PIVKA-II:一种新型乙型肝炎相关肝癌诊断标记物研究进展

目的 病毒性肝炎,尤其是乙型肝炎病毒(HBV)感染是肝细胞癌(HCC)的主要致病因素。因缺乏早期症状,大部分HCC患者确诊时已为中晚期,因此预后不良。早诊断、早治疗是肝癌诊治的重要环节,现有的监测方法似乎不能显著提高肝癌的检出率。研究证实,维生素K缺失或拮抗剂-II诱导的蛋白质(PIVKA-II)有利于肝癌的早期诊断,本文对此进行了文献复习和综述。     

基于蛋白质组学筛选获得的乙型肝炎病毒相关肝癌诊断标志物的研究进展

肝癌是世界上死亡率最高的恶性肿瘤之一,乙型肝炎病毒（HBV）是主要的致病原,然而,HBV感染相关的肝癌发病机制不明,早期诊断非常困难。蛋白质组学为肝癌研究开辟了新的途径,受到研究者的关注。本文对近3年在HBV相关肝癌发病机制、肝癌标志物筛选研究方法及已发现的肝癌诊断标志物方面取得的研究成果进行了综述。     

Biomarkers for the early diagnosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the5-year survival rate is 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α.fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers,such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article,we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC.     

Biology of hepatic cancer stem cells

Hepatocellular carcinoma (HCC) is the most commonly diagnosed malignancy of the liver and is the third most frequent cause of cancer death worldwide. Although advances in HCC detection and treatment have increased the likelihood of a cure at early stages of the disease, HCC remains largely incurable because of late presentation and tumor recurrence. Only 25% of HCC patients are deemed suitable for curative treatment, with the overall survival at just a few months for inoperable patients. Additionally, this disease is particularly difficult to treat because of the high recurrence rate, its chemotherapy-resistant nature and the premalignant nature of surrounding cirrhotic liver disease. In the past few years, compelling evidence has emerged in support of the hierarchic cancer stem cell (CSC)/tumor-initiating cell (T-IC) model for solid tumors, including HCC. Understanding the characteristics and function of CSCs in the liver has also shed light on HCC management and treatment, including the implications for prognosis, prediction and treatment resistance. In this review, a detailed summary of the recent progress in liver CSC research with regard to identification, regulation and therapeutic implications will be discussed.     

肝细胞癌的综合介入治疗

肝细胞癌（HCC）是世界范围内第五大常见肿瘤,每年新增病例超过50万。由于HCC早期症状隐匿,大多数患者在确诊时已是中晚期,失去了接受治愈性治疗的机会。而中晚期HCC患者由于肝功能损伤及肿瘤进展致预后很差,目前,以肝动脉栓塞化疗术（TACE）为主的综合介入治疗已成为中晚期HCC的主要治疗方式。本文就HCC的综合介入治疗的最新进展综述如下。     

Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and humans

Chronic infection with hepatitis B virus (HBV) is associated with the majority of hepatocellular carcinoma (HCC). The diagnosis of HCC is usually made in the late stages of the disease, when treatment options are limited and prognosis is poor. We therefore have developed a method of glycoproteomic analysis in an attempt to discover serum markers that can assist in the early detection of HBV-induced liver cancer. Briefly, a comparative method for analysis of oligosaccharides released from serum glycoproteins and for recovery and identification of proteins with aberrant glycosylation, as a function of cancer diagnosis, is described. The model we have used is the woodchuck (Marmota monax), which shares similarities in the glycosylation pattern associated with liver proteins in human HCC. In this report, we show that woodchucks diagnosed with HCC have dramatically higher levels of serum-associated core alpha-1,6-linked fucose, as compared with woodchucks without a diagnosis of HCC. The coupling of this methodology with 2D gel proteomics has permitted the identification of several glycoproteins with altered glycosylation as a function of cancer. One such glycoprotein, Golgi Protein 73 (GP73), was found to be elevated and hyperfucosylated in animals with HCC. Further, the study showed GP73 to be elevated in the serum of people with a diagnosis of HCC, providing a validation of our approach. The potential of this technology for biomarker discovery and the implications of increased levels of GP73 in liver cancer are discussed.     

Hepatocellular carcinoma: Mechanisms of progression and immunotherapy

Liver cancer is one of the most common malignancies,and various pathogenic factors can lead to its occurrence and development.Among all primary liver cancers,hepatocellular carcinoma(HCC)is the most common.With extensive studies,an increasing number of molecular mechanisms that promote HCC are being discovered.Surgical resection is still the most effective treatment for patients with early HCC.However,early detection and treatment are difficult for most HCC patients,and the postoperative recurrence rate is high,resulting in poor clinical prognosis of HCC.Although immunotherapy takes longer than conventional chemotherapy to produce therapeutic effects,it persists for longer.In recent years,the emergence of many new immunotherapies,such as immune checkpoint blockade and chimeric antigen receptor T cell therapies,has given new hope for the treatment of HCC.     

Sorafenib in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the 5th most frequent tumour disease and, at the same time, the 3rd most frequent cause of death from cancer worldwide. More than 600 000 new patients are diagnosed every year and more than 80% are diagnosed at an advance stage where surgical treatment is not indicated and systemic chemotherapy does not provide longer survival time. Sorafenib is the first substance that provides proven significant prolongation of survival time of HCC patients. This is a multikinase inhibitor with anti-proliferative and anti-angiogenic properties. Its efficacy was shown in the SHARP study that enabled licensing of sorafenib for the therapy of inoperable, metastasizing hepatocellular carcinoma, including patients with liver cirrhosis, functional class Child-Pugh A or B, in more than 60 countries worldwide, including the Czech Republic. The aim of this paper is to provide a comprehensive summary of the current treatment of HCC and, at the same time, to point out some new therapeutic approaches that, in the near future, shall certainly play a major role in the treatment of HCC.     

Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy

Hepatocellular carcinoma(HCC)is a grave primary liver cancer that has a limited therapeutic option because it is generally diagnosed later in an advanced stage due to its aggressive biologic behavior.The early detection of HCC has a great impact on the treatment efficacy and survival of patients at high risk for cancer.Potential host,environmental,and virus-related risk factors have been introduced.Hepatitis B virus(HBV)is a major cause of end-stage liver diseases such as liver cirrhosis or HCC in endemic areas,and its serologic or virologic status is considered an important risk factor.HCC risk prediction derived from the identification of major risk factors is necessary for providing adequate screening/surveillance strategies to high-risk individuals.Several risk prediction models for HBV-related HCC have been presented recently with simple,efficient,and readily available to use parameters applicable to average-or unknown-risk populations as well as high-risk individuals.Predictive scoring systems of risk estimation to assess HCC development can provide the way to an evidence-based clinical approach for cost-and effort-effective outcomes,capable of inducing a personalized surveillance program according to risk stratification.In this review,the concepts and perspectives of the risk prediction of HCC are discussed through the analysis of several risk prediction models of HBV-related HCC.     

Serum markers of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with increasing incidence worldwide. Most of patients with HCC are diagnosed at a late stage. Therefore, the prognosis of HCC patients is generally very poor with a 5-year survival rate of less than 5%. Screening strategies including alpha-fetoprotein (AFP) and ultrasound every 6 months in patients with liver cirrhosis, the major risk factor for HCC development, have been recommended to detect HCC at earlier stages amenable to effective treatment strategies. AFP, however, is a marker with poor sensitivity and specificity and the ultrasound is highly dependent on the operator's experience. Apart from AFP, lens culinaris agglutinin-reactive AFP and des-gamma carboxyprothrombin and several other biomarkers (e.g., glypican-3, human hepatocyte growth factor, and insulin-like growth factor) have been proposed as markers for HCC detection. In addition, with recently employed techniques, such as gene-expressing microarrays and proteomics, it is to be expected that new HCC-specific markers will become available in the near future. For all such proposed markers, however, the clinical usefulness has to be carefully evaluated and validated.     

Mechanisms of hepatocellular carcinoma progression

Hepatocellular carcinoma(HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells,immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.     

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer, and its incidence is increasing worldwide because of the dissemination of hepatitis B and C virus infection. Patients with cirrhosis are at the highest risk and should be monitored every 6 months. Surveillance can lead to diagnosis at early stages, when the tumour might be curable by resection, liver transplantation, or percutaneous treatment. In the West and Japan, these treatments can be applied to 30% of patients, and result in 5-year survival rates higher than 50%. Resection is indicated among patients who have one tumour and well-preserved liver function. Liver transplantation benefits patients who have decompensated cirrhosis and one tumour smaller than 5 cm or three nodules smaller than 3 cm, but donor shortage greatly limits its applicability. This difficulty might be overcome by living donation. Most HCC patients are diagnosed at advanced stages and receive palliative treatments, which have been assessed in the setting of 63 randomised controlled trials during the past 25 years. Meta-analysis shows that only chemoembolisation improves survival in well-selected patients with unresectable HCC.     

肝细胞癌生物标志物的研究进展:对于临床诊断及预后的意义

肝细胞癌(HCC)是2020年癌症死亡的第三大原因,也是全球第六大常见癌症。大多数肝癌患者在就诊时已发展为晚期癌症,尽管HCC发病率很高,但对于晚期患者的治疗方案并不多,所以提高HCC患者的早期发现率非常必要。本文总结HCC中已发现的生物标志物,希望能够为肝癌的早期诊断和预后判断提供新的视角。     

Advances in non-surgical management of primary liver cancer

Hepatocellular carcinoma(HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. There have been great improvements in the diagnosis and treatment of HCC in recent years, but the problems, including difficult diagnosis at early stage, quick progression, and poor prognosis remain unsolved. Surgical resection is the mainstay of the treatment for HCC. However, 70%-80% of HCC patients are diagnosed at an advanced stage when most are ineligible for potentially curative therapies such as surgical resection and liver transplantation. In recent years, non-surgical management for unrespectable HCC, such as percutaneous ethanol injection, percutaneous microwave coagulation therapy, percutaneous radiofrequency ablation, transcatheter arterial chemoembolization, radiotherapy, chemotherapy, biotherapy, and hormonal therapy have been developed. These therapeutic options, either alone or in combination, have been shown to control tumor growth, prolong survival time, and improve quality of life to some extent. This review covers the current status and progress of non-surgical management for HCC.     

Hepatocellular carcinoma in non-cirrhotic liver: A comprehensive review

Hepatocellular carcinoma(HCC) is the most common type of primary liver cancer, which in turns accounts for the sixth most common cancer worldwide.Despite being the 6 th most common cancer it is the second leading cause of cancer related deaths. HCC typically arises in the background of cirrhosis, however,about 20% of cases can develop in a non-cirrhotic liver. This particular subgroup of HCC generally presents at an advanced stage as surveillance is not performed in a non-cirrhotic liver. HCC in non-cirrhotic patients is clinically silent in its early stages because of lack of symptoms and surveillance imaging; and higher hepatic reserve in this population. Interestingly, F3 fibrosis in non-alcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infections are associated with high risk of developing HCC. Even though considerable progress has been made in the management of this entity, there is a dire need for implementation of surveillance strategies in the patient population at risk, to decrease the disease burden at presentation and improve the prognosis of these patients. This comprehensive review details the epidemiology, risk factors, clinical features,diagnosis and management of HCC in non-cirrhotic patients and provides future directions for research.     

Hepatocellular Carcinoma: the Impact of NAFLD

The burden of chronic liver diseases including hepatocellular carcinoma (HCC) due to non-alcoholic steatohepatitis (NASH) and metabolic syndrome (MS) is increasing worldwide. Moreover, MS and its components act as co-factors in HCC development in patients with other chronic liver diseases due to high alcohol intake or hepatitis B or C infection. Patients with NASH-related HCC are frequently older; their tumors are more frequently diagnosed in non-cirrhotic livers and at an advanced stage compared to HCC due to other etiologies. Patients with MS appear also to be at risk of post-operative complications after liver resection and transplantation. However, after adjustment for tumor burden and severity of the underlying liver disease, long-term outcomes appear to be similar for NASH-related HCC and HCC due to other etiologies. Research on preventive strategies, screening programs for patients with NASH without cirrhosis but at high risk of HCC development, and new therapeutic strategies are warranted in order to respond to this emerging menace.     

蛋白质组学技术在大肠癌肿瘤标志物研究中的应用

大肠癌是人类常见的肿瘤之一,往往被诊断出时已是中晚期,预后较差.因此,早期诊断是治疗的关键,能明显改善预后.虽然当前血清CEA和CA-199等的检测已被广泛应用于大肠癌的筛选,但其缺乏特异性和敏感性,这就需要进一步寻找新的标志物.近年来,蛋白质组学的发展已深入到生命科学的各个领域,尤其应用于肿瘤研究方面,这就为我们发现新的大肠癌标志物提供了崭新的途径.本文对蛋白质组学技术在大肠癌肿瘤标志物研究中的应用进展作简要综述.     

Surveillance for early diagnosis of hepatocellular carcinoma: How best to do it?

Surveillance for hepatocellular carcinoma(HCC)is considered a standard of care for patients with chronic liver disease who are at risk of developing this malignancy.Several studies have shown that surveillance can improve the prognosis of patients diagnosed with HCC through an increased likelihood of application of curative or effective treatments.Repetition of liver ultrasonography(US)every 6 mo is the recommended surveillance program to detect early HCCs,and a positive US has to entrain a well-defined recall policy based on contrast-enhanced,dynamic radiological imaging or biopsy for the diagnosis of HCC.Although HCC fulfills the accepted criteria regarding cost-effective cancer screening and surveillance,the implementation of surveillance in clinical practice is defective and this has a negative impact on the cost-effectiveness of the procedure.Education of both physicians and patients is of paramount importance in order to improve the surveillance application and its benefits in patients at risk of HCC.The promotion of specific educational programs for practitioners,clinicians and patients is instrumental in order to expand the correct use of surveillance in clinical practice and eventually improve HCC prognosis.     

NAFLD-Associated Hepatocellular Carcinoma: a Threat to Patients with Metabolic Disorders

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and its prevalence is increasing in relation to the epidemics of obesity and type 2 diabetes mellitus, via non-alcoholic fatty liver disease (NAFLD). Unhealthy lifestyles associated with metabolic disorders are per se risk conditions for NAFLD progression, and specific gene polymorphisms may also favor oncogenesis, particularly in the presence of advanced fibrosis or cryptogenic cirrhosis. However, NAFLD-associated HCC may also develop in non-cirrhotic NAFLD and is frequently diagnosed at a more advanced tumor stage, compared with virus/alcohol-related HCC. This highlights the need for screening programs and long-term surveillance for earlier HCC detection in patients with metabolic risk factors, a policy hindered by the large number of cases at risk, with costs unaffordable by National health systems. New screening tools and cost-utility studies are eagerly awaited to develop more appropriate programs for early detection and treatment of NAFLD-associated HCC.     

Current impact of viral hepatitis on liver cancer development: The challenge remains

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma (HCC) worldwide, and this association is likely to remain during the next decade. Moreover, viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years. In order to reduce such a burden, some major challenges must be faced. Universal vaccination against hepatitis B virus, especially in the neonatal period, is probably the most relevant primary preventive measure against the development of HCC. Moreover, considering the large adult population already infected with hepatitis B and C viruses, it is also imperative to identify these individuals to ensure their access to treatment. Both hepatitis B and C currently have highly effective therapies, which are able to diminish the risk of development of liver cancer. Finally, it is essential for individuals at high-risk of HCC to be included in surveillance programs, so that tumors are detected at an early stage. Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program. As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis, other high-risk groups of patients with hepatitis B are also candidates for surveillance. Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.