Comparison of laparoscopic vs open liver Iobectomy （segmentectomy） for hepatocellular carcinoma

AIM:To investigate the effects of laparoscopic hepa-tectomy for the treatment of hepatocellular carcinoma(HCC) .METHODS:From 2006 to January 2011,laparoscopic hepatectomies were performed on 30 cases of HCC at Northern Jiangsu People's Hospital. During this sametime period,30 patients elected to undergo conventional open hepatectomy over laparoscopic hepatectomy at the time of informed consent. The degree of invasiveness and outcomes of laparoscopic hepatectomy compared to open hepatectomy for HCC wereevalu...     

Brain metastasis of hepatocellular carcinoma： A case report and review of the literature

INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most frequent malignancies in the world.     

Expression of β-catenin in hepatocellular carcinoma

AIM: The β-catenin has been recognized as a critical member of the Wnt signaling pathway and plays an important role in the generation/differentiation of many tissues. Inappropriate activation of this pathway has been implicated in carcinogenesis. The mechanism underlying the development as well as its prognosis of hepatocellular carcinoma (HCC) has remained unclear. The purpose of this study is to analyze the expression of β-catenin in HCC in relation to histological grades and viral hepatitis backgrounds. METHODS: Thirty-two sections were selected at random from autopsy and surgical cases of HCC. Immuohistologically, the location and positivity of β-catenin expression in HCC was examined. RESULTS: Normal hepatocytes did not express β-catenin. In 78% of HCC β-catenin was expressed at the membrane of the cells, with or without cytoplasmic and/or nuclear expression. The tumor cells with well- and moderately-differentiated grades expressed frequently at the membrane and cytoplasm compared with poorly-differentiated type. Nuclear expression of β-catenin was prone to occur in the tumor cells of poorly-differentiated grade. There were 15% of hepatitis C virus (HCV) backgrounds with nuclear expression. In contrast, there was 38% with nuclear expression in hepatitis B virus (HBV) backgrounds. In nonBnonC hepatitis, no case expressed nuclear β-catenin. CONCLUSION: The β-catenin expression in HCC cells was heterogenous among types of hepatitis viral infection. Wnt signaling pathway might be deeply involved in less-differentiated HCC and HBV background.     

Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma： Possible role in tumor promotion and angiogenesis

AIM: To investigate the association of cyclooxygenase-2 (COX-2) expression with angiogenesis and the number and type of inflammatory cells (macrophages/Kupffer cells; mast cells) within primary hepatocellular carcinoma (HCC) tissues and adjacent non-tumorous (NT) tissues. METHODS: Immunohistochemistry for COX-2, CD34, CD68 and mast cell tryptase (MCT) was performed on 14 well-characterized series of liver-cirrhosis-associated HCC patients. COX-2 expression and the number of inflammatory cells in tumor lesions and surrounding liver tissues of each specimen were compared. Moreover, COX-2, CD34 staining and the number of inflammatory cells in areas with different histological degrees within each tumor sample were comparatively analyzed. RESULTS: The percentage of COX-2 positive cells was significantly higher in NT tissues than in tumors. COX-2 expression was higher in well-differentiated HCC than in poorly-differentiated tissues. Few mast cells were observed within the tumor mass, whereas a higher number was observed in the surrounding tissue, especially in peri-portal spaces of NT tissues. Abundant macrophages/ Kupffer cells were observed in NT tissues, whereas the number of cells was significantly lower in the tumor mass. However, a higher cell number was observed in the well-differentiated tumor and progressively decreased in relation to the differentiation grade. Within the tumor, a positive correlation was found between COX-2 expression and the number of macrophages/Kupffer cells and mast cells. Moreover, there was a positive correlation between CD34 and COX-2 expression in tumor tissues. Comparison between well- and poorly-differentiated HCC showed that the number of CD34-positive cells decreased with dedifferentiation. However, COX-2 was the only independent variable showing a positive correlation with CD34 in a multivariate analysis. CONCLUSION: The presence of inflammatory cells and COX-2 expression in liver tumor suggests a possible relationship with tumor angiogenesis. COX-2 expressing cells and the number of macrophages/Kupffer cells and mast cells decrease with progression of the disease.     

Overexpression of p28／gankyrin in human hepatocellular carcinoma and its clinical significance

AIM：To investigate the expression of p28/gankyringene and its role in the carcinogenetic process of human hepatocellular carcinoma(HCC).METHODS:64specimens of HCC and para-carcinoma tissues,22specimens of non-tumor liver tissues(7normal,15cirrhosis),10 specimens of normal human tissues and 5hepatoma cell lines were studied for the expression of p28/gankyrinby Northern blot.The expressionof p28/gankyrin protein was detected immunohistochemically by using the specific polyclonal antibody.RESULTS:Northern blot analysis indicated that the expression of p28/gankyrinmRNA was intensively distributed in brain and heart,weakly in lung,spleen and muscle,undetectable in digestive system including liver,pancreas,stomach,small and large intestines.p28/gankyrinmRNAwas absent in normal liver,weakly detected in liver cirrhosis and in 18of 64para-carcinoma liver tissues.In contrast,the expression of p28/gankyrinmRNA was intensitely detected in all5hepatoma cell lines tested,markedly increased in 57of 64and moderately increased in 5of64HCCsamples.In comparison with liver cirrhosis and para-carcinoma liver tissues.the average expression of p28/gankyrinmRNAin HCCwas increased3.6-(2.901±0.507vs0.805±0.252,P<0.05)and5.2-fold(2.901±0.507vs0.557±0.203,p<0.01),respectively.In addition,p28/gankyrinmRNA expression level was higher in HCCwith portal vein tumor thrombus and microscopic hepatic vein involvement(P=0.021and P=0.047,respectively).Theoverexpression of p28/gankyrin protein in HCCwas targeted in hepatic tumor cells,not in bile duct cells and other interstitial cells.Plays an important role and contributes to the metastasis potential in the process of carcinogenesis.p28/gankyrinmay become a specific biological tissue marker for the pathological diagnosis of HCC.     

Inhibitory effects of antisense RNA of HAb18G／CD147 on invasion of hepatocellular carcinoma cells in vitro

AIM: To study the inhibitory effects of antisense RNA of HAb18G/CD147 on invasion of hepatocellular carcinoma(HCC) cells in vitro. METHODS: Antisense RNA of HAb18G/CD147 vector PCI-asHAb18G was constructed by reversely inserting HAb18G/CD147 cDNA to eukaryotic expression vector PCI-neo. The HCC cell line HHCC was transfected by PCI-asHAb18G via cation liposome. Expression of HAb18G/CD147 of transfected cells selected by G418 (geneticin) was observed by immuno-histochemical SP staining and FACS (fluorescence activated cell sorting). Gelatin zymography was used to determine the effect of PCI-asHAb18G on reducing secretions of MMP-2 and MMP-9 of the transfected cells. Boyden chamber was employed to test the invasion of HCC cells in vitro. RESULTS: The construction of antisense RNA vector PCI-asHAb18G was verified correct by partial nucleotide sequencing and restricted endonuclease digestion. The expression of HAb18G/CD147 in transfected HHCC was inhibited by PCI-asHAb18G. Secretions of MMP-2 and MMP-9 of transfected HHCC were reduced and the invasion of transfected HHCC was inhibited compared to HHCC, respectively. CONCLUSION: Invasion of HCC cells can be inhibited by antisense RNA of HAb18G/CD147. HAb18G/CD147 may be used as a potential target of drugs for anti-invasion and metastasis of HCC.     

Association between the presence of H pylori in the liver and hepatocellular carcinoma： A meta-analysis

AIM： To evaluate the arguments for and against the possible roles of H pylori in hepatocellular carcinoma （HCC）.
METHODS： We performed a systematic review of all relevant studies published in the literature. A total of 103 clinical trials and reports were identified, but only 10 trials qualified under our selection criteria. A metaanalysis was carried out by a biostatistician according to the Cochrane Reviewers＇ Handbook recommended by The Cochrane Collaboration.
RESULTS： Nine case-control studies and one retrospective cross sectional study were included in the final analysis. Overall the prevalence of H pylori infection was 53.3% （129 of 242） in cases and 10.4% （29 of 280） in controls, and the summary odds ratio for the association of H pylori infection with the risk for HCC （using the fixed-effects model, which accounted for the homogeneity across the 10 studies） was determined to be 13.63 （95% CI, 7.90-23.49）.
CONCLUSION： Our analysis showed a positive association between F1 pylori infection and the risk of HCC, with an indication of possible publication bias and possible confounders due to study designs that showed results of less pronounced associations.     

Useful detection of CD147 （EMMPRIN） for pathological diagnosis of early hepatocellular carcinoma in needle biopsy samples

AIM To make clear whether CD147 (EMMPRIN)expression in pathological tumor samples with a fineneedle aspiration biopsy is useful for pathological diagnosis of early hepatocellular carcinoma (HCC).METHODS Twenty-two patients (15 men and 7 women;median age 68 years, range 56-81 years) underwent a liver tissue biopsy in order to make a diagnosis of HCC.Paraffin-embedded liver biopsy tissue samples from 22 patients were stained with anti-CD147 antibody,murine monoclonal antibody 12C3 (MAb12C3) for immunohistochemical analysis. An immunohistochemical analysis of CD147 was performed and the degree of staining compared between tumor and non-tumor tissue. In addition, the degree of staining within tumor tissue was compared according to a number of clinicopathological variables.RESULTS The degree of staining of CD147 was significantly higher in tumor tissues than non-tumor tissues, even in tumors less than 15 mm in diameter.The expression of this protein was significantly elevated in HCC tissue specimens from patients with a low value of serum AST and γ-GTP.CONCLUSION CD147 serves potentially as a pathological target for cancer detection of early HCC.     

Gadoxetic acid-enhanced MRI of macrotrabecular-massive hepatocellular carcinoma and its prognostic implications

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血清可溶性Endogin对肝硬化和肝细胞癌的诊断和鉴别诊断价值研究

目的 探讨肝硬化和肝细胞癌（HCC）患者血清可溶性Endogin（sEng）水平差异及其对鉴别诊断的临床意义。方法 2009年6月至2014年6月在我院就诊的乙型肝炎肝硬化患者77例、HCC患者54例和健康人36例,采用化学发光法检测血清甲胎蛋白（AFP）水平;采用ELISA法检测血清sEng;sEng与临床指标的相关性检验采用Pearson或Spearman相关分析;采用受试者工作特征曲线下面积（AUC）评价sEng及其联合AFP检测诊断HCC的价值;观察不同sEng水平的HCC患者3 a生存率的差异。结果 HCC患者血清sEng水平为19.71（15.16～23.56） ng/L,显著高于肝硬化患者[6.42（4.23～9.89） ng/L]和健康人[2.83（2.28～3.30） ng/L,P<0.05];HCC患者sEng与AFP水平呈正相关（r=0.660,P＜0.001）;sEng或sEng联合AFP鉴别HCC与健康人的AUC分别为0.912（95%CI：0.851～0.973）和0.951（95%CI：0.911～0.992）;sEng或sEng联合AFP鉴别HCC与肝硬化的AUC分别为0.849（95%CI：0.778～0.920）和0.920（95%CI：0.867～0.972）;高血清sEng水平（≥20.0ng/L）的HCC患者3 a生存率（24.0%）显著低于低血清sEng水平（<20.0 ng/L）者（41.4%,P<0.05）。结论 肝硬化与HCC患者血清sEng水平存在差异,可作为HCC患者诊断的参考指标。     

浸润性肺腺癌中Endoglin(CD105)的表达和血管新生状态研究

目的:对浸润性肺腺癌进行CD105的表达和血管新生状态研究,为在浸润性肺腺癌中,针对CD105的抗血管新生治疗的可能提供病理形态依据。方法:对46例浸润性肺腺癌标本进行CD31和CD105的免疫组化染色,测定肿瘤内区域及肿瘤旁形态正常肺泡组织的微脉管密度(MVD)。结果:在肿瘤旁形态正常肺泡组织中,平均MVD-CD31是106.7±41.0,在肿瘤内区域是54.5±22.6。在肿瘤旁形态正常肺泡组织中平均MVD-CD105是0.5±0.4,在肿瘤内区域是43.1±19.8。在肿瘤旁形态正常肺泡组织中MVD-CD105与MVD-CD31的比值是0.004±0.003,而在肿瘤内区域是0.781±0.104。两者之间比较差异有统计学意义(P<0.000 1)。结论:在浸润性肺腺癌肿瘤区域内血管特异性表达CD105。此发现可能会对未来以CD105为靶点的抗血管新生治疗,在浸润性肺腺癌中的应用,提供病理形态学依据。     

肝细胞肝癌微血管密度与雌激素受体表达的临床病理意义

研究肝细胞肝癌(Hepatocellular Carcinoma,HCC)微血管密度(Microvessel Density,MVD)与雌激素受体(Estrogen Receptor,ER)表达之间的关系,以及此二者与临床病理学特征之间的关系.36例HCC的患者分为ER(+)组和ER(-)组.按MVD值分为MVD＜中位值组和MVD＞中位值组,比较各组有预后意义的临床病理学参数之间的差别.ER(+)14例,ER(-)22例.全组MVD自3至121(44.67±32.15中位值为36).ER(+)的HCC为直径较小、多有完整的包膜和较低的血清AFP浓度.MVD较低的HCC多为单结节、直径较小、细胞分化较好、血清AFP浓度较低.ER含量与MVD呈负相关.由此可见(1)ER(+)或MVD较低的HCC分别比ER(-)或MVD较高的HCC恶性度较低.(2)ER与MVD均是有价值的预后指标.     

A plasmid DNA vaccine encoding the extracellular domain of porcine endoglin induces anti-tumour immune response against self-endoglin-related angiogenesis in two liver cancer models

BACKGROUND: Anti-angiogenesis therapy has showed a promising future in tumour treatment. More and more evidence suggest that endoglin is a powerful marker of angiogenesis in solid malignancies, including liver cancer. AIM: To explore whether a plasmid DNA encoding the porcine endoglin has the ability of breaking immune tolerance against endoglin-related tumour angiogenesis in mice. METHODS: A eukaryotic plasmid encoding the extracellular domain of porcine endoglin was constructed, and then used it as a xenogeneic DNA vaccine. Hepa1-6 and H22 hepatoma models were established to observe the anti-tumour activities. Western blot, enzyme-linked immunoadsorbent assay and enzyme-linked immunospot assay were used to determine the antibody characters. Immunohistochemistry and alginate-encapsulated tumour cell assay were used to observe the anti-angiogenesis effects. RESULTS: Immunotherapy with recombinant plasmid encoding extracellular domain of porcine endoglin was effective at both protective and therapeutic anti-tumour immunity in two hepatoma models. Autoantibodies against murine endoglin were identified. IgG1 and IgG2b were the major subclasses in response to recombinant plasmid encoding extracellular domain of porcine endoglin vaccination. Anti-endoglin antibody-producing B cells were significantly increased in the spleens of mice immunised with recombinant plasmid encoding extracellular domain of porcine endoglin. In addition, mouse self-immunoglobulins were found deposited on the blood vessels of recombinant plasmid encoding extracellular domain of porcine endoglin-immunised tumour tissues. The similar anti-tumour activity was induced by the adoptive transfer of the purified immunoglobulins from the sera of mice immunised with recombinant plasmid encoding extracellular domain of porcine endoglin. Furthermore, angiogenesis was apparently inhibited within the tumour tissues from the recombinant plasmid encoding extracellular domain of porcine endoglin-immunised mice, and the vascularisation of alginate balls was also reduced in recombinant plasmid encoding extracellular domain of porcine endoglin-immunised mice. Most importantly, recombinant plasmid encoding extracellular domain of porcine endoglin could really induce cytotoxic T lymphocyte-mediated cytotoxicity and inhibit cell proliferation against endothelial cells. In addition, both CD4+ and CD8+ T lymphocytes took part in the function of inhibiting tumour growth and were synergistically responsible for induction of the anti-tumour activities. CONCLUSIONS: This approach may provide an alternative strategy for liver cancer immunotherapy.     

Clinicopathological significance of expression of paxillin, syndecan-1 and EMMPRIN in hepatocellular carcinoma

AIM: To evaluate the relationship of expression of paxillin, syndecan-1 and EMMPRIN proteins with clinicopathological features in hepatocellular carcinoma (HCC). METHODS: Fifty-one patients who underwent HCC resection were recruited in the study. Paxillin, syndecan-1 and EMMPRIN proteins in HCC tissues were detected with immunohistochemical staining. RESULTS: Of 51 cases of HCC, 23 (45%) exhibited paxillin protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 24 (57%) exhibited positive expression. Positive paxillin protein expression was associated with low differentiation (r= 0.406, P= 0.004), with the presence of portal vein thrombosis (r = 0.325, P = 0.021), with extra-hepatic metastasis (r=0.346, P=0.014). Of 51 cases of HCC, 28 (55%) exhibited syndecan-1 protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 23 (55%) exhibited positive expression. Positive snydecan-1 protein expression was associated with well differentiation (r=0.491, P=0.001), with no extra-hepatic metastasis (r=0.346, P=0.014). Of 51 cases of HCC, 28 (55%) exhibited EMMPRIN protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 21 (50%) exhibited positive expression. Expression of EMMPRIN protein was not associated with serum AFP level, HBsAg status, presence of microsatellite nodule, tumor size, presence of cirrhosis and necrosis, differentiation, presence of portal vein thrombosis, extra-hepatic metastasis, disease-free survival and overall survival (P>0.05). Expression of paxillin protein was correlated conversely with the expression of syndecan-1 protein in HCC (r = -0.366, P = 0.010). CONCLUSION: Expression of paxillin and syndecan-1 proteins in HCC may affect its invasive and metastatic ability of the tumor. There may be a converse correlation between the expression of paxillin and syndecan-1 protein in HCC. Expression of EMMPRIN protein may be detected in HCC, but it may play little role in the invasion and metastasis of HCC.     

Elevation of endoglin (CD105) concentrations in serum of patients with liver cirrhosis and carcinoma

OBJECTIVE: Liver cirrhosis is considered as a premalignant state, as about 80% of hepatocellular carcinoma (HCC) is associated with liver cirrhosis. Although alpha-fetoprotein (AFP) has a high negative predictive value, its sensitivity for detecting HCC is poor. The aim of this study was to evaluate circulating endoglin (CD105) in the serum of patients with liver cirrhosis and at high risk for HCC. METHODS: CD105 and AFP serum concentrations were measured in 70 healthy and 94 nonliver-diseased controls and 130 patients with chronic liver diseases and HCC, respectively. RESULTS: Fifty-seven liver cirrhotic patients, 45 patients with liver cirrhosis plus HCC, 19 liver fibrosis patients and nine patients with HCC only were studied. Serum CD105 is significantly elevated in liver cirrhotic patients compared with healthy (P<0.0001) and nonliver-diseased controls (P<0.0001). Patients with liver cirrhosis and HCC show the highest CD105 concentrations being significantly elevated in comparison to liver cirrhosis (P=0.0006) and HCC only (P=0.0134). A stronger positive correlation exists between CD105 and AFP in the patient group suffering from liver cirrhosis and HCC (r=0.479, P=0.0015) than the obtained correlation between both markers in the group of patients diagnosed with liver cirrhosis alone (r=0.358, P=0.0073). The logistic regression model identified CD105 as an independent marker (P=0.0077, odds ratio 1.3). CONCLUSION: CD105 has the potential to be a novel complementary biomarker that has some important bearing on the risk assessment for development of HCC in cirrhotic patients.     

Novel serum microRNAs panel on the diagnostic and prognostic implications of hepatocellular carcinoma

AIM To determine a panel of serum micro RNAs(mi RNAs) that could be used as novel biomarkers for diagnosis of hepatocellular carcinoma(HCC).METHODS We initially screened 9 out of 754 serum mi RNAs by Taq Man Low Density Array in two pooled samples respectively from 35 HCC and 35 normal controls, and then validated individually by RT-qP CR in another 114 patients and 114 controls arranged in two phases. The changes of the selected mi RNAs after operation and their prognostic value were examined.RESULTS miR-375, miR-10 a, miR-122 and miR-423 were found to be significantly higher in HCC than in controls(P 0.0001), and the area under the receiver-operating-characteristic curve for the 4-miR NA panel was 0.995(95%CI: 0.985-1). All the four mi RNAs were significantly reduced after surgical removal of the tumors(P 0.0001), while still higher than normal controls(at least P 0.05)CONCLUSION The four serum miR NAs(miR-375, miR-10 a, miR-122 and miR-423) could potentially serve as novel biomarkers for the diagnostic and prognostic of HCC.     

Alpha-fetoprotein expression is a potential prognostic marker in hepatocellular carcinoma

AIM: To characterize the alpha-fetoprotein (AFP) positive and negative hepatocellular carcinoma (HCC) samples. METHODS: Thirty-seven paraffin-embedded human HCC samples were analyzed by immunohistochemistry for the following antigens: AFP, β-catenin, p53, CD44, MSH-2, MLH-1, and HNF-4. The tumors were divided into two groups based on the AFP expression. The immunophenotypic data and important clinical parameters were studied between the two groups. RESULTS: Twenty-one of the thirty-seven examined HCCs were AFP positive. Seven with nuclear p53 staining were AFP positive, while seven tumors with nuclear β-catenin staining were AFP negative. CD44 staining and high histological tumor grade were more frequent among the AFP-positive HCCs. The other immunophenotypical and dinical parameters did not show statistically significant difference in their distribution between the AFP positive and negative samples. CONCLUSION: AFP expression in HCC correlates with unfavorable prognostic factors, while nuclear β-catenin positivity is more common among the AFP-negative liver tumors. This observation supports the microarray data on in vivo human tumors.     

Expression and prognostic role of RhoA GTPases in hepatocellular carcinoma

The Rho sub-family of proteins is involved in regulating the organization of the cytoskeleton and in cell motility. Our aim is to clarify the clinical significance of Rho protein in hepatocellular carcinomas (HCC) and to determine the relationship between the level of expression and patient outcome following hepatectomy. The expression of RhoA protein in HCC and corresponding non-tumor tissues of 26 patients who underwent surgical resection was analyzed by immunoblotting. The expression level of each case was calculated as tumor/non-tumor (T/N) ratios. High expression (T/N≥1) of RhoA protein in HCC compared to the paired non-tumor tissues was recognized in 18 patients (69.2%) of 26 samples. The activity of RhoA is also increased in HCC with high expression of RhoA. The high expression of RhoA protein did not correlate with various clinical parameters. However, the disease-free survival rates of the RhoA-high expression group (T/N≥1) were significantly lower than those of the RhoA-low expression group (T/N<1) (P<0.05). The high expression of RhoA protein in HCC plays an important role in intrahepatic recurrence of patients who underwent a hepatectomy for HCC, and RhoA is a useful marker for predicting early recurrence in an early-stage HCC.