Evaluation of interleukin-6, interleukin-10 and human hepatocyte growth factor as tumor markers for hepatocellular carcinoma.

AIM: Serum alpha-fetoprotein (AFP) is the most important tumor marker for hepatocellular carcinoma (HCC). Previous reports indicated that HCC was also associated with increased levels of interleukin (IL)-6, IL-10 and hepatocyte growth factor (HGF). This study investigated the role of these cytokines as tumor markers for HCC. METHOD: A total of 128 adults were prospectively enrolled and categorized into four groups: normal subjects (n=29), chronic hepatitis B or C (n=50), non-HCC tumors (n=23) and HCC (n=26). Serum AFP, IL-6, IL-10 and HGF levels were determined in all subjects. RESULTS: The expression of IL-6 or IL-10 (> or =3 pg/ml), or high level of HGF (>1000 pg/ml) or AFP (>20 ng/ml) was observed in only 0-3% of normal subjects. Patients with HCC more frequently had higher IL-6 and IL-10 levels (p<0.05), whereas HGF levels in HCC patients were not significantly elevated compared to patients with chronic hepatitis or non-HCC tumors. Among patients with low (<20 ng/ml) AFP level, IL-6 or IL-10 expression was significantly associated with the existence of HCC (p<0.05). Patients with large (>5 cm) HCC more often had increased IL-6, IL-10 or AFP levels (p values all <0.05). CONCLUSIONS: Serum levels of IL-6 and IL-10 are frequently elevated in patients with HCC but not in benign liver disease or non-HCC tumors. IL-6 and IL-10 may help identify a subset of HCC patients with low AFP level, and may serve as complementary tumor markers in these patients.     

Impact of serum vascular endothelial growth factor on prognosis in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization

Objective:To investigate the expression level of serum vascular endothelial growth factor(VEGF) in patients with unresectable hepatocellular carcinoma(HCC) and its relationship with the clinicopathological characteristics,and to assess the impact of serum VEGF as a predictive factor for HCC prognosis during transarterial chemoembolization(TACE) treatments.Methods:Serum VEGF levels were measured using enzyme-linked immunosorbent assay(ELISA) in 60 random patients who underwent TACE or transarterial infusion(TAI) for unresectable HCC between May and September 2008 and 12 healthy volunteers were also involved in this study to serve as control.All patients’ clinicopathological features were retrospectively analyzed.Serum VEGF levels were correlated with clinicopathological features of the HCC patients.The patients’ survival rates were analyzed with Kaplan-Meier survival curves and compared by the log-rank test.The prognostic significance of serum VEGF levels and factors related to survival rate were evaluated by univariate and multivariate analysis.Results:The median serum VEGF level in the HCC patients was 285 pg/ml(range 14 1,207 pg/ml),significantly higher than that of healthy controls(P=0.021).The serum VEGF levels were significantly correlated with platelet counts(r=0.396,P=0.002) but not other clinicopathological features.Patients with serum VEGF level >285 pg/ml had worse overall survival compared with those with serum VEGF level <285 pg/ml(P=0.002).By multivariate analysis,the serum VEGF level was a significant prognostic factor.Conclusion: High serum VEGF levels may predict poor prognosis of HCC after TACE. This study highlights the importance of tumor biomarker as a prognostic predictor in TACE therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.     

Prognostic effect of steatosis on hepatocellular carcinoma patients after liver resection

Aims

Overweight/obesity is currently a common health issue that may cause many diseases, even malignancies. The influence of steatosis on long-term results of surgical treatment for hepatocellular carcinoma (HCC) is not well known. The aim of this study is to analyze the results of hepatectomy for HCC patients with steatosis.

Methods

The study included 1048 patients who underwent hepatectomy for HCC from 1999 to 2005. The patients were divided into two groups; group A patients without steatosis (n = 693) and group B patients with steatosis (n = 355). The clinicopathological data and long-term survival were analyzed.

Results

Mean tumor size in group B patients was smaller than that in group A patients (4.61 ± 3.40 vs. 5.91 ± 4.36 cm, p < 0.01). Group B patients showed lower tumor differentiation grade, lower vascular invasion rate and better 5-year overall survival compared to group A patients (61.2% vs. 50.1%, p = 0.001). By multivariate analysis, steatosis was found to be associated with well-differentiated, small-sized, and less α-fetoprotein productive tumors. When focusing on the tumors >5 cm in diameter, group B patients had better survival rate than group A patients (p = 0.041). Vascular invasion and steatosis were independent prognostic factors for the overall survival.

Conclusion

HCC in steatotic liver was less aggressive than that in non-steatotic liver. HCC patients with steatosis have better surgical outcomes than those without steatosis. Vascular invasion and steatosis were independent prognostic factors for the overall survival if tumors were >5 cm in diameter.     

High preoparative levels of serum periostin are associated with poor prognosis in patients with hepatocellular carcinoma after hepatectomy

Aims

Periostin (POSTN) is implicated in cancer development and progression. The aim of this study was to evaluate the diagnostic and prognostic significance of serum POSTN in patients with hepatocellular carcinoma (HCC) receiving curative surgery.

Methods

Enzyme-linked immunosorbent assay was performed to determine serum POSTN levels in 69 healthy volunteers, 30 patients with hepatolithiasis, 27 patients with cirrhosis, and 56 HCC patients. The relationships between serum POSTN and clinicopathologic features were analyzed. Receiver operating characteristics analysis was used to calculate diagnostic accuracy of serum POSTN, serum alpha-fetoprotein (AFP), and their combination. The prognostic impact of serum POSTN on overall survival (OS) and relapse-free survival (RFS) was also investigated.

Results

The median serum POSTN level was significantly (P < 0.05) increased in HCC patients, compared to healthy controls, patients with hepatolithiasis, and patients with liver cirrhosis. Elevated serum POSTN was only significantly associated with Edmondson grade (P = 0.007). The combination of serum POSTN and AFP had a markedly higher area under the curve (0.805 (95% confidence interval [CI]: 0.677–0.932)) than POSTN (0.582 (95% CI: 0.427–0.736)) or AFP (0.655 (95% CI: 0.504–0.806)) alone. Kaplan–Meier analysis indicated that elevated serum POSTN was associated with OS (P = 0.031) and RFS (P = 0.027). Moreover, multivariate analysis revealed elevated serum POSTN as an independent poor prognostic marker for OS and RFS.

Conclusions

Preoperative serum POSTN has limited diagnostic value in distinguishing HCC from non-malignant liver diseases, but serves as independent prognostic biomarker in HCC patients.     

Long-term outcomes in elderly patients with resectable large hepatocellular carcinoma undergoing hepatectomy

Background

In contrast to the feasibility of hepatectomy for resectable large hepatocellular carcinoma (HCC, >5?cm) in the younger patients, the concerns of benefits for the elderly patients remain in practice. This study aimed to evaluate the long-term outcomes and safety after hepatectomy in elderly patients with resectable large HCC compared with younger patients.

169例BCLCB期肝细胞癌切除术预后因素分析

目的探讨BCLCB期肝细胞癌(hepatocellular carcinoma,HCC)患者手术切除预后的影响因素。方法收集2003年3月至2007年9月169例BCLCB期HCC手术切除患者的临床病理资料,采用Kaplan-Meier法计算术后累积生存率,以Log-rank显著性检验初步筛选出可能影响HCC预后的相关因素,应用Cox回归分析进一步明确影响预后的独立因素。结果 BCLCB期HCC患者术后1、3、5年累积生存率分别为76.3%、46.0%、38.8%。单因素分析表明术前谷丙转氨酶(ALT)、肿瘤包膜、肿瘤数目、肝硬化和术后辅助治疗影响HCC术后累计生存率(P<0.05)。多因素分析表明肿瘤包膜、肿瘤数目、肝硬化和术后辅助治疗是影响HCC术后生存率的独立因素(P<0.05)。结论手术切除是BCLCB期HCC患者有效的治疗手段,肿瘤包膜、肿瘤数目、肝硬化和术后辅助治疗是其预后的独立影响因素。     

169例BCLCB期肝细胞癌切除术预后因素分析

目的探讨BCLCB期肝细胞癌（hepatocellular carcinoma,HCC）患者手术切除预后的影响因素。方法收集2003年3月至2007年9月169例BCLCB期HCC手术切除患者的临床病理资料,采用Kaplan-Meier法计算术后累积生存率,以Log-rank显著性检验初步筛选出可能影响HCC预后的相关因素,应用Cox回归分析进一步明确影响预后的独立因素。结果 BCLCB期HCC患者术后1、3、5年累积生存率分别为76.3%、46.0%、38.8%。单因素分析表明术前谷丙转氨酶（ALT）、肿瘤包膜、肿瘤数目、肝硬化和术后辅助治疗影响HCC术后累计生存率（P〈0.05）。多因素分析表明肿瘤包膜、肿瘤数目、肝硬化和术后辅助治疗是影响HCC术后生存率的独立因素（P〈0.05）。结论手术切除是BCLCB期HCC患者有效的治疗手段,肿瘤包膜、肿瘤数目、肝硬化和术后辅助治疗是其预后的独立影响因素。     

Placenta growth factor not vascular endothelial growth factor A or C can predict the early recurrence after radical resection of hepatocellular carcinoma

The purpose of this study was to evaluate the relationship between the expression of PlGF in tumor tissue and clinical outcomes in HCC patients. Tumor PlGF and vascular endothelial growth factor (VEGF)-A and VEGF-C mRNA were analyzed. Results demonstrated that patients with PlGF expression levels higher than median tended to have early recurrence compared to patients with PlGF expression lower than median (P = .031). In patients with AJCC stage II–III disease, this difference was even more significant (P = .002). In contrast, VEGF-A and VEGF-C could not predict early recurrence-free survival. Since PlGF expression correlated with early recurrence of HCC, PlGF may be an important prognostic indicator in 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.     

Prognosis of patients with intrahepatic recurrence after hepatic resection for hepatocellular carcinoma: A retrospective study

Aims

Hepatic resection is the most effective therapy for hepatocellular carcinoma (HCC); however, intrahepatic recurrence is common. Predictors of survival after intrahepatic recurrence have not been fully investigated. To clarify the prognosis and choice of treatment of intrahepatic recurrence after hepatic resection, we conducted a comparative retrospective analysis of 147 patients with HCC who underwent hepatic resection.

Methods

We retrospectively examined the relations between clinicopathologic factors, including the number of recurrent intrahepatic tumors and long-term prognosis after recurrence in 147 HCC patients who underwent resection. We also examined long-term survival after recurrence based on treatment types and recurrence pattern.

Results

Patients with multiple tumors (n = 83) showed less tumor differentiation, more frequent portal invasion, a higher alpha-fetoprotein level, and larger tumors than did patients with solitary tumor (n = 64). In the solitary tumor group, local ablation therapy and repeat hepatic resection were performed in 25 and 10, respectively. In the multiple tumor group, 59 were treated by transarterial chemoembolization. Multivariate analysis showed intraoperative blood transfusion and multiple tumors to be independent risk factors for poor cancer-related survival after recurrence. By subset analysis based on treatment types and recurrence pattern, survival after recurrence was significantly better in patients treated by local ablation therapy than those treated by other therapies in both solitary and multiple tumor groups.

Conclusions

For patients with solitary recurrence, a good prognosis is predicted. Local ablation therapy is a best candidate for treatment of solitary and multiple intrahepatic recurrences after hepatic resection.     

Significance of TNM classification in prognostic evaluation of hepatocellular carcinoma following hepatectomy

　Objective To analyze correlation between TNM classification of hepatocellular carcinoma (HCC) and disease-free survival in order to evaluate its significance in predicting the long-term result after hepatctomy. Methods A retrospective survey was carried out in 1,725 cases with HCC patients performed hepatectomy from January 1990 to December 1995. The follow-up rate was 84.5%. The prognostic factors were analyzed by Cox proportional hazards survival model and disease-free survival was calculated by Kaplan-Meier estimation. Results Univariate analysis showed thirteen clinicopathological prognostic factors including TNM staging. Multivariate analysis revealed four significant predictors such as preoperative lesion number, tumor size, daughter nodules and vascular invasion, which were encompassed in TNM classification. The 5-year disease-free survival rate were 24.6% of stage I, 38.4% of stage II, 15.9% of stage III, and 5.3% of stage IVa respectively. There was no significant difference in disease-free survival between stages I and II. Conclusion TNM staging is one of the most significant prognostic factors in predicting disease-free survival of HCC patient after hepatectomy, but some items need modifying.     

术前血清前白蛋白水平与甲胎蛋白阴性肝细胞癌患者预后的关系

目的 探讨术前血清前白蛋白（prealbumin,PA）对甲胎蛋白阴性的肝细胞癌（alpha-fetoprotein-negative hepatocellular carcinoma,AFP-NHCC）患者预后的影响。方法 回顾性分析2014年1月至2015年12月于广西医科大学附属肿瘤医院接受肝切除术的118例AFP-NHCC患者的临床资料。根据PA临界值将患者分为低PA组（<170 mg/L）和高PA组（≥170 mg/L）,采用Cox回归分析术前血清PA水平与AFP-NHCC患者预后的关系。结果 术前血清PA水平与肿瘤直径、大血管侵犯、Child-Pugh分级和BCLC分期有关（P<0.05）。Kaplan-Meier 生存分析结果显示,低PA组患者的中位生存时间较高PA组短（24.5 个月vs 36.0个月,χ²=11.689,P=0.001）。Cox 回归分析显示,低PA组的死亡风险大于高PA组（HR=2.779, 95%CI：1.406~5.492,P=0.003）,控制潜在混杂因素后这种关系依然存在。结论 术前血清低前白蛋白水平与 AFP-NHCC患者不良预后有关,可作为评估预后的指标。     

血管内皮生长因子在肝细胞癌血清中的表达意义

目的研究血管内皮生长因子(vascularendothelialgrowthfactor,VEGF)在肝细胞癌(HCC)患者周围血血清中的表达水平与肝癌临床病理特征及肝癌转移复发之间的关系.方法运用sandwich酶联免疫吸附测定法定量检测115例HCC、40例肝脏良性疾病患者和30例健康人血清中VEGF的含量.结果HCC组血清VEGF表达水平[(465.62±336.24)pg/ml]与肝脏良性疾病组[(159.54±120.58)pg/ml]、与健康人组[(123.53±51.84)pg/ml]比较,差异均有显著性(P值均=0.0001);VEGF表达阳性率分别为77.4%、25.0%和3.3%.HCC转移组患者血清VEGF表达水平与未转移组相比,差异有显著性(P=0.001).血清VEGF表达水平还与HCC合并门静脉瘤栓、肿瘤大小和TNM分期密切相关,VEGF含量随TNM分期升高而逐步升高.结论疗前HCC患者的血清VEGF表达水平,是反映HCC侵袭生长及转移潜能的有效生物学指标.     

血管内皮生长因子和基质金属蛋白酶-9在原发性肝癌中的表达及其临床意义

目的：研究血管内皮生长因子（ＶＥＧＦ）与基质金属蛋白酶－９（ＭＭＰ－９）在原发性肝癌中的表达与肝癌复发、转移的关系。方法：采用逆转录－聚合酶链式反应技术,对３９例原发性肝癌的手术切除标本（包括癌组织及癌旁肝组织）中的ＶＥＧＦ及ＭＭＰ－９基因表达进行了检测。结果：ＶＥＧＦ分别在９２％（３６／３９）的肝癌组织７９％（２６／３３）的肝硬变组织和５７．１％（４／７）的下沉肝组织中表达,ＭＭＰ－９分别基因表     

Association of HBV DNA replication with antiviral treatment outcomes in the patients with early-stage HBV-related hepatocellular carcinoma undergoing curative resection

Background: It remains unclear what the antiviral therapy affects disease?free survival (DFS) and overall survival (OS) of patients with hepatitis B virus (HBV)?related hepatocellular carcinoma (HCC) at different tumor stages and baseline HBV DNA levels. In this study, we analyzed the association of antiviral treatment with DFS and OS based on the stratifi?cation of baseline HBV DNA load in early?stage (stages I and II) HCC patients. Methods: We included 445 patients with early?stage HBV?related HCC who underwent curative resection, and then classified them into four subgroups based on baseline HBV DNA load and antiviral therapy stratification. The Kaplan–Meier and Cox regression analyses were performed to determine the association of clinical characteristics with survival. Results: The median follow?up period was 74 months. For all patients, cumulative OS rates in the antiviral group were significantly higher than those in the non?antiviral group (log?rank test, P = 0.023), whereas no significant differencesin DFS rates were observed. High baseline HBV DNA level was a risk factor associated with short DFS and OS in all patients. In patients with baseline HBV DNA levels ≥2000 IU/mL, antiviral treatment was significantly associated withprolonged DFS and OS (log?rank test, P or undetectable, antiviral treatment did not show a significant benefit in prolonging DFS and OS. Conclusions: High baseline HBV DNA levels are associated with poor prognosis in the patients with early?stage HCC, and the antiviral treatment could generate survival benefits for the patients. Therefore, antiviral treatment should be given for these patients. However, the effect of antiviral treatment on the patients with low viral load remains unclear, and further investigation is warranted.     

Serum vascular endothelial growth factor as a tumor marker for hepatocellular carcinoma in hepatitis C virus-related cirrhotic patients

BACKGROUNDHepatocellular carcinoma (HCC) accounts for 8.2% of all cancer-related deaths worldwide. Being a vascular tumor, vascular endothelial growth factor (VEGF) plays a vital role in HCC pathogenesis, growth, and spread.AIMTo determine the accuracy of serum VEGF and VEGF/platelet (PLT) as tumor markers in the early detection of HCC cases in patients with hepatitis C virus (HCV)-related liver cirrhosis.METHODSWe conducted a case-control study with HCV patients from the outpatient and inpatient hepatology clinics. Patients were classified into three groups: (1) HCC group; (2) Cirrhosis group; and (3) HCV without cirrhosis (control group). Patients were clinically evaluated, and blood samples were drawn for the analysis; serum VEGF levels were measured by a specific VEGF human recombinant enzyme-linked immunosorbent assay kit. Data from the three study groups were compared by the one-way analysis of variance or Kruskal-Wallis test. Receivers operating characteristic curves were constructed to determine the optimal cut-off values of alpha fetoprotein (AFP), VEGF, and VEGF/PLT that provided the best diagnostic accuracy. The sensitivity and specificity at the optimal cut-off value of each biomarker were then calculated. RESULTSThis study included one hundred patients (HCC, cirrhosis, and control groups: n = 40, 30, 30, respectively). HCC patients had significantly higher serum VEGF and VEGF/PLT levels than the non-HCC groups (P = 0.001). Serum VEGF and VEGF/PLT showed significant positive correlations with and HCC tumor size, stage, vascular invasion, and Child-Pugh classification. Moreover, a VEGF cut-off the value of 250 pg/mL provided 80% sensitivity and 81.7% specificity for discriminating HCC patient from non-HCC patients. Similarly, the ratio of VEGF/PLT provided sensitivity and specificity of 77.5% and 80%, respectively which is higher than the accuracy provided by AFP. The combination of AFP, VEGF, and VEGF/PLT increases the accuracy of diagnosing HCC to > 95%.CONCLUSIONIn HCV patients, serum VEGF and VEGF/PLT separately or in combination with AFP are reliable biomarkers for early and accurate HCC diagnosis.     

Overexpression of platelet-derived growth factor receptor alpha promotes tumor progression and indicates poor prognosis in hepatocellular carcinoma

Dysregulation of platelet-derived growth factor receptor alpha (PDGFRα) has been documented in various cancers. However, its role in hepatocellular carcinoma (HCC) remains unknown. We and others have examined that upregulation of PDGFRα might be involved in hepatocarcinogenesis. Here, we report that PDGFRα plays a critical role in HCC progression and prognosis. The expression of PDGFRα was markedly higher in human HCC compared to adjacent liver tissues. Although PDGFRA mRNA was decreased in HCC, PDGF-A mRNA was dramatically increased in HCC. Overexpression of PDGFRα was strongly correlated with microvessel density (MVD) of HCC (p<0.05), as well as macroscopic vascular invasion of the tumors (p<0.05). HCC patients with high PDGFRα expression displayed a shorter overall survival and a higher recurrence rate than those with low PDGFRα expression (p<0.05, respectively). Additionally, stable overexpression of PDGFRα in hepatoma cells promoted cell proliferation, migration, invasion and epithelial-mesenchymal transition in vitro. Similarly, an in vivo assay showed that PDGFRα overexpression in hepatoma cells exhibited remarkably tumorigenic potential in tumor size and weight in vivo, which displayed markedly elevated MVD than controls. Thus, our study provided the evidence that PDGFRα may serve as a candidate prognostic marker and a novel therapeutic target for HCC.     

Outcomes of hepatectomy for noncirrhotic hepatocellular carcinoma: A systematic review

BackgroundNoncirrhotic hepatocellular carcinoma (HCC) is rare. The aim of this study was to evaluate the published evidence for hepatectomy in patients with noncirrhotic HCC.MethodsA literature search was conducted in PubMed database for eligible studies from the time of inception to March 2014. Comparisons of surgical outcomes for noncirrhotic and cirrhotic HCC were pooled and analyzed by meta-analytical techniques.ResultsThirty-one observational studies comprising a total of 3771 patients who underwent hepatectomy for noncirrhotic HCC were reviewed. The median postoperative morbidity was 29.5% (range, 8.3–55.5%) and mean mortality was 2.7% (range, 0–6.5%). Median 5-year overall and disease free survival was 47.9% (range, 26–81%) and 38.0% (range, 24.0–58.4%) respectively. In comparative studies, both the 5-year disease free (odds ratio (OR): 0.61, 95% confidence interval (95% CI): 0.51–0.72; P < 0.001) and overall survival (OR: 0.61, 95% CI: 0.42–0.90; P = 0.01) in the noncirrhotic group were significantly better than those in the cirrhotic group.ConclusionsHepatectomy for noncirrhotic HCC carries low perioperative morbidity and mortality and offers favorable long-term outcomes.