TACE联合恩替卡韦治疗乙型肝炎相关原发性肝癌回顾性分析

目的观察恩替卡韦联合肝动脉化疗栓塞（transarterial chemoembolization,TACE）治疗乙型肝炎相关原发性肝癌患者的疗效。方法选取2011-05-02-2013-05-28山东省肿瘤医院乙型肝炎相关原发性肝癌患者145例,采用随机数字表法分为对照组（仅行TACE治疗）69例和观察组（TACE联合恩替卡韦抗病毒治疗）76例。随访监测治疗后4、12、24及48周肝功能、HBV DNA水平、HBeAg阴转率及转换率。疗效判断采用修正后的实体瘤治疗疗效评价标准（mRECIST）,观察患者TACE治疗后的无进展时间（progression-free survival,PFS）和总生存期（overall survival,OS）。结果两组患者ALT水平随治疗时间延长明显改善,观察组患者ALT水平在治疗24周后较对照组明显降低,P〈0.05。观察组患者HBV DNA不可测率在治疗后第4、12、24和48周分别为27.3%、36.4%、45.5%和72.7%。对照组患者HBV DNA水平无明显变化。第48周时,观察组患者HBeAg阴转率为42.9%,HBeAg转换率为14.3%;对照组患者均未出现HBeAg阴转或转换。随访至2013-11,观察组41例（53.95%）患者生存,35例（46.05%）患者死亡;对照组19例（27.53%）患者生存,50例（72.46%）患者死亡。观察组客观缓解率（objective response rate,ORR）为46.05%,对照组ORR为26.08%,两组比较差异有统计学的意义,χ2=6.216,P=0.013;观察组疾病控制率（disease control rate,DCR）为86.84%,对照组DCR为60.86%,两组比较差异有统计学意义,χ2=12.836,P=0.001。中位OS观察组为18.5个月（95%CI：15.5-21.5）,对照组为12.3个月（95%CI：9.8-14.9）,两者比较差异有统计学意义,χ2=6.857,P=0.009;中位PFS观察组为8.4个月（95%CI：6.9-9.9）,对照组为5.9个月（95%CI：4.9-6.8）,两者比较差异也有统计学意义,χ2=8.570,P=0.003。结论乙型肝炎相关的原发性肝癌患者TACE治疗后,接受恩替卡韦治疗能有效提高近期疗效,延长患者生存期,减轻TACE后肝损害,改善患者预后。     

A prospective study on the development of hepatocellular carcinoma from liver cirrhosis with persistent hepatitis B virus infection

We made a prospective study on the development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis with hepatitis B virus infection from April, 1973 to December, 1977. Seven out of 30 patients (23%) with hepatitis B surface antigen (HBsAg)-positive cirrhosis developed HCC. On the other hand, only 5.9% of the patients with HBsAg-negative liver cirrhosis developed HCC. These patients were classified into three groups according to their anti-HB core (anti-HBc) titers. When the anti-HBc titer, expressed as a dilution of serum, was 2(10) or more (Group I), 20-24% of the liver cirrhosis patients developed HCC either with or without a detectable amount of HBs Ag present in the sera. When the anti-HBc titer was 2(9) or less (Group II), only 0-5.7% developed HCC. There was no significant difference between this and the anti-HBc and HBsAg-negative group (Group III), which was 4.4%. In five individual cases from group I, HBsAg was detected in serum, and in biopsies of liver cells, before HCC could be detected by angiography and/or rising levels of alphafetoprotein (AFP). In all of these cases, the anti-HBc titer was higher than 2(10) throughout the observation period, even before the development of HCC. These findings indicate that active virus proliferation in chronic hepatitis B virus infection precedes the development of HCC as indicated by a higher anti-HBc titer. Therefore we have prepared these studies to show the pathogenic role of hepatitis B virus in the development of hepatocellular carcinoma.     

Multimodal therapy for liver cirrhosis patients with advanced hepatocellular carcinoma

Purpose  

We have previously shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced hepatocellular carcinoma (aHCC) in patients with HCV-related liver cirrhosis (C-LC) or alcoholic liver cirrhosis (A-LC) than in patients with HBV-related LC (B-LC). However, it is still unknown whether IACC actually improves the prognosis of aHCC patients with liver cirrhosis (LC), because it is difficult to perform a randomized controlled trial for patients with a poor prognosis. The aim of this study was to retrospectively assess the influence of IACC on the prognosis of aHCC.     

Hepatitis B virus serological markers in Africans with liver cirrhosis and hepatocellular carcinoma

Serum samples were collected at the time of hospitalization from 221 black Africans suffering from cirrhosis and 453 suffering from hepatocellular carcinoma (HCC). These patients came from Senegal, Burundi and Mali, and 6655 adults from different population groups in these countries were used as controls. Hepatitis B virus (HBV) serum markers, including hepatitis B surface antigen (HBsAg), anti-HBs, antibody to hepatitis B core antigen (anti-HBc), HBeAg and anti-HBe, were determined by radioimmunoassay, while alpha-fetoprotein and complexes between HBsAg and IgM were detected by ELISA tests. HBsAg was detected in 11.8-17.6% of controls as opposed to 63.3% of patients suffering from cirrhosis and 62.7% of patients suffering from HCC. There was less evidence for HBV replication in cirrhosis and HCC in older patients. A significant increase in the frequency of HBsAg/IgM complexes was found in passing from the HBsAg chronic carrier state (13.9%) to cirrhosis (29.9%) and finally to HCC (33.7%).     

Association of human hepatocellular carcinoma and cirrhosis with hepatitis B virus surface and core antigens in the liver.

Paraffin sections of livers obtained at autopsy from 50 cases of hepatocellular carcinoma (HCC), 58 cases of cirrhosis and 54 cases of other miscellaneous liver disorders (controls) were stained for both surface (HBsAg) and core (HBcAg) components of hepatitis B virus (HBV) by immunoperoxidase and immunofluorescence techniques and rigidly controlled for antigen specificity, and in addition stained by orcein for HBsAg. The material was collected from different regions of India and adequate amounts of tissue were examined in most specimens to overcome possible sampling error caused by random distributions of the antigens in liver. HBsAg was detected in 94% of HCC, 71% of cirrhosis and only 2% of control livers, while HBcAg was found in 22%, 31% and none respectively. Antigen positivity seems to be directly related to the amount of tissue examined. Peroxidase staining detected smaller amounts of HBcAg than fluorescence and was also much more convenient for identifying the antigen. Both antigens were present in 9 of 41 HCC cases, 12 of 39 cirrhosis and none of 25 controls. Most of these livers contained 1+ HBsAg and 1+ to 2+ HBcAg, an antigen expression pattern suggestive of a carrier state or, rarely, of mild chronic liver disease. Among all livers tested, HBsAg alone was present in 48, both antigens were found in 21, and HBcAg alone in none. HBsAg was seen inside tumour cells in four cases, but no tumour showed HBcAg. Most HCC was associated with cirrhosis (92%) and antigen-positive cirrhosis had a higher chance of harbouring HCC than antigen-negative disease. HBsAg was detected in all four non-cirrhotic livers associated with HCC, while two of these also had HBcAg. Active cirrhosis was very frequently associated with HBsAg. These results and the overwhelming evidence of sero-logical and epidemiological studies from various parts of the world suggest a strong association of the hepatitis B virus with HCC. The possible ways in which the two could be related are discussed.     

Difference in histological activity of non-tumorous liver tissue between hepatitis B virus- and hepatitis C virus-associated hepatocellular carcinoma without cirrhosis

To elucidate the difference in the liver carcinogenetic process during hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, non-tumorous liver tissues obtained from 10 patients who developed HBV-associated hepatocellular carcinoma (HCC) without cirrhosis were compared with those obtained from 26 patients who developed HCV-associated HCC without cirrhosis. The extent of fibrosis was similar in both groups. In contrast, necroinflammatory activities were significantly higher in patients with HCV than in patients with HBV. These results indicate that ongoing liver inflammation mediates the hepatocarcinogenesis more pronouncedly in HCV infection than in HBV infection.     

拉米夫定结合胸腺肽治疗对合并活动性肝炎肝癌术后复发的影响

目的　观察拉米夫定结合胸腺肽治疗对合并活动性肝炎肝癌术后复发的影响。方法33例合并活动性肝炎的肝癌随机分为两组 :对照组 17例 ,为单纯手术切除 ;治疗组 16例 ,为手术切除加术后拉米夫定结合胸腺肽治疗。观察两组的乙型肝炎病毒DNA(HBV DNA)清除率、乙型肝炎e抗原 (HBeAg)转阴率、复发时间和生存时间。结果　治疗组和对照组比较 ,1年后HBV DNA清除率分别为 10 0 .0 %和 6 .0 % (P <0 .0 1) ,HBeAg转阴率分别为 6 2 .5 %和 5 .9% (P <0 .0 5 ) ,1年肿瘤复发率分别为 81.3%和 95 .5 % (P >0 .0 5 ) ,中位复发时间分别为 7.0个月和 5 .0个月 (P <0 .0 1) ,中位生存时间分别为 10 .0个月和 7.0个月 (P <0 .0 1)。结论　拉米夫定结合胸腺肽治疗有助于合并活动性肝炎的肝癌患者术后清除病毒复制 ,延迟肿瘤复发 ,提高患者生存时间。     

Detection of hepatitis B virus X-region DNA in liver tissue from patients with hepatitis C virus-associated cirrhosis who subsequently developed hepatocellular carcinoma.

The risk of hepatocellular carcinoma (HCC) in patients chronically infected by hepatitis C virus (HCV) is relatively higher in Japan than in Western countries. The presence of hepatitis B virus X (HBX)-DNA in the liver tissue samples obtained on enrollment from 69 patients with HCV-associated cirrhosis who were subsequently followed in our hospital was analyzed by polymerase chain reaction (PCR). During the follow-up period of 5.7+/-3.2 years (mean +/- SD), 52 (75%) of 69 patients developed HCC. The PCR analysis indicated that the HBX-DNA sequence was detected in 25 (48%) of 52 patients who developed HCC during follow-up, but in only 3 (18%) of 17 patients who did not (P<0.05). These results suggest that HBX, a hepatitis B viral product relevant to hepatocarcinogenesis, is involved in development of HCC in some patients chronically infected by HCV in Japan.     

Prediction model of hepatocellular carcinoma in patients with hepatitis B virus-related compensated cirrhosis receiving antiviral therapy

The feasibility and performance of predicting hepatocellular carcinoma (HCC) using a combined albumin-bilirubin (ALBI) and fibrosis-4 (FIB-4)-based model remain unclear in patients with compensated cirrhosis and chronic hepatitis B (CHB) receiving long-term nucleos(t)ide analog (NA) therapy. We enrolled 1158 NA-naïve patients with compensated cirrhosis and CHB treated with entecavir or tenofovir disoproxil fumarate. The patients’ baseline characteristics, hepatic reserve, and fibrosis indices were analyzed. The combination of ALBI and FIB-4 was used to develop a prediction model of HCC. In this cohort, the cumulative incidence rates of HCC at 3, 5, and 10 years were 8.1%, 13.2%, and 24.1%, respectively. The combination of ALBI and FIB-4, Diabetes mellitus, and Alpha-fetoprotein (AFDA) were independent risk factors for HCC. The combined ALBI and FIB-4-based prediction model (i.e., AFDA) stratified the cumulative risk of HCC into three groups (with risk scores of 0, 1-3, 4-6) among all patients (P < 0.001). AFDA exhibited the highest area under the receiver operating characteristic (0.6812) for predicting HCC, which was higher than those of aMAP (0.6591), mPAGE-B (0.6465), CAMD (0.6379), and THRI (0.6356) and significantly higher than those of PAGE-B (0.6246), AASL-HCC (0.6242), and HCC-RESCUE (0.6242). Patients with a total score of 0 (n = 187, 16.1% of total patients) had the lowest cumulative HCC incidence of 3.4% at 5 years. The combined ALBI and FIB-4-based prediction model can stratify the risk of HCC in patients with compensated cirrhosis and CHB receiving NA therapy.     

Liver cell dysplasia and hepatitis B surface antigen in liver cirrhosis and hepatocellular carcinoma

Liver tissues of 223 autopsy cases of cirrhosis and hepatocellular carcinoma were examined for liver cell dysplasia in relation to hepatitis B surface antigen (HBsAg) detected with orcein stain. Liver cell dysplasia was found in 94 cases (42.2%): 37 were from cases of cirrhosis only, and 53 were from cases of cirrhosis with hepatocellular carcinoma. There was a significant difference in the overall incidence of HBsAg in cases with and without dysplasia (70.2%:32.6%). A similar difference was found in all groups, i.e., those with cirrhosis, cirrhosis with hepatocellular carcinoma, and hepatocellular carcinoma only, in which none of 11 cases of HBsAg negative had dysplasia. A good correlation was seen between the semiquantitative grade of dysplasia and the incidence of HBsAg. These findings suggest a close relationship of HBsAg with liver cell dysplasia.     

乙肝肝硬化患者抗病毒治疗后肝癌发生的危险因素分析

目的:探讨乙肝肝硬化患者抗病毒治疗后仍然进展为肝细胞肝癌的危险因素。方法:纳入2014年7月至2017年7月我院收治的72例乙肝肝硬化患者的临床资料。根据乙肝肝硬化患者抗病毒治疗满1年后是否进展为肝细胞肝癌分为肝癌组(21例)和肝硬化组(51例)。收集两组患者临床资料,采用统计软件SPSS 21.0进行数据分析,将两组间差异有统计学意义的指标作为自变量,对自变量行Logistic单因素和多因素回归分析,探究乙肝肝硬化患者进展为肝细胞肝癌的独立危险因素。结果:对比两组患者的临床资料,发现性别、年龄、家族史、糖尿病史、谷草转氨酶(AST)及抗病毒治疗12周病毒学应答指标有差异,且差异具有统计学意义(P＜0.05);对自变量行Logistic单因素和多因素回归分析,结果发现男性、年龄≥48岁和抗病毒治疗前AST≥40 U/L是乙肝肝硬化患者经抗病毒治疗后进展为肝细胞肝癌的独立危险因素(P＜0.05)。结论:男性、年龄大(≥48岁)和抗病毒治疗前AST≥40 U/L是乙肝肝硬化患者经抗病毒治疗后进展为肝细胞肝癌的独立危险因素。     

Brain metastasis from hepatocellular carcinoma associated with hepatitis B virus

Four cases of brain metastasis from hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) are reported in an area not endemic for HBV infection. Two cases are unusual, since cerebral metastases were the only secondary localization. In these cases, no other sites of metastasization were detected either before or immediately following neurosurgical treatment. In all cases the expression of pRB, p53 and p16 tumor suppressor protein was studied with immunohistochemistry, both, in the primary and metastatic lesions. The pRB expression was as follows: in two cases, lack and moderate expression were observed both, in the primary and in the metastases; in the other two, pRB was not detected. In all cases p53 expression was negative both, in the primary and the metastases. P16 expression was moderately expressed in three cases, both in the primary and the metastases. In one case it was absent. Hepatocarcinogenesis is a multistep process, in which several oncogenes and oncosuppressor genes are involved. In four unusual cases of spread to the brain, we evidenced that tumor suppressor protein expression of p16, p53, and particularly pRB (its aberrated expression is usually associated with metastasis) were altered. We also suggest that HBV and its X protein (HBX) might play an important role in such aggressive behavior of the neoplasia.     

Does hepatitis B virus cause hepatocellular carcinoma?

Evaluation of the hypothesis of an association between hepatitis and hepatocellular carcinoma (HCC), first suspected on pathologic grounds, was made easier by the discovery of hepatitis B surface antigen. Population correlation and analytical epidemiologic studies established that there is a strong and specific association between hepatitis B virus (HBV) and HCC. The association is restricted to chronically active forms of HBV infection and is universally present, equally strong in the USA and Europe as in Africa and Asia. The causal nature of the association between HBV and HCC appears indisputable, even though the pathogenesis of HBV-related HCC has not been established. There is no evidence to support any of the non-causal interpretations, i.e., that a third factor causes both persistence of HBV and HCC, or that HCC increases susceptibility to the HBV carrier state. Since about 200 million people are hepatitis B surface antigen carriers, HBV would appear to be second only to cigarette smoking as the most important known human carcinogen. However, a substantial proportion of HCC cases throughout the world show no evidence of active HBV infection; for those cases other causal agents must be invoked. Aflatoxin may be an important etiologic factor in Africa and Asia, whereas in Europe and the USA cigarette smoking and alcohol drinking are serious and numerically important suspects for hepatocellular carcinogenicity. Several other factors, including natural and synthetic chemical carcinogens, infectious agents and steroid hormones are also suspected, but the supporting evidence is weak and the numerical importance of the factors probably limited.     

Prognostic factors after liver resection for hepatocellular carcinoma with hepatitis B virus-related cirrhosis: The surgeon's role in survival

Aims

Little is known in judging significant factors that affect the outcome of hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV)-related cirrhosis undergoing liver resection. The aim of the present study is to investigate the controllable and uncontrollable poor prognostic factors for hepatectomy in patients with HBV-related cirrhosis.

Methods

Clinical and pathological data of 412 HCC patients with HBV-related cirrhosis undergoing liver resection from October 1996 to October 2006 were retrospectively reviewed and the prognostic risk factors were analyzed by univariate and multivariate analyses. Cumulative survival was calculated with respect to the number of prognostic risk factors.

Results

The significant risk factors for decreasing both the overall and disease-free survival of patients were: (1) ascites volume of more than 500 ml; (2) prothrombin time of more than 4 s; (3) serum AFP of more than 400 ng/ml; (4) tumor distribution in two lobes; (5) vascular invasion; (6) capsule absence; and (7) blood transfusion of more than 600 ml. Moreover, female gender and operation time of more than 5 h are risk factors of tumor recurrence but not for the patients' overall survival. The 3-year survival rate decreased from 100% to 0 as the number of risk factors in the patients increased from zero to four or more. Patients who had two or more preoperative risk factors were poor candidates for liver resection, with a 3-year survival rate of 8.5%.

Conclusions

The survival of HCC patients with HBV-related cirrhosis after liver resection depends on preoperative liver reserve, tumor status and blood transfusion. Tumor status cannot be altered; however, the surgeon can do a great favor to the prognosis of patients by minimizing bleeding and blood transfusion. Patients with two or more preoperative risk factors should be cautiously selected for liver resection.     

Aflatoxin B1 exposure increases the risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B virus carriers

The relation between aflatoxin B₁ (AFB₁) and cirrhosis in chronic carriers of hepatitis B virus (HBV) remains inconclusive. This case‐control study nested in a large community‐based cohort aimed to assess the effect of AFB₁ exposure on cirrhosis and HCC in chronic HBV carriers. Serum AFB₁‐albumin adduct levels at study entry were measured in 232 cirrhosis cases, 262 HCC cases and 577 controls. Multivariate‐adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. Among all chronic HBV carriers, the time intervals between study entry and diagnosis of HCC, cirrhosis, cirrhotic HCC, and non‐cirrhotic HCC were all significantly (p < 0.0001) shorter in participants with high serum levels of AFB₁‐albumin adducts than those with low/undetectable levels. There were significant dose‐response relations with serum AFB₁‐albumin adduct level at study entry for cirrhosis (p‐trend = 0.0001) and cirrhotic HCC (p‐trend < 0.0001) newly diagnosed within 9 years after entry as well as non‐cirrhotic HCC (p‐trend = 0.021) newly diagnosed within 4 years after entry. The aORs (95% CIs) for high versus undetectable serum AFB₁‐albumin adduct levels were 2.45 (1.51–3.98) for cirrhosis (p = 0.0003), 5.47 (2.20–13.63) for cirrhotic HCC (p = 0.0003), and 5.39 (1.11–26.18) for non‐cirrhotic (p = 0.0368) HCC, respectively. There remained a significant dose‐response relation between serum AFB₁‐albumin adduct level and HCC risk (p‐trend = 0.0291) in cirrhosis patients, showing an aOR (95% CI) of 3.04 (1.11–8.30) for high versus undetectable serum levels (p = 0.0299). It is concluded that AFB₁ exposure may increase the risk of cirrhosis and HCC in a dose‐response manner among chronic HBV carriers.     

Past exposure to hepatitis B virus as a risk factor for hepatocellular carcinoma in patients with chronic liver disease.

The aim of the study was to determine whether past exposure to hepatitis B virus (HBV) influences the risk of the development of hepatocellular carcinoma (HCC) in Japanese patients with chronic liver disease (CLD). We conducted a hospital-based case-control study of 141 HCC patients with CLD and 151 controls with CLD but without HCC. Past exposure to HBV was assessed by antibody to hepatitis B core antigen (anti-HBc) positivity. Ninety-two patients (65%) with HCC were anti-HBc positive compared with 65 patients (43%) with CLD alone (P < 0.01). A multivariate analysis using logistic regression modelling revealed that anti-HBc positivity significantly increased the risk of the development of HCC [odds ratio (OR) 2.0, P = 0.01]. In the anti-HBc-positive patients, a significantly increased risk of HCC was seen among the patients positive for anti-HBc alone (OR, 2.6; P < 0.01). However, a significant OR was not obtained among the patients with a transient HBV infection implied by positivity for both antibody to hepatitis B surface antigen and anti-HBc (OR, 1.5; P = 0.48). These results indicate that past exposure to HBV is a risk factor for HCC in Japanese CLD patients, especially when they have no serological evidence of immunity to HBV.     

Integration of hepatitis B virus DNA in hepatocellular carcinoma

Integration of hepatitis B virus (HBV) DNA into genomic DNA was investigated in 34 livers bearing hepatocellular carcinoma (HCC) by Southern blot hybridization using 32P-labeled, cloned and purified HBV DNA as a probe. Rehybridization of nitrocellulose paper with a probe containing only the cloning vector was performed after dehybridization to avoid possible false-positive results. Integrated HBV DNA was detected in all 9 hepatitis B surface antigen (HBsAg)-seropositive cases and 3 out of 25 (12%) HBsAg seronegative cases. The hybridization patterns of viral DNA were the same among several cancer nodules in two HCC cases with multiple liver tumors, indicating unicentric hepatocarcinogenesis in these two cases. These results, obtained with avoidance of false-positive results, showed that only a minority of HBsAg-seronegative HCC cases in Japan had demonstrable HBV DNA in the tumors studied by the Southern blot hybridization technique.