| PART IBackgroundHepatocellular carcinoma (HCC) is one of the most common and highly lethal malignancies worldwide, and it is the third most frequently diagnosed and the second leading cause of cancer death in China. The prognosis of HCC is still poor, because only about20%of all the HCC patients have the opportunity of receiving hepatic resection, which is the initial treatment for HCC. Besides, the5-year survival rate of advanced HCC patients is less than20%. HCC is asymptomatic for much of its nature history, so most of HCC patients with symptoms are late for surgical treatment. As a result, scientific and clinical studies on precaution, early diagnose and prognosis improvement of HCC have always been highlighted and dedicated. Hepatitis B virus (HBV) is the main cause of HCC in China, and HCC is also responsible for death from chronic HBV infection. However, the mechanics of progression from chronic HBV infection to liver cirrhosis and HCC are still unknown. With the development of high-throughput sequencing technology, such as gene chip, researchers can comprehensively and effectively identify genetic variants related to HCC development and progression, as well as genetically study factors that related to chronic HBV infection or virus removal using genome-wide association study (GWAS). Recently, GWAS of several tumors revealed that partial genetic variants may be associated with tumor development, progression and long-term survival. Unfortunately, GWAS related to HCC is limited and no GWAS associated with HCC survival has been reported so far. Therefore, relationship between genetic variants and HBV-related HCC remains unknown from previous reports.ObjectivesWe assume that GWAS-identified HCC and chronic HBV infection susceptibility loci might be associated with survival of HBV-related HCC patients. To prove this assumption, we conducted an association analysis between GWAS-identified HCC and chronic HBV infection susceptibility loci and HBV-related HCC patients, which is to discuss the relationship between genetic variants and survival of HBV-related HCC patients.Materials and MethodsFrom Asian-population based studies, we chose22GWAS-identified HCC or chronic HBV infection susceptibility associated single nucleotide polymorphisms (SNPs)(including14HCC susceptibility associated loci and8chronic HBV infection associated susceptibility associated loci). Peripheral blood samples from330HBV-related HCC patients were processed for DNA extraction and the most significant SNPs were genotyped using Sequenom MassARRAY. HRs and were calculated using multivariate Cox models for association analysis of different genetic variants genotypes and survival of HBV-related HCC patients.ResultsUnivariate analysis and multivariate analysis suggested that alcohol, TNM staging, treatment methods and KPS score were all risk factors for HBV-related HCC. With the mixed factors adjusted, such as ages, gender, smoking, alcohol, TNM staging and treatment methods, multivariate Cox models analysis indicated that6variants loci were significantly associated with survival of HBV-related HCC patients (P<0.05), including rs1419881, rs2275959, rs3997872, rs7453920, rs7768538and rs7821974,. Among them, minor allele of rs2275959showed an increased risk of death for HBV-related HCC, and hazard ratio (HR) was1.22(95%CI,1.01-1.46;P=0.0351). HRs for the minor alleles of the other five loci including rs141988、rs3997872、rs7453920、rs7768538and rs7821974were0.81(95%CI,0.66-0.99; P=0.0364),0.42(95%CI,0.21-0.80; P=0.009),0.57(95%CI,0.41-0.79; P=0.0009),0.66(95%CI,0.50-0.87; P=0.0026) and0.84(95%CI,0.72-0.97; P=0.0200), repectively, indicating that they significantly lower the risk of death for HBV-related HCC.ConclusionsThree HCC susceptibility associated loci (rs2275959, rs7821974and rs3997872) and Three chronic HBV infection susceptibility associated loci (rs7453920, rs7768538and rs1419881) were associated with survival of HBV-related HCC patients. Our results indicated that genetic factors play an important role in development and progression of HBV-related HCC. Further studies on molecular biological mechanisms of chronic HBV infection and HCC susceptibility associated loci in development of HBV-related HCC will be potentially valuable for prognosis evaluation and individualized therapy guidance.PART IIBackgroundTraditionally hypersplenism was considered as a contraindication to liver resections in patients with hepatocellular carcinoma (HCC) due to thrombocytopenia and leucopenia. Liver transplantation is an ideal treatment for HBV-related HCC patients with cirrhotic hypersplenism. However, problems like the scarce organ resources, high costs, and progression when waiting for donor, limit the application of liver transplantation in these patients. Therefore, it is necessary to study the surgical treatment strategy and the long-term outcome in HBV-related HCC patients with cirrhotic hypersplenism.ObjectivesThe aim of this study is to clarify the prognostic risk factors in HBV-related HCC patients with cirrhotic hypersplenism and evaluate the role of simultaneous splenectomy and hepatectomy in patients of HCC in terms of safety and long-term outcomes.Patients and MethodsFrom January2000to December2012,177HCC patients associated with cirrhotic hypersplenism underwent simultaneous hepatectomy and splenectomy (n=58) or hepatectomy alone (n=119). The liver function changes after surgery and pathological data of the two groups were analyzed and compared, and the univariate and multivariate analyses of prognosis were performed by Log-rank test and Cox proportional-hazard regression model, respectively.ResultsNo statistical significance was shown in estimated blood loss and cases needed for transfusion, postoperative morbidity, mortality, and postoperative hospital stay in the two groups. Liver functions recovered rapidly after surgery in splenectomy group and were significantly different with preoperative value. There was no difference in the overall survival (OS) or progression-free survival (PFS) between the two groups. In the multivariate analysis, elderly patients (≥55years), larger tumor size (≥5cm), histopathological grade (poor differentiation), and Child-Pugh grade (B, versus A) were independent prognostic factors (P<0.05). Subgroup analysis revealed that in TNM stage I subgroup, the PFS of splenectomy group (n=32) was significantly worse than that of non-splenectomy group (n=73); by contrast, in TNM stage II subgroup, the OS of splenectomy group (n=21) was significantly better than that of non-splenectomy group (n=29).ConclusionsConcerning about patients at TNM stage I and II, spleen-preserve strategy and concomitant splenectomy may be beneficial for long-term survival, respectively. Multivariate analysis revealed that elderly patients (>55years), larger tumor size (>5cm), histopathological grade (poor differentiation), and Child-Pugh grade (B, versus A) were independent prognostic factors. These fundamental observations may assist surgeons in evaluating the prognosis and determining the appropriate therapeutic decision for HBV-related HCC patients with cirrhotic hypersplenism. |
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