缺氧诱导因子-1α蛋白在肝癌组织中的表达及临床意义

目的 检测肝癌及癌旁组织中缺氧诱导因子-1 α(HIF-1 α)基因蛋白的表达及临床意义。方法 用免疫组织化学、western blot和RT—PCR技术检测35例肝细胞癌、26例肝硬化组织及15例正常肝组织中HIF-1 α蛋白和基因的表达情况,并分析其与临床病理特点之间的关系。 结果 免疫组织化学显示HIF-1α蛋白在肝硬化和肝癌组织中普遍表达,在肝硬化组织中的表达明显高于正常肝脏组织中的表达;但肝癌组织中因大片状坏死后伴大量纤维结缔组织增生的肝细胞条索中HIF-1 α蛋白的表达强度高于肝硬化组织,肝硬化组织HIF-1α蛋白的表达强度明显高于肝癌组织(54％与31％,x2=4.09,P<0.05);westernblot和RT-PCR结果与免疫组化结果相似。HIF-1α蛋白在肝癌组织中的表达强度与分化程度有关(x2=4.64,P<0.05),与有无肝内外转移有关(x2=7.15,P<0.05);但HIF-1α的表达与门静脉有无癌栓、预后及HBsAg表达无关。 结论 HIF-1 α蛋白在肝癌和肝硬化组织中普遍表达,且只受缺氧因素的影响,与肿瘤的分化程度和肝癌的转移有关,但与有无门静脉癌栓、HBsAg表达及预后无关,为肝癌的治疗提供新的思路。     

TRB3对人肝癌细胞增殖、凋亡、迁移的影响

目的:探讨假性蛋白激酶毛球族同源蛋白3（TRB3）在肝癌（HCC）细胞增殖、凋亡和迁移中的调控作用及机制。方法:免疫组织化学及蛋白质印迹法（Western blot）检测HCC患者癌组织及癌旁组织TRB3的表达;体外检测肝癌细胞系HepG2和Huh7细胞中TRB3的表达,同时设计小干扰RNA靶向抑制TRB3后：CCK8...     

肝癌组织中Glut1与HIF-1α表达的关系及临床意义

目的探讨肝细胞癌组织中葡萄糖转运蛋白1(Glut1)和缺氧诱导因子1α(HIF-1α)的表达情况及其临床意义,并分析两者的相关性。方法用免疫组织化学Envision法检测45例肝细胞癌、11例正常肝组织中的Glut1和HIF-1α表达情况。结果Glut1和HIF-1α在肝癌组织中的阳性率明显高于正常肝组织(P<0.05)。在肝癌组织中,Glut1和HIF-1α表达均与肿瘤大小、临床分期、有无淋巴结转移、有无门静脉癌栓有关(P<0.05)。肝癌组织中Glut1与HIF-1α表达呈正相关(r=0.583,P<0.01)。结论Glut1和HIF-1α异常表达与肝癌的发生、发展有一定关系。HIF-1α可能通过上调Glut1表达促进肝细胞癌发生。     

乙型肝炎病毒x蛋白与缺氧诱导因子-1α在肝癌中的表达及可能的调节机制

目的检测乙型肝炎病毒x蛋白(HBx)与缺氧诱导因子-1(HIF-1)α在肝癌中的表达,探讨正常氧和缺氧状态下,HBx对HIF-1α可能的调节机制。方法采用免疫组织化学染色方法检测78份原发性HCC组织标本中HBx和HIF-1α的表达,用SPSS10.0进行相关性分析;免疫荧光和Western blot检测常氧和缺氧条件下,HepG2及稳定转染HBx基因的HepG2细胞(HepG2- X)中HIF-1α的表达;流式细胞术检测常氧和缺氧状态下HepG2及HepG2-X细胞活性氧(ROS)的含量。结果78份肝癌组织标本中,HBx和HIF-1α免疫组织化学染色阳性率分别为74.36%(58/78)和69.23%(54/78),两者表达呈正相关(r=0.636,P<0.05)。免疫荧光检测表明:常氧状态下, HepG2细胞中HIF-1α的表达阴性而HepG2-X中表达阳性,主要位于细胞浆,部分位于细胞核,而缺氧状态下,HepG2和HepG2-X细胞的细胞质和细胞核均有表达。Western blot检测显示:常氧状态下,HepG2细胞中HIF-α几乎无表达,而HepG2-X明显表达。两者在缺氧1 h开始均表达,8 h达到高峰,16 h后逐渐下降,测量两者缺氧8 h时的表达,发现HepG2-X中HIF-α的表达增高。流式细胞术检测细胞ROS含量显示:在常氧状态下,HepG2-X细胞中ROS含量明显高于HepG2细胞。在缺氧状态下,二者ROS含量无显著差异,但均明显高于常氧状态下HepG2细胞的ROS含量。结论HBx及HIF-1α在人肝细胞肝癌组织中广泛表达,并显著正相关;常氧或缺氧状态下,HBx均可上调HIF-1α在HepG2细胞中表达,并且HBx对HIF-1α的这种调节作用可能通过ROS通路实现。     

肝癌组织中HIF-1α蛋白的表达与多药耐药蛋白相关性研究

目的：探讨肝癌组织中乏氧诱导因子-1α（HIF-1α）蛋白的表达与多药耐药蛋白（multi-drug resistance protein,MRP）的关系。方法收集78例原发性肝细胞癌患者肝组织和对应癌旁正常肝组织的石蜡标本,采用免疫组织化学 SP法检测原发性肝细胞癌组织及其癌旁正常肝组织中 HIF-1α和 MRP 蛋白的表达情况。结果 HIF-1α和MRP蛋白在肝癌组织中的阳性表达率明显高于癌旁正常肝组织（P〈0.05）。病理分级（Ⅲ-Ⅳ级）、TNM 分期（Ⅲ-Ⅳ期）、有门静脉癌栓、有淋巴结转移的肝癌组织中 HIF-1α的阳性表达率明显增高（P〈0.05）;病理分级（Ⅲ-Ⅳ级）、有淋巴结转移的肝癌组织中 MRP的阳性表达率明显增高（P〈0.05）。78份肝癌组织中,HIF-1α和 MRP 的表达之间呈正相关（r=0.524,P〈0.05）。结论 HIF-1α和 MRP过表达可能在肝癌的恶性增殖、分化及淋巴结转移过程中发挥重要作用,且两者在肝癌组织中的表达可能具有协同作用。     

肝癌组织、缺氧SMMC-7721细胞中HPA的表达变化及机制探讨

目的观察肝癌组织及缺氧培养的肝癌SMMC-7721细胞中乙酰肝素酶（HPA）和缺氧诱导因子-1α（HIF-1α）的表达变化,并探讨其机制。方法免疫组化法检测50例肝癌组织、28例肝癌癌旁组织、14例正常肝组织中的HPA、HIF-1α蛋白。分别采用RT-PCR和Western blot法检测常氧和缺氧培养的人肝癌SMMC-7721细胞中HPA mRNA及其蛋白。结果 HPA、HIF-1α蛋白在肝癌组织中的阳性表达率显著高于癌旁和正常肝组织（P〈0.05）;肝癌组织中HPA、HIF-1α蛋白的表达呈正相关（r=0.295,P〈0.05）。缺氧培养20 h后,SMMC-7721细胞HPA mRNA表达量（6.234±0.457）显著高于常氧培养细胞的表达量（2.910±0.137）,两者相比,P〈0.05;其HPA蛋白表达量（65 kD为1.437±0.067,50 kD为1.706±0.066）也显著高于常氧培养细胞的表达量（65 kD为1.192±0.060,50 kD为1.580±0.265）,两者相比,P〈0.05。结论肝癌组织中HPA蛋白阳性表达率升高,缺氧肝癌SMMC-7721细胞中HPAmRNA及蛋白表达量均升高,可能与缺氧导致的HIF-1α表达上调有关。     

趋化因子CCL28在缺氧诱导肝癌细胞侵袭中的作用

目的 探讨趋化因子CCL28在缺氧诱导肝癌细胞侵袭中的作用. 方法 50份肝细胞肝癌标本来自肝细胞肝癌患者,肝癌细胞株HepG2、HCCLM3为实验室冻存.用实时定量聚合酶链反应检测肝癌组织中缺氧诱导因子-1 α(HIF-1 α)和CCL28的mRNA水平.实时定量聚合酶链反应、Western blot和ELISA检测不同缺氧时间处理后肝癌细胞HepG2、HCCLM3中HIF-1α和CCL28的mRNA和蛋白表达水平.构建CCL28-siRNA下调HCCLM3细胞CCL28表达后,Transwell观察缺氧诱导的肝癌HCCLM3细胞侵袭改变.用x2检验分析HIF-1α和CCL28表达水平与临床资料相关性,Spearman双变量相关性分析HIF-1α和CCL28表达水平相关性,用单因素方差分析组间比较. 结果 HIF-1α mRNA在肝癌组织中相对表达量为0.065土0.098,CCL28 mRNA水平为0.025±0.075,Spearman双变量分析显示肝癌组织中HIF-1 α与CCL28表达水平呈高度相关性(r=0.595,P＜0.01),二者表达水平增高皆与术后复发相关(P=0.011,P=0.019).缺氧培养肝癌HepG2和HCCLM3细胞CCL28表达增高并呈时间依赖性,HepG2:HIF-1αF=873.5,CCL28 F=151.6;HCCLM3..HIF-1αF=964.5,CCL28F=285.8,P值均＜0.01.SiRNA抑制CCL28表达后,缺氧条件下HCCLM3细胞侵袭数目为(43.2±5.4)个/室、空白对照组为(54.6±9.5)个/室、阴性对照组为(58.0土3.9)个/室,缺氧条件下HCCLM3细胞侵袭细胞数比空白对照组和阴性对照组减少,P=0.011.结论 趋化因子CCL28在缺氧条件下高表达并参与缺氧诱导肝癌细胞侵袭过程.     

PITX1和Pan-ras在肝癌细胞中的表达及意义

目的研究抑癌基因PITX1和其下游癌基因Pan-ras在正常胚肝细胞株L02，肝癌细胞株HepG2和SMMC-7721中的表达，探讨其在肝癌发生发展中的作用和关系。方法应用SABC免疫组织化学染色技术和westem blot蛋白质印迹以及半定量RT-PCR检测L02、HepG2和SMMC-7721细胞株中PITX1和Pan-ras基因的表达情况，并分析其意义。结果PITX1在肝癌细胞（HepG2、SMMC-7721）中表达比正常肝细胞L02显著降低，Pan-ras在肝癌细胞（HepG2、SMMC-7721）中的表达与正常肝细胞L02相比显著升高。结论PITX1在肝癌细胞中的低表达，以及Pan-ras的高表达，可能导致肝癌无限增殖，构成了肝癌细胞信号传导网络中的重要一环。     

Fas/FasL在肝癌免疫逃避中作用的探讨

应用免疫组织化学法及脱氧核糖核酸末端转移酶介导的缺口末端标记 (Tunel)技术 ,对 41例肝癌组织中Fas、FasL表达及肝细胞凋亡进行观察和比较。结果显示 ,肝癌中Fas阳性率为 31 .71 % ,癌旁肝硬化Fas阳性率 80 .0 0 % ,癌细胞Fas表达较癌旁显著减小 ,肝癌及癌旁肝硬化FasL阳性率分别为 41 .46 %、65 .0 0 % ;FasL表达在二者间无显著差异。肝癌组织Fas、FasL表达与性别、肿瘤大小、组织分级无关。Fas表达与门静脉癌栓发生率呈负相关 ,FasL表达则与其无关。Fas抗原表达阳性的肝癌组织细胞凋亡指数明显高于Fas抗原表达阴性组。表明Fas/FasL系统在原发性肝癌肿瘤免疫逃避中起重要作用 ,Fas抗原表达在原发性肝癌门静脉癌栓形成中的作用值得进一步研究     

eIF4E在肝癌组织中的表达及意义

目的探讨eIF4E在肝癌发生发展过程中的作用。方法采用免疫组织化学S-P法检测62份肝癌组织及癌旁硬化肝组织、15份正常肝组织中eIF4E蛋白的表达情况,并分析eIF4E表达与肝癌临床病理特征的关系。结果肝癌组织中eIF4E阳性表达率显著高于癌旁硬化肝组织及正常肝组织(χ2=29.37,P<0.001),其表达与患者年龄、性别、肿瘤大小及包膜的完整程度无关,与肝癌分化程度、临床分期及有无门静脉癌栓有关。结论 eIF4E蛋白表达随肝癌分化程度降低而增高;eIF4E在肝癌的发生发展过程中可能起非常重要的作用。     

Nm23-H1 expression in intrahepatic or extrahepatic metastases of hepatocellular carcinoma

Abstract: Aims/Background: Decreased expression of nm23, a putative metastasis suppressor gene, has been reported to be related to either intrahepatic metastasis or a poor prognosis in hepatocellular carcinoma (HCC). The aim of this study was to elucidate the true role of nm23-H1 expression in both intrahepatic and distant metastases of HCC. Methods: Thirteen patients with single-nodule HCC, seven patients with HCC having satellite nodules and seven patients with HCCs having extrahepatic metastases were included in this study. The expression of nm23-H1 protein was immunohistochemically examined in both primary and metastatic nodules. Results: Ten of 13 single-nodule HCCs were found to overexpress nm23-H1 protein. All main tumors, having satellite nodules, were found to overexpress nm23-H1 protein, except for two HCCs, which only partially expressed nm23-H1 protein. Regarding the nm23-H1 expression in intrahepatic metastases, most nodules overexpressed the protein. The expression of nm23-H1 was found to be low in only one intrahepatic metastasis specimen, while its primary tumor was also found to show a low expression of nm23-H1 protein. Microscopic portal vein invasion was found in three of the five patients studied, and all cancer cells in portal invasion overexpressed nm23-H1 protein. Nm23-H1 protein was expressed in all distant metastatic tumors and the staining intensity of most metastatic nodules was similar to that of the primary tumors. Conclusions: Our study demonstrated that nm23-H1 expression did not always decrease but instead tended to increase at both intrahepatic and extrahepatic metastatic sites. Based on these findings, nm23-H1 expression is not considered to be a reliable indicator of either intrahepatic or distant metastasis in HCC.     

Role of intrahepatic tumor control in the prognosis of patients with hepatocellular carcinoma and extrahepatic metastases

Background and Aim: There has been little information about the long‐term outcome and prognostic factors in patients with hepatocellular carcinoma (HCC) and extrahepatic metastases. The purpose of this study was to investigate the clinical factors affecting survival after extrahepatic metastasis and to determine the survival benefit of controlling intrahepatic HCC. Methods: Between 2004 and 2009, a total of 240 consecutive patients with HCC and extrahepatic metastasis were recruited. Based on tumor extent, performance, and hepatic function, the patients underwent locoregional and/or systemic treatments. The treatment response of the intrahepatic tumor after extrahepatic metastasis and other prognostic parameters were analyzed retrospectively. Results: During the mean follow up of 276 days, 222 patients died; the median survival time was 146 days. Multivariate analysis revealed that Child–Pugh class A, smaller hepatic tumor size, absence of portal venous invasion, single metastatic organ involvement, and objective treatment response of the intrahepatic tumor were the favorable prognostic factors for survival. Of the 183 evaluable patients, 24 achieved complete or partial response for intrahepatic tumors after treatment. The overall survival for the 24 responders was significantly improved, with a median of 521 days, as compared to 170 days for the remaining 159 patients without objective tumor response. The leading cause of death was progressive intrahepatic tumor. Conclusions: Intrahepatic tumor status and hepatic reserve are among the significant predictors of survival in patients with HCC and extrahepatic metastases. This study indicates that even in patients with metastases from advanced HCC, therapeutic approaches to control intrahepatic tumors are important in improving patient survival.     

Expression of HIF-2α／EPAS1 in hepatocellular carcinoma

AIM:To investigate the expression of hypoxia-inducible factor (HIF)-2α/endothelial PAS domain protein1 (EPAS1) in hepatocellular carcinoma (HCC).METHODS: Expression of HIF-2α/EPAS1 was investigated immunohistochemically on paraffin-embedded sections from 97 patients with HCC.To further confirm that HIF-2α/EPAS1 in HCC tissues also correlated with angiogenesis, a parallel immunohistchemistry study of vascular endothelial growth factor (VEGF) was performed on these 97 cases.RESULTS:HIF-2α/EPAS1 could be detected in 50 of 97 cases (51.6%), including 19 weakly positive (19.8%), and 31 strongly positive (31.1%), the other 47 cases were negative(48.4%). The expression of HIF-2α/EPASlwas significantly correlated with tumor size,capsule infiltration, portal vein invasion, and necrosis. A parallel immunohistochemical analysis of VEGF demonstrated its positive correlation with capsule infiltration, portal vein invasion, and HIF-α/EPAS1 overexpression, which supported the correlation of HIF-2α/EPASlup-regulation with tumor angiogenesis. No apparent correlation was observed between HIF-2α/EPAS1 and capsular formation, presence of cirrhosis, and histological grade.CONCLUSION: HIF-2α/EPAS1 is expressed in most of HCC with capsular infiltration and portal vein invasion, which indicates a possible role of HIF-2α/EPAS1 in HCC metastasis.     

Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma

AIM： To assess the clinical features and prognosis of 151 patients with extrahepatic metastases from primary hepatocellular carcinoma （HCC）, and describe the treatment strategy for such patients. METHODS： After the diagnosis of HCC, all 995 consecutive HCC patients were followed up at regular intervals and 151 （15.2%） patients were found to have extrahepatic metastases at the initial diagnosis of primary HCC or developed such tumors during the follow-up period. We assessed their clinical features, prognosis, and treatment strategies.
RESULTS： The most frequent site of extrahepatic metastases was the lungs （47%）, followed by lymph nodes （45%）, bones （37%）, and adrenal glands （12%）. The cumulative survival rates after the initial diagnosis of extrahepatic metastases at 6, 12, 24, and 36 mo were 44.1%, 21.7%, 14.2%, 7.1%, respectively. The median survival time was 4.9 mo （range, 0-37 mo）. Fourteen patients （11%） died of extrahepatic HCC, others died of primary HCC or liver failure.
CONCLUSION： The prognosis of HCC patients with extrahepatic metastases is poor. With regard to the cause of death, many patients would die of intrahepatic HCC and few of extrahepatic metastases. Although most of HCC patients with extrahepatic metastases should undergo treatment for the primary HCC mainly, treatment of extrahepatic metastases in selected HCC patients who have good hepatic reserve, intrahepatic tumor stage （T0-T2）, and are free of portal venous invasion may improve survival.     

Clinical features of hepatocellular carcinoma with extrahepatic metastases

BACKGROUND: There are few detailed clinical reports about extrahepatic metastases of hepatocellular carcinoma (HCC). The purpose of the present study was to elucidate the clinical features of extrahepatic metastases of HCC. METHODS: The clinical records of 482 patients who had been diagnosed as having HCC during the period from January 1995 to March 2001 were retrospectively reviewed. Extrahepatic metastases had been detected in 65 patients. Clinical features of those 65 patients were analyzed. RESULTS: Patients with extrahepatic metastases had more advanced intrahepatic tumors at the first diagnosis of HCC: 73.8% of the patients with extrahepatic metastases had tumors of intrahepatic tumor stage T3 or T4 according to the TNM classification, while only 28.5% of the patients without extrahepatic metastases had tumors of T3 or T4 (P < 0.001). Vessel invasion was also detected at the first diagnosis of HCC more frequently in the patients with extrahepatic metastasis (P < 0.001). The frequent metastatic sites were lung (53.8%), bone (38.5%), and lymph node (33.8%). Other metastatic sites were the adrenal gland, peritoneum, skin, brain and muscle. The median survival time and 1-year survival rate were 7 months (range: 1-59 months) and 24.9%, respectively. Patients with Child-Pugh grade B and C (P = 0.0018) and patients with positive serum alpha-fetoprotein (P = 0.011) had significantly poor prognosis. CONCLUSIONS: Extrahepatic metastases of HCC are not rare. The possibility of extrahepatic metastases and the clinical features of extrahepatic metastases should be considered when examining patients with HCC, particularly those with advanced intrahepatic tumors, to enable precise evaluation of the spread of HCC and determination of the appropriate treatment method.     

Expression of vascular endothelial growth factor-C in human hepatocellular carcinoma

Background/Aims: Vascular endothelial growth factor‐C (VEGF‐C) is thought to be an important factor in tumor angiogenesis/lymphangiogenesis, but its role in hepatocellular carcinoma (HCC) has not yet been fully investigated. Methods: We immunohistochemically examined VEGF‐C expression in surgically resected tissues of 90 HCC. Results: In the 78 HCC with a single histological grade, VEGF‐C expression was significantly stronger in poorly differentiated HCC than in well‐ (P = 0.003) or moderately differentiated HCC (P = 0.0002). A ‘nodule‐in‐nodule’ case presented VEGF‐A expression in the well‐differentiated component and VEGF‐C expression in the moderately–poorly differentiated component. According to nodular diameter, VEGF‐C expression was significantly higher in nodules of 3.0 cm or larger (P = 0.0263). Extrahepatic metastases seen in seven cases expressed VEGF‐C. In 20 of the 28 cases who were able to be followed up, the frequency of intrahepatic recurrence tended to be higher and extrahepatic metastasis was significantly higher in the cases who had VEGF‐C expression in the tumor casts of the intrahepatic portal/hepatic vein branches than other cases without the expression (P = 0.0139). Disease‐free survival time tended to be shorter in cases with VEGF‐C expression in tumor casts of the portal/hepatic vein than in those without VEGF‐C expression (P = 0.053; log–rank test). Conclusions: VEGF‐C expression is related to the progression of HCC, and VEGF‐C expression in tumor casts of the intrahepatic portal/hepatic vein is considered to be a factor indicating recurrence/metastasis sites.     

Results of surgical treatment for recurrent hepatocellular carcinoma; comparison of outcome among patients with multicentric carcinogenesis, intrahepatic metastasis, and extrahepatic recurrence

No consensus has been reached on the indications for and effectiveness of surgery for secondary intrahepatic hepatocellular carcinoma (HCC) and extrahepatic metastasis after macroscopically complete removal of primary HCC. Secondary intrahepatic HCCs, usually regarded as recurrence are classified into those arising as a result of multicentric carcinogenesis or intrahepatic metastases derived from the primary HCC. The present study was designed to evaluate the utility of surgical treatment in relation to the pathogenesis of the secondary HCC: classified as multicentric carcinogenesis (MC), intrahepatic metastasis (IM), and extrahepatic metastasis. Thirty patients underwent extirpation of secondary HCC: 22 patients had secondary HCCs in the remnant liver (MC group;n = 8; IM group,n = 14), 6 patients had extrahepatic metastases, and 2 patients had both intrahepatic and extrahepatic metastases. Survival rates after the re-resection in the 22 patients with the secondary intrahepatic HCCs were 94.7% at 1 year, and 50.2% at 3 years postoperatively, and the 8 patients with extrahepatic metastasis had survival rates of 62.5% at 1 year, 37.5% at 3 years, and at 5 years. The survival rates after re-resection in the MC group were 100% at 1 year and 80.0% at 3 years, whereas those in the IM group were 91.7% at 1 year, and 38.1% at 3 years. Surgery can be indicated not only in patients with localized intrahepatic secondary HCCs but also in those with extrahepatic metastasis. In particular, patients with secondary HCCs arising as a result of multicentric carcinogenesis are expected to have a good prognosis.     

Intra‐arterial 5‐fluorouracil/interferon combination therapy for hepatocellular carcinoma with portal vein tumor thrombosis and extrahepatic metastases

Background and Aims: We investigated the efficacy of intra‐arterial 5‐fluorouracil (5‐FU) and systemic interferon (IFN)‐α (5‐FU‐IFN) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis in the first branch or trunk (Vp3/4) and extrahepatic metastases. Methods: We examined 17 HCC patients with Vp3/4 and extrahepatic metastases (meta group) and 31 HCC patients with Vp3/4 (non‐meta group). Baseline intrahepatic tumor factors and the hepatic reserve were similar between groups. The extrahepatic metastases of the meta group were not considered prognostic factors. Following the administration of 5‐FU/IFN to all patients, we compared the survival rates, response, time to progression (TTP), and safety between groups. Results: For intrahepatic HCC, complete response, partial response, stable disease, progressive disease, and drop out were observed in no (0%), one (6%), seven (41%), nine (53%), and no (0%) patients of the meta group, and in five (16%), seven (23%), 13 (42%), five (16%) and one (3%) patient of the non‐meta group, respectively. The response rate was significantly lower in the meta group (6% vs 39%, P = 0.018). The median TTP of intrahepatic HCC and the median survival time were significantly shorter in the meta group than in the non‐meta group (1.6 vs 6.3 months, P = 0.0001, and 3.9 months vs 10.5 months, P < 0.0001, respectively). The multivariate analysis showed that the absence of extrahepatic metastases was a significant and independent determinant of both TTP of intrahepatic HCC (P < 0.001) and overall survival (P < 0.001). No patient died of extrahepatic HCC‐related disease. Conclusions: The efficacy of 5‐FU/IFN for advanced HCC with Vp3/4 and extrahepatic metastases was markedly limited.