gene were selected and genotyped in a cohort of 448 unresectable Chinese HCC patients treated by TACE. The association of the two SNPs with the overall survival (OS) of patients was assessed by univariate and multivariate Cox proportional hazards model and Kaplan-Meier curve. Our data showed that there was no significant association between either SNP and OS of patients. However, in the stratified analysis, the variant-containing genotypes (WV+VV) of SNP rs1126497 exhibited a significant association with poorer OS in HCC patients who had portal vein tumor thrombus (PVTT) in multivariate analysis of Cox proportional hazard model (hazard ratio, 1.71; 95% confidence interval, 1.16–2.53, P = 0.007), and in Kaplan-Meier curve analysis (P = 0.023), comparing to those carrying wild-type genotype. Our results suggest that SNP rs1126497 in the EPCAM gene may serve as an independent prognosis biomarker for unresectable HCC patient with PVTT, which warranted further validating investigation.     

RASSF1A and DOK1 Promoter Methylation Levels in Hepatocellular Carcinoma,Cirrhotic and Non-Cirrhotic Liver,and Correlation with Liver Cancer in Brazilian Patients

Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide. Most cases of HCC are associated with cirrhosis related to chronic hepatitis B virus or hepatitis C virus infections. Hypermethylation of promoter regions is the main epigenetic mechanism of gene silencing and has been involved in HCC development. The aim of this study was to determine whether aberrant methylation of RASSF1A and DOK1 gene promoters is associated with the progression of liver disease in Brazilian patients. Methylation levels were measured by pyrosequencing in 41 (20 HCC, 9 cirrhotic, and 12 non-cirrhotic) liver tissue samples. Mean rates of methylation in RASSF1A and DOK1 were 16.2% and 12.0% in non-cirrhotic, 26.1% and 19.6% in cirrhotic, and 59.1% and 56.0% in HCC tissues, respectively, showing a gradual increase according to the progression of the disease, with significantly higher levels in tumor tissues. In addition, hypermethylation of RASSF1A and DOK1 was found in the vast majority (88%) of the HCC cases. Interestingly, DOK1 methylation levels in HCC samples were significantly higher in the group of younger (<40 years) patients, and higher in moderately differentiated than in poorly differentiated tumors (p < 0.05). Our results reinforce the hypothesis that hypermethylation of RASSF1A and DOK1 contributes to hepatocarcinogenesis and is associated to clinicopathological characteristics. RASSF1A and DOK1 promoter hypermethylation may be a valuable biomarker for early diagnosis of HCC and a potential molecular target for epigenetic-based therapy.     

Quality Assessment of Clinical Practice Guidelines on the Treatment of Hepatocellular Carcinoma or Metastatic Liver Cancer

Objectives

To assess the quality of the currently available clinical practice guidelines (CPGs) for hepatocellular carcinoma, and provide a reference for clinicians in selecting the best available clinical protocols.

Methods

The databases of PubMed, MEDLINE, Web of Science, Chinese Biomedical Literature database (CBM), China National Knowledge Infrastructure (CNKI), WanFang, and relevant CPGs websites were systematically searched through March 2014. CPGs quality was appraised using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument, and data analysis was performed using SPSS 13.0 software.

Results

A total of 20 evidence-based and 20 expert consensus-based guidelines were included. The mean percentage of the domain scores were: scope and purpose 83% (95% confidence interval (CI), 81% to 86%), clarity of presentation 79% (95% CI, 73% to 86%), stakeholder involvement 39% (95% CI, 30% to 49%), editorial independence 58% (95% CI, 52% to 64%), rigor of development 39% (95% CI, 31% to 46%), and applicability 16% (95% CI, 10% to 23%). Evidence-based guidelines were superior to those established by consensus for the domains of rigor of development (p<0.001), clarity of presentation (p = 0.01) and applicability (p = 0.021).

Conclusions

The overall methodological quality of CPGs for hepatocellular carcinoma and metastatic liver cancer is moderate, with poor applicability and potential conflict of interest issues. The evidence-based guidelines has become mainstream for high quality CPGs development; however, there is still need to further increase the transparency and quality of evidence rating, as well as the recommendation process, and to address potential conflict of interest.     

Distinct Distribution Pattern of Hepatitis B Virus Genotype C and D in Liver Tissue and Serum of Dual Genotype Infected Liver Cirrhosis and Hepatocellular Carcinoma Patients

Aims

The impact of co-infection of several hepatitis B virus (HBV) genotypes on the clinical outcome remains controversial. This study has for the first time investigated the distribution of HBV genotypes in the serum and in the intrahepatic tissue of liver cirrhotic (LC) and hepatocellular carcinoma (HCC) patients from India. In addition, the genotype-genotype interplay and plausible mechanism of development of HCC has also been explored.

Methods

The assessment of HBV genotypes was performed by nested PCR using either surface or HBx specific primers from both the circulating virus in the serum and replicative virus that includes covalently closed circular DNA (cccDNA) and relaxed circular DNA (rcDNA) of HBV from the intrahepatic tissue. The integrated virus within the host chromosome was genotyped by Alu-PCR method. Each PCR products were cloned and sequences of five randomly selected clones were subsequently analysed.

Results

HBV/genotype D was detected in the serum of all LC and HCC patients whereas the sequences of the replicative HBV DNA (cccDNA and rcDNA) from the intrahepatic tissue of the same patients revealed the presence of both HBV/genotype C and D. The sequences of the integrated viruses exhibited the solo presence of HBV/genotype C in the majority of LC and HCC tissues while both HBV/genotype C and D clones were found in few patients in which HBV/genotype C was predominated. Moreover, compared to HBV/genotype D, genotype C had higher propensity to generate double strand breaks, ER stress and reactive oxygen species and it had also showed higher cellular homologous-recombination efficiency that engendered more chromosomal rearrangements, which ultimately led to development of HCC.

Conclusions

Our study highlights the necessity of routine analysis of HBV genotype from the liver tissue of each chronic HBV infected patient in clinical practice to understand the disease prognosis and also to select therapeutic strategy.     

丙型肝炎病毒诱发肝细胞癌的分子机制

丙型肝炎是由丙型肝炎病毒(hepatitis C virus,HCV)引起的一种肝脏疾病。肝细胞癌(hepatocellular carcinoma,HCC)是人类最常见的恶性肿瘤之一。大量实验和临床研究表明,HCV的感染是导致肝细胞癌的主要因素之一。尽管目前可以通过直接抗病毒药物治疗HCV感染,但是患肝细胞癌的风险仍然存在。HCV诱发肝细胞癌是一个多步骤过程,其可能是通过病毒因子直接作用和/或通过引起慢性炎症诱发肝癌。因此,需要更好地了解HCV诱发肝细胞癌的分子机制,为肝细胞癌的防治提供研究基础。本文就近年来国内外对丙型肝炎病毒直接作用诱发肝细胞癌的分子机制进行综述,具体从血管生成、细胞凋亡、细胞增殖、上皮 间质转化、脂肪变性和氧化应激6个方面进行阐述,以期更好地了解HCV诱发肝细胞癌的分子机制,为肝细胞癌的防治提供研究基础。