Dig Dis Sci (2007) 52:776782

DOI 10.1007/s10620-006-9541-2

ORIGINAL PAPER

Clinical Evaluation of Lens Culinaris Agglutinin-Reactive

-Fetoprotein and Des- -Carboxy Prothrombin in Histologically
Proven Hepatocellular Carcinoma in the United States
Brian I. Carr Futoshi Kanke Margaret Wise
Shinji Satomura

Received: 27 March 2006 / Accepted: 25 July 2006 / Published online: 26 January 2007
C Springer Science+Business Media, Inc. 2006

Abstract There is no established clinical role for the lens

culinaris agglutinin-reactive fraction of -fetoprotein (AFPL3%) and des- -carboxy prothrombin (DCP) in the management of the U.S. hepatocellular carcinoma (HCC) patient
population. In order to clarify the clinical usefulness and
characteristics of AFP-L3% and DCP, a prospective study
was performed on United States patients having histologically proven hepatocellular carcinoma. Ninety-nine histologically proven HCC patients, who were diagnosed with
unresectable cancer between July 1999 and March 2001 at
the Liver Cancer Center of the University of Pittsburgh Medical Center, were included for analysis. The sensitivity of
AFP-L3%, DCP, and AFP was 61.6%, 72.7%, and 67.7%,
respectively. The highest sensitivity, 85.9%, was obtained
in the combination of three markers. Statistically significant
differences were observed for portal vein invasion in AFPL3% and AFP levels (P = 0.0059 and P = 0.0360, respectively). DCP was significantly associated with metastasis
(P = 0.0368). There were significant associations between
AFP-L3% and AFP results and patient survival (P = 0.0150
and P = 0.0020, respectively). AFP-L3%, platelet count,and
albumin showed a significant difference with respect to outB. I. Carr (
)
Liver Cancer Center, Starzl Transplantation Institute,
University of Pittsburgh Medical Center,
E1552 BST, 200 Lothrop Street, Pittsburgh,
Pennsylvania 15213, USA
e-mail: carrbi@upmc.edu
F. Kanke S. Satomura
Diagnostics Division, Wako Pure Chemical Industries, Ltd.,
Osaka, Japan
M. Wise
Diagnostics Division, Wako Chemicals USA, Inc.,
Richmond, Virginia, USA
Springer

comes on Coxs proportional hazard model (P = 0.0059,

P = 0.0073, and P = 0.0265, respectively). The combination
of AFP-L3%, DCP, and AFP was determined to be superior
for detection of HCC compared with each marker alone or
to other combinations. AFP-L3% was significantly related
to portal vein invasion and patient outcomes and appears to
be a useful prognostic marker for HCC.
Keywords Lens culinaris agglutinin-reactive fraction of
-fetoprotein . Des- -carboxy prothrombin (DCP) .
-Fetoprotein . Hepatocellular carcinoma . Prognosis

Introduction
Hepatocellur carcinoma (HCC) is one of the most prevalent
cancers in humans. It is the fifth most common neoplasm in
the world and the third most common cause of cancer-related
death [1]. In the United States, the incidence of HCC has increased approximately 80% over the past 2030 years, and it
is estimated that more than 18,000 new cases occur each year
[2]. The most powerful risk factor for development of HCC
is the existence of liver cirrhosis, regardless of its etiology
[3]. Among cirrhotics, viral infection, such as hepatitis virus
B (HBV) and hepatitis virus C (HCV), and high alcohol intake are associated with the highest risk [47]. Recently, the
American Association for the Study of Liver Diseases published guidelines for HCC and stated that the early detection
of HCC is an essential issue since HCC patients can receive
effective treatments such as hepatic resection, liver transplantation, and precutaneous ablation [8]. However, there are no
widely accepted approaches to regular surveillance in the
United States. Therefore, most HCC patients are diagnosed
at later or more advanced stages, usually when the tumor
is nonresectable. As a consequence, the overall survival of

Dig Dis Sci (2007) 52:776782

patients diagnosed with HCC remains poor. Recent advances in imaging, such as a multidetector computed tomography (CT) and magnetic resonance imaging (MRI),
have improved the early radiologic diagnosis of HCC [9
14]. Currently, the only generally available serologic marker
for HCC surveillance, diagnosis, and monitoring is serum
-fetoprotein (AFP). The combination of ultrasonography
and AFP is commonly used for surveillance of HCC [15].
However, it has been recognized that AFP has limited sensitivity and specificity for HCC, and ultrasonography is operator skilldependent and limited in its ability to differentiate
HCC from nonneoplastic nodules [16, 17]. Many centers use
CT and AFP. However, there is no evidence to support that
this is good practice.
Recently, the lens culinaris agglutinin-reactive fraction
of -fetoprotein (AFP-L3) [1828] and des- -carboxy prothrombin (DCP) [2937] have become widely used for HCC
diagnosis and follow-up as serologic tumor markers in Japan.
AFP-L3 is a variant of AFP, based on the sugar chain structure. AFP-L3 has an additional 16 fucose residue appended to N-acetylglucosamine at the reducing end, and
AFP-L3 production is observed mainly in malignant cells.
DCP is an abnormal prothrombin protein that is generated
as a result of an acquired defect in the posttranslational carboxylation of the prothrombin precursor in HCC cells. Since
AFP-L3% and DCP in serum behave independently, they
have the potential to complement each other for the diagnosis and monitoring of HCC [36, 3841]. However, there
are no published data in the U.S. HCC population concerning their potential usefulness together. In order to clarify
the clinical usefulness and characteristics of AFP-L3% and
DCP, a prospective study was performed with patients having
histolologically proven HCC in the United States.

Materials and methods

Patients
Ninety-nine histologically proven HCC patients, who were
diagnosed between July 1999 and March 2001 at the Liver
Cancer Center of the University of Pittsburgh Medical
Center, Starzl Transplantation Institute, were included for
analysis. Clinical and laboratory information was prospectively gathered from the medical records. The diagnosis of
HCC was done by percutaneous core biopsy. All patients
were unresectable, and 98 patients received transarterial
chemoembolization (TACE). None of the patients received
liver transplantation. Blood was drawn within 4 weeks of
HCC diagnosis. The serum samples were frozen at 70 C
until measurement. Of 99 HCC patients, tumor number, portal vein invasion, vascularity, and metastasis information
was available for 97. Ninety-two patients had tumor size

777

information available (two had diffuse tumor in the liver).

This novel tumor marker study was approved by the Institutional Review Board of the University of Pittsburgh Medical
Center, and informed consent was obtained from all patients.
Tumor marker measurement
Serum AFP-L3%, which is the ratio of AFP-L3 to total AFP,
and DCP were measured on an automated analyzer, called
LiBASys (Liquid-Phase Binding Assay System), which is
manufactured by Wako Pure Chemical Industries, Ltd.,
Osaka, Japan [4244]. AFP was tested by an immunochemiluminescent assay (ADVIA Centaur immunoassay system;
Bayer Healthcare, Tarrytown, NY, USA). The cutoff value
for AFP-L3% was set at 10% according to a previous study
[20]. Cutoff values for DCP and AFP were 200 mAU/ml and
25 ng/ml, respectively, which are used at our hospital.
Statistical analysis
The results are expressed as the mean SD or median
and range. In univariate analyses, statistical significance was
determined using the Kruskal-Wallis and chi-square test. In
multivariate analyses, Coxs proportional hazard model was
used with a continuous variable. The survival rate was calculated by Kaplan-Meiers method, and the difference was
analyzed by the generalized Wilcoxon test. All P values
< 0.05 were considered statistically significant.
Results
Study population
Clinical characteristics of 99 patients are reported in
Table 1. Seventy-eight patients were male (78.8%) and 21
patients were female (21.1%). The median patient age was
67.0 years (range, 1993 years). The positive percentages of
HBV, HCV, and HCV + HBV were 5.1%, 29.3%, and 3.0%,
respectively. Thirteen patients had no underlying liver disease (13.1%), 6 patients had chronic hepatitis (CH) (6.1%),
77 patients had liver cirrhosis (LC), and 3 patients had other
diseases (3.0%). Tumor characteristics of 99 patients are
listed in Table 2 in terms of number, size, portal vein invasion, vascularity, and metastasis. Platelet count, prothrombin time, bilirubin, albumin, alkaline phosphatase, and glutamyl transpeptidase, in addition to AFP-L3%, DCP, and
AFP, were evaluated as a liver function serum marker. The
distribution of these markers is summarized in Table 3.
Sensitivity of AFP-L3%, DCP, and AFP
Sensitivity of AFP-L3%, DCP, and AFP was 61.6%, 72.7%,
and 67.7%, for each independent marker, respectively
Springer

778

Dig Dis Sci (2007) 52:776782

Table 1

Demographics of the study population

Demographics
Age
< 60
60
Sex
Male
Female
Ethnic
White
Black
Underlying liver disease
Chronic hepatitis
Liver cirrhosis
Other
No disease
Hepatitis virus
HBV

n (%)

36 (36.4)
63 (63.6)
78 (78.8)
21 (21.2)
97 (98.0)
2 (2.0)
6 (6.1)
77 (77.8)
3 (3.0)
13 (13.1)
5 (5.1)

(Table 4). When the combinations of these markers were

analyzed, AFP-L3% + AFP had a sensitivity of 73.7%,
AFP-L3% + DCP had a sensitivity of 84.8%, DCP + AFP
had a sensitivity of 84.8%, and AFP-L3% + DCP + AFP
had a sensitivity of 85.9%.

Table 2

Tumor characteristics of study population

Characteritics
Number
1
2
3
4
No data
Tumor size (cm; Maximum)
2
2.15.0
5.1
No data
Portal vein invasion
+

No data
Vascularity
Hypo.
Hetero.
Hyper.
No data
Metastasis
+

No data

Springer

n (%)

19 (19.2)
21 (21.2)
10 (10.1)
47 (47.5)
2 (2.0)
5 (5.1)
38 (38.4)
49 (49.5)
7 (7.1)
25 (25.3)
72 (72.7)
2 (2.0)
19 (19.2)
44 (44.4)
34 (34.3)
2 (2.0)
43 (43.4)
54 (54.5)
2 (2.0)

Table 3

Serum markers of the study population

Serum markers

Median

Range

AFP-L3% (%)
DCP (mAU/ml)
AFP (ng/ml)
Platelet count ( 104 l)
Prothrobmin time (sec)
Billrubin (mg/dl)
Albumin (g/dl)
Alkaline phosphatase (units/L)
Gamma glutamyl transpeptidase
(units/L)

99
99
99
99
99
99
99
99
99

20.0
1008
121
15.5
12.7
0.9
3.5
147
182

0.599.5
9.9295115
1.92005000
3.9100.9
10.618.4
0.19.2
2.34.6
68854
25908

Tumor characteristics with respect to AFP-L3%,

DCP, and AFP
Table 5 reports the relationship between tumor characteristics and AFP-L3%, DCP, and AFP. None of the three
markers presented any significant relationship with respect
to tumor size and vascularity. However, there was significant
relationship between tumor number and AFP (p = 0.0440).
Statistically significant differences were observed for portal
vein invasion in AFP-L3% positive and AFP positive results (P = 0.0059 and P = 0.0360 respectively). Only DCP
levels were significantly associated with metastasis of HCC
(P = 0.0368).
Survival rate with respect to AFP-L3%, DCP, and AFP
Figure 1 provides survival data for the positive and negative
groups of AFP-L3%, DCP, and AFP. Overall survival rates
at 6 and 12 months were 60.5% and 51.0%, respectively. The
survival rates of AFP-L3% positive cases at 6 and 12 months
were 51.0% and 45.1%, and those for AFP-L3% negative
cases at 6 and 12 months were 74.8% and 61.0%. A significant difference between AFP-L3% positive and negative
cases in the survival rate was observed by the generalized
Wilcoxon test (P = 0.0150). With respect to AFP, the survival rate of patients with positive AFP levels was significantly lower than those of patients with negative AFP levels
Table 4 Sensitivities of AFP-L3%, DCsP
and AFP
Tumor markers

Sensitivity
(%)

AFP-L3%
DCP
AFP
AFP-L3% + DCP
AFP-L3% + AFP
DCP + AFP
AFP-L3% + DCP + AFP

61.6
72.7
67.7
84.8
73.7
84.8
85.9

Dig Dis Sci (2007) 52:776782

779

(P = 0.0020). Six- and 12-month survival rates of AFP positive cases were 48.3% and 38.9%. The survival rates for
AFP negative cases at 6 and 12 months were 85.3% and
74.9%, respectively. DCP alone was not associated with the
cumulative survival rate (P = 0.9581).

0.1661
21/11
33/32
31/28

23/15

0.4397

35/36

19/7

0.0368

0.0360
0.9504
28/4
7/13/12
44/21
12/31/22

Metastasis

Portal vein invasion

Vascularity

Hypo./Hetero.
/Hyper.
/+

38/21
10/28/21

34/4
9/16/13

0.0059
0.6233

49/22
11/37/23

23/3
8/7/11

0.0524
0.8741

0.0440
0.1997
9/10/1/12
2/16/14
10/11/9/35
3/22/35
0.7331
0.1193
Number
Size (cm)

1/2/3/ 4
2.0/2.1 to
5.0/ 5.1

12/10/8/29
2/21/31

7/11/2/18
3/17/18

0.7570
0.2909

16/11/8/36
4/23/39

3/10/2/11
1/15/10

Negative
AFP
Positive
Negative
AFP-L3%
Positive
Tumor characteristics

Table 5

Tumor characteristics with respect to AFP-L3%,DCP and AFP

p value

DCP
Positive

Negative

p value

p value

Patient outcome with respect to serum markers

The relationship between patient outcome and serum markers including AFP-L3 %, DCP, AFP, platelet count, prothrombin time, bilirubin, albumin, alkaline phosphatase, and
-glutamyl transpeptidase was analyzed by Coxs proportional hazard model (Table 6). AFP-L3%, platelet count, and
albumin showed significance with respect to patient outcome
(P = 0.0059, P = 0.0073, and P = 0.0265, respectively).

Discussion
HCC is one of those cancers that have been difficult to treat
adequately, since most patients with HCC have either underlying cirrhosis or advanced cancer or both. The severity of the
underlying cirrhosis has a profound effect on all treatment
decisions and limits all treatment modalities. Although the
American Association for the Study of Liver Diseases published guidelines for HCC last year [8], it has not been long
since the publication. Therefore, there are still no common
screening and surveillance programs in the United States,
and most patients with HCC rarely present with symptoms
until there is advanced-stage cancer or end-stage liver disease, when curative treatment is not possible. These facts are
closely related to the current status of poor survival of HCC
patients [45]. AFP and ultrasonography have most commonly been used for HCC surveillance [15]. However, the
sensitivity and specificity of AFP are dependent on the cutoff
value, and ultrasonography is operator skill-dependent [16,
17]. Obviously, sophisticated strategies and new tools are
necessary, and a new serologic tumor marker would be useful for changing the present situation. Although AFP-L3%
and DCP are widely recognized as useful tumor markers for
HCC in Japan, no comparative data on AFP-L3% and DCP
in the U.S. HCC population have been published. Therefore,
an assessment of these markers in a U.S. HCC population is
necessary to determine the clinical usefulness of AFP-L3%
and DCP.
In this study, AFP-L3%, DCP, and AFP showed > 60%
sensitivity. Moreover, the combinations of AFP-L3% +
DCP, DCP + AFP, or AFP-L3% + DCP + AFP had
> 80% sensitivity. According to previous publications, AFPL3% and DCP, each as independent markers, showed a higher
specificity than AFP alone [19, 20, 22, 32, 33, 37]. The combination of AFP-L3% and DCP might be the best panel to
detect HCC.
Springer

780
A

100%

p=0.0150
80%
Survival rate: %

Fig. 1 Survival rate of

AFP-L3% (A), DCP (B), and
AFP (C). Solid line, patients
with positive results for each
marker; dashed line, patients
with negative results for each
marker

Dig Dis Sci (2007) 52:776782

60%

AFP-L3% Positive
AFP-L3% Negative

40%
20%
0%
0

10

15

20

25

Months

B 100%
p=0.9581
Survival rate: %

80%
60%

DCP Positive
DCP Negative

40%
20%
0%
0

10

15

20

25

Months

C 100%
p=0.0020
Survival rate: %

80%
60%

AFP Positive
AFP Negative

40%
20%
0%
0

10

15

20

25

Months

An appropriate treatment at the right time is important

to improve the mortality and survival of HCC patients. In
this regard, many Japanese study groups have reported that
AFP-L3% had a tendency to show positivity in the worst
prognosis cases of HCC [26, 28]. In the current study,
AFP-L3% was significantly associated with portal vein invasion and presented a strong statistical relationship to patient outcome. AFP-L3% could thus be a useful tool for
determination of proper treatments and prognostic evaluation, since portal vein invasion is related to recurrence
Springer

and survival after treatment. On the other hand, although

DCP showed significance in metastasis, there was no association between DCP results and patient survival. These
results are different from previous reports [46, 47]. Since
previous results came only from Japanese HCC patients,
these discrepancies might possibly be caused by ethnic differences or differences in HCC populations. In order to
clarify the usefulness of AFP-L3% and DCP as a prognostic marker, a prospective study is needed in the U.S. HCC
population.

Dig Dis Sci (2007) 52:776782

781

Table 6 Coxs proportional hazard model of patient outcome with

respect to serum markers
Serum marker

SE ()

p value

AFP-L3%
DCP
AFP
Platelet count
Prothrombin time
Bilirubin
Albumin
Alkaline
phosphatase
Gamma glutamyl
transpeptidase

0.0147
1.801 106
5.091 107
3.074 106
0.1925
0.2251
0.6902
0.0022

0.0054
3.504 106
5.838 107
1.1464 106
0.1362
0.1281
0.3110
0.0016

0.0059
0.6072
0.3832
0.0073
0.1576
0.0790
0.0265
0.1737

0.0009

0.3164

0.0010

In conclusion, the combination of AFP-L3%, DCP, and

AFP was demonstrated to be superior in the detection of HCC
compared with each marker alone. Since AFP-L3% was
significantly related to portal vain invasion and patient outcome, AFP-L3% has the potential to be a prognostic marker
for HCC.
Acknowledgment This work was supported in part by NIH Grant CA
82723 (to B.I.C.).

References
1. Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world
cancer burden globocan 2000. Int J Cancer 94:153156
2. El-Serag HB (2004) Hepatocellular carcinoma: recent trends in the
United States. Gastroenterology 127:S27S34
3. Zaman SN, Melia WM, Johnson RD, Portmann BC, Johnson PJ,
Williams R (1985) Risk factors in development of hepatocellular
carcinoma in cirrhosis: prospective study of 613 patients. Lancet
1:13571360
4. Poynard T, Aubert A, Lazizi Y, et al (1991) Independent risk factors for hepatocellular carcinoma in French drinkers. Hepatology
13:896901
5. Colombo M, Franchis Rd, Ninno ED, et al. (1991) Hepatocellular
carcinoma in Italian patients with cirrhosis. N Engl J Med 325:675
680
6. Tsukuma H, Hiyama T, Tanaka S, et al. (1993) The factors for hepatocellular carcinoma among patients with chronic liver disease. N
Engl J Med 328:17971801
7. Chevret S, Trinchet JC, Mathieu D, Rached AA, Beaugrand M,
Chastang C (1999) A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. J Hepatol
31:133141
8. Bruix J SMPGC, American Association for the Study of Liver
Diseases (2005) Management of hepatocellular carcinoma. Hepatology 42:12081236
9. Shinagawa T, Ohto M, Kimura K, et al. (1984) Diagnosis and clinical features of small hepatocellular carcinoma eith emphasis on
the utility of real-time ultrasonography. Gastroenterology 86:495
502
10. Ikeda K, Saitoh S, Koida I, et al. (1993) Diagnosis and follow-up of
small hepatocellular carcinoma with selective intraarterial digital
subtraction angiography. Hepatology 17:10031007

11. Oka H, Tamori A, Kuroki T, Kobayashi K, Yamamoto S (1994)

Prospective study of -fetoprotein in cirrhotic patients monitored
for development of hepatocellular carcinoma. Hepatology 19:61
66
12. Takayasu K, Moriyama N, Muramatsu Y, et al. (1990) The diagnosis of small hepatocellular carcinoma: efficacy of various imaging
procedures in 100 patients. AJR 155:4954
13. Takayasu K, Furukawa H, Wakao F, et al. (1995) CT diagnosis
of early hepatocellular carcinoma: sensitivity, findings, and CTpathologic correlation. AJR 164:885890
14. Ebara M, Ohto M, Watanabe Y, et al. (1986) Diagnosis of small
hepatocellular carcinoma: Correlation of MR imaging and tumor
histologic studies. Radiology 159:371377
15. Daniele B, Bencivenga A, Megna AS, Tinessa V (2004) Fetoprotein and ultrasonography screening for hepatocellular carcinoma. Gastroenterology 127:S108S12
16. Bruix J, Sherman M, Llovet JM, et al. (2001) Clinical management
of hepatocellular carcinoma. Conclusion of the Barcelona-2000
EASL conference. European Association for the Study of the Liver.
J Hepatol 35:421430
17. Sheu JC, Sung JL, Chen DS, et al. (1985) Early detection of hepatocellular carcinoma by real-time ultrasonography. A prospective
study. Cancer 56:660666
18. Taketa K, Sekiya C, Namiki M, et al. (1990) Lectin-reactive profiles
of alpha-fetoprotein characterizing hepatocellular carcinoma and
related conditions. Gastroenterology 99:508518
19. Taketa K, Endo Y, Sekiya C, et al. (1993) A collaborative study for
the evaluation of lectin-reactive a-fetoproteins in early detection of
hepatocellular carcinoma. Cancer Res 53:1923
20. Oka H, Saito A, Ito K, et al. (2001) Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to
the percentage of lens culinaris agglutinin-reactive a-fetoprotein. J
Gastroenterol Hepatol 16:13781383
21. Sato Y, Nakata K, Kato Y, et al. (1993) Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein.
N Engl J Med 328:18021806
22. Shiraki K, Takase K, Tameda Y, Hamada M, Kosaka Y, Nakano
T (1995) A clinical study of lectin-reactive alpha-fetoprotein as
an early indicator of hepatocellular carcinoma in the follow-up of
cirrhotic patients. Hepatology 22:802807
23. Yamashita F, Tanaka M, Satomura S, Tanikawa K (1995) Monitoring of lectin-reactive a-fetoprotein in patients with hepatocellular
carcinoma treated using transcatheter arterial embolization. Eur J
Gastroenterol Hepatol 7:627633
24. Yamashita F, Tanaka M, Satomura S, Tanikawa K (1996) Prognostic significance of lens culinaris agglutinin A-reactive a-fetoprotein
in small hepatocellular carcinomas. Gastroenterology 111:996
1001
25. Hayashi K, Kumada T, Nakano S, et al. (1999) Usefulness
of measurement of lens culinaris agglutinin-reactive fraction
of -fetoprotein as a marker of prognosis and recurrence of
small hepatocellular carcinoma. Am J Gastroenterol 94:3028
3033
26. Kumada T, Nakano S, Takeda I, et al. (1999) Clinical utility of
lens culinaris aggulutinin-reactive alpha-fetoprotein in small hepatocellular carcinoma: special reference to imaging diagnosis. J
Hepatol 30:125130
27. Tanaka M, Saito A, Ito K, et al. (2000) Lens culinaris agglutininreactive alpha-fetoprotein (AFP-L3) is the most significant prognostic factor for hepatocellular carcinoma after therapy. Hepatology 34:233A
28. Tada T, Kumada T, Toyoda H, et al. (2005) Relationship between
lens culinaris agglutinin-reactive -fetoprotein and pathologic features of hepatocellular carcinoma. Liver Int 25:16
29. Ono M, Ohta H, Ohhira M, Sekiya C, Namiki M (1990) Measurement of immunoreactive prothrombin precursor and vitamin-K
Springer

782

30.

31.

32.

33.

34.

35.

36.

37.

38.

Dig Dis Sci (2007) 52:776782

dependent gamma-carboxylation in human hepatocellular carcinoma tissues: decreased carboxylation of prothrombin precursor
as a cause of des-gamma-carboxyprothrombin synthesis. Tumor
Biol 11:319326
Liebman HA (1989) Isolation and characterization of a hepatomaassociated abnormal (des-gamma carboxy) prothrombin. Cancer
Res 49:64936497
Aoyagi Y, Oguro M, Yanagi M, et al. (1996) Clinical significance of
simultaneous determination of alpha-fetoprotein and des-gamma
carboxyprothrombin in monitoring recurrence in patients with hepatocellular carcinoma. Cancer 77:17811786
Mita Y, Aoyagi Y, Yanagi M, Suda T, Suzuki Y, Asakura H (1998)
The usefulness of determining des-gamma carboxyprothrombin by
sensitive enzyme immunoassay in the early diagnosis of patients
with hepatocellular carcinoma. Cancer 82:16431648
Nomura F, Ishijima M, Kuwa K, Tanaka N, Nakai T, Ohnishi K
(1999) Serum des-gamma carboxyprothrombin levels determined
by a new generation of sensitive immunoassay in patients with
small-sized hepatocellular carcinoma. Am J Gastroenterol 94:650
654
Izuno K, Fujiyama S, Yamasaki K, Sato M, Sato T (1995) Early
detection of hepatocellular carcinoma associated with cirrhosis by
combined assay of des-gamma carboxy prothrombin and alphafetoprotein: a prospective study. Hepatogastroenterology 42:387
393
Ikoma J, Kaito M, Ishihara T, et al. (2002) Early diagnosis of hepatocellular carcinoma using a sensitive assay for serum des-gamma
carboxy prothrombin: a prospective study. Hepatogastroenterology
49:235238
Shimauchi Y, Tanaka M, Kuromatsu R, et al. (2000) A simultaneous monitoring of lens culinaris aggulutinin A-reactive alphafetoprotein and des-gamma carboxyprothrombin as an early diagnosis of hepatocellular carcinoma in the follow-up of cirrhotic
patients. Oncol Rep 7:249256
Ishii M, Gama H, Chida N, et al. (2000) Simultaneous measurements of serum alpha-fetoprotein and protein induced by vitamin
K absence for detecting hepatocellular carcinoma. Am J Gastroenterol 95:10361040
Fujiyama S, Tanaka M, Maeda S, Ashihara H, Hirata R, Tomita K
(2002) Tumor markers in early diagnosis, follow-up and manage-

Springer

39.

40.

41.

42.

43.

44.

45.

46.

47.

ment of patients with hepatocellular carcinoma. Oncology 62:57

63
Okuda H, Nakanishi T, Takatsu K, et al. (2002) Clinicopathologic
features of patients with hepatocellular carcinoma seropositive for
a-fetoprotein-L3 and seronegative for des-g-carboxy prothrombin
in comparison with those seropositive for des-g-carboxy prothrombin alone. J Gastroenterol Hepatol 17:772778
Okuda H, Saito A, Haruyama K, et al. (2004) Unique clinicaopathological features of patients with primary malignant hepatic tumors who are seropositive for lectin-reactive -fetoprotein
alone: report of five cases. J Gastroenterol Hepatol 19:113119
Okuda H, Saito A, Shiratori K, Yamamoto M, Takasaki K, Nakano
M (2005) Clinicopathologic feature of patients with primary malignant hepatic tumors seropositive for a-fetoprotein-L3 alone in
comparison with other patients seropositive for a-fetoprotein-L3.
J Gastroenterol Hepatol 20:759764
Katoh H, Nakamura K, Tanaka T, Satomura S, Matsuura S (1998)
Automatic and simultaneous analysis of Lens culinaris agglutininreactive alpha-fetoprotein ratio and total alpha-fetoprotein concentration. Anal Chem 70:21102114
Yamagata Y, Katoh H, Nakamura K, Tanaka T, Satomura S, Matsuura S (1998) Determination of alpha-fetoprotein concentration
based on liquid-phase binding assay using anion exchange chromatography and sulfated peptide introduced antibody. J Immunol
Methods 212:161168
Yamagata Y, Shimizu K, Nakamura K, et al. (2003) Simultaneous
determination of percentage of Lens culinaris agglutinin-reactive
alpha-fetoprotein and alpha-fetoprotein concentration using the
LiBASys clinical auto-analyzer. Clin Chim Acta 327:5967
El-Serag HB, Mason AC, Key C (2001) Trends in survival of
patients with hepatocellular carcinoma between 1977 and 1996 in
the United States. Hepatology 33:6265
Hamamura K, Shiratori Y, Shiina S, et al. (2000) Unique clinical characteristics of patients with hepatocellular carcinoma who
present with plasma des-gamma-carboxy prothrombin and low
serum alpha-fetoprotein. Cancer 88:15571564
Koike Y, Shiratori Y, Sato S, et al. (2001) Des-gamma-carboxy
prothrombin as a useful predisposing factor for the development of
portal venous invasion in patients with hepatocellular carcinoma:
a prospective analysis of 227 patients. Cancer 91:561569