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.     

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.     

Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment

Hepatocellular carcinoma(HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or Cinfection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase Ⅰ clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC.     

Hepatocellular carcinoma surveillance:An evidence-based approach

Hepatocellular carcinoma(HCC) makes up 75%-85% of all primary liver cancers and is the fourth most common cause of cancer related death worldwide. Chronic liver disease is the most significant risk factor for HCC with 80%-90% of new cases occurring in the background of cirrhosis. Studies have shown that early diagnosis of HCC through surveillance programs improve prognosis and availability of curative therapies. All patients with cirrhosis and high-risk hepatitis B patients are at risk for HCC and should undergo surveillance. The recommended surveillance modality is abdominal ultrasound(US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with non-alcoholic fatty liver disease(NAFLD). With the current obesity epidemic and rise in the prevalence of NAFLD, abdominal computed tomography or magnetic resonance imaging may be indicated as the primary screening modality in these patients. The addition of alpha-fetoprotein to a surveillance regimen is thought to improve the sensitivity of HCC detection.Further investigation of serum biomarkers is needed. Semiannual screening is the suggested surveillance interval. Surveillance for HCC is underutilized and low adherence disproportionately affects certain demographics such as nonCaucasian race and low socioeconomic status.     

Is inconsistency of α-fetoprotein level a good prognosticator for hepatocellular carcinoma recurrence?

AIM: To identify the clinical outcomes of hepatocellular carcinoma (HCC) patients with inconsistent α-fetoprotein (AFP) levels which were initially high and then low at recurrence.METHODS: We retrospectively included 178 patients who underwent liver resection with high preoperative AFP levels (≥ 200 ng/dL). Sixty-nine HCC patients had recurrence during follow-up and were grouped by their AFP levels at recurrence: group I, AFP ≤ 20 ng/dL (n = 16); group II, AFP 20-200 ng/dL (n = 24); and group III, AFP ≥ 200 ng/dL (n = 29). Their preoperative clinical characteristics, accumulated recurrence rate, and recurrence-to-death survival rate were compared. Three patients, one in each group, underwent liver resection twice for primary and recurrent HCC. AFP immunohistochemistry of primary and recurrent HCC specimens were examined.RESULTS: In this study, 23% of patients demonstrated normal AFP levels at HCC recurrence. The AFP levels in these patients were initially high. There were no significant differences in clinical characteristics between the three groups except for the mean recurrence interval (21.8 ± 14.6, 12.3 ± 7.7, 8.3 ± 6.6 mo, respectively, P < 0.001) and survival time (40.2 ± 19.9, 36.1 ± 22.4, 21.9 ± 22.0 mo, respectively, P = 0.013). Tumor size > 5 cm, total bilirubin > 1.2 mg/dL, vessel invasion, Child classification B, group III, and recurrence interval < 12 mo, were risk factors for survival rate. Cox regression analysis was performed and vessel invasion, group III, and recurrence interval were independent risk factors. The recurrence interval was significant longer in group I (P < 0.001). The recurrence-to-death survival rate was significantly better in group II (P = 0.016). AFP staining was strong in the primary HCC specimens and was reduced at recurrence in group I specimens.CONCLUSION: Patients in group I with inconsistent AFP levels had a longer recurrence interval and worse recurrence-to-death survival rate than those in group II. This clinical presentation may be caused by a delay in the detection of HCC recurrence.     

Diagnostic and therapeutic management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is an increasing health problem, representing the second cause of cancerrelated mortality worldwide. The major risk factorfor HCC is cirrhosis. In developing countries, viral hepatitis represent the major risk factor, whereas in developed countries, the epidemic of obesity, diabetes and nonalcoholic steatohepatitis contribute to the observed increase in HCC incidence. Cirrhotic patients are recommended to undergo HCC surveillance by abdominal ultrasounds at 6-mo intervals. The current diagnostic algorithms for HCC rely on typical radiological hallmarks in dynamic contrast-enhanced imaging, while the use of α-fetoprotein as an independent tool for HCC surveillance is not recommended by current guidelines due to its low sensitivity and specificity. Early diagnosis is crucial for curative treatments. Surgical resection, radiofrequency ablation and liver transplantation are considered the cornerstones of curative therapy, while for patients with more advanced HCC recommended options include sorafenib and trans-arterial chemoembolization. A multidisciplinary team, consisting of hepatologists, surgeons, radiologists, oncologists and pathologists, is fundamental for a correct management. In this paper, we review the diagnostic and therapeutic management of HCC, with a focus on the most recent evidences and recommendations from guidelines.     

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.     

Poor prognosis for hepatocellular carcinoma with transarterial chemoembolization pre-transplantation:Retrospective analysis

AIM: To investigate whether transarterial chemoembolization(TACE) before liver transplantation(LT) improves long-term survival in hepatocellular carcinoma(HCC) patients.METHODS: A retrospective study was conducted among 204 patients with HCC who received LT from January 2002 to December 2010 in PLA General Hospital. Among them, 88 patients received TACE before LT. Prognostic factors of serum α-fetoprotein(AFP), intraoperative blood loss, intraoperative blood transfusion, disease-free survival time, survival time with tumor, number of tumor nodules, tumor size, tumor number, presence of blood vessels and bile duct invasion, lymph node metastasis, degree of tumor differentiation, and preoperative liver function were determined in accordance with the Child-TurcottePugh(Child) classification and model for end-stage liver disease. We also determined time of TACE before transplant surgery and tumor recurrence and metastasis according to different organs. Cumulative survival rate and disease-free survival rate curves were prepared using the Kaplan-Meier method, and the logrank and χ2 tests were used for comparisons.RESULTS: In patients with and without TACE before LT, the 1, 3 and 5-year cumulative survival rate was 70.5% ± 4.9% vs 91.4% ± 2.6%, 53.3% ± 6.0% vs 83.1% ± 3.9%, and 46.2% ± 7.0% vs 80.8% ± 4.5%, respectively. The median survival time of patients with and without TACE was 51.857 ± 5.042 mo vs 80.930 ± 3.308 mo(χ2 = 22.547, P < 0.001, P < 0.05). The 1, 3 and 5-year disease-free survival rates for patients with and without TACE before LT were 62.3% ± 5.2% vs98.9% ± 3.0%, 48.7% ± 6.7% vs 82.1% ± 4.1%, and 48.7% ± 6.7% vs 82.1% ± 4.1%, respectively. The median survival time of patients with and without TACE before LT was 50.386 ± 4.901 mo vs 80.281 ± 3.216 mo(χ2 = 22.063, P < 0.001, P < 0.05). TACE before LT can easily lead to pulmonary or distant metastasis of the primary tumor. Although there was no significant difference between the two groups, the chance of metastasis of the primary tumor in the group with TACE was significantly higher than that of the group without TACE.CONCLUSION: TACE pre-LT for HCC patients increased the chances of pulmonary or distant metastasis of the primary tumor, thus reducing the long-term survival rate.     

Should a radiological diagnosis of hepatocellular carcinoma be routinely confirmed by a biopsy? Yes

Hepatocellular carcinoma (HCC) represents approximately 85 to 90% of all primary liver cancers (PLC) and every year, more than 560,000 people are diagnosed as affected by this cancer.The identification of risk factors for HCC prompted the creation of screening and surveillance programs in patients affected by chronic liver diseases with the aim of detecting HCC nodules as soon as possible and provide effective and hopefully curative therapyA correct diagnosis is of paramount importance for the surveillance program as well as for the choice of the appropriate therapy. Both in the diagnosis of small HCC and in the choice of the therapy for locally advanced HCC the diagnosis must be certain.Improvements of the radiological imagine techniques have surely enhanced both early diagnosis and tumor staging, allowing a reasonably accurate diagnosis, but cannot provide the certainty that in clinical practice is essential for an adequate workout.Therefore, the histopatological definition of the tumor is imperative both for an appropriate therapy and for an accurate prognostic evaluation.     

Hepatocellular carcinoma-specific immunotherapy with synthesized α1,3-galactosyl epitope-pulsed dendritic cells and cytokine-induced killer cells

AIM: To evaluate the safety and clinical efficacy of a new immunotherapy using both α-Gal epitope-pulsed dendritic cells (DCs) and cytokine-induced killer cells.METHODS: Freshly collected hepatocellular carcinoma(HCC) tumor tissues were incubated with a mixture of neuraminidase and recombinant α1,3-galactosyltransferase (α1,3GT) to synthesize α-Gal epitopes on carbohydrate chains of the glycoproteins of tumor membranes. The subsequent incubation of the processed membranes in the presence of human natural an...     

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.     

Assessment of the correlation between serum prolidase and alpha-fetoprotein levels in patients with hepatocellular carcinoma

AIM: To determine the predictive value of increased prolidase activity that reflects increased collagen turnover in patients with hepatocellular carcinoma(HCC).METHODS: Sixty-eight patients with HCC(mean age of 69.1 ± 10.1), 31 cirrhosis patients(mean age of59.3 ± 6.3) and 33 healthy volunteers(mean age of51.4 ± 12.6) were enrolled in this study. Univariate and multivariate analysis were used to evaluate the association of serum α-fetoprotein(AFP) values with HCC clinicopathological features, such as tumor size,number and presence of vascular and macrovascular invasion. The patients with HCC were divided into groups according to tumor size, number and presence of vascular invasion(diameters; ≤ 3 cm, 3-5 cmand ≥ 5 cm, number; 1, 2 and ≥ 3, macrovascular invasion; yes/no). Barcelona-clinic liver cancer(BCLC)criteria were used to stage HCC patients. Serum samples for measurement of prolidase and alphafetoprotein levels were kept at-80 ℃ until use.Prolidase levels were measured spectrophotometrically and AFP concentrations were determined by a chemiluminescence immunometric commercial diagnostic assay.RESULTS: In patients with HCC, prolidase and AFP values were evaluated according to tumor size, number,presence of macrovascular invasion and BCLC staging classification. Prolidase values were significantly higher in patients with HCC compared with controls(P 0.001). Prolidase levels were significantly associated with tumor size and number(P 0.001, P = 0.002,respectively). Prolidase levels also differed in patients in terms of BCLC staging classification(P 0.001).Furthermore the prolidase levels in HCC patients showed a significant difference compared with patients with cirrhosis(P 0.001). In HCC patients grouped according to tumor size, number and BCLC staging classification, AFP values differed separately(P = 0.032,P = 0.038, P = 0.015, respectively). In patients with HCC, there was a significant correlation(r = 0.616; P 0.001) between prolidase and AFP values in terms of tumor size, number and BCLC staging classification,whereas the presence of macrovascular invasion did not show a positive association with serum prolidase and AFP levels.CONCLUSION: Considering the levels of both serum prolidase and AFP could contribute to the early diagnosing of hepatocellular carcinoma.     

Surveillance for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) appears mainly in patients with underlying liver disease and it is recognized as one of the most important causes of death in this population. Early detection by surveillance has been suggested as an effective tool for reducing cancer-specific mortality and the most accepted strategy is semiannual abdominal ultrasound in those patients at risk of HCC development. The benefit of HCC surveillance is proven by a randomized-controlled study, several prospective or retrospective analyses, and multiple modeling studies and according to the current scientific evidence, surveillance of HCC should be recommended and widely implemented. Major efforts should be done for improving the diagnostic accuracy of the screening tools and for better identifying those patients at risk of HCC development in whom a surveillance program would be cost-effective.     

Hepatocellular carcinoma in Korea: introduction and overview]

Hepatocellular carcinoma (HCC) is a highly malignant, generally fatal neoplasm arising from hepatocytes. HCC accounts for over 80% of all primary liver cancers which ranks fourth among the organ-specific causes of cancer-related deaths worldwide. HCC is particularly prevalent in Korea where the age standardized incidence rate is 46.5 per 100,000 population. Infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) or presence of liver cirrhosis are important risk factors for HCC development globally. Infection with HBV is the most important risk for HCC in Asia except Japan. The high incidence rate of HCC in Korea is thought to be related to the high carrier rate (5-6%) of HBV, which is currently being fought via a nationwide vaccination program. Although progress has been made in the management of HCC including chemoembolization and local ablation therapy, there has been little overall reduction in HCC mortality during the past 20 years. Recently, five year survival rate of primary liver cancer is 9.6% in Korea. Such poor prognosis of HCC results from the late detection of cancer, an aggressive tumor biology and underlying chronic liver diseases. Only a limited proportion of patients are candidates for potentially curative forms of treatment. Therefore efforts should be directed toward an effective surveillance program. The early detection of HCC is the important approach in reducing HCC mortality in the short term. Because almost eighty percent of HCC is diagnosed in late stage, we launched a nationwide surveillance program to screen high risk groups (HBV or HCV carriers or liver cirrhosis, over 40 years old) and formulated the Korean practice guideline for the diagnosis and treatment of HCC with special emphasis on advanced stage of HCC.     

Prostate-specific membrane antigen expression in hepatocellular carcinoma,cholangiocarcinoma, and liver cirrhosis

BACKGROUNDPrimary liver cancer includes three subtypes: Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and combined hepatocellular carcinoma. Patients with primary liver cancer experienced poor prognosis and high mortality, so early detection of liver cancer and improved management of metastases are both key strategies to reduce the death toll from liver cancer. Prostate-specific membrane antigen (PSMA) expression in the tumor-associated neovasculature of nonprostate malignancies including liver cancer has been reported recently, but conclusive evidence of PSMA expression based on the pathological type of liver cancer remains limited.AIMTo study the expression of PSMA in HCC, CCA, and liver cirrhosis.METHODSA total of 446 formalin-fixed paraffin-embedded (FFPE) liver tumor and liver cirrhosis tissue samples were obtained retrospectively from the Pathology Department of Tongji Hospital. Immunohistochemistry was used to detect PSMA expression in these 446 FFPE liver biopsy specimens (213 HCC, 203 CCA, and 30 liver cirrhosis). The tumor compartment and the associated neovascular endothelium were separately analyzed. PSMA expression was examined by two certified pathologists, and the final results were presented in a 4-point scoring system (0-3 points). Correlation between PSMA expression and clinicopathological information was also assessed.RESULTSPSMA was expressed primarily in the neovascular endothelium associated with tumors. The positive rate of PSMA staining in HCC was significantly higher than that in CCA (86.8% vs 79.3%; P = 0.001) but was only 6.6% in liver cirrhosis (P = 0.000). HCC cases had more 3-score PSMA staining than CCA had (89/213, 41.8% vs 35/203, 17.2%; P = 0.001). PSMA expression correlated positively with the stage and grade of HCC and CCA. In both liver cancer subtypes, there were more PSMA⁺ cases in stages III–V diseases than in stages I and II. High staining intensity of PSMA was more frequently observed in liver cancers at high grade and advanced stage. There was no significant association of PSMA expression with sex, age, region, α-fetoprotein, hepatitis B surface antigen, or tumor size in both tumor subtypes.CONCLUSIONNeovascular PSMA may be a promising marker to differentiate HCC from liver cirrhosis and a prognostic marker for anti-tumor angiogenesis therapy for HCC.     

肝细胞癌患者血浆SPINK1水平及其与患者预后的关系分析

目的 分析肝细胞癌（HCC）患者血浆丝氨酸蛋白酶抑制剂Kazal 1型（SPINK1）水平及与其患者术后预后的关系。方法 2014年5月~2015年9月我院收治的HCC患者80例、肝硬化患者40例,选择正常人30例,所有纳入对象在晨起空腹取静脉血,采用ELISA法测定血浆SPINK1和甲胎蛋白（AFP）水平,绘制受试者工作特征曲线（ROC）,评价血浆SPINK1和AFP对HCC的诊断效能,并分析术前血浆SPINK1水平与HCC患者预后的关系。结果 HCC患者血浆SPINK1为（2.4±0.3） μg/L,显著高于肝硬化患者的（2.0±0.2） μg/L或正常人的（1.3±0.1） μg/L,肝硬化患者血浆SPINK1水平显著高于正常人（P<0.05）;HCC患者血浆AFP水平为（125.7±14.5） μg/L,显著高于肝硬化患者的（35.4±4.2）μg/L或正常人的【（3.6±0.5）μg/L,P<0.05】;ROC曲线分析结果显示,以1.70 μg/L为截断点,血浆SPINK1水平诊断HCC的灵敏度为77.2%,特异度为67.6%,而以最佳截断点为124.8μg/L,血浆AFP 水平则分别为63.4%和62.5%;42例术前血浆SPINK1水平>1.7 μg/L的HCC患者术后总生存期（OS）为（12.2±1.3） m,无瘤生存期（DFS）为（11.2±1.2） m,显著短于38例血浆SPINK1<1.7 μg/L组的（20.5±2.1） m和（15.7±1.9） m,而复发率为38.1%,显著高于术前血浆SPINK1<1.7 μg/L患者的18.4%（x²=5.18,P<0.05）。结论 HCC患者血浆SPINK1呈高水平状态,SPINK1诊断HCC的灵敏度、特异度较AFP高,且SPINK1与HCC患者预后密切相关,临床可将其作为HCC肿瘤标志物。     

Diagnostic Value of Serum Level of Soluble Tumor Necrosis Factor Receptor IIα in Egyptian Patients With Chronic Hepatitis C Virus Infection and Hepatocellular Carcinoma

Background:

The prognosis of hepatocellular carcinoma (HCC) is unfavorable and needs serum markers that could detect it early to start therapy at a potentially curable phase.

Objectives:

The aim of this study was to determine the value of serum soluble tumor necrosis factor (TNF) receptor-IIα (sTNFR-IIα) in diagnosis of HCC in patients with chronic hepatitis C virus (HCV) infection.

Patients and Methods:

The study was performed on 110 subjects who were classified into five groups. Group I included 20 patients with chronic noncirrhotic HCV infection and persistently normal transaminases for ≥6 months. Group II included 20 patients with chronic noncirrhotic HCV infection and elevated transaminases. Group III included 20 patients with Chronic HCV infection and liver cirrhosis. Group IV included 20 patients with chronic HCV infection with liver cirrhosis and HCC. Group V included 30 healthy age and sex-matched controls. Medical history was taken from all participants and they underwent clinical examination and abdominal ultrasonography. in addition, the following laboratory tests were requested: liver function tests, complete blood count, HBsAg, anti-HCVAb, HCV-RNA by qualitative PCR, and serum levels of α-fetoprotein (AFP) and sTNFR-IIα.

Results:

The serum level of sTNFR-IIα was significantly higher in patients with HCC in comparison to the other groups. A positive correlation was found between the serum levels of sTNFR-IIα and AST and ALT in patients of group-II. Diagnosis of HCC among patients with HCV infection and cirrhosis could be ascertained when sTNFR-IIα is assessed at a cutoff value of ≥ 250 pg/mL.

Conclusions:

Serum sTNFR-IIα could be used as a potential serum marker in diagnosing HCC among patients with HCV infection.     

Value of α-fetoprotein in association with clinicopathological features of hepatocellular carcinoma

AIM:To explore the relationship between α-fetoprotein(AFP) and various clinicopathological variables and different staging system of hepatocellular carcinoma(HCC) thoroughly.METHODS:A retrospective cohort study of consecutive patients diagnosed with HCC between January 2008 and December 2009 in West China Hospital was enrolled in our study.The association of serum AFP values with the HCC clinicopathological features was analysed by univariate and multivariate analysis,such as status of hepatitis B virus(HBV) infection,tumor size,tumor number,vascular invasion and degree of tumor differentiation.Also,patients were divided into four groups at the time of enrollment according to different cutoff values for serum value of AFP(≤ 20 μg/L,21-400 μg/L,401-800 μg/L,and ≥ 801 μg/L),to compare the positive rate of patient among four groups stratified by various clinicopathological variables.And the correlation of different kinds of tumor staging systems,such as TNM,Barcelona Clinic Liver Cancer(BCLC) staging classification and China staging,were compared with the serum concentration of AFP.RESULTS:A total of 2304 HCC patients were enrolled in this study totally;the mean serum level of AFP was 555.3 ± 546.6 μg/L.AFP levels were within the normal range(< 20 μg/L) in 27.4%(n = 631) of all the cases.81.4%(n = 1875) patients were infected with HBV,and those patients had much higher serum AFP level compared with non-HBV infection ones(573.9 ± 547.7 μg/L vs 398.4 ± 522.3 μg/L,P < 0.001).The AFP level in tumors ≥ 10 cm(808.4 ± 529.2 μg/L) was significantly higher(P < 0.001) than those with tumor size 5-10 cm(499.5 ± 536.4 μg/L) and with tumor size ≤ 5 cm(444.9 ± 514.2 μg/L).AFP levels increased significantly in patients with vascular invasion(694.1 ± 546.9 μg/L vs 502.1 ± 543.1 μg/L,P < 0.001).Patients with low tumor cell differentiation(559.2 ± 545.7 μg/L) had the significantly(P = 0.007) highest AFP level compared with high differentiation(207.3 ± 420.8 μg/L) and intermediate differe     

Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy

The incidence and mortality of hepatocellular carcinoma(HCC) have fallen dramatically in China and elsewhere over the past several decades. Nonetheless, HCC remains a major public health issue as one of the most common malignant tumors worldwide and one of the leading causes of death caused by cancer in China. Hepatocarcinogenesis is a very complex biological process associated with many environmental risk factors and factors in heredity, including abnormal activation of cellular and molecular signaling pathways such as Wnt/β-catenin, hedgehog, MAPK, AKT, and ERK signaling pathways, and the balance between the activation and inactivation of the proto-oncogenes and anti-oncogenes, and the differentiation of liver cancer stem cells. Molecule-targeted therapy, a new approach for the treatment of liver cancer, blocks the growth of cancer cells by interfering with the molecules required for carcinogenesis and tumor growth, making it both specific and selective. However, there is no one drug completely designed for liver cancer, and further development in the research of liver cancer targeted drugs is now almost stagnant. The purpose of this review is to discuss recent advances in our understanding of the molecular mechanisms underlying the development of HCC and in the development of novel strategies for cancer therapeutics.