Clinical utility of protein induced by vitamin K absence in patients with chronic hepatitis B virus infection
- Authors:
- Published online on: August 24, 2012 https://doi.org/10.3892/br.2012.4
- Pages: 122-128
Abstract
Introduction
Vietnam is one of the countries in the Western part of the Pacific-Ocean, with a high rate of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). At present, the prevalence of HBV infection in Vietnam is more than 8%, and in some regions it may be up to 25% (1–4). Vietnamese HBV strains share characteristics of mutations in the core promoter and enhancement II region of the X gene in its genome, similar to HBV strains from China, Hong Kong and Japan. These mutations are risk factors for the development of severe liver diseases and HCC (5–8). HBV is the leading cause of HCC in Vietnam, with an incidence only less than that of lung and stomach cancer in males (9,10). Recently, the Vietnamese government has made serious efforts to persuade individuals, particularly parents of neonates, to join the HBV vaccination program nationwide. However, partly due to the living standards and the differences in medical services available in the cities and countryside, and partly due to lack of awareness, not all newborn babies have been vaccinated at present. Serum α-fetoprotein (AFP) is used as a routine test, although magnetic resonance imaging (MRI) and computed tomography (CT) scans are only available in large cities or in major provincial hospitals. Additionally, MRI and CT scans are expensive for ordinary Vietnamese individuals. Ultrasound (US) examination was introduced in Vietnam over 20 years ago, however, good operators are working only in big hospitals at present.
The above reasons render HCC a major health problem in Vietnam, with an incidence >15/100,000 population (10,11). Several HCC patients present in hospitals when the conditions are irreversible, while a number of patients have liver tumor of a diameter >5 cm. Multiple tumors within a liver parenchyma or liver cirrhosis (LC) are extremely severe and may result in multi-organ metastasis. Liver tumor resection, transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection (PEIT) and radiofrequency ablation (RFA) are the key methods for the treatment of HCC in Vietnam. However, early diagnosis of a liver tumor remains a challenge. Similar to other countries in the world, the serum AFP test, ultrasound examination or the combination thereof are common methods for screening HCC at present. However, ultrasound depends on the skill of the operator, the body mass index of patients and is limited in differentiating HCC from non-neoplastic nodules. In addition, varying sensitivity and specificity of AFP has been observed in different population studies, thus several patients are likely to be lost (12–18). At present, newer and better markers are required for the detection, surveillance and post-therapy follow-up of HCC. AFP is currently the only tumor marker used in the clinical diagnosis of HCC in Vietnam. However, few studies are available regarding the development of new clinically applied markers for the detection of HCC in Vietnamese patients (19). Moreover, none of those studies have focused on protein induced by vitamin K absence or antagonist-II (PIVKA-II). Since Liebman et al first reported a high level of PIVKA-II in HCC patients (20), several clinical studies have been conducted to evaluate the role of PIVKA-II in different patient populations worldwide (21–31). Although several studies have reported heterogeneous results in assessing the role of PIVKA-II in HCC patients, a number of these studies have proven PIVKA-II to be a better tumor marker when compared to AFP, in diagnosis as well as regarding tumor size, progression of disease, vascular invasion and differentiating cancer lesions from non-malignant diseases (31–36). The present study is the first to evaluate the role of PIVKA-II in the diagnosis of HCC in HBV-infected Vietnamese patients.
Materials and methods
Patients
A total of 166 consecutive chronic HBV-infected patients (139 male and 27 female, mean age 39.8±16.4 years) from 15 different provinces in Northern Vietnam were enrolled in the study [41 HCC, 43 LC, 26 chronic hepatitis B (CH) and 56 asymptomatic carriers (ASC)]. The patients with a previous medical history of antiviral treatment and HCC therapy or co-infection with hepatitis C virus (HCV), human immuno-deficiency virus (HIV) were excluded. The HCC lesions developed in patients with LC. This study was performed in accordance with the principles of the Declaration of Helsinki and was approved by the Ethnics Committee of Bach Mai Hospital, Hanoi, Vietnam.
Clinical diagnostic criteria
Chronic HBV infection was confirmed based on the medical history of the HBV status or positive HBV surface antigen (HBsAg) test was carried out twice in the serum for at least 6 months. HCC confirmation was based on the pathophysiologic examination or two-imaging modality with typical findings of liver tumor that included the characteristics of a high density mass in the arterial phase and a low density mass in the portal phase on dynamic CT scan or MRI. The final diagnosis was evaluated by two different histologists or radiologists unaware of additional clinicobiochemical information on patients. LC and CH was diagnosed based on clinical examination and biochemical test in combination with ultrasound, CT scan and MRI, with or without upper gastrointestinal endoscopy. ASC was evaluated by chronic HBV infection, without any clinical signs/symptoms or abnormality of a biochemical test and US examination.
AFP, PIVKA-II, HBV-DNA and HBV genotype tests
The sera of collected patients were stored at −40°C until use for further examinations at the Kobe University Graduate School of Medicine. The AFP levels were evaluated using the Microwell ELISA. The AFP test (Hope Laboratories, Pacoima, CA, USA) and PIVKA-II levels were examined using Eitest PIVKA-II (Eisai Co., Ltd. Tokyo, Japan), according to the manufacturer’s instructions. HBV-DNA was extracted from 200 μl of sera, using a QIAamp DNA blood mini kit (QIAGEN GmbH, Hilden, Germany), following the manufacturer’s instructions. The HBV-DNA levels were confirmed by real-time PCR with a set of primers and TaqMan probe located in the S gene, as previously described (32) and HBV genotype was classified by PCR-RFLP, as previously reported (33).
Statistical analysis
The Chi-square, Fisher’s exact and Mann-Whitney U tests (Wilcoxon rank-sum test), Kruskal-Wallis one-way analysis of variance, receiver operating characteristic (ROC), univariate and multivariate analyses were carried out to analyze the data using the Stata software 8.0 (StataCorp LP, College Station, TX, USA). P<0.05 was considered to indicate a statistically significant difference.
Results
Clinical characteristics of the patient population
Table I shows the characteristics of the study population. The mean age of the patients was 39.8±16.4 years (range, 17–75), with the mean age in the ASC group being the youngest (22.8±7.3 years) and it was significantly younger compared to the other groups (P<0.0001). The mean age in the LC and the HCC groups (50.8±12.4 and 49.8±12.4 years, respectively) was also higher (42.6±13.5 years) compared to the CH group (P<0.05). The male to female ratio showed no difference in the LC, CH and ASC groups (38/5, 20/6 and 42/14, respectively), although it was significantly higher (39/2) in the HCC, compared to the CH and ASC groups (P<0.05 and P<0.01). The positive prevalence for HBV e antigen (HBeAg) in CH (3.8%) was significantly lower compared to the other groups (P<0.05, P<0.01 and P<0.001). However, the positive prevalence of anti-HBe antibody in CH was higher compared to the ASC group (69.2 vs. 35.7%, P<0.01).
The prevalence of the HBV genotype B in the CH and ASC was significantly higher compared to the LC and HCC groups (88.5, 80.4, 60.5 and 56.1%, respectively) (P<0.05 and P<0.01), whereas the prevalence of HBV genotype C in the LC (39.5%) and HCC (43.9%) groups was higher compared to the CH (11.5%) and ASC (19.6%) groups. Together with the status of HBeAg and anti-HBe, the HBV-DNA level in CH (4.4±1.7 log copies/ml) was significantly lower compared to the other groups (P<0.05, P<0.01 and P<0.001). The HBV-DNA level was the highest in the LC (6.2±1.8 log copies/ml), although not significantly, compared to the HCC (5.8±1.9 log copies/ml) and ASC (5.4±2.3 log copies ml) groups. The AFP level was the highest in the HCC group, showing no significant difference compared to the LC and CH groups. The PIVKA-II level was significantly higher in the HCC compared to the other groups, while the PIVKA-II level in the LC was higher compared to the CH and ASC groups (P<0.05 and P<0.001).
Characteristics of AFP and PIVKA-II in HCC
The comparison of sensitivity and specificity in AFP and PIVKA-II is shown in Table II. The levels of AFP and PIVKA-II showed a gradual increase from the cut-off level (AFP 20 ng/ml and PIVKA-II 40 mAU/ml) to 2.5, 5, 10 and 20 times over the cut-off level of each marker. At each compared level, the sensitivity of PIVKA-II was significantly higher compared to the AFP (P=0.01, P=0.018, P=0.011 and P=0.007), while the specificity of AFP was higher compared to PIVKA-II, although this difference was not significant (P>0.05). The significance of the combination of these two markers was also examined and compared. Fig. 1 shows that the combination of the two markers had a significantly higher specificity than either AFP (P=0.018) or PIVKA-II (P<0.001), and a significantly lower sensitivity compared to PIVKA-II alone (P=0.003), although not significantly lower compared to AFP (P>0.05).
 | Table II.Sensitivity and specificity for the detection of HCC using different cut-off levels of AFP and PIVKA-II. |
The characteristics of liver tumor in association with AFP and PIVKA-II in 41 HCC patients are shown in Table III. Portal vein thrombosis was present in 36.6% (15/41) of patients, with several liver tumors located in the right (53.6%) or in both the left and right lobes (34.2%), while few tumors were presented in the left lobe (12.2%). In the present study, the liver tumors had a diameter <3 cm, while the number of patients with a diameter of liver tumor <5 cm was ∼70.7%. AFP showed no significant association with any tumor characteristics, including portal thrombosis, tumor localization, number or size. By contrast, the PIVKA-II level in HCC patients with portal vein thrombosis was significantly higher compared to patients without portal vein thrombosis (32,860±29,954 vs. 6,590±16,312 mAU/ml, P=0.0025). In addition, PIVKA-II was correlated with multiple tumors as compared to single tumors (12,496±24,021 vs. 19,729±26,7207 mAU/ml, P=0.087). To further compare AFP and PIVKA-II, ROC was applied to analyze the data (Fig. 2). The analysis demonstrated that PIVKA-II was the better marker compared to AFP in HBV-infected Vietnamese patients. The area under ROC (AUC) of PIVKA-II was higher compared to AFP (0.7525 vs. 0.6663, P=0.0785).
Univariate and multivariate analyses of risk factors for LC and HCC
The risk factors of LC and HCC are shown in Tables IV and V using univariate and multivariate analyses. In Table IV, age (≥50 years), gender (male), HBV genotype C, HBV-DNA (≥5.0 log copies/ml), AFP (≥20 ng/ml) and PIVKA-II (≥40 mAU/ml) were the risk factors of LC by univariate analysis. By multivariate analysis, however, only age (≥50 years) and PIVKA-II (≥40 mAU/ml) were the independent risk factors of LC, although not for AFP (≥20 ng/ml). Similar findings are shown in the data of Table V, i.e., the variables age (≥50 years), gender (male), HBV genotype C, AFP (≥20 ng/ml) and PIVKA-II (≥40 mAU/ml) were the risk factors of HCC by univariate analysis. However, by multivariate analysis, only PIVKA-II (≥40 mAU/ml) was the independent risk factor of HCC. Nevertheless, the odds ratio of AFP was relatively high, 2.1 (0.92–4.9) and P=0.076.
Discussion
Screening is crucial to the early diagnosis of cancer. At present, there are different methods and medications to cure cancer patients, however, the earlier the diagnosis the better the clinical outcomes. The combination of ultrasound and serum AFP test is the most common method to screen HCC due to its being cost-effective, non-invasive and available globally. However, these tests are limited regarding clinical practice (12–18,34,36), thus a number of patients are lost. Moreover, differentiating cancer lesions from nodules in cirrhotic patients is challenging. At present, a new HCC surveillance method is urgently required to identify cost-effective and easy to use novel biomarkers suitable for clinical activity that may replace the serum AFP test, particularly in the diagnosis of HCC in cirrhotic patients at an early stage of liver tumor (11,17,18,35). PIVKA-II is one of the novel candidate markers for the detection of HCC. In a physiological process, glutamic acids located in the N-terminal of the prothrombin precursor are converted to γ-carboxyl glutamic acids by vitamin K-dependent carboxylase. PIVKA-II is produced when this pathway is disturbed in the absence of vitamin K, or when a vitamin K antagonist is used. Liebman et al first reported PIVKA-II in 1984 (20). PIVKA-II has since been considered a specific marker for the detection of liver cancer in HCC patients, and is studied worldwide. Most recently, PIVKA-II has also been demonstrated to be highly present in advanced gastric cancer patients (37,38).
Wang et al reported that the sensitivity of PIVKA-II in detecting HCC was superior to AFP in patients with liver tumor of a diameter >3 cm, as well as in patients with liver tumor size 2–3 or <2 cm (28). However, a study comprising Japanese patients showed that the sensitivity and utility of PIVKA-II for the diagnosis of HCC was lower compared to AFP in the case of a small liver tumor (<3 cm), but higher compared to AFP in case of a large tumor (>5 cm) (23). Durazo et al conducted a study in the American population focusing on HBV-infected ethnic Asians, and found that PIVKA-II had the highest sensitivity and positive predicting value compared to AFP and AFP-L3 (39. Thus, the authors recommended that PIVKA-II be used as the main serum test for HCC detection (39). Another American study comprising mainly non-hispanic white, HCV-infected patients, also reported PIVKA-II to be more sensitive and specific compared to AFP when differentiating HCC from non-malignant chronic liver diseases (29). By contrast, results obtained from the HALT-C trial group in different American ethnicities demonstrated AFP to be more sensitive compared to PIVKA-II or APF-L3 in the detection of early or very early stages of HCC with a new cut-off level of 10.9 ng/ml (24,25), while another study found neither AFP nor PIVKA-II to be optimal for the detection of HCC but served a complementary role to ultrasound in the detection of early HCC (25). In addition, the combination of AFP and PIVKA-II may increase the sensitivity up to 91% (25). In the present study on HBV-infected Vietnamese patients and HCC tumors >3 cm, the data have shown that PIVKA-II has a significantly higher sensitivity compared to AFP at different analyzed serum levels (Table II), although the combination of these tumor markers only enhances the specificity (Fig. 1) as previously reported in a study on American subjects (25). The decreased sensitivity when combining PIVKA-II to AFP in the present study was consistent with the results obtained from a recent study on Indian patients (31). The results of the present study have again shown that the liver tumor markers, AFP and PIVKA-II, are likely to be affected by etiologies of liver diseases, patient demographics, stages of liver disease and the characteristics of the HCC tumor. Thus, in the future, large-scale population studies are required worldwide to examine the role of liver tumor markers.
The number of tumors, liver tumor size and vascular invasion indicate a poor prognosis of HCC patients (40–45). When compared to AFP and AFP-L3, PIVKA-II is a good predictor for portal vein thrombosis and microvascular invasion (26,27,30). The present study reports that the level of AFP and PIVKA-II in HCC patients with portal vein thrombosis is higher compared to HCC patients without portal vein thrombosis. However, a statistically significant difference was only found for PIVKA-II (32,860±29,954 vs. 6,590±16,312 mAU/ml, P=0.0025), as opposed to AFP (427±342 vs. 297±362 ng/ml, P>0.05). Demonstrating a certain percentage of sensitivity (Table II), PIVKA-II was found to be a better marker compared to AFP as it is a strong independent factor for predicting LC and HCC in HBV-infected Vietnamese patients (Tables IV and V), while ROC analysis demonstrates that the area under the ROC of PIVKA-II in the present study is also higher compared to AFP (0.7525 vs. 0.6663, P=0.0785). In contrast to a previous study (28), findings of the present study have shown that PIVKA-II is not more strongly correlated to liver tumor size than AFP, partly due to the HCC patients in the study having a tumor size of more than 3 cm, with approximately 70.7% of them with a liver tumor size of more than 5 cm. In addition, PIVKA-II and AFP levels in the present study were also relatively high in patients with LC and CH (Table I).
In conclusion, the data in this first cross-sectional study on examining the role of PIVKA-II in HBV-infected Vietnamese patients indicate that PIVKA-II is likely to be a good marker in the detection of HCC, the prediction of portal vein thrombosis, as well as complementing the ultrasound in clinical utility for screening HCC. However, further studies are required to determine whether PIVKA-II is a better marker for the diagnosis of HCC in chronic HBV-infected Vietnamese patients.
References
|
Truong BX and Bang NV: The prevalence of HBV infection, HCV infection, co-infection of HBV/HCV and HBV genotype in the border region between Vietnam and China in Batxat district, Laocai province. Vietnam J Med Res. 64:52–59. 2009. | |
|
Duong TH, Nguyen PH, Henley K and Peters M: Risk factors for hepatitis B infection in rural Vietnam. Asian Pac J Cancer Prev. 10:97–102. 2009.PubMed/NCBI | |
|
Nguyen VT, McLaws ML and Dore GJ: Highly endemic hepatitis B infection in rural Vietnam. J Gastroenterol Hepatol. 22:2093–2100. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Hipgrave DB, Nguyen TV, Vu MH, Hoang TL, Do TD, Tran NT, Jolley D, Maynard JE and Biggs BA: Hepatitis B infection in rural Vietnam and the implications for a national program of infant immunization. Am J Trop Med Hyg. 69:288–294. 2003.PubMed/NCBI | |
|
Truong BX, Yano Y, Seo Y, et al: Variations in the core promoter/pre-core region in HBV genotype C in Japanese and Northern Vietnamese patients. J Med Virol. 79:1293–1304. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Truong BX, Seo Y, Yano Y, et al: Genotype and variations in core promoter and pre-core regions are related to progression of disease in HBV-infected patients from Northern Vietnam. Int J Mol Med. 19:293–299. 2007.PubMed/NCBI | |
|
Huy TT, Ushijima H, Quang VX, Ngoc TT, Hayashi S, Sata T and Abe K: Characteristics of core promoter and precore stop codon mutants of hepatitis B virus in Vietnam. J Med Virol. 74:228–236. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Truong BX, Yano Y, Seo Y, et al: T1653 mutation (C to T1653) in the box-alpha of X gene in relation to genotype, HBV-DNA level and HBeAg status in HBV-infected Vietnamese patiens. Vietnam J Med Res. 45:26–31. 2006. | |
|
Vuong DA, Velasco-Garrido M, Lai TD and Busse R: Temporal trends of cancer incidence in Vietnam, 1993–2007. Asian Pac J Cancer Prev. 11:739–745. 2010.PubMed/NCBI | |
|
Anh PT and Duc NB: The situation with cancer control in Vietnam. Jpn J Clin Oncol. 32(Suppl): S92–S97. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of world burden cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Sheu JC, Sung JL, Chen DS, et al: Early detection of hepatocellular carcinoma by real-time ultrasonography. A prospective study. Cancer. 56:660–666. 1985. View Article : Google Scholar : PubMed/NCBI | |
|
Oka H, Tamori A, Kuroki T, Kobayashi K and Yamamoto S: Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology. 19:61–66. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Di Bisceglie AM and Hoofnagle JH: Elevation in serum alphafetoprotein levels in patients with chronic hepatitis B. Cancer. 64:2117–2120. 1989. | |
|
Bruix J, Sherman M, Llovet JM, et al: Clinical management of hepatocellular carcinoma. Conclusion of the Barcelona-2000 EASL conference. European Association for the Study of the liver. J Hepatol. 35:421–430. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Sherman M: Surveillance for hepatocellular carcinoma. Semin Oncol. 28:450–459. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Gupta S, Bent S and Kohlwes J: Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systemic review and critical analysis. Ann Intern Med. 139:46–50. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Marrero JA and Lok AS: Newer markers for hepatocellular carcinoma. Gastroenterology. 127(5 Suppl 1): S113–S119. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Khien VV, Mao HV, Chinh TT, Ha PT, Bang MH, Lac BV, Hop TV, Tuan NA, Don LV, Taketa K and Satomura S: Clinical evaluation of lectin-reactive alpha-fetoprotein-L3 in histology-proven hepatocellular carcinoma. Int J Biol Markers. 16:105–111. 2001. | |
|
Liebman HA, Furie BC, Tong MJ, Blanchard RA, Lo KJ, Lee SD, Coleman MS and Furie B: Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Eng J Med. 310:1427–1431. 1984. View Article : Google Scholar : PubMed/NCBI | |
|
Cui R, He J, Zhang F, Wang B, Ding H, Shen H, Li Y and Chen X: Diagnostic value of protein induced by vitamin K absence (PIVKA-II) and hepatoma-specific band of serum gamma-glutamyl transferase (GGTII) as hepatocellular carcinoma marker complementary to alpha-fetoprotein. Br J Cancer. 88:1878–1882. 2003. View Article : Google Scholar | |
|
Nagaoka S, Yatsuhashi H, Hamada H, Yano K, Matsumoto T, Daikoku M, Arisawa K, Ishibashi H, Koga M, Sata M and Yano M: The des-gamma carboxy prothrombin index is a new prognostic indicator for hepatocellular carcinoma. Cancer. 98:2671–2677. 1993. View Article : Google Scholar : PubMed/NCBI | |
|
Nakamura S, Nouso K, Sakaguchi K, Ito YM, Ohashi Y, Kobayashi Y, Toshikuni N, Tanaka H, Miyake Y, Matsumoto E and Shiratori Y: Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. Am J Gastroenterol. 101:2038–2043. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Marrero JA, Feng Z, Wang Y, et al: Alpha-fetoprotein, des-gamma-carboxy prothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology. 137:110–118. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, Morgan TR, Kim HY, Lee WM, Bonkovsky HL and Dienstag JL; HALT-C Trial Group: Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology. 138:439–502. 2010.PubMed/NCBI | |
|
Miyaaki H, Nakashima O, Kurogi M, Eguchi K and Kojiro M: Lens culinaris agglutinin-reactive alpha-fetoprotein and protein induced by vitamin K absence II are potential indicators of a poor prognosis: a histopathological study of surgically resected hepatocellular carcinoma. J Gastroenterol. 42:962–968. 2007. View Article : Google Scholar | |
|
Shirabe K, Itoh S, Yoshizumi T, Soejima Y, Taketomi A, Aishima S and Maehara Y: The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma-with special reference of the serum levels of des-gamma-carboxy prohrombin. J Surg Oncol. 95:235–240. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Wang CS, Lin CL, Lee HC, Chen KY, Chiang MF, Chen HS, Lin TJ and Liao LY: Usefulness of serum des-gamma-carboxy prothrombin in detection of hepatocellular carcinoma. World J Gastroenterol. 11:6115–6119. 2005.PubMed/NCBI | |
|
Marrero JA, Su GL, Wei W, Emick D, Conjeevaram HS, Fontana RJ and Lok AS: Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients. Hepatology. 37:1114–1121. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Koike Y, Shiratori Y, Sato S, Obi S, Teratani T, Imamura M, Yoshida H, Shiina S and Omata M: 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. 91:561–569. 2001. View Article : Google Scholar | |
|
Sharma B, Srinivasan R, Chawla YK, Kapil S, Saini N, Singla B, Chakraborthy A, Kalra N, Duseja A and Dhiman RK: Clinical utility of prothrombin induced by vitamin K absence in the detection of hepatocellular carcinoma in Indian population. Hepatol Int. 4:569–576. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Abe A, Inoue K, Tanaka T, Kato J, Kajiyama N, Kawaguchi R, Tanaka S, Yoshiba M and Kohara M: Quantitation of hepatitis B virus genomic DNA by real time detection PCR. J Clin Microbiol. 37:2899–2903. 1999.PubMed/NCBI | |
|
Mizokami M, Nakano T, Orito E, Tanaka Y, Sakugawa H, Mukaide M and Robertson BH: Hepatitis B virus genotype assignment using restriction fragment length polymorphism pattern. FEBS Lett. 450:66–71. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Sato T, Tateishi R, Yoshida H, et al: Ultrasound surveillance for early detection of hepatocellular carcinoma among patients with hepatitis C. Hepatol Int. 3:544–550. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Forner A, Vilana R, Ayuso C, et al: Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology. 47:97–104. 2008. View Article : Google Scholar | |
|
Nguyen MH, Garcia RT, Simpson PW, Wright TL and Keeffe EB: Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis. Hepatology. 36:410–417. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Takano S, Honda I, Watanabe S, Soda H, Nagata M, Hoshino I, Takenouchi T and Miyazaki M: PIVKA-II-producing advanced gastric cancer. Int J Clin Oncol. 9:330–333. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Takahashi Y, Inoue T and Fukusato T: Protein induced by vitamin K absence or antagonist-II-producing gastric cancer. World J Gastrointest Pathophysiol. 1:129–136. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Durazo FA, Blatt LM, Corey WG, Lin JH, Han S, Saab S, Busuttil RW and Tong MJ: Des-gamma-carboxy prothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol. 23:1541–1548. 2008. View Article : Google Scholar | |
|
Iwatsuki S, Dvorchik I, Marsh JW, Madariaga JR, Carr B, Fung JJ and Starzl TE: Liver transplantation for hepatocellular carcinoma: a proposal of a prognostic scoring system. J Am Coll Surg. 191:389–394. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Hemming AW, Cattral MS, Reed AI, Van Der Werf WJ, Greig PD and Howard RJ: Liver transplantation for hepatocellular carcinoma. Ann Surg. 233:652–659. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A and Gennari L: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 334:693–699. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Mazzaferro V, Chun YS, Poon RT, Schwartz ME, Yao FY, Marsh JW, Bhoori S and Lee SG: Liver transplantation for hepatocellular carcinoma. Ann Surg Oncol. 15:1001–1007. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Yao FY, Ferrell L, Bass NM, Bacchetti P, Ascher NL and Roberts JP: Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl. 8:765–774. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Yao FY: Liver transplantation for hepatocellular carcinoma: beyond the Milan criteria. Am J Transplant. 8:1982–1989. 2008. View Article : Google Scholar : PubMed/NCBI |
