Quality of life and hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common and rapidly fatal cancer ranking third among the leading causes of cancer-related deaths. Potentially curative therapies like surgery, transplant and ablation are not an option for most patients as they are often diagnosed when the disease is advanced. Liver directed therapy and oral targeted therapies are used in these patients to prolong life and palliate symptoms of the cancer and associated liver failure. Overall survival remains poor and hence health-related quality of life (HRQoL) is of paramount importance in these patients. As novel therapies are developed to improve outcomes, a comprehensive knowledge of available tools to assess impact on QoL is needed. Hence we reviewed all the studies in HCC patients published within the last 13 years from 2001-2013 which assessed HRQoL as a primary or secondary endpoint. A total of 45 studies and 4 meta-analysis were identified. Commonly used tools were European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (15 studies) and the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire (FACT-Hep) (14 studies). Of the 45 publications which incorporated HRQoL as end-point only 24 were clinical trials, 17/24 (71%) assessed systemic therapies while 7/24 (29%) assessed liver-directed therapies. Majority of the publications (trials + retrospective reviews) that had HRQoL as an endpoint in HCC patients were studies evaluating liver-directed therapies (23/45 or >50%). We discuss the measures included in the tools, their interpretation, and summarize existing QoL data that will help design future HCC trials.     

Radiofrequency ablation or microwave ablation combined with transcatheter arterial chemoembolization in treatment of hepatocellular carcinoma by comparing with radiofrequency ablation alone简

Objective：To compare radiofrequency ablation （RFA） or microwave ablation （MWA） and transcatheter arterial chemoembolization （TACE） with RFA or MWA monotherapy in hepatocellular carcinoma （HCC）.Methods：A prospective,randomized,controlled trial was conducted on 94 patients with HCC ≤7 cm at a single tertiary referral center from June 2008 to June 2010 at the Department of Hepatobiliary Surgery,the Second Affiliated Hospital of Southeast University.The patients were randomly assigned into the TACERFA or TACE-MWA （combined treatment group） and the RFA-alone or MWA-alone groups （control group）.The primary end point was overall survival.The secondary end point was recurrence-free survival,and the tertiary end point was adverse effects.Results：Until the time of censor,17 patients in the TACE-RFA or TACE-MWA group had died.The median follow-up time of the patients who were still alive for the TACE-RFA or TACE-MWA group was 47.5±11.3 months （range,29 to 62 months）.The 1-,3-and 5-year overall survival for the TACE-RFA or TACE-MWA group was 93.6％,68.1％ and 61.7％,respectively.Twenty-five patients in the RFA or MWA group had died.The median follow-up time of the patients who were still alive for the RFA or MWA group was 47.0±12.9 months （range,28 to 62 months）.The 1-,3-and 5-year overall survival for the RFA or MWA group was 85.1％,59.6％ and 44.7％,respectively.The patients in the TACE-RFA or TACE-MWA group had better overall survival than the RFA or MWA group [hazard ratio （HR）,0.526; 95％ confidence interval （95％ CO,0.334-0.823; P=0.002],and showed better recurrence-free survival than the RFA or MWA group （HR,0.582; 95％ CI,0.368-0.895; P=0.008）.Conclusions：RFA or MWA combined with TACE in the treatment of HCC ≤7 cm was superior to RFA or MWA alone in improving survival by reducing arterial and portal blood flow due to TACE with iodized oil before RFA.     

Th22 cells are associated with hepatocellular carcinoma development and progression

Objective： IL-22-producing CD4＋ T helper cells （Th22 cells） have been identified as major inducers of tissue inflammation and immune responses. Currently, no previous study explored the role of Th22 cells in the pathogenesis of hepatocellular carcinoma （HCC）. The study aimed to determine the biological function of Th22 cells and its effector IL-22 in HCC patients. Methods： Forty-five HCC patients and 19 healthy controls were recruited and their peripheral blood was collected. The flesh HCC tissues, adjacent HCC tissues and ten normal liver tissues were also collected. Flow cytometry analysis was used to determine the frequencies of circulating Th22 cells and Thl7 cells. Serum IL-22 levels were tested by enzyme-linked immtmosorbent assay （ELISA）. Immunohistochemical staining and real-time polymerase chain reaction （PCR） were used to detect IL-22 protein and mRNA in tissues specimens, respectively. Results： Circulating Th22 cells, Thl7 cells and serum IL-22 levels were significantly elevated in HCC patients compared with those of healthy controls （P〈0.001）. Th22 cells were showed to be positively correlated with IL-22 in HCC patients （P〈0.05）, but not in healthy controls. No significant differences were found in HCC patients with HBeAg positivity or negativity in term of Th22 cells and serum IL-22 levels. The expression of IL-22 protein and mRNA was highest in HCC tissues, followed by adjacent HCC tissues and normal liver tissues. Furthermore, Th22 cells, serum IL-22 levels and IL-22 mRNA were elevated at stage III-IV compared with stage I-II of HCC （P〈0.05）. Conclusions： Elevation of circulating Th22 cells and IL-22 may be implicated in the pathogenesis of HCC, and potentially be cellular targets for therapeutic intervention.     

LYRIC在人肝癌组织中的表达及其临床意义

目的： 检测LYRIC分子在肝癌和癌旁组织中的表达,探讨LYRIC分子与肝癌患者临床病理特征的关系及其对预后判断的指导意义。 方法： 收集2005年1月至2013年12月沈阳军区总医院和中国医科大学附属盛京医院的87例肝癌患者肝癌及其癌旁组织切除标本,采用Real-time PCR和免疫组织化学染色等方法从基因和蛋白水平检测肝癌患者的癌组织及相应的癌旁组织中LYRIC分子的表达,结合患者病理指标、病理分型和预后随访资料分析LYRIC分子表达的临床意义。 结果： 在基因水平检测发现, LYRIC 基因在56例肝癌组织中表达高于癌旁组织,高表达率为64.7%（56/87）;在蛋白水平检测发现,LYRIC蛋白在87例肝癌组织中均表达,且在肝癌组织中的表达显著高于癌旁组织（2.16±0.87 vs 1.63±0.88, P =0 000 1）。在肝癌组织中LYRIC分子的高、低表达可较好地预测肝癌患者的预后情况,LYRIC分子高表达患者预后较差（Log-rank10.236, P =0.001）;多因素分析提示,LYRIC高表达（HR=2.19）、转移（HR=2.44）及肿瘤分期（HR=2.01）是影响肝癌总体生存期的独立危险因素,而与肿瘤直径及是否有病毒感染无关。 结论： LYRIC分子在肝癌组织中高表达,且其表达水平与肝癌的临床分期、转移能力和临床预后密切相关,是肝癌潜在的预后判断指标。     

微波消融术联合肝动脉介入栓塞术治疗肝细胞癌的临床研究

目的：比较微波消融术（ microwave ablation,MWA）联合或者不联合经肝动脉化疗栓塞术（ transcathe-ter arterial chemoembolization,TACE）治疗肝细胞癌（ HCC）的临床疗效以及不良反应。方法：选择89例2006年10月至2009年7月入我院治疗的肿瘤直径≤5cm的原发性肝细胞癌患者,采用随机数字法分为MWA联合TACE组（n=44）或者单独MWA组（n=45）进行随机对照研究,观察两组患者的总生存率（OS）、无复发生存率（ RFS）以及不良反应。结果：所有患者均治疗成功,随访时间为7-62个月,随访结束时联合组患者死亡15人,微波组死亡23人。联合组、微波组分别有16人、25人出现疾病进展。1年、2年、3年OS分别为86.4%,74.4%,61.8%和77.4%,63.6%,50.0%。对应的RFS为72.4%,61.6%,45.8%和61.7%,52.2%,39.8%。联合组的OS以及RFS高于单纯微波组（风险比率HR为0.323,95%CI为0.295-0.351,P=0.002;风险比率HR为0.258,95%CI为0.230-0.286,P=0.02）。研究过程中无治疗相关性死亡。对相关因素进行Logistic回归分析,治疗分配、肿瘤大小、肿瘤数目是OS相关预后因素,治疗分配、肿瘤大小是RFS相关预后因子。结论：MWA联合TACE术治疗病灶≤5cm的HCC患者疗效优于单独的MWA治疗疗效。     

Polymorphism of XRCC1 and the frequency of mutation in codon 249 of the p53 gene in hepatocellular carcinoma among Guangxi population, China

In hepatocellular carcinoma (HCC), hotspot mutation in codon 249 of the p53 gene has been associated with exposure to aflatoxin B1 (AFB1). While the polymorphism of DNA repair gene X-ray repair cross-complementary group 1 (XRCC1) Arg399Gln may be related with AFB1-DNA adducts and gene mutations. Five hundred one HCCs were included in this study to investigate the role of the XRCC1 codon 399 polymorphism on hotspot mutation in codon 249 of the p53 gene. The genotypes of XRCC1 codon 399 and p53 codon 249 were examined by PCR-RFLP. The HCC patients with XRCC1 genotypes with 399 Gln (namely: XRCC1-AG/GG) exhibited a significantly higher frequency of the p53 hotspot mutations in codon 249 than those with the wild-type homozygote of XRCC1 [namely: XRCC1-AA, adjusted odds ratio (OR) = 6.77, 95% confidence interval (CI) = 4.34-10.57]. Compared with those individuals who did express XRCC1-AA as reference (OR = 1), moreover, individuals featuring XRCC1-AG/GG and AFB1-DNA adducts did experience a significantly greater frequency of the hotspot mutation in codon 249 of the p53 gene (adjusted OR = 28.37, 95% CI = 13.19-61.02, P < 0.01). This study suggests that the XRCC1 Arg399Gln polymorphism and AFB1-DNA adducts are associated with the increased frequency of the p53 mutations in codon 249.     

Synergistic antitumor efficacy of sequentially combined paclitaxel with sorafenib in vitro and in vivo NSCLC models harboring KRAS or BRAF mutations

Interferon-gamma (IFN-γ) is a pleiotropic cytokine with immunomodulatory, anti-viral, and anti-proliferative effects. In this study, we examined the effects of IFN-γ on autophagy and cell growth in human hepatocellular carcinoma (HCC) cells. IFN-γ inhibited cell growth of Huh7 cells with non-apoptotic cell death. IFN-γ induced autophagosome formation and conversion/turnover of microtubule associated protein 1 light chain 3 (LC3) protein. Furthermore, overexpression of IRF-1 also induced autophagy in Huh7 cells. Silencing IRF-1 expression with target small hairpin RNA blocked autophagy induced by IFN-γ. Silencing of the autophagy signals Beclin-1 or Atg5 attenuated the inhibitory effect of IFN-γ on Huh7 cells with decreased cell death. Additionally, IFN-γ activated autophagy in freshly cultured human HCC cells. Together, these findings show that IFN-γ induces autophagy through IRF-1 signaling pathway and the induction of autophagy contributes to the growth-inhibitory effect of IFN-γ with cell death in human liver cancer cells.     

Bortezomib enhances radiation-induced apoptosis in solid tumors by inhibiting CIP2A

Previously, we demonstrated that cancerous inhibitor of protein phosphatase 2A (CIP2A) mediates bortezomib-induced apoptosis in hepatocellular carcinoma cells. Herein, we report that bortezomib sensitizes solid tumor cells to radiation-induced apoptosis. Treatment with a combination of bortezomib and radiation downregulated CIP2A in a dose-dependent manner in solid tumor cells. Knockdown of CIP2A enhanced radiation-induced apoptosis in cancer cells, and ectopic expression of CIP2A in cancer cells abolished radiation-induced apoptosis. Finally, our in vivo data showed that bortezomib and radiation combination treatment decreased tumor growth significantly. Thus, bortezomib sensitized solid tumor cells to radiation through the inhibition of CIP2A.     

肝细胞癌相关DNA甲基化诊断生物标志物的筛选及验证

目的 筛选肝细胞癌(hepatocellular carcinoma,HCC)相关的甲基化CpG诊断生物标志物.方法 下载癌症基因组图谱(the cancer genome atlas,TCGA)中HCC的DNA甲基化和表达数据进行生物信息学分析,获得候选CpG位点.采用焦磷酸测序及qRT?PCR检测50例早期HCC组...     

Aes对肝癌细胞恶性生物学行为的影响

背景与目的:Aes(amino-terminal enhancer of split,Aes)是一种能够与转录因子结合调节转录活性的蛋白,以往的研究显示其在发育过程中起重要作用,近期研究发现Aes可参与结肠癌转移。本研究旨在观察外源Aes在肝癌细胞中的定位以及其对肝癌细胞增殖、侵袭和迁移能力的影响。方法:构建pEGFP-Aes表达载体,并通过LipofectamineTM2000将其转入Aes低表达的肝癌细胞系HepG2中,蛋白质印迹法(Westernblot)检测外源Aes的表达,荧光显微镜观察pEGFP-Aes在细胞中的定位,应用细胞计数盒(Cell CountingKit)-8检测转染Aes后细胞增殖活力变化;划痕实验检测转染前后细胞迁移能力的变化;Transwell实验检测Aes对细胞侵袭能力的影响。结果:Aes在HepG2中表达较低,将Aes转入肝癌细胞系HepG2,Aes在细胞核和细胞质中都有表达,并且在细胞核中形成点状浓积,Aes对肝癌细胞HepG2的增殖无显著影响,但能抑制HepG2的侵袭和迁移能力(P<0.05)。结论:Aes对肝癌细胞恶性表型的影响主要是抑制其侵袭和迁移能力。