Research ArticleClinical Studies

Relation Between Antibody to Hepatitis B Core Antigen and Survival after Curative Therapy for Non-B Non-C Hepatocellular Carcinoma

HIROKI NISHIKAWA, YUKIO OSAKI, AKIRA ARIMOTO, RYUICHI KITA and TORU KIMURA
Anticancer Research May 2013, 33 (5) 2211-2219;

Abstract

Background/Aim: We aimed to examine the relationship between antibodies to hepatitis B core antigen (anti-HBc) positivity and survival in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC) who underwent curative treatment. Patients and Methods: A total of 260 patients with NBNC-HCC who underwent curative therapy were analyzed. They included 124 anti-HBc-positive patients (47.7%) and 136 anti-HBc-negative patients (52.3%). Overall survival (OS) and recurrence-free survival (RFS) rates were compared. Results: The 3-year cumulative OS rates were 75.9% in the anti-HBc-positive group and 82.3% in the anti-HBc-negative group (p=0.069). The corresponding RFS rates were 29.8% in the anti-HBc-positive group and 43.0% in the anti-HBc-negative group (p=0.001). Multivariate analyses identified anti-HBc positivity (p=0.006), aspartate aminotransferase ≥40 IU/l (p=0.037) and des-γ-carboxy prothrombin ≥100 mAU/ml (p=0.046) as significant adverse predictors were linked to RFS. Conclusion: Anti-HBc positivity can be a useful predictor for recurrence in patients with NBNC-HCC after curative therapy.

Hepatocellular carcinoma (HCC) is a major health problem worldwide. It is the fifth most common type of cancer in the world and the third most common cause of cancer-related death (1-3). Although most cases of HCC are associated with viral infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, a substantial proportion of HCC patients are negative for markers of HBV-surface antigen (HBsAg) and HCV antibody (HCVAb) [non-B non-C HCC (NBNC-HCC)]. The frequency of NBNC-HCC has been reported to range from 5-15% (4-6), and the number of patients with NBNC-HCC in Japan is currently increasing (7).

HCC frequently recurs after treatment, leading to high mortality. Recurrence only occurs at intrahepatic sites in 68-96% of patients (8, 9). Hence, the identification of predictive factors and effective management of HCC recurrence are essential for improving survival, even after curative treatment.

The serum antibody to hepatitis B core antigen (anti-HBc), which indicates a past history of HBV infection, has recently been attracting attention as a predictor of liver carcinogenesis in patients with various kinds of background liver diseases (5, 6, 10-14). HBV DNA may be present in a latent form, even after seroclearance of HBsAg, referred to as occult HBV infection (10, 15). Anti-HBc is reported to be a surrogate marker for such latent carriers (16). Moreover, previous studies indicated that the so-called occult HBV infection, reflected by anti-HBc positivity, was highly-prevalent in a number of patient sub-groups, including those with HCV infection, cryptogenic liver disease, and HCC, and may play an important role in liver carcinogenesis (5, 12, 17-20).

Several studies have reported on the relationship between anti-HBc positivity and liver carcinogenesis in HCV-related liver disease (10-12, 14). Moreover, HBV DNA was found to be integrated into the human genome in NBNC-HCC, causing hepatocarcinogenesis (21). However, it remains unknown whether anti-HBc positivity constitutes an additional risk, in terms of poorer survival after curative therapy for NBNC-HCC. The aim of the present study was, therefore, to examine the relationship between anti-HBc positivity and survival of patients with NBNC-HCC who underwent curative treatment.

Patients and Methods

Patients. A total of 1,636 treatment-naïve patients with HCC received curative therapy at our institution between June 2001 and July 2012. Curative therapy was defined as therapy resulting in no apparent viable tumor on dynamic computed tomography (CT) performed within one month after initial treatment. Out of these, 283 patients (17.3%) had NBNC-HCC, negative for both HBsAg and HCVAb. Patients with excessive alcohol intake (n=21) and patients with primary biliary cirrhosis (n=2) were excluded from the study. Excessive alcohol consumption was defined as an alcohol intake >80 g/day (22). A total of 260 patients were thus analyzed in the present study (Figure 1). After diagnosis of HCC, the most appropriate therapeutic procedure was selected by discussions with surgeons and physicians, according to the tumor characteristics and underlying liver functional reserve of each patient. Patients were classified into two groups: anti-HBc-positive group (n=124, 47.7%) and anti-HBc-negative group (n=136, 52.3%). Overall survival (OS) and recurrence-free survival (RFS) rates were compared between the two groups. A diagnosis of diabetes mellitus was based on past medical history or 75-g oral glucose tolerance test results (23).

Written informed consent was obtained from all patients prior to each therapy, and the study protocol complied with all of the provisions of the Declaration of Helsinki. This study was approved by the Ethics Committee of Osaka Red Cross Hospital, Japan (approval number, 433) and the need for written informed consent in the current study was waived because the data were analyzed retrospectively and anonymously. The present study comprised of a retrospective analysis of patient records registered in our database, and all treatments were conducted in an open-label manner.

HCC diagnosis. HCC was diagnosed using abdominal ultrasound and dynamic CT scans (hyperattenuation during the arterial phase in all or some part of the tumor and hypoattenuation in the portal-venous phase) and/or magnetic resonance imaging (MRI), based mainly on the recommendations of the American Association for the Study of Liver Diseases (24). Arterial- and portal-phase dynamic CT images were obtained at approximately 30 s and 120 s, respectively, after the injection of the contrast material. HCC stage was determined using the Liver Cancer Study Group of Japan staging system (25). HCC was confirmed pathologically only in patients who underwent surgery.

Serological studies. HBsAg and anti-HBc were detected using commercial enzyme immunoassay kits (Dainabot, Tokyo, Japan) (26). The results of anti-HBc assays were expressed as the percentage of inhibition, and the specimen was considered to be anti-HBc-positive when the percentage of inhibition was >50% (27). HCVAb was assessed using second-generation assays (Dainabot) (26).

Follow-up. Follow-up after each therapy consisted of periodic blood tests and monitoring of tumor markers, including α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), using chemiluminescent enzyme immunoassays (Lumipulse PIVKAII Eisai, Eisai, Tokyo, Japan). Dynamic CT scans and/or MRI were obtained every 2-4 months after each therapy. Chest CT, whole-abdominal CT, brain MRI, and bone scintigraphy were performed when extrahepatic HCC recurrence was suspected.

Statistical analysis. Data were analyzed using univariate and multivariate analyses. Continuous variables were compared using unpaired t-tests and categorical variables were compared using Fisher's exact tests. Time-to-recurrence was defined as the interval between each therapy and first confirmed recurrence. For analysis of RFS, follow-up ended at the time of first recurrence; other patients were censored at their last follow-up visit or the time of death from any cause without recurrence. For analysis of OS, follow-up ended at the time of death from any cause, and the remaining patients were censored at the last follow-up visit. The cumulative OS and RFS rates were calculated using the Kaplan–Meier method, and tested using the log-rank test. Factors with a p-value <0.1 in univariate analysis were subjected to multivariate analysis using the Cox proportional hazards model. These statistical methods were used to estimate the interval from initial treatment. Data were analyzed using SPSS software (SPSS Inc., Chicago, IL, USA) for Microsoft Windows. Data are expressed as means±standard deviation (SD). Values of p<0.05 were considered to be statistically significant.

Figure 1.
Figure 1.

Study profile. Anti-HBc indicates antibody to hepatitis B core antigen.

Results

Baseline characteristics. The baseline characteristics of the patients in the two groups are shown in Table I. The median observation periods were 3.0 years (range=0.3-10.3 years) in the anti-HBc-positive group and 3.1 years (range=0.3-11.4 years) in the anti-HBc-negative group.

In the anti-HBc-positive group, surgical resection was performed in 50 patients (40.3%), percutaneous ablation therapy such as radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI), in 65 patients (52.4%), and transcatheter arterial chemoembolization (TACE) in nine patients (7.3%). In the anti-HBc-negative group, surgical resection was performed in 67 patients (49.3%), RFA or PEI in 59 patients (43.4%), and TACE in 10 patients (7.4%) (p=0.326). There were no significant differences in baseline characteristics between the two groups (p=0.041), except in terms of gender.

Cumulative OS and RFS rates. The 1-, 3- and 5-year cumulative OS rates were 95.2%, 75.9% and 49.8%, respectively, in the anti-HBc-positive group and 95.6%, 82.3% and 68.6%, respectively, in the anti-HBc-negative group (p=0.069) (Figure 2A). The corresponding RFS rates were 65.1%, 29.8% and 14.0%, respectively, in the anti-HBc-positive group and 78.9%, 43.0% and 36.7%, respectively, in the anti-HBc-negative group (p=0.001) (Figure 2B).

View this table:
Table I.

Baseline characteristics of the anti-HBc-postive and the anti-HBc-negative groups.

Univariate and multivariate analyses of factors contributing to OS. Univariate analysis identified the following factors as being significantly associated with OS for all cases (n=260): Child–Pugh classification (p=0.015); HCC stage (p=0.001); tumor number (p=0.001); total bilirubin >1 mg/dl (p=0.020); serum albumin >4.0 g/dl (p<0.001); aspartate aminotransferase (AST) >40 IU/l (p=0.039); prothrombin time >80% (p=0.014) and DCP >100 mAU/ml (p=0.001) (Table II). The hazard ratios (HRs) and 95% confidence intervals (CIs) calculated using multivariate analysis for the 10 factors with p-values of <0.1 in univariate analysis are detailed in Table II. Serum albumin >4.0 g/dl (p=0.036) and DCP >100 mAU/ml (p<0.001) were found to be significant predictors linked to OS in multivariate analysis.

Univariate and multivariate analyses of factors contributing to RFS. Univariate analysis identified the following factors as being significantly associated with RFS for all cases (n=260): anti-HBc positivity (p=0.001); Child–Pugh classification (p=0.001); HCC stage (p<0.001); tumor number (p<0.001); serum albumin >4.0 g/dl (p=0.004); AST >40 IU/l (p=0.006); platelets >13×104/mm3 (p=0.036); prothrombin time >80% (p<0.001) and AFP >10 ng/ml (p=0.045) (Table III). The HRs and 95% CIs calculated using multivariate analysis for the 10 factors with p-values of <0.1 in univariate analysis are detailed in Table III. Anti-HBc positivity (p=0.006), AST >40 IU/l (p=0.037) and DCP >100 mAU/ml (p=0.046) were found to be significant adverse prognostic factors linked to RFS.

Causes of death. Forty-seven patients in the anti-HBc-positive group (37.9%) died during the follow-up period. The causes of death were HCC recurrence in 29 patients, liver failure in 14 patients and miscellaneous causes in four patients. Thirty-seven patients in the anti-HBc-negative group (27.2%) died during the follow-up period, and the causes of death were HCC recurrence in 18 patients, liver failure in 12 patients and miscellaneous causes in seven patients.

HCC recurrence. In the present study, 95 patients with anti-HBc-positive status (76.6%) and 72 anti-HBc-negative (52.9%) had HCC recurrence during the follow-up period. The patterns of HCC recurrence after initial treatment in the anti-HBc-positive group were: single HCC recurrence in the liver in 35 patients; multiple HCC recurrences in the liver: in 48 patients, with lung metastases in six, with lymph node metastases in one, with peritoneal dissemination in three patients, with portal-vein tumor invasion in one; and with bile duct invasion in one patient. The patterns of HCC recurrence after initial treatment in the anti-HBc-negative group were: single HCC recurrence in the liver in 31 patients; multiple HCC recurrences in the liver: in 36 patients, with lymph node metastases in four, and with lung metastases in one patient.

Figure 2.
Figure 2.

Overall (OS) and recurrence-free survival (RFS) rates. A: Cumulative OS rates in anti-HBc-positive (n=124) and anti-HBc-negative cases (n=136). Anti-HBc indicates the antibody against hepatitis B core antigen. The 1-, 3- and 5-year cumulative OS rates were 95.2%, 75.9% and 49.8%, respectively, in the anti-HBc-positive group and 95.6%, 82.3% and 68.6%, respectively, in the anti-HBc-negative group (p=0.069). B: Cumulative RFS rates in anti-HBc-positive (n=124) and anti-HBc-negative cases (n=136). The 1-, 3- and 5-year cumulative RFS rates were 65.1%, 29.8% and 14.0%, respectively, in the anti-HBc-positive group and 78.9%, 43.0% and 36.7%, respectively, in the anti-HBc-negative group (p=0.001).

Figure 3.
Figure 3.

Overall (OS) and recurrence-free survival (RFS) rates in male patients. A: Cumulative OS rates in anti-HBc-positive (n=102) and anti-HBc-negative male patients (n=97). Anti-HBc indicates the antibody against hepatitis B core antigen. The difference was not significant (p=0.356). B: Cumulative RFS rates in anti-HBc-positive (n=102) and anti-HBc-negative males (n=97). The difference was significant (p=0.019).

Figure 4.
Figure 4.

Overall (OS) and recurrence-free survival (RFS) rates in female patients. A: Cumulative OS rates in anti-HBc-positive (n=22) and anti-HBc-negative female patients (n=39). Anti-HBc indicates antibody to hepatitis B core antigen. The difference was significant (p=0.015). B: Cumulative RFS rates in anti-HBc-positive (n=22) and anti-HBc-negative females (n=39). The difference was significant (p=0.017).

Figure 5.
Figure 5.

Overall (OS) and recurrence-free survival (RFS) rates in patients with Child–Pugh A class disease. A: Cumulative OS in anti-HBc-positive (n=101) and anti-HBc-negative Child–Pugh A groups (n=122). Anti-HBc indicates the antibody against hepatitis B core antigen. The difference was significant (p=0.045). B: Cumulative RFS rates in anti-HBc-positive (n=101) and anti-HBc-negative Child–Pugh A groups (n=122). The difference was significant (p=0.001).

Figure 6.
Figure 6.

Overall (OS) and recurrence-free survival (RFS) rates in patients with Child–Pugh B class disease. A: Cumulative OS rates in anti-HBc-positive (n=23) and anti-HBc-negative Child–Pugh B groups (n=14). Anti-HBc indicates the antibody against hepatitis B core antigen. The difference was not significant (p=0.672). B: Cumulative RFS rates in anti-HBc-positive (n=23) and anti-HBc-negative Child–Pugh B patients (n=14). The difference was not significant (p=0.554).

Treatment methods for the first HCC recurrence in the anti-HBc-positive group were: surgical resection in three patients; percutaneous ablation therapy in 40 patients; TACE in 28 patients; systemic chemotherapy in five patients; and no specific treatment for 19 patients. Treatment methods for the first recurrence in the anti-HBc-negative group were: surgical resection in six patients; percutaneous ablation therapy in 37 patients; TACE in 16 patients; systemic chemotherapy in two patients; and no specific treatment for 11 patients.

Sub-group analyses according to gender. The proportion of male patients in the anti-HBc-positive group was significantly higher than in the anti-HBc-negative group. We, therefore, performed sub-group analyses according to gender. There was no significant difference in terms of OS between male patients in the two groups [102 male patients (82.3%) in the anti-HBc-positive group and 97 (71.3%) in the anti-HBc-negative group] (p=0.356), but the difference in RFS was significant (p=0.019) (Figure 3A and B). Both OS (p=0.015) and RFS (p=0.017) differed significantly between female patients in the two groups [22 female patients (17.7%) in the anti-HBc-positive group and 39 (28.7%) in the anti-HBc-negative group] (Figure 4A and B).

Sub-group analyses according to Child–Pugh classification. Marginal significance was observed between the two groups in terms of Child–Pugh classification (p=0.075), and we therefore performed sub-group analyses according to Child–Pugh classification. Significant differences were observed in both OS (p=0.045) and RFS (p=0.001) between the two groups in patients with Child–Pugh A [101 patients (81.5%) in the anti-HBc-positive group and 122 (89.7%) in the anti-HBc-negative group] (Figure 5A and B). In contrast, no significant differences between the two groups were found in either OS (p=0.672) or RFS (p=0.554) in patients with Child–Pugh B [23 patients (18.5%) in the anti-HBc-positive group and 14 (10.3%) in the anti-HBc-negative group] (Figure 6A and B).

Discussion

To the best of our knowledge, this is the first reported comparative study to investigate the relationship between anti-HBc positivity and survival in patients with NBNC-HCC who underwent curative therapy.

The results showed that anti-HBc positivity was the strongest predictor associated with RFS in multivariate analysis, although anti-HBc positivity was not significantly associated with OS in multivariate analysis. However, when patients with liver-unrelated deaths were excluded (four patients in the anti-HBc-positive group and seven patients in the anti-HBc-negative group), the difference in OS between the two groups reached statistical significance (p=0.032, data not shown). These results suggest that anti-HBc positivity could be a useful marker for survival after curative therapy for NBNC-HCC, and that patients with anti-HBc-positive NBNC-HCC should be closely-monitored, even after curative therapy.

View this table:
Table II.

Univariate and multivariate analysis of factors contributing to overall survival for all cases (n=260).

View this table:
Table III.

Univariate and multivariate analysis of factors contributing to recurrence-free survival for all cases (n=260).

Kusakabe et al. reported that 18 (40.0%) out of 45 patients with NBNC-HCC were anti-HBc-positive (20), compared with 124 patients (47.7%) in the current study. The reason for the slightly higher proportion of anti-HBc-positive cases in our study is unclear. Ikeda et al. reported that in patients with NBNC liver cirrhosis, occult HBV infection increased the initial carcinogenesis rate, with a HR of 8.25 (95% CI=2.01-33.93) (13), while in our analysis, anti-HBc positivity increased the HCC recurrence rate after curative therapy with a HR of 1.567 (95% CI=1.140-2.155), indicating that anti-HBc positivity was more strongly associated with initial, than with second carcinogenesis in patients with NBNC liver disease.

The anti-HBc-positive group included significantly more male patients compared with the anti-HBc-negative group in the current study. Ohki et al., in a large study of patients with NBNC liver disease, also reported a significantly higher proportion of male patients in the anti-HBc-positive group compared with the anti-HBc-negative group (10). Moreover, our sub-group analysis according to gender identified significant differences in terms of both OS and RFS in female patients, whereas the difference only reached significance in terms of RFS in male patients. This suggests that anti-HBc positivity may affect the clinical course in women with NBNC-HCC more than in men.

In the present study, the anti-HBc-positive group had more advanced liver cirrhosis compared with the anti-HBc-negative group, although the difference did not reach significance. Previous studies also found that anti-HBc positivity was correlated with advanced liver cirrhosis (11, 12), and our results were consistent with these reports. Interestingly, subgroup analyses according to Child–Pugh classification revealed significant differences between the two groups in both OS and RFS in patients with Child–Pugh A, while no significant differences in either OS or RFS were found in patients with Child–Pugh B. Our results thus indicate that anti-HBc positivity is associated with survival in patients with NBNC-HCC with less advanced cirrhosis, who have undergone curative treatment.

Multivariate analysis identified high DCP levels as a significant adverse prognostic factor linked to both OS and RFS. High DCP levels indicate biologically aggressive HCC (28). Kaibori et al. reported that preoperative serum DCP levels were a prognostic indicator in NBNC-HCC (4). Our results were in agreement with their reports, implying that patients with NBNC-HCC with high pre-treatment DCP levels need close observation even after curative therapy in order to optimize their clinical outcomes.

Serum albumin levels were significantly linked to OS in multivariate analysis. Patients with liver cirrhosis and low serum albumin levels can develop protein-energy malnutrition with increased catabolism (29). Protein-energy malnutrition is associated with high morbidity and mortality because of an increased risk of life-threatening complications, such as severe infections and bleeding, resulting in poor survival and reduced quality of life (30). A high proportion of patients with HCC have concurrent liver cirrhosis. Branched chain amino-acid treatment may be effective for these patients (31).

Elevated serum AST levels were significantly associated with RFS, and almost significantly (p=0.055) with OS in multivariate analysis. Kawamura et al. performed a large retrospective study and reported that an AST level ≥40 IU/l was an independent predictive factor for HCC development in patients with non-alcoholic fatty liver disease (32). Elevation of AST levels is also considered to be a useful predictor in terms of HCC recurrence after curative treatment for NBNC-HCC.

There are several limitations to the present study. Firstly, this was a single-center retrospective study. Secondly, the median observation periods for the two groups were relatively short for survival analysis. Larger prospective studies with longer observation periods are, thus, needed to confirm these results. However, the current study demonstrated that anti-HBc positivity was associated with poor survival of patients with NBNC-HCC who underwent curative therapy. Anti-HBc positivity should, thus, be taken into account when assessing the risk of HCC recurrence in patients with NBNC-HCC.

Acknowledgements

The Authors would like to thank Haruko Takada for data collection.

Footnotes

  • Conflicts of Interest

    The Authors have not received any financial support for this study and have no conflicts of interest to declare.

  • Received March 5, 2013.
  • Revision received April 6, 2013.
  • Accepted April 9, 2013.

References

  1. ↵
    1. Livraghi T,
    2. Mäkisalo H,
    3. Line PD
    : Treatment options in hepatocellular carcinoma today. Scand J Surg 100: 22-29, 2011.
    OpenUrlPubMed
    1. El-Serag HB
    : Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142: 1264-1273, 2012.
    OpenUrlCrossRefPubMed
  3. ↵
    1. de Lope CR,
    2. Tremosini S,
    3. Forner A,
    4. Reig M,
    5. Bruix J
    : Management of HCC. J Hepatol 56(Suppl 1): S75-S87, 2012.
    OpenUrlPubMed
  4. ↵
    1. Kaibori M,
    2. Ishizaki M,
    3. Matsui K,
    4. Kwon AH
    : Clinicopathologic characteristics of patients with non-B non-C hepatitis virus hepatocellular carcinoma after hepatectomy. Am J Surg 204: 300-307, 2012.
    OpenUrlPubMed
  5. ↵
    1. Yotsuyanagi H,
    2. Shintani Y,
    3. Moriya K,
    4. Fujie H,
    5. Tsutsumi T,
    6. Kato T,
    7. Nishioka K,
    8. Takayama T,
    9. Makuuchi M,
    10. Iino S,
    11. Kimura S,
    12. Koike K
    : Virologic analysis of non-B, non-C hepatocellular carcinoma in Japan: Frequent involvement of hepatitis B virus. J Infect Dis 181: 1920-1928, 2000.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Utsunomiya T,
    2. Shimada M
    : Molecular characteristics of non-cancerous liver tissue in non-B non-C hepatocellular carcinoma. Hepatol Res 41: 711-721, 2011.
    OpenUrlPubMed
  7. ↵
    1. Umemura T,
    2. Kiyosawa K
    : Epidemiology of hepatocellular carcinoma in Japan. Hepatol Res 37(Suppl 2): S95-S100, 2007.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Zhou WP,
    2. Lai EC,
    3. Li AJ,
    4. Fu SY,
    5. Zhou JP,
    6. Pan ZY,
    7. Lau WY,
    8. Wu MC
    : A prospective, randomized, controlled trial of preoperative transarterial chemoembolization for resectable large hepatocellular carcinoma. Ann Surgery 249: 195-202, 2009.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Nishikawa H,
    2. Osaki Y,
    3. Kita R,
    4. Kimura T,
    5. Inuzuka T,
    6. Takeda H,
    7. Nakajima J,
    8. Matsuda F,
    9. Sakamoto A,
    10. Henmi S,
    11. Hatamaru K,
    12. Saito S,
    13. Nasu A
    : Transcatheter arterial infusion chemotherapy prior to radiofrequency thermal ablation for single hepatocellular carcinoma reduces the risk of intrahepatic distant recurrence. Int J Oncol 41: 903-909, 2012.
    OpenUrlPubMed
  10. ↵
    1. Ohki T,
    2. Tateishi R,
    3. Goto E,
    4. Sato T,
    5. Masuzaki R,
    6. Imamura J,
    7. Goto T,
    8. Kanai F,
    9. Kato N,
    10. Shiina S,
    11. Yoshida H,
    12. Kawabe T,
    13. Omata M
    : Influence of anti-HBc seropositivity on the risk of hepatocellular carcinoma in HCV-infected patients after adjusting for confounding factors. J Viral Hepat 17: 91-97, 2010.
    OpenUrlPubMed
  11. ↵
    1. Squadrito G,
    2. Pollicino T,
    3. Cacciola I,
    4. Caccamo G,
    5. Villari D,
    6. La Masa T,
    7. Restuccia T,
    8. Cucinotta E,
    9. Scisca C,
    10. Magazzu D,
    11. Raimondo G
    : Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients. Cancer 106: 1326-1330, 2006.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Ikeda K,
    2. Marusawa H,
    3. Osaki Y,
    4. Nakamura T,
    5. Kitajima N,
    6. Yamashita Y,
    7. Kudo M,
    8. Sato T,
    9. Chiba T
    : Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carci-noma: A prospective study. Ann Intern Med 146: 649-656, 2007.
    OpenUrlPubMed
  13. ↵
    1. Ikeda K,
    2. Kobayashi M,
    3. Someya T,
    4. Saitoh S,
    5. Hosaka T,
    6. Akuta N,
    7. Suzuki F,
    8. Suzuki Y,
    9. Arase Y,
    10. Kumada H
    : Occult hepatitis B virus infection increases hepatocellular carcinogenesis by eight times in patients with non-B, non-C liver cirrhosis: A cohort study. J Viral Hepat 16: 437-443, 2009.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Lok AS,
    2. Everhart JE,
    3. Di Bisceglie AM,
    4. Kim HY,
    5. Hussain M,
    6. Morgan TR,
    7. HALT-C Trial Group
    : Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in United States patients with chronic hepatitis C. Hepatology 54: 434-442, 2011.
    OpenUrlPubMed
  15. ↵
    1. Shiota G,
    2. Oyama K,
    3. Udagawa A,
    4. Tanaka K,
    5. Nomi T,
    6. Kitamura A,
    7. Tsutsumi A,
    8. Noguchi N,
    9. Takano Y,
    10. Yashima K,
    11. Kishimoto Y,
    12. Suou T,
    13. Kawasaki H
    : Occult hepatitis B virus infection in HBs antigen-negative hepatocellular carcinoma in a Japanese population: Involvement of HBx and p53. J Med Virol 62: 151-158, 2000.
    OpenUrlPubMed
  16. ↵
    1. Jilg W,
    2. Sieger E,
    3. Zachoval R,
    4. Schätzl H
    : Individuals with antibodies against hepatitis B core antigen as the only serological marker for hepatitis B infection: High percentage of carriers of hepatitis B and C virus. J Hepatol 23: 14-20, 1995.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Cacciola I,
    2. Pollicino T,
    3. Squadrito G,
    4. Cerenzia G,
    5. Orlando ME,
    6. Raimondo G
    : Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med 341: 22-26, 1999.
    OpenUrlCrossRefPubMed
    1. Chemin I,
    2. Zoulim F,
    3. Merle P,
    4. Arkhis A,
    5. Chevallier M,
    6. Kay A,
    7. Cova L,
    8. Chevallier P,
    9. Mandrand B,
    10. Trépo C
    : High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology. J Hepatol 34: 447-454, 2001.
    OpenUrlCrossRefPubMed
    1. Shintani Y,
    2. Yotsuyanagi H,
    3. Moriya K,
    4. Fujie H,
    5. Tsutsumi T,
    6. Takayama T,
    7. Makuuchi M,
    8. Kimura S,
    9. Koike K
    : The significance of hepatitis B virus DNA detected in hepatocellular carcinoma of patients with hepatitis C. Cancer 88: 2478-2486, 2000.
    OpenUrlPubMed
  20. ↵
    1. Kusakabe A,
    2. Tanaka Y,
    3. Orito E,
    4. Sugauchi F,
    5. Kurbanov F,
    6. Sakamoto T,
    7. Shinkai N,
    8. Hirashima N,
    9. Hasegawa I,
    10. Ohno T,
    11. Ueda R,
    12. Mizokami M
    : A weak association between occult HBV infection and non-B non-C hepatocellular carcinoma in Japan. J Gastroenterol 42: 298-305, 2007.
    OpenUrlPubMed
  21. ↵
    1. Tamori A,
    2. Nishiguchi S,
    3. Kubo S,
    4. Narimatsu T,
    5. Habu D,
    6. Takeda T,
    7. Hirohashi K,
    8. Shiomi S
    : HBV DNA integration and HBV-transcript expression in non-B, non-C hepatocellular carcinoma in Japan. J Med Virol 71: 492-498, 2003.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Hassan MM,
    2. Hwang LY,
    3. Hatten CJ,
    4. Swaim M,
    5. Li D,
    6. Abbruzzese JL,
    7. Beasley P,
    8. Patt YZ
    : Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 36: 1206-1213, 2002.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Alberti KG,
    2. Zimmet PZ
    : Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus- provisional report of a WHO consultation. Diabet Med 15: 539-553, 1998.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Bruix J,
    2. Sherman M,
    3. Practice Guidelines Committee,
    4. American Association for the Study of Liver Diseases
    : Management of hepatocellular carcinoma. Hepatology 42: 1208-1236, 2005.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Liver Cancer Study Group of Japan
    : The general rules for the clinical and pathological study of primary liver cancer. Jpn J Surg 19: 98-129, 1989.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Marusawa H,
    2. Osaki Y,
    3. Kimura T,
    4. Ito K,
    5. Yamashita Y,
    6. Eguchi T,
    7. Kudo M,
    8. Yamamoto Y,
    9. Kojima H,
    10. Seno H,
    11. Moriyasu F,
    12. Chiba T
    : High prevalence of anti-hepatitis B virus serological markers in patients with hepatitis C virus-related chronic liver disease in Japan. Gut pp. 45284-45288, 1999.
  27. ↵
    1. Marusawa H,
    2. Uemoto S,
    3. Hijikata M,
    4. Ueda Y,
    5. Tanaka K,
    6. Shimotohno K,
    7. Chiba T
    : Latent hepatitis B virus infection in healthy individuals with antibodies to hepatitis B core antigen. Hepatology pp. 31488-31495, 2000.
  28. ↵
    1. Kobayashi M,
    2. Ikeda K,
    3. Kawamura Y,
    4. Yatsuji H,
    5. Hosaka T,
    6. Sezaki H,
    7. Akuta N,
    8. Suzuki F,
    9. Suzuki Y,
    10. Saitoh S,
    11. Arase Y,
    12. Kumada H
    : High serum des-gamma-carboxy prothrombin level predicts poor prognosis after radiofrequency ablation of hepatocellular carcinoma. Cancer 115: 571-580, 2009.
    OpenUrlPubMed
  29. ↵
    1. Lautz HU,
    2. Selberg O,
    3. Körber J,
    4. Bürger M,
    5. Müller MJ
    : Protein-calorie malnutrition in liver cirrhosis. Clin Investig 70: 478-486, 1992.
    OpenUrlPubMed
  30. ↵
    1. Italian Multicentre Cooperative Project on Nutrition in Liver Cirrhosis
    : Nutritional status in cirrhosis. J Hepatology 21: 317-335, 1994.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Nishikawa H,
    2. Osaki Y,
    3. Inuzuka T,
    4. Takeda H,
    5. Nakajima J,
    6. Matsuda F,
    7. Henmi S,
    8. Sakamoto A,
    9. Ishikawa T,
    10. Saito S,
    11. Kita R,
    12. Kimura T
    : Branched-chain amino acid treatment before transcatheter arterial chemoembolization for hepatocellular carcinoma. World J Gastroenterol 18: 1379-1384, 2012.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Kawamura Y,
    2. Arase Y,
    3. Ikeda K,
    4. Seko Y,
    5. Imai N,
    6. Hosaka T,
    7. Kobayashi M,
    8. Saitoh S,
    9. Sezaki H,
    10. Akuta N,
    11. Suzuki F,
    12. Suzuki Y,
    13. Ohmoto Y,
    14. Amakawa K,
    15. Tsuji H,
    16. Kumada H
    : Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma. Am J Gastroenterol 107: 253-261, 2012.
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Relation Between Antibody to Hepatitis B Core Antigen and Survival after Curative Therapy for Non-B Non-C Hepatocellular Carcinoma
HIROKI NISHIKAWA, YUKIO OSAKI, AKIRA ARIMOTO, RYUICHI KITA, TORU KIMURA
Anticancer Research May 2013, 33 (5) 2211-2219;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

Keywords