Challenges of incorporating gene expression data to predict HCC prognosis in the age of systems biology

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The recurrence of HCC after curative treatments is currently a major hurdle. Identification of subsets of patients with distinct prognosis provides an opportunity to tailor therapeutic approaches as well as to select the patients with specific sub-phenotypes for targeted therapy. Thus, the development of gene expression profiles to improve the prediction of HCC prognosis is important for HCC management. Although several gene signatures have been evaluated for the prediction of HCC prognosis, there is no consensus on the predictive power of these signatures. Using systematic approaches to evaluate these signatures and combine them with clinicopathologic information may provide more accurate prediction of HCC prognosis. Recently, Villanueva et al developed a composite prognostic model incorporating gene expression patterns in both tumor and adjacent tissues to predict HCC recurrence. In this commentary, we summarize the current progress in using gene signatures to predict HCC prognosis, and discuss the importance, existing issues and future research directions in this field.     

Changing role of histopathology in the diagnosis and management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and fatal cancer in the world. HCC frequently presents with advanced disease, has a high recurrence rate and limited treatment options, which leads to very poor prognosis. This warrants urgent improvement in the diagnosis and treatment. Liver biopsy plays very important role in the diagnosis and prognosis of HCC, but with technical advancements and progression in the field of imaging, clinical guidelines have restricted the role of biopsy to very limited situations. Biopsy also has its own problems of needle tract seeding of tumor, small risk of complications, technical and sampling errors along with interpretative errors. Despite this, tissue analysis is often required because imaging is not always specific, limited expertise and lack of advanced imaging in many centers and limitations of imaging in the diagnosis of small, mixed and other variant forms of HCC. In addition, biopsy confirmation is often required for clinical trials of new drugs and targeted therapies. Tissue biomarkers along with certain morphological features, phenotypes and immune-phenotypes that serve as important prognostic and outcome predictors and as decisive factors for therapy decisions, add to the continuing role of histopathology. Advancements in cancer biology and development of molecular classification of HCC with clinic pathological correlation, lead to discovery of HCC phenotypic surrogates of prognostic and therapeutically significant molecular signatures. Thus tissue characteristics and morphology based correlates of molecular subtypes provide invaluable information for management and prognosis. This review thus focuses on the importance of histopathology and resurgence of role of biopsy in the diagnosis, management and prognostication of HCC.     

X连锁凋亡抑制蛋白在肝细胞癌中的表达及其对患者术后复发的影响

目的 探讨肝细胞癌组织中X连锁凋亡抑制蛋白(XIAP)的表达及其对患者术后复发的影响.方法 应用免疫组织化学方法检测72例肝细胞癌组织及其癌旁组织中XJAP的表达,分析其表达与肝细胞癌临床病理因素的关系及在患者术后复发中的意义.结果 HCC组织中XIAP阳性表达率明显高于癌旁组织(x2=7.03,P＜0.01).XIA...     

An evidence-based multidisciplinary approach to the management of hepatocellular carcinoma (HCC): the Alberta HCC algorithm

Hepatocellular carcinoma (HCC) is one of only a few malignancies with an increasing incidence in North America. Because the vast majority of HCCs occur in the setting of a cirrhotic liver, management of this malignancy is best performed in a multidisciplinary group that recognizes the importance of liver function, as well as patient and tumour characteristics. The Barcelona Clinic Liver Cancer (BCLC) staging system is preferred for HCC because it incorporates the tumour characteristics (ie, tumour-node-metastasis stage), the patient's performance status and liver function according to the Child-Turcotte-Pugh classification, and then links the BCLC stage to recommended therapeutic interventions. However, the BCLC algorithm does not recognize the potential role of radiofrequency ablation for very early stage HCC, the expanding role of liver transplantation in the management of HCC, the role of transarterial chemoembolization in single large tumours, the potential role of transarterial radioembolization with 90Yttrium and the limited evidence for using sorafenib in Child- Turcotte-Pugh class B cirrhotic patients. The current review article presents an evidence-based approach to the multidisciplinary management of HCC along with a new algorithm for the management of HCC that incorporates the BCLC staging system and the authors' local selection criteria for resection, ablative techniques, liver transplantation, transarterial chemoembolization, transarterial radioembolization and sorafenib in Alberta.     

Molecular targeted therapy for hepatocellular carcinoma:Current and future

Hepatocellular carcinoma(HCC)is one of the most frequent tumors worldwide.The majority of HCC cases occur in patients with chronic liver disease.Despite regular surveillance to detect small HCC in these patients,HCC is often diagnosed at an advanced stage.Because HCC is highly resistant to conventional systemic therapies,the prognosis for advanced HCC patients remains poor.The introduction of sorafenib as the standard systemic therapy has unveiled a new direction for future research regarding HCC treatment.However,given the limited efficacy of the drug,a need exists to look beyond sorafenib.Many molecular targeted agents that inhibit different pathways involved in hepatocarcinogenesis are under various phases of clinical development,and novel targets are being assessed in HCC.This review aims to summarize the efforts to target molecular components of the signaling pathways that are responsible for the development and progression of HCC and to discuss perspectives on the future direction of research.     

肝癌相关基因表达的荧光定量PCR检测及分子诊断指数的建立

目的:研究肝细胞癌相关基因表达,建立肝癌分子诊断指数,以期能更准确的诊断肝癌.方法:采用实时荧光定量PCR检测40例肝细胞癌患者癌组织和配对的癌旁2 cm及手术切缘组织、10例肝硬化组织、10例正常肝脏组织中11个基因的表达,以管家基因G3PDH为对照,2-ΔΔCT法计算目的基因相对表达量,挑选出特异性好且与正常肝、肝...     

Molecular prognostic prediction in liver cirrhosis

The natural history of cirrhosis varies and therefore prognostic prediction is critical given the sizable patient population. A variety of clinical prognostic indicators have been developed and enable patient risk stratification although their performance is somewhat limited especially within relatively earlier stage of disease. Molecular prognostic indicators are expected to refine the prediction, and potentially link a subset of patients with molecular targeted interventions that counteract poor prognosis. Here we overview clinical and molecular prognostic indicators in the literature, and discuss critical issues to successfully define, evaluate, and deploy prognostic indicators as clinical scores or tests. The use of liver biopsy has been diminishing due to sampling variability on fibrosis assessment and emergence of imaging- or lab test-based fibrosis assessment methods. However, recent rapid developments of genomics technologies and selective molecular targeted agents has highlighted the need for biopsy tissue specimen to explore and establish molecular information-guided personalized/stratified clinical care, and eventually achieve “precision medicine”.     

ECPKA 在肝细胞癌中的诊断价值

目的：探讨血清细胞外蛋白激酶 A（ECPKA）在肝细胞癌（HCC）诊断中的价值。方法采用病例对照研究方法,收集研究对象的环境因素、疾病史及健康状况信息;检测血清中 ECPKA 和 AFP 活性。利用 Logistic 回归模型分析血清 ECPKA 与 HCC 的关系,对 ECPKA 进行 Box-Cox 正态转换后,计算 ROC 曲线下面积及其95％可信区间。将ECPKA 和 AFP 转化为有序数据后,拟合 Logistic 回归模型,计算 ECPKA、AFP 及二者同时存在时的 ROC 曲线下面积及其95％可信区间,并进行两两比较。根据 Youden 指数最大原则,并结合 Logistic 回归分析结果及 ROC 曲线,确定最佳临界值。结果 HCC 患者血清 ECPKA 表达水平为（15．579±7．441）U／mL,健康对照为（5．277±3．190）U／mL,两组间差异有统计学意义（P ＜0．05）。单因素和多因素 Logistic 回归结果显示,ECPKA 粗 OR 值及调整年龄和性别后 OR 值分别为1．48（1．37,1．59）和1．49（1．38,1．61）。ROC 曲线下面积为0．908（0．870,0．946）。将 ECPKA 和 AFP 转换为有序数据后,ECPKA＋AFP、ECPKA 和 AFP ROC 曲线下面积分别为0．931（0．897,0．967）、0．895（0．858,0．932）和0．789（0．721,0．838）。ECPKA 和 ECPKA＋AFP 的 ROC 曲线下面积均高于 AFP,u 值分别为3．38和4．70（均 P ＜0．01）;ECPKA 与ECPKA＋AFP 之间的差异无统计学意义（u＝1．41,P ＝0．079）。根据约登指数最大原则,结合 Logistic 回归结果及 ROC曲线,选择10 U／mL 为 ECPKA 的最佳临界值,此时,灵敏度为75．25％,特异度为91．87％,阳性预测值为69．72％,阴性预测值为93．72％。结论 HCC 患者血清中 ECPKA 表达显著上调,ECPKA 可能是一个新的、有价值的 HCC 诊断的替代指标。     

KLF6在肝细胞癌中的表达及在肝癌细胞系中对增殖和凋亡的影响

目的 检测抑癌基因KLF6在人肝细胞癌中的表达情况,探讨KLF6在肝癌细胞系中对细胞增殖及凋亡的影响.方法 分别用荧光定量PCR、RT-PCR 和Western blot 、免疫组织化学方法检测肝细胞癌、癌旁组织及正常肝组织中KL F6 基因mRNA 及蛋白水平的表达情况.构建KLF-6基因的真核表达质粒,用MTT法检...     

Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma

The prevalence of hepatocellular carcinoma (HCC) worldwide parallels that of persistent infection with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV). According to recommendations by the World Health Organization guidelines for HBV/HCV, alpha-fetoprotein (AFP) testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients. These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades. In recent years, however, the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010, the European Association for the Study of the Liver in 2012, and the National Comprehensive Cancer Network in 2014. Other biomarkers, including the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxyprothrombin, Dickkopf-1, midkine, and microRNA, are being studied in this regard. Furthermore, increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors. Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment. However, further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.     

肝细胞癌变过程中核转录因子-κB表达的基础与临床研究

目的观察肝细胞癌（HCC）形成过程中核转录因子-kB（NF-kB）动态改变及临床价值。方法雄性SD大鼠以2-乙酰氨基芴（2-FAA）制备肝癌模型，经病理组织学分析肝细胞形态学变化，定量观察NF-kB动态变化。并以自身配对法收集经手术切除后的肝癌及其癌周组织，定量分析肝癌组织中NF-kB表达及病理学特征。结果诱癌后肝细胞发生颗粒样变性、不典型增生、到高分化肝细胞癌形成；在此过程中，NF-kB表达呈梯度增加。NF-kB阳性表达呈棕黄色颗粒状染色，癌组织NF-kB点灶状表达，定位于胞浆和细胞核；癌周组织NF-kB主要定位于胞浆，未见细胞核阳性。人肝癌组NF-kB明显高于癌周组织（P〈0．01），癌组织NF-kB表达阳性率为100％，癌周组织为68．6％（X^2=13．1，P〈0．01）。其表达与分化程度、肿瘤数目和肿瘤直径无关。结论NF-kB表达参与肝癌的发生、发展,活性抑制可能是肝癌基因治疗的新靶点。     

原发性肝癌基因治疗的研究进展

针对原发性肝癌的传统治疗方法疗效欠佳、预后较差，基因治疗成为新的研究方向和热点。新的基因治疗策略不断涌现，载体系统不断更新，导人方法不断优化，动物模型不断改进，本文就以上方面进行综述。     

Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age

The kinase inhibitor sorafenib is the only systemic therapy proven to have a positive effect on survival of patients with advanced hepatocellular carcinoma(HCC).After development of sorafenib and its introduction as a therapeutic agent used in the clinic,several critical questions have been raised.Clinical parameters and biomarkers predicting sorafenib efficacy are the most important issues that need to be elucidated.Although it is difficult to know the responders in advance using conventional characteristics of patients,there are specific serum cytokines and/or gene amplification in tumor tissues that have been reported to predict efficacy of sorafenib.Risk and benefits of continuation of sorafenib beyond radiological progression is another issue to consider because no other standard therapy for advanced HCC as yet exists.In addition,effectiveness of the expanded application of sorafenib is still controversial,although a few studies have shed some light on combinational treatment with sorafenib for intermediate-stage HCC.Recently,over 50 relevant drugs have been developed and are currently under investigation.The efficacy of some of these drugs has been extensively examined,but none have demonstrated any superiority over sorafenib,so far.However,there are several drugs that have shown efficacy for treatment after sorafenib failure,and these are proceeding to further studies.To address these issues and questions,we have done extensive literature review and summarize the most current status of therapeutic application of sorafenib.     

人原发性肝细胞癌中总基因组DNA甲基化变化的研究

目的：研究原发性肝细胞癌组织中总基因组DNA甲基化水平及其与病理学及生物学行为的关系。方法：以甲基化酶温育3H-腺苷甲硫氨酸掺入、液闪计数法分析33例中晚期肝癌手术标本的癌灶和癌旁组织细胞内总基因组DNA甲基化水乎，并以10例正常肝组织作对照比较。结果：肝癌灶内的DNA甲基化水平显著低于癌旁组织（P＜0．05）和正常对照肝组织（P＜0．01），其甲基化水平降低程度与肿瘤的大体形态（多发性或单灶性．结节型或区块型）有关，而与组织学改变（Edmondson分级）、门脉癌栓有否及血清AFP水平无明显关系。结论：人原发性肝细胞癌组织中DNA的甲基化水平有显著降低，值得进一步研究肝细胞癌组织个别癌基因片段甲基化及mRNA表达状况。     

Glypican-3蛋白在肝细胞癌患者血清和组织中的表达及意义

目的:探讨肝细胞癌(HCC)患者血清和组织中Glypican-3(GPC3)蛋白的表达及临床意义.方法:收集HCC患者27例和肝良性病变患者28例的术前1d空腹血清及组织标本,采用Western blot检测血清中GPC3蛋白,同时采用免疫组织化学SP法检测组织标本中GPC3的表达情况.结果:27例HCC患者HCC组织、癌旁组织和远癌肝组织中GPC3蛋白阳性的表达率分别为81.5%,0%和0%(HC:23.4689,P<0.001),术前血清中GPC3蛋白阳性率分别为55.6%;28例肝良性病变患者组织和血清中阳性率均为0%;GPC3蛋白对HCC诊断的敏感性为55.6%,特异性为100%,误诊率为0%.HCC患者血清中GPC3蛋白表达与其瘤体大小和病理分级之间差异有显著性(P<0.05),而与患者年龄、性别、HBsAg及AFP值之间差异无显著性(P>0.05).结论:GPC3蛋白在HCC患者血清和组织中有较高的表达,对诊断HCC有较高的敏感性和特异性,可作为HCC早期诊断的标志物.