FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 328:1802-1806 June 24, 1993 Number 25 Next

Abstract Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background The sugar-chain structures of circulating alpha-fetoprotein in patients with hepatocellular carcinomas differ from those in patients with cirrhosis. We studied the reactivity of alpha-fetoprotein with two lectins, Lens culinaris agglutinin A and erythroagglutinating phytohemagglutinin, to monitor the evolution of hepatocellular carcinoma in patients with cirrhosis.

Methods Among 361 patients with cirrhosis caused mainly by chronic hepatitis B or hepatitis C virus infection, 33 with base-line serum alpha-fetoprotein concentrations 30 ng per milliliter were found to have hepatocellular carcinomas during a mean follow-up of 35 months. The lectin-reactive profiles of the alpha-fetoprotein in the serum of these 33 patients were analyzed and compared with those in the serum of 32 patients with cirrhosis who had increased base-line serum alpha-fetoprotein concentrations and were followed for at least 24 months but in whom hepatocellular carcinoma did not develop.

Results At the time of tumor detection, 24 (73 percent) of the 33 patients with cirrhosis and hepatocellular carcinoma had higher percentages of L. culinaris agglutinin A-reactive alpha-fetoprotein (alpha-fetoprotein L3), erythroagglutinating phytohemagglutinin-reactive alpha-fetoprotein (alpha-fetoprotein P4+P5), or both than the 32 patients with cirrhosis but no hepatocellular carcinoma. Among the 24 patients, one or both of the markers were first elevated 3 to 18 months before the hepatocellular carcinoma was detected by imaging techniques.

Conclusions Measurements of the alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 fractions of serum alpha-fetoprotein allow the differentiation of hepatocellular carcinoma from cirrhosis in some cases and serve as predictive markers for the development of hepatocellular carcinoma during the follow-up of patients with cirrhosis.

Human alpha-fetoprotein has one asparagine-linked biantennary oligosaccharide per molecule¹¹. On the basis of this structure, microheterogeneity of the sugar component of alpha-fetoprotein was studied by affinity chromatography and affinity electrophoresis, with several lectins having specificity for different oligosaccharides^12,13,14. The serum alpha-fetoprotein of patients with hepatocellular carcinoma is characterized by greater proportions of alpha-fetoprotein that reacts with Lens culinaris agglutinin A and erythroagglutinating phytohemagglutinin than the serum alpha-fetoprotein of patients with benign chronic liver diseases^{15,16,17,18,19}. The methods used to determine the lectin reactivity of alpha-fetoprotein in these studies were cumbersome and insensitive, with detection limits of 100 ng per milliliter. Recently, more sensitive methods using lectin-affinity electrophoresis coupled with antibody-affinity blotting were developed to detect reactions of alpha-fetoprotein with these lectins²⁰. We undertook this study to determine the lectin reactivity of alpha-fetoprotein, using kits based on these methods that had a detection limit of 20 to 30 ng per milliliter, in patients with cirrhosis who had hepatocellular carcinomas and those who did not.

Methods

We studied 361 patients with cirrhosis who were admitted to our hospital between 1980 and 1990 and were regularly followed, with measurements of serum alpha-fetoprotein and ultrasonography or computed tomography of the liver every three months. The diagnosis of cirrhosis was made by liver biopsy in all the patients. Seventy-six of the 361 patients had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at base line (Table 1). Of these 76 patients, 33 (43 percent) were found to have hepatocellular carcinomas during a mean follow-up period of 35 months (range, 3 to 91); 24 were men and 9 were women, and they were 36 to 73 years of age (mean [±SD], 54 ±9). Tests for hepatitis B surface antigen and anti-hepatitis C antibody (second generation) were positive in 10 and 23 of these 33 patients, respectively. The diagnosis of hepatocellular carcinoma was based on histologic findings in tissue obtained at the time of surgery or ultrasonography-guided tumor biopsy in 20 patients, and on characteristic appearances on ultrasonography, computed tomography, and angiography in 13 patients.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of 361 Patients with Cirrhosis at Base Line, According to Measurement of Serum Alpha-Fetoprotein.

 
Hepatocellular carcinomas also developed during follow-up in 23 of 285 patients (8 percent) who had base-line serum alpha-fetoprotein concentrations of less than 30 ng per milliliter. During the same period, there were 32 patients with cirrhosis (26 men and 6 women), 28 to 81 years of age (mean, 50 ±14), who had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at base line and who were followed for at least 24 months but in whom hepatocellular carcinomas did not develop. Tests for hepatitis B surface antigen and anti-hepatitis C antibody were positive in 13 and 18 of these patients, respectively; both tests were negative in the remaining patient. The patients with cirrhosis in whom hepatocellular carcinomas did not develop during follow-up served as controls. Another 11 patients had base-line serum alpha-fetoprotein concentrations similar to those of the controls and did not have hepatocellular carcinomas, but were not studied in detail during follow-up.

Serum alpha-fetoprotein concentrations were measured in duplicate by radioimmunoassay with kits obtained from Dainabot Radioisotope (Tokyo, Japan). The coefficient of variation of the assay was less than 7 percent, and the values in normal subjects were less than 10 ng per milliliter. Serum samples with values of 30 ng per milliliter or more were stored at -20 °C for the later analysis of lectin-reactive profiles. The proportions of L. culinaris agglutinin A-reactive alpha-fetoprotein (alpha-fetoprotein L3) and erythroagglutinating phytohemagglutinin-reactive alpha-fetoprotein (alpha-fetoprotein P4+P5) were measured by lectin-affinity electrophoresis, coupled with antibody-affinity blotting with alpha-fetoprotein Differentiation Kits L and P (Wako Pure Chemical Industries, Osaka, Japan). Alpha-fetoprotein L3 is considered to have sugar chains fucosylated at the core of asparagine-linked N-acetylglucosamine, whereas the sugar-chain structure of alpha-fetoprotein P4+P5 remains to be determined²¹. In the assay used, serum alpha-fetoprotein was separated by lectin-affinity electrophoresis with 1 percent agarose gels containing either 0.2 mg of L. culinaris agglutinin A or 0.26 mg of erythroagglutinating phytohemagglutinin per milliliter of solution.

The bands of alpha-fetoprotein thus separated were transferred to nitrocellulose membranes precoated with affinity-purified polyclonal horse antihuman alpha-fetoprotein antibodies²⁰. The membranes were washed with TRIS-buffered saline containing 0.05 percent Tween 20 and treated with F(ab')₂ fragments of rabbit antihuman alpha-fetoprotein antibodies for 30 minutes at 37 °C. After washing with Tween 20-TRIS-buffered saline, the membranes were allowed to react with horseradish peroxidase-conjugated goat antirabbit IgG antibodies for 30 minutes at 37 °C. The membranes were again washed, and the alpha-fetoprotein bands were visualized by the tetrazolium method of Taketa²².

The intensities of the bands of alpha-fetoprotein were quantitated by densitometry. From the intensities thus determined, the percent distribution of alpha-fetoprotein was calculated. The results for individual bands were expressed as percentages of the intensity of total alpha-fetoprotein binding to each lectin. With the electrophoretic numbering system proposed by Taketa et al.,²³ the major bands of alpha-fetoprotein were numbered consecutively from the anode, and the band numbers suffixed to the capitalized initial letters of the lectins used: for example, alpha-fetoprotein L1, L2, and L3 for L. culinaris agglutinin A, and alpha-fetoprotein P1, P2, P3, P4, and P5 for erythroagglutinating phytohemagglutinin. The bands of alpha-fetoprotein in serum are shown in Figure 1. Among patients with alpha-fetoprotein P4+P5, approximately 70 percent had discrete bands for P4 and P5; in the remaining patients, these two bands were incompletely resolved. Although alpha-fetoprotein L2 and alpha-fetoprotein P1 and P3 were not detected in this study, alpha-fetoprotein L2 and alpha-fetoprotein P1 are characteristically present in patients who have alpha-fetoprotein-producing extrahepatic tumors, and alpha-fetoprotein P3 is frequently found in patients who have fulminant hepatitis²⁴. The variabilities of the values for alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 in the same subjects were less than 8 percent²⁵.

View larger version (10K): [in this window] [in a new window]   Figure 1. Representative Patterns of Alpha-Fetoprotein Bands Separated by Lectin-Affinity Electrophoresis in the Serum of a Patient with Cirrhosis Who Had Hepatocellular Carcinoma and the Serum of One Who Did Not. LCA-A denotes electrophoresis in agarose gel containing L. culinaris agglutinin A, and E-PHA electrophoresis in agarose gel containing erythroagglutinating phytohemagglutinin. Lanes 1 and 3 show bands in the serum of a patient with cirrhosis. Lanes 2 and 4 show bands in the serum of a patient with cirrhosis and hepatocellular carcinoma. The zeros denote the starting point of the migration.

 
Statistical Analysis

All the results are expressed as means ±SD. The statistical analyses were performed with Student's t-test and the chi-square test. All P values were two-tailed, and P values of less than 0.05 were considered to indicate statistical significance.

Results

Clinical Features of Hepatocellular Carcinomas Detected by Imaging Techniques

The clinical features of the hepatocellular carcinomas in the 33 patients when first detected by ultrasonography or computed tomography are shown in Table 2. Twenty-nine patients (88 percent) had unifocal tumors, and the rest had multifocal tumors. The tumors were 3 cm or less in diameter in 21 (72 percent) of the 29 patients with unifocal tumors, as were 7 of the 9 tumors in the 4 patients with multifocal tumors.

View this table: [in this window] [in a new window]   Table 2. Clinical Features of Hepatocellular Carcinomas in 33 Patients with Cirrhosis at the Time of Detection of the Tumor.

 
Comparison of Serum Alpha-Fetoprotein Concentrations in Patients with Cirrhosis with and without Hepatocellular Carcinoma

The serum alpha-fetoprotein concentrations ranged from 30 to 460 ng per milliliter (median, 72) at base line in the 32 patients with cirrhosis who were followed for at least two years but in whom hepatocellular carcinoma did not develop. The values in this group fluctuated during follow-up, and ranged from 5 to 270 ng per milliliter (median, 32) after two years. The serum alpha-fetoprotein concentrations ranged from 30 to 1240 ng per milliliter (median, 75) at base line and from 30 to 7080 ng per milliliter (median, 275) at the time of tumor detection in the 33 patients with cirrhosis in whom hepatocellular carcinoma developed during follow-up. Only 8 (24 percent) of the 33 patients with cirrhosis in whom hepatocellular carcinoma developed had serum alpha-fetoprotein concentrations above 500 ng per milliliter at the time of detection of the tumor.

Proportions of Alpha-Fetoprotein L3 and Alpha-Fetoprotein P4+P5 in Patients with Cirrhosis with and without Hepatocellular Carcinoma

The mean proportion of alpha-fetoprotein L3 in the 33 patients with cirrhosis and hepatocellular carcinoma at the time of tumor detection was significantly higher than the base-line values in the 32 patients with cirrhosis without hepatocellular carcinoma at base line (22 ±19 percent vs. 5 ±5 percent, P<0.001) (Figure 2). Similarly, the mean proportion of alpha-fetoprotein P4+P5 was significantly higher in the patients with cirrhosis and hepatocellular carcinoma than in the patients with cirrhosis without hepatocellular carcinoma (22 ±14 percent vs. 8 ±5 percent, P<0.001) (Figure 2). The percentage of alpha-fetoprotein L3 did not correlate with the percentage of alpha-fetoprotein P4+P5 in the patients with cirrhosis and hepatocellular carcinoma (P>0.05) (Figure 3).

View larger version (67K): [in this window] [in a new window]   Figure 2. Proportions of Alpha-Fetoprotein L3 and Alpha-Fetoprotein P4+P5 in the Serum of Patients Who Had Cirrhosis with and without Hepatocellular Carcinoma. Bars are means ±SD.

 

View larger version (39K): [in this window] [in a new window]   Figure 3. Correlation between the Percentages of Alpha-Fetoprotein L3 and Alpha-Fetoprotein P4+P5 in Patients with Cirrhosis and Hepatocellular Carcinoma. The dotted lines show cutoff values of 15 percent for alpha-fetoprotein L3 and 18 percent for alpha-fetoprotein P4+P5.

 
When the cutoff values for alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 were set at 15 percent and 18 percent, respectively, which were the mean base-line percentages plus 2 SD in the 32 patients with cirrhosis who did not have hepatocellular carcinoma, none of the patients in whom hepatocellular carcinoma later developed had elevated values at base line. In contrast, 18 (55 percent) of the 33 patients with cirrhosis and hepatocellular carcinoma had elevated percentages of alpha-fetoprotein L3 and 18 (55 percent) of them had elevated percentages of alpha-fetoprotein P4+P5 at the time of diagnosis of hepatocellular carcinoma. Consequently, 24 (73 percent) of 33 patients with cirrhosis and hepatocellular carcinoma had elevated percentages of one or both of these forms of alpha-fetoprotein at the time of tumor detection. The total follow-up period before the detection of hepatocellular carcinoma in these 24 patients was 32 ±25 months, whereas the total follow-up period in the remaining 9 patients in whom hepatocellular carcinoma developed was 43 ±17 months (P>0.05). The serum alpha-fetoprotein concentrations at the time of detection of hepatocellular carcinoma did not differ between the two groups (P>0.05). Of the 23 patients with cirrhosis who had base-line serum alpha-fetoprotein concentrations of less than 30 ng per milliliter and in whom hepatocellular carcinoma later developed, 12 had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at the time of tumor detection. When the fractions of alpha-fetoprotein were analyzed in serum obtained from these 12 patients at the time of tumor detection, 8 (67 percent) had elevated percentages of alpha-fetoprotein L3, alpha-fetoprotein P4+P5, or both.

Among the 24 patients with cirrhosis who had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at base line and elevated percentages of alpha-fetoprotein L3 or alpha-fetoprotein P4+P5 when hepatocellular carcinoma was detected, serum samples obtained before the detection of the tumor by imaging techniques were analyzed retrospectively. An elevated percentage of alpha-fetoprotein L3 or alpha-fetoprotein P4+P5 was first detected in eight patients (33 percent) in samples obtained 3 months before the tumor was detected, in six patients (25 percent) in samples obtained 6 months before detection, in seven patients (29 percent) in samples obtained 12 months before detection, and in three patients (12 percent) in samples obtained 18 months before detection.

Discussion

Hepatocellular carcinomas develop during the natural history of cirrhosis, with an annual incidence of 3 to 10 percent^4,26. To detect hepatocellular carcinomas at an early stage,^4,6 close follow-up of patients with cirrhosis is therefore important in order to provide optimal therapy²⁷. In addition, liver transplantation is a promising treatment for small hepatocellular carcinomas detected on regular clinical monitoring, but not for those that have become symptomatic²⁸. Serum alpha-fetoprotein concentrations are often elevated in patients with hepatocellular carcinomas, but they can also be elevated in patients with benign chronic liver disease^29,30. More specific markers are therefore needed to evaluate patients with cirrhosis who have increased serum alpha-fetoprotein concentrations, when tumors cannot be detected by imaging techniques.

We found 33 patients with cirrhosis who had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at base line and in whom hepatocellular carcinomas developed during follow-up periods averaging 35 months, but 43 patients with cirrhosis in whom hepatocellular carcinomas did not develop during follow-up had similar base-line serum alpha-fetoprotein concentrations. At the time of tumor detection, the serum alpha-fetoprotein concentrations were nearly four times higher than at base line, but in 76 percent of patients the values were similar to those in the patients with cirrhosis who did not have hepatocellular carcinoma. Measurement of the different fractions of alpha-fetoprotein permitted a better distinction between these two groups. When we used cutoff values for alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 based on the results in the patients with cirrhosis in whom hepatocellular carcinoma did not develop and who had elevated ( 30 ng per milliliter) serum alpha-fetoprotein concentrations at base line, the specificity of alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 for hepatocellular carcinoma was very high, as evidenced by the exclusion of all 32 patients with cirrhosis but no hepatocellular carcinoma. These two markers were expressed independently in the patients with cirrhosis and hepatocellular carcinoma, and their combined use yielded a sensitivity of 73 percent for hepatocellular carcinoma. These results are similar to those described by Taketa et al.,²⁴ although the sensitivity was slightly lower in our study. The difference was probably due to differences in the stage of hepatocellular carcinoma, because the study by Taketa et al. included more patients with advanced hepatocellular carcinomas. Aoyagi et al.³¹ reported a similar sensitivity, and a specificity of 96 percent, for the proportion of alpha-fetoprotein L3, measured as the fucosylation index of alpha-fetoprotein, in patients with hepatocellular carcinoma.

Among the patients with cirrhosis and hepatocellular carcinoma who had elevated percentages of either alpha-fetoprotein L3 or alpha-fetoprotein P4+P5 at the time of detection of the cancer, we found that the markers were first elevated 3 to 18 months before the tumor was detected by imaging techniques. These results suggest that a patient with cirrhosis who has an elevated percentage of alpha-fetoprotein L3 or alpha-fetoprotein P4+P5 either has hepatocellular carcinoma or will have a clinically detectable lesion in 12 to 18 months, although the absence of an increase in these markers does not exclude the diagnosis of hepatocellular carcinoma.

Source Information

From the First Department of Internal Medicine, Nagasaki University School of Medicine (Y.S., K.N., Y.K., M.S., S.N.), and the Health Research Center, Nagasaki University (N.I., T.K.), both in Nagasaki; the Department of Public Health, Okayama University Medical School, Okayama (K.T.); and Sanraku Hospital, Tokyo (Y.E.) -- all in Japan.

Address reprint requests to Dr. Nagataki at the First Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852, Japan.

References

1. Parkin DM, Stjernsward J, Muir CS. Estimates of the worldwide frequency of twelve major cancers. Bull World Health Organ 1984;62:163-182. [Medline]
2. Nishioka K, Watanabe J, Furuta S, et al. A high prevalence of antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan. Cancer 1991;67:429-433. [CrossRef][Medline]
3. Kubo Y, Okuda K, Musha H, Nakashima T. Detection of hepatocellular carcinoma during a clinical follow-up of chronic liver disease: observation in 31 patients. Gastroenterology 1978;74:578-582. [Medline]
4. Oka H, Kurioka N, Kim K, et al. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 1990;12:680-687. [Medline]
5. Shinagawa T, Ohto M, Kimura K, et al. Diagnosis and clinical features of small hepatocellular carcinoma with emphasis on the utility of real-time ultrasonography: a study in 51 patients. Gastroenterology 1984;86:495-502. [Medline]
6. Ebara M, Ohto M, Shinagawa T, et al. Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis: a study in 22 patients. Gastroenterology 1986;90:289-298. [Medline]
7. Bloomer JR, Waldmann TA, McIntire KR, Klatskin G. alpha-Fetoprotein in nonneoplastic hepatic disorders. JAMA 1975;233:38-41. [Abstract]
8. Alpert E, Feller ER. alpha-Fetoprotein (AFP) in benign liver disease: evidence that normal liver regeneration does not induce AFP synthesis. Gastroenterology 1978;74:856-858. [Medline]
9. Okuda K. Early recognition of hepatocellular carcinoma. Hepatology 1986;6:729-738. [Medline]
10. Lok ASF, Lai CL. alpha-Fetoprotein monitoring in Chinese patients with chronic hepatitis B virus infection: role in the early detection of hepatocellular carcinoma. Hepatology 1989;9:110-115. [Medline]
11. Yoshima H, Mizuochi T, Ishii M, Kobata A. Structure of the asparagine-linked sugar chains of alpha-fetoprotein purified from human ascites fluid. Cancer Res 1980;40:4276-4281. [Free Full Text]
12. Smith CJ, Kelleher PC. alpha₁-Fetoprotein: separation of two molecular variants by affinity chromatography with concanavalin A-agarose. Biochim Biophys Acta 1973;317:231-235. 
13. Kerckaert J-P, Bayard B, Biserte G. Microheterogeneity of rat, mouse and human alpha₁-fetoprotein as revealed by polyacrylamide gel electrophoresis and by crossed immuno-affinoelectrophoresis with different lectins. Biochim Biophys Acta 1979;576:99-108. [Medline]
14. Alpert E, Drysdale JW, Isselbacher KJ, Schur PH. Human alpha-fetoprotein: isolation, characterization, and demonstration of microheterogeneity. J Biol Chem 1972;247:3792-3798. [Free Full Text]
15. Breborowicz J, Mackiewicz A, Breborowicz D. Microheterogeneity of alpha-fetoprotein in patient serum as demonstrated by lectin affino-electrophoresis. Scand J Immunol 1981;14:15-20. [CrossRef][Medline]
16. Miyazaki J, Endo Y, Oda T. Lectin affinities of alpha-fetoprotein in liver cirrhosis, hepatocellular carcinoma and metastatic liver tumor. Acta Hepatol Jpn 1981;22:1559-68.
17. Buamah PK, Harris R, James OFW, Skillen AW. Lentil-lectin-reactive alpha-fetoprotein in the differential diagnosis of benign and malignant liver disease. Clin Chem 1986;32:2083-2084. [Free Full Text]
18. Taketa K, Ichikawa E, Akamatsu K, et al. Increased asialo-alpha-fetoprotein in patients with alpha-fetoprotein-producing tumors: demonstration by affinity electrophoresis with erythroagglutinating phytohemagglutinin of Phaseolus vulgaris lectin. Tumour Biol 1985;6:533-544. [Medline]
19. Du MQ, Hutchinson WL, Johnson PJ, Williams R. Differential alpha-fetoprotein lectin binding in hepatocellular carcinoma: diagnostic utility at low serum levels. Cancer 1991;67:476-480. [CrossRef][Medline]
20. Taketa K, Ichikawa E, Taga H, Hirai H. Antibody-affinity blotting, a sensitive technique for the detection of alpha-fetoprotein separated by lectin affinity electrophoresis in agarose gels. Electrophoresis 1985;6:492-497. [CrossRef]
21. Taketa K. alpha-Fetoprotein: reevaluation in hepatology. Hepatology 1990;12:1420-1432. [Medline]
22. Taketa K. A tetrazolium method for peroxidase staining: application to the antibody-affinity blotting of alpha-fetoprotein separated by lectin affinity electrophoresis. Electrophoresis 1987;8:409-414. [CrossRef]
23. Taketa K, Ichikawa E, Umetsu K, Suzuki T. Allomyrina dichotoma lectin-nonreactive alpha-fetoprotein in hepatocellular carcinoma and other tumors: comparison with Ricinus communis agglutinin-I. Cancer Lett 1986;31:325-331. [Medline]
24. Taketa K, Sekiya C, Namiki M, et al. Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions. Gastroenterology 1990;99:508-518. [Medline]
25. Shimizu K, Taniichi T, Satomura S, Matsuura S, Taga H, Taketa K. Establishment of assay kits for the determination of microheterogeneities of alpha-fetoprotein using lectin-affinity electrophoresis. Clin Chim Acta 1993;214:3-12. [CrossRef][Medline]
26. Colombo M, de Franchis R, Del Ninno E, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991;325:675-680. [Abstract]
27. Nakata K, Khan KN, Nagataki S. Transcatheter arterial embolization of hepatic neoplasms. Crit Rev Oncol Hematol 1992;13:93-105. [Medline]
28. Van Thiel DH, Carr BI, Yokoyama I, Iwatsuki S, Starzl TE. Liver transplantation as a treatment of hepatocellular carcinoma. In: Tabor E, Di Bisceglie AM, Purcell RH, eds. Etiology, pathology, and treatment of hepatocellular carcinoma in North America. Houston: Gulf, 1992:309-15.
29. Hirai H. Hepatocellular cancer. Tumour Biol 1987;8:86-93. [Medline]
30. Furukawa R, Tajima H, Nakata K, et al. Clinical significance of serum alpha-fetoprotein in patients with liver cirrhosis. Tumour Biol 1984;5:327-338. [Medline]
31. Aoyagi Y, Suzuki Y, Isemura M, et al. The fucosylation index of alpha-fetoprotein and its usefulness in the early diagnosis of hepatocellular carcinoma. Cancer 1988;61:769-774. [CrossRef][Medline]

Abstract Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

This article has been cited by other articles:

• Zinkin, N. T., Grall, F., Bhaskar, K., Otu, H. H., Spentzos, D., Kalmowitz, B., Wells, M., Guerrero, M., Asara, J. M., Libermann, T. A., Afdhal, N. H. (2008). Serum Proteomics and Biomarkers in Hepatocellular Carcinoma and Chronic Liver Disease. Clin. Cancer Res. 14: 470-477 [Abstract] [Full Text]  
• Wang, X., Gu, J., Ihara, H., Miyoshi, E., Honke, K., Taniguchi, N. (2006). Core Fucosylation Regulates Epidermal Growth Factor Receptor-mediated Intracellular Signaling. J. Biol. Chem. 281: 2572-2577 [Abstract] [Full Text]  
• Guan, M., Rodriguez-Madoz, J. R., Alzuguren, P., Gomar, C., Kramer, M. G., Kochanek, S., Prieto, J., Smerdou, C., Qian, C. (2006). Increased Efficacy and Safety in the Treatment of Experimental Liver Cancer with a Novel Adenovirus-Alphavirus Hybrid Vector. Cancer Res. 66: 1620-1629 [Abstract] [Full Text]  
• Hertl, M., Cosimi, A. B. (2005). Liver Transplantation for Malignancy. The Oncologist 10: 269-281 [Abstract] [Full Text]  
• Ling, C.-Q., Li, B., Zhang, C., Zhu, D.-Z., Huang, X.-Q., Gu, W., Li, S.-X. (2005). Inhibitory effect of recombinant adenovirus carrying melittin gene on hepatocellular carcinoma. Ann Oncol 16: 109-115 [Abstract] [Full Text]  
• Yoon, S. K., Lim, N. K., Ha, S.-A., Park, Y. G., Choi, J. Y., Chung, K. W., Sun, H. S., Choi, M. J., Chung, J., Wands, J. R., Kim, J. W. (2004). The Human Cervical Cancer Oncogene Protein Is a Biomarker for Human Hepatocellular Carcinoma. Cancer Res. 64: 5434-5441 [Abstract] [Full Text]  
• Martinez-Duncker, I., Michalski, J.-C., Bauvy, C., Candelier, J.-J., Mennesson, B., Codogno, P., Oriol, R., Mollicone, R. (2004). Activity and tissue distribution of splice variants of {alpha}6-fucosyltransferase in human embryogenesis. Glycobiology 14: 13-25 [Abstract] [Full Text]  
• Noda, K., Miyoshi, E., Gu, J., Gao, C.-X., Nakahara, S., Kitada, T., Honke, K., Suzuki, K., Yoshihara, H., Yoshikawa, K., Kawano, K., Tonetti, M., Kasahara, A., Hori, M., Hayashi, N., Taniguchi, N. (2003). Relationship between Elevated FX Expression and Increased Production of GDP-L-Fucose, a Common Donor Substrate for Fucosylation in Human Hepatocellular Carcinoma and Hepatoma Cell Lines. Cancer Res. 63: 6282-6289 [Abstract] [Full Text]  
• Benson III, A. B., Mitchell, E., Abramson, N., Klencke, B., Ritch, P., Burnham, J. P., McGuirt, C., Bonny, T., Levin, J., Hohneker, J. (2002). Oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma. Ann Oncol 13: 576-581 [Abstract] [Full Text]  
• Okada, S. (2001). Cancer Chemoprevention as Adjuvant Therapy for Hepatocellular Carcinoma. Jpn J Clin Oncol 31: 357-358 [Full Text]  
• Ido, A., Uto, H., Moriuchi, A., Nagata, K., Onaga, Y., Onaga, M., Hori, T., Hirono, S., Hayashi, K., Tamaoki, T., Tsubouchi, H. (2001). Gene Therapy Targeting for Hepatocellular Carcinoma: Selective and Enhanced Suicide Gene Expression Regulated by a Hypoxia-inducible Enhancer Linked to a Human {{alpha}}-Fetoprotein Promoter. Cancer Res. 61: 3016-3021 [Abstract] [Full Text]  
• Wang, W., Li, W., Ikeda, Y., Miyagawa, J.-I., Taniguchi, M., Miyoshi, E., Sheng, Y., Ekuni, A., Ko, J. H., Yamamoto, Y., Sugimoto, T., Yamashita, S., Matsuzawa, Y., Grabowski, G. A., Honke, K., Taniguchi, N. (2001). Ectopic expression of {{alpha}}1,6 fucosyltransferase in mice causes steatosis in the liver and kidney accompanied by a modification of lysosomal acid lipase. Glycobiology 11: 165-174 [Abstract] [Full Text]  
• Tradati, F., Colombo, M., Mannucci, P.M., Rumi, M.G., De Fazio, C., Gamba, G., Ciavarella, N., Rocino, A., Morfini, M., Scaraggi, A., Taioli, E., Italian Hemophilia Centers, t. S. G. o. t. A. o. (1998). A Prospective Multicenter Study of Hepatocellular Carcinoma in Italian Hemophiliacs With Chronic Hepatitis C. Blood 91: 1173-1177 [Abstract] [Full Text]  
• Muto, Y., Moriwaki, H., Ninomiya, M., Adachi, S., Saito, A., Takasaki, K. T., Tanaka, T., Tsurumi, K., Okuno, M., Tomita, E., Nakamura, T., Kojima, T., The Hepatoma Prevention Study Group, (1996). Prevention of Second Primary Tumors by an Acyclic Retinoid, Polyprenoic Acid, in Patients with Hepatocellular Carcinoma. NEJM 334: 1561-1568 [Abstract] [Full Text]  
• (1993). A NEW ALPHA-FETOPROTEIN MEASUREMENT AIDS LIVER CANCER DIAGNOSIS. JWatch General 1993: 7-7 [Full Text]