Clinical Value Of Antiviral Therapy And Tissue-associated Protein Markers In Assessing The Prognosis Of Patients With Hepatocellular Carcinoma After Hepatectomy

BackgroundHepatocellular Carcinoma (HCC) is the most common aggressive tumor and second leading cause of cancer-related death in the world. At present, surgery is the preferred treatment method for hepatocellular carcinoma, Others including liver transplantation, radiofrequency ablation and percutaneous ethanol injection, transarterial chemoembolization, molecular targeted therapy, immunotherapy and traditional Chinese medicine therapy.However, patients with HCC hadn’t specific symptoms at early stage and mostly lost the opporunity of surgical therapy when liver cancer was detected at advanced stage. Patients with poor long-term survival due to high rate of recurrence and early relapse of HCC after operation, even performed curative therapy.Studies have shown that the postoperative recurrence of HCC after 5 years as high as 70%～80%, even small HCC reaches 43.5% Recurrence of liver cancer has become the main factor influencing the long-term survival of patients, which is the main reason for postoperative death. In China,more than 80% HCC is progressed by viral hepatitis and cirrhosis.Hepatitis B virus infection has become the most common cause of the development of liver cancer.In patients with chronic heatitis B virus infection,studies have shown that the abnormal increase of hepatitis B virus deoxynucleotide acid(HBV DNA) is an independent risk factor for HCC in oncogenesis and recurrence,and seriously restricting the recovery of residual liver function in HCC.Relative to other factors for liver cancer patients after surgery,the timely and effective anti-viral therapy can significantly reduce the level of HBV DNA and improve the prognosis of patients with HCC.It is worth noting that the carcinogensis is a very complicated process, involving many factors include genetics,abnormal signaling pathways,tumor microenvironment,tumor stem cells and so on. So how to effectively predict the prognosis of liver cancer become a notable problem.Abnormal proliferation is one of the important biological behaviour of tumor cells, the tumor recurrence and survival rate were significant correlation with proliferation activity.Ki67 exists in cell nucleus is a nonhistones nucleoprotein, which can accurately reflect cell proliferation activity, and that was used to assess the tumor biological behaviour. Ki67 is closely related to the process of cell mitosis,it’s highest expression in the G2 and M phases of the cell cycle and degradation disappeared without expression, thereby can differentiate between normal cells and tumor cells. More and more studies show that the higher expression of Ki67 in lots of tumors such as gastric cancer, breast cancer, rectal cancer,colon cancer,liver cancer.And it’s expression level maybe related to the development of liver neoplasms and the prognosis of HCC.Evaluation of Ki67 expression may have important clinical significance for study of biological behavious, judgement of harmfulness,guideline of treatment, and prediction of prognosis.The main characteristic of malignant tumor is that proliferation rapidly,which requires a lot of energy to supply the process.Glutl is a main carrier-mediated glucose transport in mammalian cells, it’s not only involved in normal physiological processes also correlation with chronic complications of diabetes and cancer,the increase tumor cells uptake of glucose by increasing the transmembrane transport of Glutl.A number of studies have shown that the Glutl expression correlated with the prognosis of patients,and higher expression of Glutl has become an important indicator for many tumors such as kidney cancer, lung cancer, breast cancer, colorectal cancer and ovarian cancer.Glutl is regulated by the changes of microenvionment in tumor tissue,and correlated with the cell mutation.The higher expression of Glutl can enhance tumor metabolism,promote tumor proliferation rate,provide energy support for tumor growth and increase the capacity of invasion and metastasis,which lead to higher recurrence rate and poor prognosis for postoperative patients.After using siRNA or antisense oligonucleotides-peptide polymer targeting inhibit the Glutl expression,the proliferation,invasion and metastasis had been significantly decresed in hepatocellular carcinoma. So theory confirmed that Glutl as a therapeutic target for liver cancer is practicable.Chapter I Clinical research of antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after hepatectomyObjective Recent advances in treatment modalities have improved the survival rate of patients with hepatocellular carcinoma (HCC). However, hepatitis B virus (HBV)-related HCC has a much higher recurrence rate all the time.In this article, we investigate the effect of antiviral therapy for HBV-related HCC after radical hepatectomy.Methods A consecutive series of 113 patients with HBV-related HCC undergoing liver resection in Guangdong General Hospital from January 2005 to June 2012 were retrospectively reviewed, including 44 treated cases received hepatectomy and antiviral therapy,69 control cases received hepatectomy only. The 1,3,5-year disease free survival(DFS) rates and liver function at the time of HCC recurrence were compared between the two groups.Results In addition to differences in HBV DNA,other indicators showed no statistically significant difference between the two groups in preoperative general data. Kaplan-Meier was used to analysis the postoperative 1,3,5-year DFS rates were 81.8%、38.6%、26.7% vs.73.9%、26.5%、13.6% in the treatment group and control group,respectively (P=0.038). Total of 88 in 113 cases experienced HCC recurrence during the follow-up period,32 cases in the treatment group and others in the control group.Recurrence and metastasis sites were liver(72 cases),lung(3 cases), thoracic vertebra(2 cases),liver and lung(4 cases), abdominal and pelvic cavity and liver(7 cases).compared with the control group(n=56), the Child-Pugh score and levels of ALT、HBV DNA were significantly reduced in the treatment group at the time of HCC recurrence,but the level of Albumin was significantly increased,the order of which is [(5.41±0.76) vs.(6.14±1.55), P=0.014]. [(38.2±20.9) vs. (48.0±20.3), P=0.046]. [<2.70vs. (5.23±1.49),P<0.001]. [(38.7±3.3) vs. (36.5±4.2), P=0.047].Conclusion Patients with high HBV DNA levels at HCC onset show significantly higher HCC recurrence rates compared to patients with low HBV DNA levels. Antiviral therapy was associated with a higher DFS among patients with HBV-related HCC after liver resection, and contributed to improving remnant liver function.Chapter Ⅱ Expression and prognosis significance of Ki67 and Glutl in hepatocellular carcinomaObjective To investigate the expression of Ki67 and Glutl in hepatocellular carcinoma and tumor-adjacent normal liver tissues, and combined with corresponding clinical features and prognostic indicators,and explored the relationship between the expression of Ki67 and Glutl and the prognosis of hepatocellular carcinoma after curative.Methods 61 hepatocellular carcinoma and 20 tumor-adjacent normal liver samples were collected from General Surgical Department of Guangdong General Hospital from January 2008 to June 2012. The expression of Ki67 and Glutl protein were detected by Immunohistochemistry in 61 HCC tissues and 20 tumor-adjacent normal liver tissues,61 HCC cases were divided into two groups:early recurrence group (< 2 years) and late recurence group(≥2 years), and analysising the revelant clinical pathological characteristics and prognosis.Results Immunohistochemistry was used to detected the expression of Ki67 and Glutl in hepatocellular carcinoma and tumor-adjacent normal liver tissue. Our study suggest that the positive expression rate of Ki67 was 72.1%(44/61) in HCC tisssue, and correlated strongly with tumor size(P=0.039) and Edmonson grade (χ2=4.475,P=0.034), but wasn’t correlated with patients’gender,age, vascular invasion or not, capsular invasion or not, HBV DNA and alpha-fetoprotein level, (P>0.05).20 cases of normal liver tissues could not be detected, there was a significant difference between the two groups (P<0.05). The positive expression rate of Glutl was 62.3%(38/61) in HCC tisssue, and correlated with Edmonson grade (χ2=8.435, P=0.004), but wasn’t correlated with patient’s gender,age, tumor size,vascular invasion or not, capsular invasion or not, HBV DNA and alpha-fetoprotein level, (P>0.05).20 cases of normal liver tissues could not be detected, there was a significant difference between the two groups (P<0.05).Setting 2-year was the cut-off point for relapse time,the expression of Ki67 was significantly higher in early recurrence group compared with late recurence group(84.8%vs. 57.1%,χ2=5.784,P=0.016).In the Glutl-positive expression cases,the expression of Ki67 was higher than Glutl-negative expression cases.Using Spearman rank correlation analysis, there is a positive correlation between Ki67 and Glutl (r=0.377, P=0.003).The followed-up end time was June 2014, the period of following-up was 3-78 months and median follow-up time was 52 months. For all patients,the postoperative 1,3 and 5-year cumulative survival rates were 88.5%,56.9% and 46.5%,respectively. The median survival time was 35.5 months for Ki67-positive expression group, the 1,3 and 5-year overall survival rates of Ki67 positive group and negative group were 86.4%,49.1%,41.8% and 94.1%,76.5%,58.8%,respectively. There was significant difference between two groups(P=0.042). The median survival time was 36.0 months for Glutl-positive expression group, the 1,3 and 5-year overall survival rates of Glutl positive group and negative group were 86.8%,47.4%,36.0% and 91.3%,73.0%,63.9%,respectively. There was significant difference between two groups(P=0.040).Conclusion1. Ki67 and Glutl expression were more higher in hepatocellular carcinoma than in tumor-adjacent normal liver tissue, indicate that the development and progression of liver neoplasms maybe related to the higher expression of Ki67 and Glutl.2. The expression of Ki67 was higher in hepatocellular carcinoma as the accretion of tumor and Edmondson grade was higher in the tumor. Ki67 and Glut1 expression were significantly higher in the group of early recurrence relative to the group of late recurrence in hepatocellular carcinoma. These indicate that Ki67 and Glutl can promote the growth,invasion and metastasis as well as the role of dedifferentiation in hepatocellular carcinoma.3. Survival analyses further indicated that the higher expression of Ki67 and Glutl significantly reduces the overall 5-year survival rate of liver cancer patients, both could be regard as important parameters in malignant degree and poor prognosis of hepatocellular carcinoma. The expression of Ki67 is positively correlated with the level of Glutl in hepatocellular carcinoma, The combined detection of Ki67 and Glutl can help clinicians to understand biological behaviour, guidance of liver cancer treatment, and evaluation of prognosis.