Japanese Journal of Clinical Oncology 30:75-81 (2000)
© 2000 Foundation for Promotion of Cancer Research
What Patients Can Survive Disease Free After Complete Resection for Hepatocellular Carcinoma?: A Multivariate Analysis
1First Department of Surgery and 2Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo and 3Biometric Analysis Department, Shionogi & Co., Ltd., Osaka, Japan
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Background: Although there have been extensive studies to determine risk factors affecting survival after resection for hepatocellular carcinoma (HCC), we still do not know which patients can survive disease free after curative resection. This study was undertaken to determine independent risk factors affecting the length of disease-free survival.
Methods: 171 patients, who survived disease free more than 1 year after curative resection, were divided into four groups according to the disease-free period: Group I (n = 96) for the patients with intrahepatic recurrence between 1 and 3 postoperative years, Group II(n = 27) for those between 3 and 5 years, Group III (n = 40) for those between 5 and 10 years and Group IV (n = 8) for those without recurrence within 10 years. The 37 variables (host factors, tumor factors, non-tumor liver factors, surgical factors) were compared among the four groups. Activity of hepatitis and hepatic fibrosis was scored by the Histological Activity Index (HAI). In a multivariate study, possible prognostic variables with a statistical difference in the disease-free survival rate among each category were preliminarily selected from the 37 variables and the independent variables were finally selected using a proportional hazard analysis.
Results: The patients’ age, indocyanine green retention rate, microscopic tumor capsular invasion and portal invasion, cell differentiation, extent of hepatectomy, aggressiveness of chronic hepatitis and inflammatory activity assessed by HAI score were significantly different among the four groups. In the multivariate analysis, the following variables were selected as the independent determinants favorable for achieving a longer disease-free period: younger age, lower indocyanine green retention rate, solitary HCC with expansive growth, no microscopic portal invasion and lower activity of co-existing hepatitis.
Conclusions: The importance of inflammatory activity in addition to aging, hepatic reserve and tumor characteristics was confirmed as a risk factor for recurrence by multivariate analysis. To achieve better disease-free survival, not only early detection but also suppression of co-existing hepatitis is necessary.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The prognosis of hepatocellular carcinoma (HCC) after hepatic resection has been markedly improved over the past 10 years by virtue of widespread screening for high-risk population, advances in imaging modality, indication of hepatic resection (1–4), technical refinement of hepatectomy and innovation of multidisciplinary modalities such as transarterial embolization (TAE) (5), percutaneous ethanol injection (6) and microwave coagulation therapy (7,8), for intrahepatic recurrence. There are several factors limiting long-term survival. One is frequent intrahepatic micrometastasis via the portal vein as a major drainage vessel of the HCC (9,10), which enhances intrahepatic recurrence along with a limitation of resection range by co-existing chronic liver disease. Metachronous multicentric growth of HCC also constitutes another cause of intrahepatic recurrence (11–13). In fact, the survival rate drops to 24% at 10 years even after curative resections (14).
There have been extensive studies, mostly focusing on tumor characteristics (15–17), to determine what factors affect the crude survival after hepatectomy. Our previous multivariate studies demonstrated the importance of macroscopic portal invasion and intrahepatic metastasis (15) and also tumor DNA ploidy pattern as the prognostic factors (18). These analyses were carried out in patients including non-curative resections for advanced HCCs. Therefore, the importance of the tumor stage has been much stressed as a prognostic factor.
In the present study, subjects were limited to more favorable patients who were expected to have a curative resection. Non-tumor variables such as activity of hepatitis and degree of liver fibrosis were included in addition to conventional prognostic variables such as hepatic functions, tumor characteristics and surgical factors for a multivariate analysis to determine crucial factors affecting posthepatectomy disease-free period.
|
PATIENTS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Subjects
A total of 419 patients underwent liver resection for HCC between January 1981 and December 1990 in our department. Of these, 201 patients, who had an intra- and/or extrahepatic recurrence (s) or died within 1 postoperative year, were excluded from the study. The 47 patients, who died later than 1 postoperative year due to progressive liver disease (n = 19), ruptured esophageal varices (n = 7) or other systemic disease (n = 11), were also excluded. There were 10 patients who were lost to follow-up. The remaining 171 patients were divided into the following four groups according to the length of disease-free period: Group I (n = 96) for those with recurrence in a period between 1 and 3 postoperative years, Group II (n = 27) for those with recurrence in a period between 3 and 5 years, Group III (n = 40) for those with recurrence in a period between 5 and 10 years and Group IV (n = 8) for those without recurrence within 10 years. The diagnosis of intrahepatic recurrence was made by serial ultrasonography and/or computed tomography combined with serum tumor markers such as
-fetoprotein (AFP) and PIVKA-II (19). Ultrasonographically guided needle biopsy was carried out for a suspicious lesion to obtain a definite diagnosis.
Host Factors
The host factors included age, gender distribution, viral serological marker, alcohol drinking history, smoking history, transfusion history and history of preoperative transarterial embolization (TAE). The liver function factors included indocyanine green retention rate at 15 min (ICG R15), serum albumin (ALB), serum total bilirubin (T-Bil), prothrombin time (PT) and serum aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT). The patients, who had been drinking more than 86 g/day of alcohol (ethanol) for 10 years or more, were regarded as habitual drinkers.
Tumor Factors
The tumor factors included AFP as a tumor marker, tumor size, macroscopic growth type (expansive vs. infiltrative growth), macroscopic portal invasion (Vp), intrahepatic metastasis (IM) and tumor stage (TNM classification) (20). Histological parameters, such as cell differentiation, histological pattern, tumor capsule formation (fc), capsule infiltration (fc-inf), portal invasion (vp) and intrahepatic metastasis (im), were also included. The 23 patients (14 patients in Group I, six in Group II, three in Group III), in whom massive tumor necrosis was induced by preoperative TAE, were excluded from the analysis concerning the tumor factors. The cell differentiation was divided into well, moderate and poor according to the classification by the Primary Liver Cancer Study Group (21). Multicentric occurrence of HCC in the resected specimen was defined as follows (22): one tumor consisting of very well-differentiated HCC in a replacing growth pattern and the other one without macroscopic portal invasion for multiple lesions.
Non-tumor Liver Factors
The liver pathology was classified as normal, chronic hepatitis and cirrhosis. The patients classified as chronic hepatitis were subdivided into chronic persistent hepatitis (CPH) and chronic aggressive hepatitis (CAH) (23). Inflammatory activity and fibrosis were graded in all patients according to the histological activity index (HAI score) by Knodell et al. (24) as follows. The scores for three features (degree of periportal hepatocellular necrosis and bridging, degree of intralobular degeneration and focal hepatocellular necrosis and degree of portal inflammation) were totaled for the grading of inflammatory activity in an individual case. The staging of the liver fibrosis was scored 0 for no fibrosis, 1 for fibrous portal expansion, 3 for bridging fibrosis and 4 for cirrhosis. The HAI score in each patient was expressed as the average of the scores in three visual fields more than 1 cm apart from the tumor edge and the liver capsule.
Surgical Factors
The type of hepatectomy, operation time, amount of intraoperative blood transfusion, weight of resected specimen, status of resection margin and surgical curability (curability A vs. curability B) (14) were also compared among the four groups.
Statistical Analysis
Comparison of each factor among the four groups
Each category of the host factors, tumor factors, non-tumor livers and surgical factors was compared among the four groups. A chi-squared test was used for comparison of the dichotomous variables and one-way ANOVA for that of the continuous variables. A probability value <0.05 was considered statistically significant.
Univariate and multivariate analyses
First, the disease-free survival rates, estimated by the Kaplan–Meier method, were statistically compared between the categories in each factor listed in Tables 1–4, using three analyses of log-rank test, generalized Kruskal–Wallis test and simple variate proportional hazard analysis. Then, the possible prognostic factors, which showed a statistical difference among the categories by any of the three analyses, were selected. Second, we employed multivariate proportional hazard analysis (25) on these potential prognostic factors and selected independent prognostic factors from them according to a stepwise method with an F value of 0.20 in and out.
|
|
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Comparison of Each Factor Among the Four Groups
Host factors
The mean patient age was lower in Group IV (p < 0.05) (Table 1). Female prevalence was slightly higher in Group IV but there were no significant differences among the four groups. The other host factors such as HBs antigen (HBsAg) positivity, smoking history, transfusion history and preoperative TAE showed no significant differences. Of the liver function, only ICG R15 in Group IV was significantly lower. Results of the other liver function tests such as ALB, T-Bil, PT and liver enzymes (AST and ALT) were not statistically different, although the liver enzymes tended to be lower in Group IV.
Tumor factors
The AFP value and its positivity showed no significant differences (Table 2). There was no statistical difference in the macroscopic tumor factors such as tumor size, tumor stage, Vp, IM and growth pattern, although the multicentric growth type accounted for about 10% in Groups I, II and III in contrast to 0% in Group IV. On the other hand, regarding the microscopic tumor factors, fc-inf and vp had significantly lower positivity in Groups III and IV, and the proportion of the well-differentiated HCCs was significantly higher in Group IV (Table 3). The histological pattern of the HCCs was similar in the four groups.
|
|
Non-tumor liver factors
1. Pathology. The proportion of normal liver was higher in Group IV, while those of chronic hepatitis and cirrhosis were similar between the groups (Table 3). Among the patients with chronic hepatitis, the proportion of CAH was significantly higher in Group I.
2. HAI score. The mean HAI score, assessing the activity of hepatitis, was 5.2 ± 1.9 in Group I, 5.1 ± 2.0 in Group II, 4.1 ± 2.1 in Group III and 3.6 ± 2.5 in Group IV, showing that the longer the disease-free period, the lower was the HAI score (Fig. 1). The HAI scores in Groups I and II were significantly higher than those in Group III (p < 0.05). Even in the selected patients without microscopic portal invasion or intrahepatic metastasis, in whom the risk for intrahepatic recurrence originating from latent intrahepatic micrometastasis was minimal, the HAI score tended to be lower in the patients with longer disease-free period. In contrast, the degree of fibrosis was similar in the four groups (Fig. 2).
|
|
Surgical factors
Concerning the resection range, the proportion of hepatic lobectomy was significantly higher in Group IV than in the other three groups (p < 0.05) (Table 4). The amount of blood transfusion, operation time, specimen weight, status of resection margin and surgical curability (A or B) were not significantly different among the four groups.
Univariate analysis
Twenty-one variables were determined to be statistically significant possible prognostic factors by any of the three analyses, log-rank test, generalized Kruskal–Wallis test and simple variate proportional hazard analysis (Table 5): seven of the host factors (age, ICG R15, ALB, ALT, AST, T-Bil, preoperative TAE), eight of the tumor factors (macroscopic growth type, IM, tumor stage, histological pattern, cell differentiation, fc, sf and vp), two of the non-tumor liver factors (HAI score and histopathology) and four of the surgical factors (type of hepatectomy, status of resection margin, curability, specimen weight).
|
Multivariate analysis
The seven independent prognostic factors were finally selected from the 21 variables by stepwise multivariate analysis (Table 6): number of the nodule (single vs. multiple), macroscopic growth type (expansive or infiltrative), microscopic portal invasion, age, ICG R15, HAI inflammatory score and activity of chronic hepatitis. The solitary HCCs with expansive growth and without microscopic portal invasion were favorable for achieving better disease-free survival. Aging, higher ICG retention rate and higher activity of co-existing hepatitis were unfavorable conditions limiting the disease-free survival.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
There are some studies reporting that gender (14,26) or alcohol consumption (27–29) may contribute to hepatocellular carcinogenesis. In fact, in our study, the proportions of male and habitual alcoholics were low in the longer disease-free survivors, although the multivariate analysis did not select these factors.
In our previous studies (2–4), which determined the predictive factors for posthepatectomy liver failure in patients with co-existing chronic liver disease, ICG R15, age and extent of hepatectomy were selected as the predictors in the multivariate analysis. Interestingly, ICG R15 and age also were recognized as the crucial risk factors for intrahepatic recurrence in this study. The patients who survived more than 10 years without recurrence were younger and had better ICG R15. Therefore, better hepatic reserve and younger age may be biologically favorable conditions for avoiding metachronous carcinogenesis. In fact, some studies pointed out aging and ICG R15 as independent risk factors for the development of HCC in cirrhotic patients (30) and for recurrence in HCC patients (31,32).
Generally, postoperative prognosis in patients with malignancies are closely related to the tumor stage. However, in the present study, which excluded the patients with early recurrences or deaths within 1 year, some macroscopic tumor factors such as tumor size, macroscopic portal invasion and tumor stage were underestimated, although these are strong prognostic factors in overall HCC populations (9,15). Instead of such macroscopic tumor factors, microscopic intrahepatic metastasis, microscopic portal invasion and tumor growth pattern were selected as the independent risk factors for later intrahepatic recurrence. This suggests that intrahepatic recurrence, originating from the latent, micrometastatic lesion, will appear later than 1 postoperative year. Tumor cell differentiation (21), which was significantly different among the four groups, was not selected as an independent variable. This is probably because cell differentiation is highly correlated with the development of the microscopic portal invasion (27).
Intrahepatic recurrence also originates from metachronous carcinogenesis. This concept can clearly be derived from our result that the proportion of HCC patients without microscopic portal invasion and intrahepatic metastasis accounted for 11% (14/123) in Groups I and II and 31% (15/48) in Groups III and IV. Thus, weight of risk factors causing intrahepatic recurrences shifts from the microscopic tumor spread to metachronous carcinogenesis in the time course of postoperative period.
The viral serostatus strongly affects the incidence of metachronous carcinogenesis after curative resection for HCC. There have been studies reporting that hepatitis C virus (HCV)-related HCCs have a higher incidence of metachronous carcinogenesis in contrast to non-HCV-related HCCs (13,33,34). As the present study included the early series, in which anti-HCV antibody could not be determined, HCV serostatus was not added as a variable for the multivariate analysis. In our series of hepatectomized patients since 1991, the 142 patients positive for anti-HCV had an HAI score of 6.1 ± 1.6, which was significantly higher than 4.8 ± 2.3 for the 33 patients positive for HBsAg or 4.4 ± 2.6 for the 21 patients negative for both anti-HCV and HBsAg (unpublished data). Hence, HAI score can be a substitute for HCV serostatus. In this study, both the histologically determined activity of hepatitis and HAI score were selected as the independent risk factors in spite of having a similar implication. A distinction of chronic persistent hepatitis from chronic aggressive hepatitis was made only in the subpopulation with chronic hepatitis, not including the cirrhotic patients, whereas the HAI score was determined in all patients. Therefore, it is presumed that the HAI score was selected as an independent variable because the cirrhotic patients accounted for a large portion of this series.
Several studies have reported that cirrhotic change may be a strong risk factor for hepatic carcinogenesis (35,36). In contrast, the proportion of co-existing liver cirrhosis and the degree of fibrosis were similar in the four groups and were not selected as an independent variable in our study. This may suggest that not fibrosis, established secondarily to persisting inflammation, but persistent inflammation per se would be a more important factor contributing to hepatocarcinogenesis.
The extent of hepatectomy is limited mainly by hepatic reserve (1–4). Limitation of resection range carries a risk of leaving minute transportal intrahepatic metastasis behind even after apparently curative resection (15). In fact, the proportion of hepatic lobectomy was lowest in Group I. However, none of the surgical factors was determined as an independent variable.
This study demonstrated that the disease-free survival length can be affected by tumor characteristics, hepatic reserve, activity of co-existing hepatitis and age. Hepatic reserve and age are the prognostic factors which we are unable to control. However, tumor factor and activity of co-existing hepatitis can be controlled by early resection and early suppression of persistent inflammation by new drugs, such as ribavirin (37) and lamivudine (38).
|
FOOTNOTES |
|---|
+ For reprints and all correspondence: Naoki Yamanaka, First Department of Surgery, Hyogo College of Medicine, 1–1, Mukogawa-cho, Nishinomiya, Japan 663-8501Abbreviations: HCC, hepatocellular carcinoma; HAI, histological activity index; ICG R15, indocyanine green retention rate at 15 min; ALB, serum albumin; T-Bil, serum total bilirubin; PT, prothrombin activity; AST, aspartate aminotransaminase; ALT, alanine aminotransaminase; TAE, transarterial embolization; AFP,
-fetoprotein; Vp, macroscopic portal invasion; IM, macroscopic intrahepatic metastasis; fc, capsule formation; fc-inf, capsule infiltration; sf, septum formation; vp, microscopic portal invasion; im, microscopic intrahepatic metastases; CPH, chronic persistent hepatitis; CAH, chronic aggressive hepatitis; SE, standard error 
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1 Okamoto E, Kyo A, Yamanaka N, Tanaka N, Kuwata K. Prediction of the safe limits of hepatectomy by combined volumetric and functional measurements in patients with impaired hepatic function. Surgery 1984;95:586–91.[Web of Science][Medline]
2 Yamanaka N, Okamoto E, Oriyama T, Fujimoto J, Furukawa K, Kawamura E, et al. A prediction scoring system to select the surgical treatment of liver cancer. Ann Surg 1994;219:342–6.[Web of Science][Medline]
3 Yamanaka N, Okamoto E, Kuwata K, Tanaka N. A multiple regression equation for prediction of posthepatectomy liver failure. Ann Surg 1984;200:658–63.[Web of Science][Medline]
4 Yamanaka N, Okamoto E. How do we determine the safe limit of hepatectomy based on multiple crucial factors? J Hep Bil Pancr Surg 1997;4:235–40.
5 Yamada R, Sato M, Kawabata M. Hepatic artery embolization in 120 patients with hepatocellular carcinoma. Radiology 1983;148:397–401.
6 Shiina S, Tagawa K, Niwa Y, Unuma T, Komatsu Y, Yoshiura K, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. Am J Roentgenol 1993;160:1023–8.
7 Yamanaka N, Tanaka T, Oriyama T, Furukawa K, Tanaka W, Okamoto E. Microwave coagulonecrotic therapy for hepatocellular carcinoma. World J Surg 1996;20:1076–81.[Web of Science][Medline]
8 Sato M, Watanabe Y, Ueda S, Iseki S, Abe Y, Sato N, et al. Microwave coagulation therapy for hepatocellular carcinoma. Gastroenterology 1996;110:1507–14.[Web of Science][Medline]
9 Okamoto E, Yamanaka N, Toyosaka A, Tanaka N, Yabuki K. Current status of hepatic resection in the treatment of hepatocellular carcinoma. In: Okuda K, Ishak KG, editors. Neoplasms of the Liver. New York: Springer 1987;105–16.
10 Yamanaka N, Okamoto E, Fujiwara S, Kato T, Fujimoto J, Oriyama T, et al. Do the tumor cells of hepatocellular carcinomas dislodge into the portal venous stream during hepatic resection? Cancer 1992;70:2263–7.[Web of Science][Medline]
11 Takenaka K, Adachi E, Nishizaki T, Hiroshige K, Ikeda T, Tsuneyoshi M, et al. Possible multicentric occurrence of hepatocellular carcinoma: a clinicopathological study. Hepatology 1994;19:889–94.[Web of Science][Medline]
12 Belghiti J, Panis Y, Farges O, Benhamou JP, Fekete F. Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg 1991;214:114–7.[Web of Science][Medline]
13 Yamanaka N, Tanaka T, Tanaka W, Yamanaka J, Yasui C, Kuroda N, et al. Correlation of hepatitis virus serologic status with clinicopathologic features in patients undergoing hepatectomy for hepatocellular carcinoma. Cancer 1997;79:1509–15.[Web of Science][Medline]
14 Okamoto E, Yamanaka N, Oriyama T, Fujimoto J, Furukawa K, Kawamura E, et al. Determinants of long-term survival following hepatectomy for hepatocellular carcinoma, with special reference to patients surviving more than 10 years. J Hep Bil Pancr Surg 1994;2:107–12.
15 Yamanaka N, Okamoto E, Toyosaka A, Mitsunobu M, Fujihara S, Kato T, et al. Prognostic factors after hepatectomy for hepatocellular carcinomas. Cancer 1990;65:1104–10.[Web of Science][Medline]
16 Shirabe K, Kanematsu T, Matsumata T, Adachi E, Akazawa K, Sugimachi K. Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate and multivariate analysis. Hepatology 1991;14:802–5.[Web of Science][Medline]
17 Lai ECS, Ng IOL, Ng MMT, Lok ASF, Tam PC, Fan ST, et al. Long-term results of resection for large hepatocellular carcinoma: a multivariate analysis of clinicopathological features. Hepatology 1990;11:815–8.[Web of Science][Medline]
18 Fujimoto J, Okamoto E, Yamanaka N, Toyosaka A, Mitsunobu M. Flow cytometric DNA analysis of hepatocellular carcinoma. Cancer 1991;67:939–44.[Web of Science][Medline]
19 Liebman HA, Furie BC, Tong MJ, Blanchard RA, Lo KJ, Coleman MS, et al. Des-
-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med 1984;310:1427–31.[Abstract]
20 Hemanek P, Sobin LH. TNM Classification of Malignant Tumors, 4th ed. International Union Against Cancer. Berlin: Springer 1987.
21 Liver Cancer Study Group of Japan. Classification of Primary Liver Cancer. Tokyo: Kanehara 1997.
22 Tsuda H, Oda T, Sakamoto M, Hirohashi S. Different pattern of chromosomal allele loss in multiple hepatocellular carcinomas as evidence of their multifocal origin. Cancer Res 1992;52:1504–9.
23 De Groote J, Desmet VJ, Gedigk P, Korb G, Popper H, Poulsen H, et al. A classification of chronic hepatitis. Lancet 1968;2:626–8.[Medline]
24 Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431–5.[Web of Science][Medline]
25 Cox DR. Regression models and life tables. J R Stat Soc 1972;B34:187–220.
26 Nagasue N, Kohno H, Chang YC, Hayashi T, Utsumi Y, Nakamura T, et al. Androgen and estrogen receptors in hepatocellular carcinoma and the surrounding liver in women. Cancer 1989;63:112–6.[Web of Science][Medline]
27 Kennmochi K, Sugihara S, Kojiro M. Relationship of pathologic grade of hepatocellular carcinoma (HCC) to tumor size and demonstration of tumor cells of multiple different grade in single HCC. Liver 1987;7:18–26.[Web of Science][Medline]
28 Peters RL. Pathology of hepatocellular carcinoma. In: Okuda K, Peters RL, editors. Hepatocellular Carcinoma. Wiley: London 1976;109–12.
29 Adachi S, Moriwaki H, Muto Y, Yamada Y, Fukutomi Y, Shimazaki M, et al. Reduced retinoid content in hepatocellular carcinoma with special reference to alcohol consumption. Hepatology 1991;14:776–80.[Web of Science][Medline]
30 Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993;18:47–53.[Web of Science][Medline]
31 Falksson G, Cnaan A, Schutt AJ, Ryan LM, Falkson HC. Prognostic factors for survival in hepatocellular carcinoma. Cancer Res 1988;48:7314–8.
32 Ikeda K, Saitoh S, Tsubota A, Arase Y, Chayama K, Kumada H, et al. Risk factors for tumor recurrence and prognosis after curative resection of hepatocellular carcinoma. Cancer 1993;71:19–25.[Web of Science][Medline]
33 Takenaka K, Yamamoto K, Taketomi A, Itasaka H, Adachi E, Shirabe K, et al. A comparison of the surgical results in patients with hepatitis B versus hepatitis C-related hepatocellular carcinoma. Hepatology 1995;22:20–4.[Web of Science][Medline]
34 Mazzanti R, Messerini L, Monsacchi L, Buzzelli G, Zignego AL, Foschi M, et al. Chronic viral hepatitis induced by hepatitis C but not hepatitis B virus infection correlates with increased liver angiogenesis. Hepatology 1997;25:229–34.[Web of Science][Medline]
35 Oka H, Kurioka N, Kim K, Kanno T, Kuroki T, Mizoguchi Y, et al. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 1990;12:680–7.[Web of Science][Medline]
36 Tarao K, Shimizu A, Ohkawa S, Harada M, Ito Y, Tamai S, et al. Development of hepatocellular carcinoma associated with increases in DNA synthesis in the surrounding cirrhosis. Gastroenterology 1992;103:595–600.[Web of Science][Medline]
37 Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg A, Weiland O. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. Lancet 1998;351:83–7.[Web of Science][Medline]
38 Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med 1995;333:1657–61.
Received July 2, 1999; accepted October 29, 1999.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Sakon, H. Nagano, S. Nakamori, K. Dono, K. Umeshita, T. Murakami, H. Nakamura, and M. Monden Intrahepatic Recurrences of Hepatocellular Carcinoma After Hepatectomy: Analysis Based on Tumor Hemodynamics Arch Surg, January 1, 2002; 137(1): 94 - 99. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||