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��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������_�	��0��bjbj	0�bb�-,�������������8N�� D�"&,&,&,&'''�������$'��٬X2��'''''2�,&,&�˧�-�-�-'�,&,&j���-'��-�-�����,&�����E�p"������)Zd�NV��0���^1�O+�1�����1�ƍ�''�-'''''2�2��-'''�''''��������������������������������������������������������������������1�'''''''''� �:	Estimation of Des-gamma-carboxyprothrombin Rather than Alpha Fetoprotein  Elevates the Diagnostic Performance of Hepatocellular Carcinoma among Upper Egyptian Hepatitis C Patients

Abdel-Hamid, NM1, Wahid2, AM and Helaly2, T
Department of Biochemistry,  College of Pharmacy, Kafrelsheikh1 and Minia2 Universities, Kafrelsheikh and  Minia, Egypt. 

Abstract
Hepatocellular carcinoma (HCC) is the fifth most frequent neoplasm and the third most common cause of cancer-related death in the world. This study aims to evaluate the usefulness of des-gamma-carboxyprothrombin (DCP) rather than alpha fetoprotein  (AFP) in early speculation of HCC, through comparing the levels of DCP and AFP in three equal groups ( 20 individuals/ each), HCC, chronic HCV patients +/- interferon-�2+ribavirin (IF-�2 +RV) treatment, to normal healthy individuals (20 individuals). This,  to evaluate if the DCP can be accredited as a better diagnostic tool for HCC patients.
All cases were subjected to the following investigations:  routine liver function tests, HCV antibody titer, serum levels of AFP and plasma DCP.
The results revealed  that sensitivity of DCP was higher than AFP in detecting HCC (85% versus 65% of AFP), whereas the specificity of DCP was lower than that of AFP (72.5% versus 97.5% for AFP) among HCV patients. Recommendation, these results suggest that regular screening for HCV is a must, being a global risk factor for HCC, as well as,  simultaneous estimation  of both AFP and DCP in an attempt to allow early diagnosis of HCC. 
Keywords: Alpha fetoprotein, Diagnosis, Des-gamma-carboxyprothrombin,   Hepatitis C virus, Hepatocellular carcinoma, Interferon-�2+Ribavirin. 

1Corresponding author: Dr Nabil Mohie Abdel-Hamid, Diagnostic Laboratory, Abtal El-Faluga Street, Mit-Gomre, Dakahlia, Egypt. E-mail:  HYPERLINK "mailto:nabilmohie@yahoo.com" nabilmohie@yahoo.com

Introduction

Hepatocellular carcinoma (HCC) is one of the most frequent human cancers worldwide, with 1 million of newly diagnosed cases each year. Although knowledge about HCC is expanding exponentially, treatment and prevention of HCC is still a big challenge, and requires thorough understanding of the molecular mechanisms of hepatocarcinogenesis. This disease is responsible for more than 500, 000 deaths per year. The incidence ranges from <10 cases per 100, 000 persons in North America and Western Europe to 50-150 cases per 100, 000 persons in parts of Africa and Asia, where HCC is responsible for a large number of cancer deaths  ADDIN EN.CITE  ADDIN EN.CITE.DATA [1-4]. 
Approximately, 75�80% of primary liver cancers are attributable to persistent viral infections. HCC develops in more than 80% of cases in cirrhotic livers with an annual incidence of 2-5%. Cirrhosis is the major risk factor for hepatocellular carcinoma and cirrhotic patients should be screened for early detection of HCC  ADDIN EN.CITE  ADDIN EN.CITE.DATA [5, 6]. Although Ultra Sonography (US) and conventional tumor markers such as �-fetoprotein are widely used for HCC detection in clinical scenes, they still do not provide an entirely satisfactory solution to detect HCC at the early stage. For instance, abdominal US is the only tool recommended to screen patients with cirrhosis at present. However, its sensitivity in detecting small HCC (namely those below 1-2 cm) is rather low. The strongest information predicting prognosis and thus also possibly driving treatment strategy, are obtained, in fact, only from histological examination of the tumor on a resected specimen, which clearly is not available at the time of diagnosis  ADDIN EN.CITE <EndNote><Cite ExcludeYear="1"><Author>Jain</Author><RecNum>1149</RecNum><record><rec-number>1149</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1149</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jain, S.</author><author>Singhal, S.</author><author>Lee, P.</author><author>Xu, R.</author></authors></contributors><titles><title>Molecular genetics of hepatocellular neoplasia</title><secondary-title>Am J Transl Res</secondary-title></titles><pages>105-18</pages><volume>2</volume><number>1</number><edition>2010/02/26</edition><dates></dates><isbn>1943-8141 (Electronic)</isbn><accession-num>20182587</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=20182587</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[7].Surveillance programs are therefore recommended for the early detection of HCC, aiming at increasing the number of patients suitable for curative treatments. This points out the urgent need for new surveillance tools of patients at risk, mainly cirrhotic patients, for detection of HCC in the early stage.
Serum alpha fetoprotein (AFP) is the most widely used tumor marker in diagnosing patients with HCC and has been proven to have capability of prefiguring the prognosis. Furthermore, some other tumor markers, such as glypican-3, gamma-glutamyl transferees II(GGT), alpha-L-fucosidase, transforming growth factor-beta 1 and tumor-specific growth factor, have been indicated to be supplementary to AFP in the detection process. AFP mRNA has shown to correlate with the metastasis and recurrence of HCC, and it may be the most useful marker to prefigure the prognosis, some other markers, such as gamma-glutamyl transferase mRNA, vascular endothelial growth factor, and interleukin-8, could also be used as prognostic indicators and the simultaneous determination of AFP with these markers may detect the recurrence of HCC at its earlier period ADDIN EN.CITE  ADDIN EN.CITE.DATA [8, 9]. Alpha fetoprotein (AFP) is a fetal specific glycoprotein produced primarily by the fetal liver. Normally, its serum concentration falls rapidly after birth and its synthesis in adult life is repressed. However, greater than 70% of HCC patients have a high serum concentration of AFP because of the tumor excretion. Serum AFP remains the most useful tumor marker in screening HCC patients. The serum concentration of 20 ng/ml, is the most commonly used cut-off value to differentiate HCC patients from healthy adults. However, some investigations have showed that the cut-off value is fluctuant in different ethnic groups [ ADDIN EN.CITE <EndNote><Cite><Author>Soresi</Author><Year>2003</Year><RecNum>1313</RecNum><record><rec-number>1313</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1313</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Soresi, M.</author><author>Magliarisi, C.</author><author>Campagna, P.</author><author>Leto, G.</author><author>Bonfissuto, G.</author><author>Riili, A.</author><author>Carroccio, A.</author><author>Sesti, R.</author><author>Tripi, S.</author><author>Montalto, G.</author></authors></contributors><auth-address>Cattedra di Medicina Interna, Cattedra di Metodologia Clinica, Dpt di Medicina Clinica e delle Patologie Emergenti, Universita di Palermo, Italy.</auth-address><titles><title>Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma</title><secondary-title>Anticancer Res</secondary-title></titles><pages>1747-53</pages><volume>23</volume><number>2C</number><edition>2003/06/25</edition><keywords><keyword>Aged</keyword><keyword>Area Under Curve</keyword><keyword>Carcinoma, Hepatocellular/blood/*diagnosis/pathology</keyword><keyword>Diagnosis, Differential</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/blood/diagnosis</keyword><keyword>Liver Neoplasms/blood/*diagnosis/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neoplasm Staging</keyword><keyword>ROC Curve</keyword><keyword>Regression Analysis</keyword><keyword>Retrospective Studies</keyword><keyword>alpha-Fetoproteins/*analysis</keyword></keywords><dates><year>2003</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>0250-7005 (Print)&#xD;0250-7005 (Linking)</isbn><accession-num>12820452</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=12820452</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[10]].On the other hand some reports have indicated that it has limited utility of differentiating HCC from benign hepatic disorders for its high false-positive and false-negative rates and patients with acute exacerbation of viral hepatitis but no HCC may also have markedly increased AFP levels ADDIN EN.CITE  ADDIN EN.CITE.DATA [11].
Des-gamma-carboxyprothrombin (DCP), a protein induced by vitamin K absence or antagonist II (PIVKA-II), is an abnormal product from liver carboxylation disturbance during the formation of thrombogen. Its mean serum concentration, which is not correlated to serum levels of AFP, is obviously elevated in HCC patients compared to healthy adults and patients with nonmalignant hepatopathy. Serum and tissue DCP have been proved to be more useful than AFP in differentiating HCC from nonmalignant hepatopathy and in detecting patients with small HCC  ADDIN EN.CITE <EndNote><Cite><Author>Gotoh</Author><Year>2003</Year><RecNum>1237</RecNum><record><rec-number>1237</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1237</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gotoh, M.</author><author>Nakatani, T.</author><author>Masuda, T.</author><author>Mizuguchi, Y.</author><author>Sakamoto, M.</author><author>Tsuchiya, R.</author><author>Kato, H.</author><author>Furuta, K.</author></authors></contributors><auth-address>Department of Clinical Chemistry, National Cancer Center Hospital, Tokyo, Japan.</auth-address><titles><title>Prediction of invasive activities in hepatocellular carcinomas with special reference to alpha-fetoprotein and des-gamma-carboxyprothrombin</title><secondary-title>Jpn J Clin Oncol</secondary-title></titles><pages>522-6</pages><volume>33</volume><number>10</number><edition>2003/11/19</edition><keywords><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/blood supply/*chemistry/pathology</keyword><keyword>Hepatitis B Surface Antigens/analysis</keyword><keyword>Hepatitis C/complications</keyword><keyword>Hepatitis C Antibodies/analysis</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/blood supply/*chemistry/pathology</keyword><keyword>Neoplasm Invasiveness</keyword><keyword>Predictive Value of Tests</keyword><keyword>Protein Precursors/*blood</keyword><keyword>Prothrombin</keyword><keyword>ROC Curve</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/*analysis</keyword></keywords><dates><year>2003</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0368-2811 (Print)&#xD;0368-2811 (Linking)</isbn><accession-num>14623921</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=14623921</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[12].The sensitivity and specificity of serum DCP (at the cut-off value of 125, ng/ml) in discriminating HCC from nonmalignant hepatopathy were 89% and 86.7% respectively, which were much better than those of AFP (at the cut-off value of 11 ng/ml). Furthermore, the simultaneous determination of DCP and other tumor markers, such as AFP and AFP-L3 may have a greater accuracy than the determination of each of them alone  ADDIN EN.CITE  ADDIN EN.CITE.DATA [13-15]. Besides the purpose of screening HCC, serum DCP could also be used as a prognostic indicator for HCC patients and may be more useful than AFP in reflecting the invasive characteristics of HCC. It has been reported that patients with DCP seropositive and AFP seronegative have a higher frequency of HCC with a distinct margin, large nodule more than 3 cm. Moreover, the simultaneous of serum DCP levels and tissue DCP expression is more valuable than either factor alone in pursuing the prognosis of patients  ADDIN EN.CITE <EndNote><Cite><Author>Motola-Kuba</Author><Year>2006</Year><RecNum>1350</RecNum><record><rec-number>1350</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1350</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Motola-Kuba, D.</author><author>Zamora-Valdes, D.</author><author>Uribe, M.</author><author>Mendez-Sanchez, N.</author></authors></contributors><auth-address>Department of Biomedical Research and Liver Unit, Medica Sur Clinic &amp; Foundation, Mexico City, Mexico.</auth-address><titles><title>Hepatocellular carcinoma. An overview</title><secondary-title>Ann Hepatol</secondary-title></titles><pages>16-24</pages><volume>5</volume><number>1</number><edition>2006/03/15</edition><keywords><keyword>Age Distribution</keyword><keyword>Aged</keyword><keyword>Biopsy, Needle</keyword><keyword>Carcinoma, Hepatocellular/*diagnosis/*epidemiology/surgery</keyword><keyword>Causality</keyword><keyword>Female</keyword><keyword>Hepatectomy/methods</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Incidence</keyword><keyword>Liver Neoplasms/*diagnosis/*epidemiology/surgery</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Mexico/epidemiology</keyword><keyword>Middle Aged</keyword><keyword>Neoplasm Staging</keyword><keyword>Prognosis</keyword><keyword>Risk Assessment</keyword><keyword>Risk Factors</keyword><keyword>Sex Distribution</keyword><keyword>Survival Analysis</keyword></keywords><dates><year>2006</year><pub-dates><date>Jan-Mar</date></pub-dates></dates><isbn>1665-2681 (Print)</isbn><accession-num>16531960</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16531960</url></related-urls></urls><electronic-resource-num>446254 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>[16].
The present study aims to evaluate the accuracy of DCP as a tumor marker in diagnosing HCC, compare the level of DCP and AFP in HCC patients, in chronic HCV patients +/- interferon-�2+ribavirin (IF-�2 +RV) treatment, define the level of each tumor marker with the best sensitivity and specificity for HCC diagnosis and finally, evaluate if the combination of DCP with AFP gives better diagnosis for HCC.

Patients and Methods
Patients
This study was conducted as a collaboration between the Department of Biochemistry, College of Pharmacy, Minia University and  Sohag Cancer Center at Sohag Health Insurance Hospitals, South Egypt,  between January 2009 to February 2011. The study included 80 individuals grouped as follows: Group 1: 20 healthy volunteers, gender matched to other groups with the following clinical conditions: apparently healthy, normal clinical examination, abdominal ultrasonography, liver function tests and seronegative for HCV markers. Group II:  20 patients with HCC regardless the etiology with the following clinical diagnosis: deterioration of health, right hypochondrial pain and hepatomegaly with nodular surface, the abdominal ultrasonography showing hepatic focal lesions (single or multiple) or heterogeneous areas in the liver. Positive histopathological examination of liver biopsy or aspirate for malignancy (only when the patient's clinical condition and prothrombin time and concentration allowed the performance) and/or raised AFP above 400 ng/ml. Group III: 20 patients with chronic HCV, matched in gender to group I with the following clinical conditions: fatigue, anorexia, with high aminotransferase values and hyperbilirubinemia. They were not under interferon-�2+ribavirin (IF-�2 +RV) treatment.  Group IV:  20 patients with chronic HCV, under IF-�2 (weekly subcutaneous single dose, 160 ug/ampoule ,) plus RV (1200 mg/ day, per oral as e doses after meals) for one year:  this group of patients matches to  group I in gender, with the same diagnosis as group III. 
All cases were subjected to the following investigations: complete history of patients attending Sohag Cancer Center at Sohag Health Insurance Hospitals through patient files, full clinical examination, including general and abdominal examination with stress on the size of the liver and spleen. Abdominal US was performed to assess the status of the liver and spleen to detect the presence of ascites. Ultrasonographically guided percutaneous needle biopsy from the liver was taken. Laboratory investigations included liver function tests with the aim of investigating the status of the liver in all patients and to exclude liver disease in control subjects. Liver function tests included serum bilirubin both total, direct and indirect, serum albumin, AST, ALT activities, Prothrombin time (PT) and concentration. Hepatitis C viral antibodies were detected by automated ELISA. Serological tests for HCV markers were performed to assess the possible role of the virus in the etiology of HCC. Serum AFP, Plasma DCP were finally measured. 

Sample collection
10 ml venous blood were withdrawn from each individual, 1.8 ml were immediately mixed with 0.2 ml tri-sodium citrate for estimation of PT and concentration. The rest of the blood was divided into 2 portions, one smaller, anti-coagulated for DCP estimation, the rest left to clot and centrifuged afterwards for other investigations. The rest of plasma and serum were separated in aliquots and frozen at -70�C for measurement of DCP and AFP.   

HCV antibody assay
Micro plates coated with HCV-specific synthetic antigens derived from "core" and "NS" regions encoding for conservative immunodominant antigenic determinants (core, NS3, NS4, and NS5) were used for this assay according to manufacturers' instructions (Ortho HCV Core-Ab Irma Test; Mitsubishi Kagaku Iatron, Japan). 
AFP (A1-fetoprotein)
Sandwich principle was employed to determine the AFP concentration via ELISA technique according to manufacturers' instructions (Anogen, Canada)  ADDIN EN.CITE  ADDIN EN.CITE.DATA [17-19]. 
Des-gamma-carboxyprothrombin 
DCP was measured using commercially available ELISA kit (Asserachrom PIVKA II kit, Stago, France), according to the manufactures� instructions ADDIN EN.CITE <EndNote><Cite><Author>AMIRAL</Author><Year>1990</Year><RecNum>1392</RecNum><record><rec-number>1392</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1392</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>AMIRAL, J.</author><author>GROSLEY, M .</author><author>PLASSART, V. </author><author>MIMILLA, F. </author><author>CORBEL, L. </author><author>CHAMBRETIE, B.</author></authors></contributors><titles><title>A new monoclonal based test for the assay of Decarboxy-Prothrombin (DCP) in hepatocarcinomas</title><secondary-title>geht de Mulhouse</secondary-title></titles><dates><year>1990</year></dates><urls></urls></record></Cite><Cite><Author>HIRSCHAUER</Author><Year>1991</Year><RecNum>1393</RecNum><record><rec-number>1393</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1393</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>HIRSCHAUER, C.</author><author>AMIRAL, J.</author><author>MARCELLIN, P. </author><author>GUILLIN, M. C.</author><author>BEZEAUD, A.</author></authors></contributors><titles><title>Immunoassay for DeCarboxy Prothrombin using a monoclonal antibody:. clinical usefulness as a tumor marker for hepatocellular carcinoma</title></titles><pages>1056</pages><volume>65</volume><dates><year>1991</year></dates><urls></urls></record></Cite></EndNote>[20, 21]. 
Calculation of sensitivity and specificity of AFP and DCP:
Sensitivity: the capacity of the test to correctly identify affected individuals in a population "TRUE POSITIVES". The greater the sensitivity, the smaller the number of identified case "false negatives".

Sensitivity= TP/ (TP+FN), where TP = true positive, and FN = false negative
Specificity: the capacity of the test to correctly exclude individuals who are free of the disease "TRUE NEGATIVES". The greater the specificity, the fewer "false positives" will be included.

Specificity= TN/ (TN+FP), where TN = true negative, and FP = false positive.

Results
In the present study, the male/ female percentages and age ranges are shown in  Table 1.

Liver function tests in patients infected with chronic HCV and HCC: 
ALT and AST serum activities were significantly (P< 0.001) up-regulated in the HCC and HCV groups (groups II, III, IV), compared to control (group I), (Table 2). A highly significant difference in total and direct bilirubin in groups II, and III respectively, compared to control. Moreover, HCC patients (group II) showed a non significant decrease in serum albumin, compared to control. The mean prothrombin time (PT) in HCC group and non-malignant HCV groups (III, IV) showed a highly significant elevation, compared to control. Regarding the prothrombin concentration (PC), a highly significant decrease in group (II, III, IV),  was shown. Moreover, 85.6% of the patients in the HCC group included in this study were reported to have HCV infection (Table 2). 


Alpha fetoprotein (AFP) and Des-gamma-carboxy prothrombin (DCP) 
Both AFP and DCP serum values of HCC patients showed highly significant increase, compared to non-malignant groups (I, III, IV) (Table 3). Our results also showed that the sensitivity of DCP was higher than AFP in detecting HCC patients (85% versus 65% of AFP). In our data, the increase in sensitivity of DCP from 85% and AFP from 65% to 90% (Table 4) in detecting HCC was found by the complementary use of the two markers.

Discussion
The increasing incidence of HCC, compounded by the fact that the majority of these tumors were diagnosed at a late stage when curative treatment were not possible ADDIN EN.CITE <EndNote><Cite><Author>Wilson</Author><Year>2005</Year><RecNum>1315</RecNum><record><rec-number>1315</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1315</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wilson, J. F.</author></authors></contributors><auth-address>jenwilson@acponline.org</auth-address><titles><title>Liver cancer on the rise</title><secondary-title>Ann Intern Med</secondary-title></titles><pages>1029-32</pages><volume>142</volume><number>12 Pt 1</number><edition>2005/06/22</edition><keywords><keyword>Carcinoma, Hepatocellular/diagnosis/*epidemiology/prevention &amp;</keyword><keyword>control/therapy</keyword><keyword>Humans</keyword><keyword>Japan/epidemiology</keyword><keyword>Liver Neoplasms/diagnosis/*epidemiology/prevention &amp; control/therapy</keyword><keyword>United States/epidemiology</keyword></keywords><dates><year>2005</year><pub-dates><date>Jun 21</date></pub-dates></dates><isbn>1539-3704 (Electronic)&#xD;0003-4819 (Linking)</isbn><accession-num>15968025</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=15968025</url></related-urls></urls><electronic-resource-num>142/12_Part_1/1029 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>[22], has prompted the international community into performing regular surveillance of high risk individuals. Unfortunately, surveillance programmers are hindered by the poor performance of the commonly used serum marker, namely AFP  ADDIN EN.CITE <EndNote><Cite><Author>Bruix</Author><Year>2001</Year><RecNum>1226</RecNum><record><rec-number>1226</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1226</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bruix, J.</author><author>Sherman, M.</author><author>Llovet, J. M.</author><author>Beaugrand, M.</author><author>Lencioni, R.</author><author>Burroughs, A. K.</author><author>Christensen, E.</author><author>Pagliaro, L.</author><author>Colombo, M.</author><author>Rodes, J.</author></authors></contributors><auth-address>Liver Unit, Digestive Disease Institute, Hospital Clinic, IDIBAPS, Barcelona, Catalonia, Spain. jbruix@clinic.ub.es</auth-address><titles><title>Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver</title><secondary-title>J Hepatol</secondary-title></titles><pages>421-30</pages><volume>35</volume><number>3</number><edition>2001/10/11</edition><keywords><keyword>Carcinoma, Hepatocellular/epidemiology/etiology/*therapy</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Liver Neoplasms/epidemiology/etiology/*therapy</keyword><keyword>Prognosis</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2001</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0168-8278 (Print)&#xD;0168-8278 (Linking)</isbn><accession-num>11592607</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11592607</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[23]. Even in combination with abdominal US. A tremendous amount of effort has been and continues to be applied to the search for improved HCC biomarkers. As yet, none has proved superior to AFP in performance, but in combination some may have complimentary roles in HCC arising on a background of viral hepatitis  ADDIN EN.CITE  ADDIN EN.CITE.DATA [24].
Sex and age of patients included in this study 
In the present study, the male to female among the HCC group (Table 1), was comparable to other reports elsewhere  ADDIN EN.CITE  ADDIN EN.CITE.DATA [25-27]. In Europe, the ration ranges from 4 to 5: 1, while in, 3.2:1, Japan,3.7:1, and in Gambia 2.8:1. Men are more likely to consume alcohol, smoke cigarettes, and have increased iron stores. Non-environmental endogenous factors that may also affect males adversely such as higher body mass index and higher levels of androgenic hormones ADDIN EN.CITE <EndNote><Cite><Author>El-Serag</Author><Year>2007</Year><RecNum>1379</RecNum><record><rec-number>1379</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1379</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>El-Serag, H. B.</author><author>Rudolph, K. L.</author></authors></contributors><auth-address>Michael E. DeBakey Veterans Administration Medical Center and Baylor College of Medicine, Houston Center for Quality of Care and Utilization Studies, Houston, Texas, USA. hasheme@bcm.tmc.edu</auth-address><titles><title>Hepatocellular carcinoma: epidemiology and molecular carcinogenesis</title><secondary-title>Gastroenterology</secondary-title></titles><pages>2557-76</pages><volume>132</volume><number>7</number><edition>2007/06/16</edition><keywords><keyword>Age Distribution</keyword><keyword>Carcinoma, Hepatocellular/chemically</keyword><keyword>induced/*epidemiology/*etiology/genetics</keyword><keyword>Continental Population Groups</keyword><keyword>Diabetes Complications</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Liver Cirrhosis/complications</keyword><keyword>Liver Diseases/complications</keyword><keyword>Liver Neoplasms/*epidemiology/*genetics</keyword><keyword>Obesity/complications</keyword><keyword>Risk Factors</keyword><keyword>Sex Distribution</keyword><keyword>United States</keyword><keyword>World Health</keyword></keywords><dates><year>2007</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0016-5085 (Print)&#xD;0016-5085 (Linking)</isbn><accession-num>17570226</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17570226</url></related-urls></urls><electronic-resource-num>S0016-5085(07)00799-8 [pii]&#xD;10.1053/j.gastro.2007.04.061</electronic-resource-num><language>eng</language></record></Cite></EndNote>[28]- ADDIN EN.CITE <EndNote><Cite><Author>Badawi</Author><Year>1999</Year><RecNum>1210</RecNum><record><rec-number>1210</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1210</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Badawi, A. F.</author><author>Michael, M. S.</author></authors></contributors><auth-address>Laboratory of Pharmacogenetics, University of Prince Edward Island, Charlottetown, Canada. abadawi@upei.ca</auth-address><titles><title>Risk factors for hepatocellular carcinoma in Egypt: the role of hepatitis-B viral infection and schistosomiasis</title><secondary-title>Anticancer Res</secondary-title></titles><pages>4565-9</pages><volume>19</volume><number>5C</number><edition>2000/01/29</edition><keywords><keyword>Carcinoma, Hepatocellular/*etiology/immunology/parasitology/virology</keyword><keyword>Case-Control Studies</keyword><keyword>Egypt</keyword><keyword>Female</keyword><keyword>Hepatitis B/*complications/immunology</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*etiology/immunology/parasitology/virology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk Factors</keyword><keyword>Schistosomiasis/*complications</keyword></keywords><dates><year>1999</year><pub-dates><date>Sep-Oct</date></pub-dates></dates><isbn>0250-7005 (Print)&#xD;0250-7005 (Linking)</isbn><accession-num>10650811</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=10650811</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[29]. 
HCC affects all ages. In Asian and African countries, the morbidity peak is reached in adolescence (20 and 40 years). HCC has also been observed in babies and infants  ADDIN EN.CITE <EndNote><Cite><Author>Yamazaki</Author><Year>2007</Year><RecNum>1311</RecNum><record><rec-number>1311</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1311</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yamazaki, Y.</author><author>Kakizaki, S.</author><author>Sohara, N.</author><author>Sato, K.</author><author>Takagi, H.</author><author>Arai, H.</author><author>Abe, T.</author><author>Katakai, K.</author><author>Kojima, A.</author><author>Matsuzaki, Y.</author><author>Mori, M.</author></authors></contributors><auth-address>Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, 371-8511 Gunma, Japan.</auth-address><titles><title>Hepatocellular carcinoma in young adults: the clinical characteristics, prognosis, and findings of a patient survival analysis</title><secondary-title>Dig Dis Sci</secondary-title></titles><pages>1103-7</pages><volume>52</volume><number>4</number><edition>2007/03/24</edition><keywords><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Carcinoma, Hepatocellular/*diagnosis/mortality/virology</keyword><keyword>Female</keyword><keyword>Hepatitis B Surface Antigens/analysis</keyword><keyword>Hepatitis C Antibodies/analysis</keyword><keyword>Humans</keyword><keyword>Japan</keyword><keyword>Liver Neoplasms/*diagnosis/mortality/virology</keyword><keyword>Male</keyword><keyword>Prognosis</keyword><keyword>Survival Rate</keyword></keywords><dates><year>2007</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0163-2116 (Print)&#xD;0163-2116 (Linking)</isbn><accession-num>17380407</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17380407</url></related-urls></urls><electronic-resource-num>10.1007/s10620-006-9578-2</electronic-resource-num><language>eng</language></record></Cite></EndNote>[30]- ADDIN EN.CITE <EndNote><Cite><Author>McGlynn</Author><Year>2001</Year><RecNum>1380</RecNum><record><rec-number>1380</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1380</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McGlynn, K. A.</author><author>Tsao, L.</author><author>Hsing, A. W.</author><author>Devesa, S. S.</author><author>Fraumeni, J. F., Jr.</author></authors></contributors><auth-address>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. mcglynnkmail.nih.gov</auth-address><titles><title>International trends and patterns of primary liver cancer</title><secondary-title>Int J Cancer</secondary-title></titles><pages>290-6</pages><volume>94</volume><number>2</number><edition>2001/10/23</edition><keywords><keyword>Aflatoxin B1/adverse effects</keyword><keyword>Carcinoma, Hepatocellular/*epidemiology</keyword><keyword>Cholangiocarcinoma/*epidemiology</keyword><keyword>Female</keyword><keyword>Hepatitis C, Chronic/complications</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Liver Neoplasms/*epidemiology</keyword><keyword>Male</keyword><keyword>Registries</keyword><keyword>Time Factors</keyword></keywords><dates><year>2001</year><pub-dates><date>Oct 15</date></pub-dates></dates><isbn>0020-7136 (Print)&#xD;0020-7136 (Linking)</isbn><accession-num>11668511</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11668511</url></related-urls></urls><electronic-resource-num>10.1002/ijc.1456 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>[31]. The mean age of HCC is significantly higher than those of chronic hepatitis patients with and without interferon treatment, which is similar to some other reports  ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2005</Year><RecNum>1230</RecNum><record><rec-number>1230</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1230</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, C. S.</author><author>Lin, C. L.</author><author>Lee, H. C.</author><author>Chen, K. Y.</author><author>Chiang, M. F.</author><author>Chen, H. S.</author><author>Lin, T. J.</author><author>Liao, L. Y.</author></authors></contributors><auth-address>Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, No. 10, Sec. 4, Ren-ai Road, Da-an District Taipei City 106, Taiwan, China.</auth-address><titles><title>Usefulness of serum des-gamma-carboxy prothrombin in detection of hepatocellular carcinoma</title><secondary-title>World J Gastroenterol</secondary-title></titles><pages>6115-9</pages><volume>11</volume><number>39</number><edition>2005/11/08</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Biological Markers/*blood</keyword><keyword>Carcinoma, Hepatocellular/*blood/*diagnosis</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*blood/*diagnosis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Protein Precursors/*blood</keyword><keyword>Prothrombin</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Tumor Markers, Biological/blood</keyword></keywords><dates><year>2005</year><pub-dates><date>Oct 21</date></pub-dates></dates><isbn>1007-9327 (Print)&#xD;1007-9327 (Linking)</isbn><accession-num>16273636</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16273636</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[32].   
Liver indices in tested groups:
ALT and AST activities were increased in HCC and HCV groups, compared to the control group. These results were comparable to previous reports [ ADDIN EN.CITE <EndNote><Cite><Author>Lopez</Author><Year>1996</Year><RecNum>1319</RecNum><record><rec-number>1319</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1319</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lopez, J. B.</author><author>Balasegaram, M.</author><author>Thambyrajah, V.</author><author>Timor, J.</author></authors></contributors><auth-address>Division of Endocrinology, Institute for Medical Research, Kuala Lumpur, Malaysia.</auth-address><titles><title>The value of liver function tests in hepatocellular carcinoma</title><secondary-title>Malays J Pathol</secondary-title></titles><pages>95-9</pages><volume>18</volume><number>2</number><edition>1996/12/01</edition><keywords><keyword>Adult</keyword><keyword>Alanine Transaminase/blood</keyword><keyword>Alkaline Phosphatase/blood</keyword><keyword>Aspartate Aminotransferases/blood</keyword><keyword>Bilirubin/analysis</keyword><keyword>Carcinoma, Hepatocellular/*diagnosis/enzymology</keyword><keyword>Humans</keyword><keyword>L-Lactate Dehydrogenase/blood</keyword><keyword>*Liver Function Tests</keyword><keyword>Liver Neoplasms/*diagnosis/enzymology</keyword><keyword>Reference Values</keyword><keyword>Serum Albumin/analysis</keyword><keyword>gamma-Glutamyltransferase/blood</keyword></keywords><dates><year>1996</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0126-8635 (Print)&#xD;0126-8635 (Linking)</isbn><accession-num>10879229</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=10879229</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[33]].Both serum total and direct bilirubin, they were significantly elevated in HCC and non-treated HCV, compared to control group. Moreover, HCC patients (group II) showed a significant decrease of serum albumin relative to the control group, reflecting a decreased synthetic ability of the liver cells. These results coincide  to some previous observations  ADDIN EN.CITE  ADDIN EN.CITE.DATA [5, 34, 35]. 
HCC group (II) and nonmalignant hepatitis C groups (III and IV) showed a highly statistically significant elevation in the mean PT with corresponding PC depression, comparing with control group (I). These results are comparable to the findings of Raedle etal.,  ADDIN EN.CITE <EndNote><Cite><Author>Raedle</Author><Year>1998</Year><RecNum>1385</RecNum><record><rec-number>1385</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1385</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Raedle, J.</author><author>Oremek, G.</author><author>Truschnowitsch, M.</author><author>Lorenz, M.</author><author>Roth, W. K.</author><author>Caspary, W. F.</author><author>Zeuzem, S.</author></authors></contributors><auth-address>Second Department of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.</auth-address><titles><title>Clinical evaluation of autoantibodies to p53 protein in patients with chronic liver disease and hepatocellular carcinoma</title><secondary-title>Eur J Cancer</secondary-title></titles><pages>1198-203</pages><volume>34</volume><number>8</number><edition>1998/12/16</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Autoantibodies/analysis</keyword><keyword>Carcinoma, Hepatocellular/*immunology</keyword><keyword>Chronic Disease</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Diseases/immunology</keyword><keyword>Liver Neoplasms/immunology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Tumor Suppressor Protein p53/*immunology</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>1998</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0959-8049 (Print)&#xD;0959-8049 (Linking)</isbn><accession-num>9849479</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=9849479</url></related-urls></urls><electronic-resource-num>S0959804998000562 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>[36].
HCV antibody and AFP testing
In the present study 85.6% of the patients in the HCC group were noticed to have HCV infection. Similar results were found elsewhere;  as 70%  ADDIN EN.CITE  ADDIN EN.CITE.DATA [37, 38], 84%  ADDIN EN.CITE <EndNote><Cite><Author>Mabrouk</Author><Year>1997</Year><RecNum>1293</RecNum><record><rec-number>1293</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1293</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mabrouk, G. M.</author></authors></contributors><auth-address>Dept. of Biochemistry, Faculty of Medicine, Ain Shams University, Cairo, Egypt.</auth-address><titles><title>Prevalence of hepatitis C infection and schistosomiasis in Egyptian patients with hepatocellular carcinoma</title><secondary-title>Dis Markers</secondary-title></titles><pages>177-82</pages><volume>13</volume><number>3</number><edition>1997/12/24</edition><keywords><keyword>Animals</keyword><keyword>Carcinoma, Hepatocellular/*etiology</keyword><keyword>Egypt/epidemiology</keyword><keyword>Female</keyword><keyword>Hepatitis C/*epidemiology</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*etiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prevalence</keyword><keyword>Schistosomiasis/*epidemiology</keyword></keywords><dates><year>1997</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0278-0240 (Print)&#xD;0278-0240 (Linking)</isbn><accession-num>9405930</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=9405930</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[39], 75.8%   ADDIN EN.CITE  ADDIN EN.CITE.DATA [40, 41] and 65%  ADDIN EN.CITE  ADDIN EN.CITE.DATA [42-44] in Japan. Lower rates were found in some other areas in Egypt  ADDIN EN.CITE  ADDIN EN.CITE.DATA [45], where HCV prevalence among HCC patients was found to be 30%. This discrepancy in prevalence rates might be due to cultural and hygienic difference in individuals contributing in the surveillances. 
There was an increased risk of HCC accompanying HCV infection  ADDIN EN.CITE  ADDIN EN.CITE.DATA [46-48]. In the present study, most of HCC patients were seropositive to HCV. This could be explained on the basis that chronic hepatitis always progresses to cirrhosis, ultimately developing HCC  ADDIN EN.CITE  ADDIN EN.CITE.DATA [48-51]. It was shown, that in spite of the pitfalls of using AFP as a marker of HCC, it is commonly used as one of the screening tools in combination with ultrasonography  ADDIN EN.CITE <EndNote><Cite><Author>Yuen</Author><Year>2005</Year><RecNum>1209</RecNum><record><rec-number>1209</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1209</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yuen, M. F.</author><author>Lai, C. L.</author></authors></contributors><auth-address>Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. yuenmf@netvigator.com</auth-address><titles><title>Serological markers of liver cancer</title><secondary-title>Best Pract Res Clin Gastroenterol</secondary-title></titles><pages>91-9</pages><volume>19</volume><number>1</number><edition>2005/03/11</edition><keywords><keyword>Biological Markers/blood</keyword><keyword>Glypicans</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*diagnosis</keyword><keyword>Membrane Proteins/blood</keyword><keyword>Neoplasm Proteins/blood</keyword><keyword>Plant Lectins</keyword><keyword>Protein Precursors/blood</keyword><keyword>Prothrombin</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Serologic Tests</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2005</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1521-6918 (Print)&#xD;1521-6918 (Linking)</isbn><accession-num>15757806</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=15757806</url></related-urls></urls><electronic-resource-num>S1521-6918(04)00145-3 [pii]&#xD;10.1016/j.bpg.2004.10.003</electronic-resource-num><language>eng</language></record></Cite></EndNote>[52]. Though some clinicians find AFP to be of no use for screening, Tremolola et al.  ADDIN EN.CITE <EndNote><Cite><Author>Tremolda</Author><Year>1989</Year><RecNum>1383</RecNum><record><rec-number>1383</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1383</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tremolda, F.</author><author>Benevegnu, L.</author><author>Drago, C.</author><author>Casarin, C.</author><author>Cechetto, A.</author><author>Realdi, G.</author><author>Ruol, A.</author></authors></contributors><auth-address>Instituto di Oncologia sperimentale e clinica, Universita di Reggio Calabria, Sede di Catanzaro.</auth-address><titles><title>Early detection of hepatocellular carcinoma in patients with cirrhosis by alphafetoprotein, ultrasound and fine-needle biopsy</title><secondary-title>Hepatogastroenterology</secondary-title></titles><pages>519-21</pages><volume>36</volume><number>6</number><edition>1989/12/01</edition><keywords><keyword>Biopsy, Needle</keyword><keyword>Carcinoma, Hepatocellular/*diagnosis/epidemiology/etiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver/pathology</keyword><keyword>Liver Cirrhosis/*complications</keyword><keyword>Liver Neoplasms/*diagnosis/epidemiology/etiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prevalence</keyword><keyword>Ultrasonography</keyword><keyword>alpha-Fetoproteins/*analysis</keyword></keywords><dates><year>1989</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0172-6390 (Print)&#xD;0172-6390 (Linking)</isbn><accession-num>2482242</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=2482242</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[53] demonstrated that the sensitivity can reach up to 100% by combining AFP measurement and ultrasonography. 
In our work, AFP values among HCC patients showed highly significant increase, rather than the nonmalignant groups (I, III, IV) (Table 3). Yuen and lay  ADDIN EN.CITE <EndNote><Cite><Author>Yuen</Author><Year>2005</Year><RecNum>1209</RecNum><record><rec-number>1209</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1209</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yuen, M. F.</author><author>Lai, C. L.</author></authors></contributors><auth-address>Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. yuenmf@netvigator.com</auth-address><titles><title>Serological markers of liver cancer</title><secondary-title>Best Pract Res Clin Gastroenterol</secondary-title></titles><pages>91-9</pages><volume>19</volume><number>1</number><edition>2005/03/11</edition><keywords><keyword>Biological Markers/blood</keyword><keyword>Glypicans</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*diagnosis</keyword><keyword>Membrane Proteins/blood</keyword><keyword>Neoplasm Proteins/blood</keyword><keyword>Plant Lectins</keyword><keyword>Protein Precursors/blood</keyword><keyword>Prothrombin</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Serologic Tests</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2005</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1521-6918 (Print)&#xD;1521-6918 (Linking)</isbn><accession-num>15757806</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=15757806</url></related-urls></urls><electronic-resource-num>S1521-6918(04)00145-3 [pii]&#xD;10.1016/j.bpg.2004.10.003</electronic-resource-num><language>eng</language></record></Cite></EndNote>[52]showed that AFP levels do not correlate with tumor size, histological grades, intrahepatic metastases and portal vein thrombosis.
Des-gamma-carboxy prothrombin (DCP), a protein produced in the absence of vitamin K and is an abnormal product from disturbed carboxylation during the formation of prothrombin. In fact, many reports stated that it is more specific for HCC than AFP and is less often elevated in cirrhotic patients without HCC. Thus, the combination of DCP with AFP might be even more sensitive and specific ADDIN EN.CITE  ADDIN EN.CITE.DATA [15, 32]. 
Yuen and Lai concluded that DCP is an excellent marker for monitoring the treatment efficacy, indication of complete clearance of HCC after curative treatment, and recurrence of HCC in the future. The serum half-life of DCP is around 40-70 hours, much shorter than that of AFP,5-7 days. Unlike total AFP, DCP is found to correlate with the stage of the HCC as well as survival  ADDIN EN.CITE <EndNote><Cite><Author>Yuen</Author><Year>2005</Year><RecNum>1209</RecNum><record><rec-number>1209</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1209</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yuen, M. F.</author><author>Lai, C. L.</author></authors></contributors><auth-address>Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. yuenmf@netvigator.com</auth-address><titles><title>Serological markers of liver cancer</title><secondary-title>Best Pract Res Clin Gastroenterol</secondary-title></titles><pages>91-9</pages><volume>19</volume><number>1</number><edition>2005/03/11</edition><keywords><keyword>Biological Markers/blood</keyword><keyword>Glypicans</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*diagnosis</keyword><keyword>Membrane Proteins/blood</keyword><keyword>Neoplasm Proteins/blood</keyword><keyword>Plant Lectins</keyword><keyword>Protein Precursors/blood</keyword><keyword>Prothrombin</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Serologic Tests</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2005</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1521-6918 (Print)&#xD;1521-6918 (Linking)</isbn><accession-num>15757806</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=15757806</url></related-urls></urls><electronic-resource-num>S1521-6918(04)00145-3 [pii]&#xD;10.1016/j.bpg.2004.10.003</electronic-resource-num><language>eng</language></record></Cite></EndNote>[52].
In the present study, DCP values of HCC group showed a highly significant increase upon comparison with the non malignant groups (I, III, and IV) (Table 3). The sensitivity of DCP was higher than AFP in detecting HCC patients (85% versus 65%), a result quite similar to previous report  ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2005</Year><RecNum>1230</RecNum><record><rec-number>1230</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1230</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, C. S.</author><author>Lin, C. L.</author><author>Lee, H. C.</author><author>Chen, K. Y.</author><author>Chiang, M. F.</author><author>Chen, H. S.</author><author>Lin, T. J.</author><author>Liao, L. Y.</author></authors></contributors><auth-address>Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, No. 10, Sec. 4, Ren-ai Road, Da-an District Taipei City 106, Taiwan, China.</auth-address><titles><title>Usefulness of serum des-gamma-carboxy prothrombin in detection of hepatocellular carcinoma</title><secondary-title>World J Gastroenterol</secondary-title></titles><pages>6115-9</pages><volume>11</volume><number>39</number><edition>2005/11/08</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Biological Markers/*blood</keyword><keyword>Carcinoma, Hepatocellular/*blood/*diagnosis</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*blood/*diagnosis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Protein Precursors/*blood</keyword><keyword>Prothrombin</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Tumor Markers, Biological/blood</keyword></keywords><dates><year>2005</year><pub-dates><date>Oct 21</date></pub-dates></dates><isbn>1007-9327 (Print)&#xD;1007-9327 (Linking)</isbn><accession-num>16273636</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16273636</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[32]. Some studies reported that the unsatisfactory performance of AFP in the diagnosis of HCC, was due to the high false positive and false negative results  ADDIN EN.CITE <EndNote><Cite><Author>Bruix</Author><Year>2001</Year><RecNum>1226</RecNum><record><rec-number>1226</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1226</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bruix, J.</author><author>Sherman, M.</author><author>Llovet, J. M.</author><author>Beaugrand, M.</author><author>Lencioni, R.</author><author>Burroughs, A. K.</author><author>Christensen, E.</author><author>Pagliaro, L.</author><author>Colombo, M.</author><author>Rodes, J.</author></authors></contributors><auth-address>Liver Unit, Digestive Disease Institute, Hospital Clinic, IDIBAPS, Barcelona, Catalonia, Spain. jbruix@clinic.ub.es</auth-address><titles><title>Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver</title><secondary-title>J Hepatol</secondary-title></titles><pages>421-30</pages><volume>35</volume><number>3</number><edition>2001/10/11</edition><keywords><keyword>Carcinoma, Hepatocellular/epidemiology/etiology/*therapy</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Liver Neoplasms/epidemiology/etiology/*therapy</keyword><keyword>Prognosis</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2001</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0168-8278 (Print)&#xD;0168-8278 (Linking)</isbn><accession-num>11592607</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11592607</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[23].On the other hand, our results showed specificity of DCP lower than that of AFP (72.5% versus 97.5%),  comparable to elsewhere statement  ADDIN EN.CITE  ADDIN EN.CITE.DATA [54]. 
In our data, the increase in sensitivity of DCP and AFP (Table 4) in detecting HCC was found by the simultaneous use of the two markers. Similar results was reported  ADDIN EN.CITE  ADDIN EN.CITE.DATA [13, 55-60], suggesting that DCP and AFP together could be useful for the evaluation of tumor progression, prediction of patient outcome and treatment efficacy. Fujiyama ADDIN EN.CITE <EndNote><Cite><Author>Fujiyama</Author><Year>2002</Year><RecNum>1304</RecNum><record><rec-number>1304</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1304</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fujiyama, S.</author><author>Tanaka, M.</author><author>Maeda, S.</author><author>Ashihara, H.</author><author>Hirata, R.</author><author>Tomita, K.</author></authors></contributors><auth-address>Third Department of Internal Medicine, Kumamoto University School of Medicine, Japan.</auth-address><titles><title>Tumor markers in early diagnosis, follow-up and management of patients with hepatocellular carcinoma</title><secondary-title>Oncology</secondary-title></titles><pages>57-63</pages><volume>62 Suppl 1</volume><edition>2002/03/01</edition><keywords><keyword>Animals</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/*diagnosis/metabolism/therapy</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*diagnosis/metabolism/therapy</keyword><keyword>Protein Precursors/analysis</keyword><keyword>Prothrombin/analysis</keyword><keyword>Tumor Markers, Biological/*analysis</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2002</year></dates><isbn>0030-2414 (Print)&#xD;0030-2414 (Linking)</isbn><accession-num>11868787</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11868787</url></related-urls></urls><electronic-resource-num>ocl2a057 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>[61] concluded that since DCP in serum has half life of about 40-70 hours, it can reflect the therapeutic efficacy on HCC much more promptly than AFP which has a half  life of 5-7 days, and the mutual use of both may raise diagnostic performance. We found little correlation between DCP and AFP in HCC patients. This finding was similar to previous studies  ADDIN EN.CITE  ADDIN EN.CITE.DATA [13, 56, 61-63] which showed that no correlation exists between DCP and AFP and the combined measurement of these two markers appears to be useful in the diagnosis of hepatocellular carcinoma. Yoshida[ ADDIN EN.CITE <EndNote><Cite><Author>Yoshida</Author><Year>2002</Year><RecNum>1270</RecNum><record><rec-number>1270</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1270</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yoshida, S.</author><author>Kurokohchi, K.</author><author>Arima, K.</author><author>Masaki, T.</author><author>Hosomi, N.</author><author>Funaki, T.</author><author>Murota, M.</author><author>Kita, Y.</author><author>Watanabe, S.</author><author>Kuriyama, S.</author></authors></contributors><auth-address>Third Department of Internal Medicine, Kagawa Medical University, Kagawa 761-0793, Japan.</auth-address><titles><title>Clinical significance of lens culinaris agglutinin-reactive fraction of serum alpha-fetoprotein in patients with hepatocellular carcinoma</title><secondary-title>Int J Oncol</secondary-title></titles><pages>305-9</pages><volume>20</volume><number>2</number><edition>2002/01/15</edition><keywords><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/diagnosis/*metabolism/*pathology</keyword><keyword>Humans</keyword><keyword>Lectins/*metabolism</keyword><keyword>*Plant Lectins</keyword><keyword>Protein Precursors/blood/metabolism</keyword><keyword>Prothrombin/metabolism</keyword><keyword>Radioimmunoassay</keyword><keyword>Tumor Markers, Biological/blood/*metabolism</keyword><keyword>alpha-Fetoproteins/*metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1019-6439 (Print)&#xD;1019-6439 (Linking)</isbn><accession-num>11788893</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11788893</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[64]] concluded that AFP and DCP may reflect the different biological characteristics of HCC and the combination of both markers may be necessary for evaluating the clinical states of HCC. 
Conclusively, the simultaneous determination of both markers improved the sensitivity and is more effective in the diagnosis of HCC, in our study among HCC Egyptian patients. Although the specificity of AFP seems higher than that of DCP, the higher sensitivity of the latter makes it more efficient in HCC management and prediction among HCV carriers as sensitivity issue is greatly looked for in cases already under risk and other cost effective imaging modalities easily augment sensitivity destination.
Conflict of interest
All authors have none to declare.
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10.1111/j.1572-0241.2000.01978.x.
64.	Yoshida S, Kurokohchi K, Arima K, Masaki T, Hosomi N, Funaki T, Murota M, Kita Y, Watanabe S & Kuriyama S (2002) Clinical significance of lens culinaris agglutinin-reactive fraction of serum alpha-fetoprotein in patients with hepatocellular carcinoma. Int J Oncol 20, 305-309. 

Table 1: Age and sex variations in the selected groups of patients and the control (Mean � S.E, N=20) 
Group I
(Control)Group II 
(HCC)Group III ( Non 
treated HCV patients)Group IV(Treated HCV patients)Age (years)49�355�245.2�1.446.5�1.3SexFemale%20351010Male%80659090
Table 2: Liver function tests of all groups of patients and the control (Mean � S.E, N=20): 
Group I
(Control)Group II
 (HCC)Group III ( Non 
treated HCV
 patients)Group IV
(Treated 
HCV patients)ALT (U/L)27.0�2.170.2�14.0**92.3�17.0***70.0�13.3**AST (U/L)22.0�1.099.0�15.6***81.2�11.4***59.8�9.4**Albumin (g/dl)4.0�0.11.40�0.9***4.0�0.23.4�0.10**Total bilirubin (mg/dl)0.5�0.041.9�0.24*** 1.2�0.3**1.04�0.08*Direct bilirubin(mg/dl)0.15�0.010.95�0.15***0.50�0.1**0.36�0.03*PT( Seconds)11.6�0.0514.81�0.6***14.40�0.3***14.3�0.33***PC92.3�0.7671.8�3.9***69.6�2.1***83.2�3.3*
All groups are compared to control.  NS: P>0.05, * P<0.05, ** P<0.01, *** P<0.001.





Table 3: Alpha fetoprotein and des-gamma carboxy prothrombin blood levels in groups of patients against control group (Mean � S.E, N=20):
Group I
(Control)Group II
(HCC)Group III (Non 
treated HCV patients)Group IV( Treated HCV patients)Serum AFP 
(ng/ml)32.25�3.6 924.7�92.2*** 629.9�69.5***
321.8�27.4***Plasma DCP  (ng/ml) 1.21�0.08
216.3�49.6***
175.3�32.6***
118.8�26.5***All groups are compared to control.  *** P<0.001.

Table 4: DCP and AFP sensitivity and specificity in HCC versus nonmalignant groups (III and IV):

Specificity %Sensitivity %Cut-off (ng/ml)72.585DCP <12 97.565AFP <121 











 PAGE   \* MERGEFORMAT 18




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$��gd*<�$�Gd�A$]�Ga$gd*<�.:pv?�|. ��A!�"�#��$��%��������D<EndNote><Cite><Author>Saffroy</Author><Year>2004</Year><RecNum>1166</RecNum><record><rec-number>1166</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1166</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saffroy, R.</author><author>Pham, P.</author><author>Lemoine, A.</author><author>Debuire, B.</author></authors></contributors><auth-address>Laboratoire de biochimie-biologie moleculaire, Hopital Paul Brousse, Villejuif. raphael.saffroy@pbr.ap-hop-paris.fr</auth-address><titles><title>[Molecular biology and hepatocellular carcinoma: current status and future prospects]</title><secondary-title>Ann Biol Clin (Paris)</secondary-title></titles><pages>649-56</pages><volume>62</volume><number>6</number><edition>2004/11/26</edition><keywords><keyword>Carcinoma, Hepatocellular/*genetics</keyword><keyword>DNA, Neoplasm/analysis</keyword><keyword>Genetic Markers/genetics</keyword><keyword>Genome, Human</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*genetics</keyword><keyword>Molecular Biology</keyword><keyword>Tumor Markers, Biological/analysis</keyword></keywords><dates><year>2004</year><pub-dates><date>Nov-Dec</date></pub-dates></dates><orig-pub>Biologie moleculaire et carcinome hepatocellulaire: donnees actuelles et developpements futurs. Prix international de la SFBC 2003.</orig-pub><isbn>0003-3898 (Print)&#xD;0003-3898 (Linking)</isbn><accession-num>15563423</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=15563423</url></related-urls></urls><language>fre</language></record></Cite><Cite><Author>Abou-Alfa</Author><Year>2006</Year><RecNum>1145</RecNum><record><rec-number>1145</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1145</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abou-Alfa, G. K.</author></authors></contributors><auth-address>Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. abou-alg@mskcc.org</auth-address><titles><title>Hepatocellular carcinoma: molecular biology and therapy</title><secondary-title>Semin Oncol</secondary-title></titles><pages>S79-83</pages><volume>33</volume><number>6 Suppl 11</number><edition>2006/12/21</edition><keywords><keyword>Carcinoma, Hepatocellular/*genetics/*therapy</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*genetics/*therapy</keyword><keyword>Molecular Biology</keyword></keywords><dates><year>2006</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0093-7754 (Print)&#xD;0093-7754 (Linking)</isbn><accession-num>17178294</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17178294</url></related-urls></urls><electronic-resource-num>S0093-7754(06)00392-7 [pii]&#xD;10.1053/j.seminoncol.2006.10.015</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Parkin</Author><Year>2006</Year><RecNum>1170</RecNum><record><rec-number>1170</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1170</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parkin, D. M.</author></authors></contributors><auth-address>Clinical Trials Service Unit and Epidemiological Studies Unit, University of Oxford, Headington, UK. max.parkin@ctsu.ox.ac.uk</auth-address><titles><title>The global health burden of infection-associated cancers in the year 2002</title><secondary-title>Int J Cancer</secondary-title></titles><pages>3030-44</pages><volume>118</volume><number>12</number><edition>2006/01/13</edition><keywords><keyword>AIDS-Related Opportunistic Infections/epidemiology</keyword><keyword>Africa/epidemiology</keyword><keyword>Americas/epidemiology</keyword><keyword>Animals</keyword><keyword>Asia/epidemiology</keyword><keyword>Cholangiocarcinoma/epidemiology/parasitology</keyword><keyword>Developed Countries/*statistics &amp; numerical data</keyword><keyword>Developing Countries/*statistics &amp; numerical data</keyword><keyword>Epstein-Barr Virus Infections/complications</keyword><keyword>Helicobacter Infections/complications</keyword><keyword>Helicobacter pylori</keyword><keyword>Hepatitis B/complications/epidemiology</keyword><keyword>Hepatitis C/complications/epidemiology</keyword><keyword>Humans</keyword><keyword>Infection/*complications/*epidemiology/microbiology/parasitology/virology</keyword><keyword>Lymphoma/epidemiology/virology</keyword><keyword>Neoplasms/*epidemiology/microbiology/parasitology/virology</keyword><keyword>Opisthorchiasis/complications</keyword><keyword>Opisthorchis</keyword><keyword>Papillomaviridae</keyword><keyword>Papillomavirus Infections/complications</keyword><keyword>Prevalence</keyword><keyword>Sarcoma, Kaposi/epidemiology</keyword><keyword>Schistosoma haematobium</keyword><keyword>Schistosomiasis/complications</keyword><keyword>Stomach Neoplasms/epidemiology/microbiology</keyword><keyword>Tumor Virus Infections/complications</keyword><keyword>*World Health</keyword></keywords><dates><year>2006</year><pub-dates><date>Jun 15</date></pub-dates></dates><isbn>0020-7136 (Print)&#xD;0020-7136 (Linking)</isbn><accession-num>16404738</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16404738</url></related-urls></urls><electronic-resource-num>10.1002/ijc.21731</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Mizokami</Author><Year>2005</Year><RecNum>1171</RecNum><record><rec-number>1171</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1171</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mizokami, M.</author><author>Tanaka, Y.</author></authors></contributors><auth-address>Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. mizokami@med.nagoya-cu.ac.jp</auth-address><titles><title>Tracing the evolution of hepatitis C virus in the United States, Japan, and Egypt by using the molecular clock</title><secondary-title>Clin Gastroenterol Hepatol</secondary-title></titles><pages>S82-5</pages><volume>3</volume><number>10 Suppl 2</number><edition>2005/10/20</edition><keywords><keyword>Antimony/administration &amp; 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carcinoma.</title><secondary-title>IJIB</secondary-title></titles><periodical><full-title>IJIB</full-title></periodical><pages>196-2001.</pages><volume>3</volume><number>3</number><dates><year>2008</year></dates><urls></urls></record></Cite><Cite><Author>Zhou</Author><Year>2006</Year><RecNum>1165</RecNum><record><rec-number>1165</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1165</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhou, L.</author><author>Liu, J.</author><author>Luo, F.</author></authors></contributors><auth-address>Division of Biotherapy for Cancer, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang, Chengdu 610041, Sichuan Province, China.</auth-address><titles><title>Serum tumor markers for detection of hepatocellular carcinoma</title><secondary-title>World J 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Cirrhosis/*complications</keyword><keyword>Liver Neoplasms/diagnosis/*ethnology/virology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Retrospective Studies</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Tumor Markers, Biological/blood</keyword><keyword>alpha-Fetoproteins/*metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0270-9139 (Print)&#xD;0270-9139 (Linking)</isbn><accession-num>12143050</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=12143050</url></related-urls></urls><electronic-resource-num>S0270913902000472 [pii]&#xD;10.1053/jhep.2002.34744</electronic-resource-num><language>eng</language></record></Cite></EndNote>D<EndNote><Cite><Author>Cui</Author><Year>2002</Year><RecNum>1386</RecNum><record><rec-number>1386</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1386</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cui, R.</author><author>Wang, B.</author><author>Ding, H.</author><author>Shen, H.</author><author>Li, Y.</author><author>Chen, X.</author></authors></contributors><auth-address>Liver Research Center, Beijing Friendship Hospital, Capital University of Medical Sciences, Beijing 100050, China. cuirutao@sina.com</auth-address><titles><title>Usefulness of determining a protein induced by vitamin K absence in detection of hepatocellular carcinoma</title><secondary-title>Chin Med J (Engl)</secondary-title></titles><pages>42-5</pages><volume>115</volume><number>1</number><edition>2002/04/05</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/blood/*diagnosis/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/blood</keyword><keyword>Liver Neoplasms/blood/*diagnosis/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Protein Precursors/*blood</keyword><keyword>Prothrombin</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2002</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0366-6999 (Print)&#xD;0366-6999 (Linking)</isbn><accession-num>11930656</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11930656</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Shimizu</Author><Year>2002</Year><RecNum>1387</RecNum><record><rec-number>1387</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1387</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shimizu, A.</author><author>Shiraki, K.</author><author>Ito, T.</author><author>Sugimoto, K.</author><author>Sakai, T.</author><author>Ohmori, S.</author><author>Murata, K.</author><author>Takase, K.</author><author>Tameda, Y.</author><author>Nakano, T.</author></authors></contributors><auth-address>First Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie 514-8597, Japan.</auth-address><titles><title>Sequential fluctuation pattern of serum des-gamma-carboxy prothrombin levels detected by high-sensitive electrochemiluminescence system as an early predictive marker for hepatocellular carcinoma in patients with cirrhosis</title><secondary-title>Int J Mol Med</secondary-title></titles><pages>245-50</pages><volume>9</volume><number>3</number><edition>2002/02/12</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/*blood/diagnosis/etiology</keyword><keyword>Chemiluminescent Measurements</keyword><keyword>Electrochemistry</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/*blood/complications</keyword><keyword>Liver Neoplasms/*blood/diagnosis/etiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Protein Precursors/*blood/chemistry</keyword><keyword>Prothrombin/chemistry</keyword><keyword>Sensitivity and Specificity</keyword><keyword>*Tumor Markers, Biological</keyword><keyword>alpha-Fetoproteins/metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1107-3756 (Print)&#xD;1107-3756 (Linking)</isbn><accession-num>11836630</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11836630</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Okuda</Author><Year>2000</Year><RecNum>1388</RecNum><record><rec-number>1388</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1388</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Okuda, H.</author><author>Nakanishi, T.</author><author>Takatsu, K.</author><author>Saito, A.</author><author>Hayashi, N.</author><author>Takasaki, K.</author><author>Takenami, K.</author><author>Yamamoto, M.</author><author>Nakano, M.</author></authors></contributors><auth-address>Institute of Gastroenterology, Tokyo Women&apos;s Medical University, Tokyo, Japan.</auth-address><titles><title>Serum levels of des-gamma-carboxy prothrombin measured using the revised enzyme immunoassay kit with increased sensitivity in relation to clinicopathologic features of solitary hepatocellular carcinoma</title><secondary-title>Cancer</secondary-title></titles><pages>544-9</pages><volume>88</volume><number>3</number><edition>2000/01/29</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/blood/*diagnosis/pathology</keyword><keyword>Female</keyword><keyword>Hepatectomy</keyword><keyword>Humans</keyword><keyword>Immunoenzyme Techniques/instrumentation/*methods</keyword><keyword>Liver Neoplasms/blood/*diagnosis/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Protein Precursors/*blood/*metabolism</keyword><keyword>Prothrombin/*metabolism</keyword><keyword>*Reagent Kits, Diagnostic</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2000</year><pub-dates><date>Feb 1</date></pub-dates></dates><isbn>0008-543X (Print)&#xD;0008-543X (Linking)</isbn><accession-num>10649245</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=10649245</url></related-urls></urls><electronic-resource-num>10.1002/(SICI)1097-0142(20000201)88:3&lt;544::AID-CNCR8&gt;3.0.CO;2-F [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>D<EndNote><Cite><Author>Cui</Author><Year>2002</Year><RecNum>1386</RecNum><record><rec-number>1386</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1386</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cui, R.</author><author>Wang, B.</author><author>Ding, H.</author><author>Shen, H.</author><author>Li, Y.</author><author>Chen, X.</author></authors></contributors><auth-address>Liver Research Center, Beijing Friendship Hospital, Capital University of Medical Sciences, Beijing 100050, China. cuirutao@sina.com</auth-address><titles><title>Usefulness of determining a protein induced by vitamin K absence in detection of hepatocellular carcinoma</title><secondary-title>Chin Med J (Engl)</secondary-title></titles><pages>42-5</pages><volume>115</volume><number>1</number><edition>2002/04/05</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/blood/*diagnosis/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/blood</keyword><keyword>Liver Neoplasms/blood/*diagnosis/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Protein Precursors/*blood</keyword><keyword>Prothrombin</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2002</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0366-6999 (Print)&#xD;0366-6999 (Linking)</isbn><accession-num>11930656</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11930656</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Shimizu</Author><Year>2002</Year><RecNum>1387</RecNum><record><rec-number>1387</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1387</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shimizu, A.</author><author>Shiraki, K.</author><author>Ito, T.</author><author>Sugimoto, K.</author><author>Sakai, T.</author><author>Ohmori, S.</author><author>Murata, K.</author><author>Takase, K.</author><author>Tameda, Y.</author><author>Nakano, T.</author></authors></contributors><auth-address>First Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie 514-8597, Japan.</auth-address><titles><title>Sequential fluctuation pattern of serum des-gamma-carboxy prothrombin levels detected by high-sensitive electrochemiluminescence system as an early predictive marker for hepatocellular carcinoma in patients with cirrhosis</title><secondary-title>Int J Mol Med</secondary-title></titles><pages>245-50</pages><volume>9</volume><number>3</number><edition>2002/02/12</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/*blood/diagnosis/etiology</keyword><keyword>Chemiluminescent Measurements</keyword><keyword>Electrochemistry</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/*blood/complications</keyword><keyword>Liver Neoplasms/*blood/diagnosis/etiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Protein Precursors/*blood/chemistry</keyword><keyword>Prothrombin/chemistry</keyword><keyword>Sensitivity and Specificity</keyword><keyword>*Tumor Markers, Biological</keyword><keyword>alpha-Fetoproteins/metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1107-3756 (Print)&#xD;1107-3756 (Linking)</isbn><accession-num>11836630</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11836630</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Okuda</Author><Year>2000</Year><RecNum>1388</RecNum><record><rec-number>1388</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1388</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Okuda, H.</author><author>Nakanishi, T.</author><author>Takatsu, K.</author><author>Saito, A.</author><author>Hayashi, N.</author><author>Takasaki, K.</author><author>Takenami, K.</author><author>Yamamoto, M.</author><author>Nakano, M.</author></authors></contributors><auth-address>Institute of Gastroenterology, Tokyo Women&apos;s Medical University, Tokyo, Japan.</auth-address><titles><title>Serum levels of des-gamma-carboxy prothrombin measured using the revised enzyme immunoassay kit with increased sensitivity in relation to clinicopathologic features of solitary hepatocellular carcinoma</title><secondary-title>Cancer</secondary-title></titles><pages>544-9</pages><volume>88</volume><number>3</number><edition>2000/01/29</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/blood/*diagnosis/pathology</keyword><keyword>Female</keyword><keyword>Hepatectomy</keyword><keyword>Humans</keyword><keyword>Immunoenzyme Techniques/instrumentation/*methods</keyword><keyword>Liver 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purification</keyword></keywords><dates><year>1986</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0009-9147 (Print)&#xD;0009-9147 (Linking)</isbn><accession-num>2430738</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=2430738</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Abelev</Author><Year>1974</Year><RecNum>1390</RecNum><record><rec-number>1390</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1390</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abelev, G.I.</author></authors></contributors><titles><title>Alpha-fetoprotein as a marker of embryo-specific differentiation in normal and human 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H.</author><author>Sauerbruch, T.</author><author>Caselmann, W. 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Y.</author></authors></contributors><auth-address>Department of Gastrointestinal Oncology and Digestive Diseases, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. mhassan@mdanderson.org</auth-address><titles><title>The role of hepatitis C in hepatocellular carcinoma: a case control study among Egyptian patients</title><secondary-title>J Clin Gastroenterol</secondary-title></titles><pages>123-6</pages><volume>33</volume><number>2</number><edition>2001/07/27</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antibodies, Helminth/blood</keyword><keyword>Carcinoma, Hepatocellular/diagnosis/immunology/*virology</keyword><keyword>Case-Control Studies</keyword><keyword>Comorbidity</keyword><keyword>Egypt</keyword><keyword>Female</keyword><keyword>Hepatitis B Surface Antigens/blood</keyword><keyword>Hepatitis B, Chronic/diagnosis/immunology</keyword><keyword>Hepatitis C Antibodies/blood</keyword><keyword>Hepatitis C, Chronic/*diagnosis/immunology</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/diagnosis/immunology/*virology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Risk Factors</keyword><keyword>Schistosomiasis mansoni/diagnosis/immunology</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0192-0790 (Print)&#xD;0192-0790 (Linking)</isbn><accession-num>11468438</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11468438</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Montalto</Author><Year>2002</Year><RecNum>1280</RecNum><record><rec-number>1280</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1280</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Montalto, G.</author><author>Cervello, M.</author><author>Giannitrapani, L.</author><author>Dantona, F.</author><author>Terranova, A.</author><author>Castagnetta, L. 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M.</author><author>Zaghloul, A. S.</author><author>El-Serag, H. B.</author><author>Soliman, O.</author><author>Patt, Y. Z.</author><author>Chappell, C. L.</author><author>Beasley, R. P.</author><author>Hwang, L. Y.</author></authors></contributors><auth-address>Department of Gastrointestinal Oncology and Digestive Diseases, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. mhassan@mdanderson.org</auth-address><titles><title>The role of hepatitis C in hepatocellular carcinoma: a case control study among Egyptian patients</title><secondary-title>J Clin Gastroenterol</secondary-title></titles><pages>123-6</pages><volume>33</volume><number>2</number><edition>2001/07/27</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antibodies, Helminth/blood</keyword><keyword>Carcinoma, Hepatocellular/diagnosis/immunology/*virology</keyword><keyword>Case-Control Studies</keyword><keyword>Comorbidity</keyword><keyword>Egypt</keyword><keyword>Female</keyword><keyword>Hepatitis B Surface Antigens/blood</keyword><keyword>Hepatitis B, Chronic/diagnosis/immunology</keyword><keyword>Hepatitis C Antibodies/blood</keyword><keyword>Hepatitis C, Chronic/*diagnosis/immunology</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/diagnosis/immunology/*virology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Risk Factors</keyword><keyword>Schistosomiasis mansoni/diagnosis/immunology</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0192-0790 (Print)&#xD;0192-0790 (Linking)</isbn><accession-num>11468438</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11468438</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Montalto</Author><Year>2002</Year><RecNum>1280</RecNum><record><rec-number>1280</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1280</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Montalto, G.</author><author>Cervello, M.</author><author>Giannitrapani, L.</author><author>Dantona, F.</author><author>Terranova, A.</author><author>Castagnetta, L. A.</author></authors></contributors><auth-address>Institute of Internal Medicine, Institute of Development Biology, CNR, University of Palermo, Palermo, Italy. gmontal@unipa.it</auth-address><titles><title>Epidemiology, risk factors, and natural history of hepatocellular carcinoma</title><secondary-title>Ann N Y Acad Sci</secondary-title></titles><pages>13-20</pages><volume>963</volume><edition>2002/07/04</edition><keywords><keyword>Aflatoxin B1/toxicity</keyword><keyword>Alcohols/adverse effects</keyword><keyword>Carcinoma, Hepatocellular/*epidemiology/etiology/prevention &amp;</keyword><keyword>control/virology</keyword><keyword>Hepacivirus/physiology</keyword><keyword>Hepatitis B/*complications/immunology/prevention &amp; control</keyword><keyword>Hepatitis B virus/physiology</keyword><keyword>Hepatitis C/*complications/immunology/prevention &amp; control</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*epidemiology/etiology/prevention &amp; control/virology</keyword><keyword>Risk Factors</keyword><keyword>Viral Hepatitis Vaccines/therapeutic use</keyword></keywords><dates><year>2002</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0077-8923 (Print)&#xD;0077-8923 (Linking)</isbn><accession-num>12095924</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=12095924</url></related-urls></urls><language>eng</language></record></Cite></EndNote>�D<EndNote><Cite><Author>Tsukuma</Author><Year>1993</Year><RecNum>1262</RecNum><record><rec-number>1262</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1262</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tsukuma, H.</author><author>Hiyama, T.</author><author>Tanaka, S.</author><author>Nakao, M.</author><author>Yabuuchi, T.</author><author>Kitamura, T.</author><author>Nakanishi, K.</author><author>Fujimoto, I.</author><author>Inoue, A.</author><author>Yamazaki, H.</author><author>et al.,</author></authors></contributors><auth-address>Department of Field Research, Center for Adult Diseases, Osaka, Japan.</auth-address><titles><title>Risk factors for hepatocellular carcinoma among patients with chronic liver disease</title><secondary-title>N Engl J Med</secondary-title></titles><pages>1797-801</pages><volume>328</volume><number>25</number><edition>1993/06/24</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Carcinoma, Hepatocellular/blood/diagnosis/*etiology</keyword><keyword>Chronic Disease</keyword><keyword>Confidence Intervals</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Hepatitis/*complications</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/*complications</keyword><keyword>Liver Neoplasms/blood/diagnosis/*etiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Proportional Hazards Models</keyword><keyword>Risk Factors</keyword><keyword>Tumor Markers, Biological/analysis</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>1993</year><pub-dates><date>Jun 24</date></pub-dates></dates><isbn>0028-4793 (Print)&#xD;0028-4793 (Linking)</isbn><accession-num>7684822</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=7684822</url></related-urls></urls><electronic-resource-num>10.1056/NEJM199306243282501</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Lopez</Author><Year>2005</Year><RecNum>1328</RecNum><record><rec-number>1328</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1328</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lopez, J. B.</author></authors></contributors><auth-address>Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia. jbhlopez@tm.net.my</auth-address><titles><title>Recent developments in the first detection of hepatocellular carcinoma</title><secondary-title>Clin Biochem Rev</secondary-title></titles><pages>65-79</pages><volume>26</volume><number>3</number><edition>2006/02/02</edition><dates><year>2005</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0159-8090 (Print)&#xD;0159-8090 (Linking)</isbn><accession-num>16450014</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16450014</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Enriquez</Author><Year>1994</Year><RecNum>1302</RecNum><record><rec-number>1302</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1302</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Enriquez, J.</author><author>Fuchs, K.</author><author>Martinez Cerezo, F. J.</author><author>Seminago, R.</author><author>Madoz, P.</author><author>Torras, J.</author><author>Roggendorf, M.</author></authors></contributors><auth-address>Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.</auth-address><titles><title>Demonstration of HCV-RNA and HBV-DNA in the serum of HBsAg negative patients with hepatocellular carcinoma</title><secondary-title>Eur J Epidemiol</secondary-title></titles><pages>189-94</pages><volume>10</volume><number>2</number><edition>1994/04/01</edition><keywords><keyword>Aged</keyword><keyword>Base Sequence</keyword><keyword>Carcinoma, Hepatocellular/*complications</keyword><keyword>Chronic Disease</keyword><keyword>DNA, Viral/*blood</keyword><keyword>Female</keyword><keyword>Hepacivirus/*genetics/physiology</keyword><keyword>Hepatitis B/*blood/*complications/epidemiology</keyword><keyword>Hepatitis B Surface Antigens/*blood</keyword><keyword>Hepatitis B virus/*genetics</keyword><keyword>Hepatitis C/*blood/*complications/epidemiology</keyword><keyword>Humans</keyword><keyword>Liver Diseases/*complications</keyword><keyword>Liver Neoplasms/*complications</keyword><keyword>Male</keyword><keyword>Molecular Sequence Data</keyword><keyword>Polymerase Chain Reaction</keyword><keyword>RNA, Viral/*blood</keyword><keyword>Virus Replication</keyword></keywords><dates><year>1994</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0393-2990 (Print)&#xD;0393-2990 (Linking)</isbn><accession-num>7813697</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=7813697</url></related-urls></urls><language>eng</language></record></Cite></EndNote>�D<EndNote><Cite><Author>Tsukuma</Author><Year>1993</Year><RecNum>1262</RecNum><record><rec-number>1262</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1262</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tsukuma, H.</author><author>Hiyama, T.</author><author>Tanaka, S.</author><author>Nakao, M.</author><author>Yabuuchi, T.</author><author>Kitamura, T.</author><author>Nakanishi, K.</author><author>Fujimoto, I.</author><author>Inoue, A.</author><author>Yamazaki, H.</author><author>et al.,</author></authors></contributors><auth-address>Department of Field Research, Center for Adult Diseases, Osaka, Japan.</auth-address><titles><title>Risk factors for hepatocellular carcinoma among patients with chronic liver disease</title><secondary-title>N Engl J Med</secondary-title></titles><pages>1797-801</pages><volume>328</volume><number>25</number><edition>1993/06/24</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Carcinoma, Hepatocellular/blood/diagnosis/*etiology</keyword><keyword>Chronic Disease</keyword><keyword>Confidence Intervals</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Hepatitis/*complications</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/*complications</keyword><keyword>Liver Neoplasms/blood/diagnosis/*etiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Proportional Hazards Models</keyword><keyword>Risk Factors</keyword><keyword>Tumor Markers, Biological/analysis</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>1993</year><pub-dates><date>Jun 24</date></pub-dates></dates><isbn>0028-4793 (Print)&#xD;0028-4793 (Linking)</isbn><accession-num>7684822</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=7684822</url></related-urls></urls><electronic-resource-num>10.1056/NEJM199306243282501</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Lopez</Author><Year>2005</Year><RecNum>1328</RecNum><record><rec-number>1328</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1328</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lopez, J. 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J.</author><author>Seminago, R.</author><author>Madoz, P.</author><author>Torras, J.</author><author>Roggendorf, M.</author></authors></contributors><auth-address>Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.</auth-address><titles><title>Demonstration of HCV-RNA and HBV-DNA in the serum of HBsAg negative patients with hepatocellular carcinoma</title><secondary-title>Eur J Epidemiol</secondary-title></titles><pages>189-94</pages><volume>10</volume><number>2</number><edition>1994/04/01</edition><keywords><keyword>Aged</keyword><keyword>Base Sequence</keyword><keyword>Carcinoma, Hepatocellular/*complications</keyword><keyword>Chronic Disease</keyword><keyword>DNA, Viral/*blood</keyword><keyword>Female</keyword><keyword>Hepacivirus/*genetics/physiology</keyword><keyword>Hepatitis B/*blood/*complications/epidemiology</keyword><keyword>Hepatitis B Surface Antigens/*blood</keyword><keyword>Hepatitis B virus/*genetics</keyword><keyword>Hepatitis C/*blood/*complications/epidemiology</keyword><keyword>Humans</keyword><keyword>Liver Diseases/*complications</keyword><keyword>Liver Neoplasms/*complications</keyword><keyword>Male</keyword><keyword>Molecular Sequence Data</keyword><keyword>Polymerase Chain Reaction</keyword><keyword>RNA, Viral/*blood</keyword><keyword>Virus Replication</keyword></keywords><dates><year>1994</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0393-2990 (Print)&#xD;0393-2990 (Linking)</isbn><accession-num>7813697</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=7813697</url></related-urls></urls><language>eng</language></record></Cite></EndNote>HD<EndNote><Cite><Author>Darwish</Author><Year>2001</Year><RecNum>1341</RecNum><record><rec-number>1341</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1341</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Darwish, M. 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M.</author></authors></contributors><auth-address>Department of Internal Medicine, St. Louis University School of Medicine, MO 63104, USA.</auth-address><titles><title>Hepatitis C and hepatocellular carcinoma</title><secondary-title>Hepatology</secondary-title></titles><pages>34S-38S</pages><volume>26</volume><number>3 Suppl 1</number><edition>1997/09/26</edition><keywords><keyword>*Carcinoma, Hepatocellular/prevention &amp; control/virology</keyword><keyword>Disease Progression</keyword><keyword>*Hepatitis C/physiopathology</keyword><keyword>Humans</keyword><keyword>*Liver Neoplasms/prevention &amp; control/virology</keyword><keyword>Mass Screening</keyword><keyword>Risk Factors</keyword></keywords><dates><year>1997</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0270-9139 (Print)&#xD;0270-9139 (Linking)</isbn><accession-num>9305661</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=9305661</url></related-urls></urls><electronic-resource-num>10.1002/hep.510260706</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Anthony</Author><Year>2001</Year><RecNum>1201</RecNum><record><rec-number>1201</rec-number><foreign-keys><key app='EN' db-id='0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2'>1201</key></foreign-keys><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Anthony, P. P.</author></authors></contributors><auth-address>Department of Histopathology, Royal Devon &amp; Exeter Healthcare NHS Trust, Wonford, Exeter EX2 5AD, UK.</auth-address><titles><title>Hepatocellular carcinoma: an overview</title><secondary-title>Histopathology</secondary-title></titles><pages>109-18</pages><volume>39</volume><number>2</number><edition>2001/08/09</edition><keywords><keyword>Animals</keyword><keyword>Carcinoma, Hepatocellular/metabolism/*pathology/virology</keyword><keyword>Hepacivirus/genetics</keyword><keyword>Hepatitis B/pathology/virology</keyword><keyword>Hepatitis B virus/genetics</keyword><keyword>Hepatitis C/pathology/virology</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Liver Neoplasms/metabolism/*pathology/virology</keyword><keyword>Tumor Markers, Biological/analysis</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0309-0167 (Print)&#xD;0309-0167 (Linking)</isbn><accession-num>11493326</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11493326</url></related-urls></urls><electronic-resource-num>his1188 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>�D<EndNote><Cite><Author>Saito</Author><Year>1990</Year><RecNum>1309</RecNum><record><rec-number>1309</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1309</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saito, I.</author><author>Miyamura, T.</author><author>Ohbayashi, A.</author><author>Harada, H.</author><author>Katayama, T.</author><author>Kikuchi, S.</author><author>Watanabe, Y.</author><author>Koi, S.</author><author>Onji, M.</author><author>Ohta, Y.</author><author>et al.,</author></authors></contributors><auth-address>Department of Enteroviruses, National Institute of Health, Tokyo, Japan.</auth-address><titles><title>Hepatitis C virus infection is associated with the development of hepatocellular carcinoma</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title></titles><pages>6547-9</pages><volume>87</volume><number>17</number><edition>1990/09/01</edition><keywords><keyword>Blood Transfusion</keyword><keyword>Carcinoma, Hepatocellular/*complications</keyword><keyword>Female</keyword><keyword>Hepatitis B/diagnosis</keyword><keyword>Hepatitis B Antibodies/analysis</keyword><keyword>Hepatitis B Surface Antigens/analysis</keyword><keyword>Hepatitis C/*complications/diagnosis</keyword><keyword>Hepatitis, Viral, Human/*complications</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*complications</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1990</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0027-8424 (Print)&#xD;0027-8424 (Linking)</isbn><accession-num>2168552</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=2168552</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Purcell</Author><Year>1997</Year><RecNum>1336</RecNum><record><rec-number>1336</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1336</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Purcell, R.</author></authors></contributors><auth-address>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0740, USA.</auth-address><titles><title>The hepatitis C virus: overview</title><secondary-title>Hepatology</secondary-title></titles><pages>11S-14S</pages><volume>26</volume><number>3 Suppl 1</number><edition>1997/09/26</edition><keywords><keyword>Animals</keyword><keyword>Disease Susceptibility</keyword><keyword>Epitopes</keyword><keyword>Genetic Variation</keyword><keyword>Genome, Viral</keyword><keyword>Hepacivirus/*genetics/immunology/*physiology</keyword><keyword>Humans</keyword><keyword>Virion/physiology</keyword></keywords><dates><year>1997</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0270-9139 (Print)&#xD;0270-9139 (Linking)</isbn><accession-num>9305657</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=9305657</url></related-urls></urls><electronic-resource-num>10.1002/hep.510260702</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Anthony</Author><Year>2001</Year><RecNum>1201</RecNum><record><rec-number>1201</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1201</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Anthony, P. P.</author></authors></contributors><auth-address>Department of Histopathology, Royal Devon &amp; Exeter Healthcare NHS Trust, Wonford, Exeter EX2 5AD, UK.</auth-address><titles><title>Hepatocellular carcinoma: an overview</title><secondary-title>Histopathology</secondary-title></titles><pages>109-18</pages><volume>39</volume><number>2</number><edition>2001/08/09</edition><keywords><keyword>Animals</keyword><keyword>Carcinoma, Hepatocellular/metabolism/*pathology/virology</keyword><keyword>Hepacivirus/genetics</keyword><keyword>Hepatitis B/pathology/virology</keyword><keyword>Hepatitis B virus/genetics</keyword><keyword>Hepatitis C/pathology/virology</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Liver Neoplasms/metabolism/*pathology/virology</keyword><keyword>Tumor Markers, Biological/analysis</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0309-0167 (Print)&#xD;0309-0167 (Linking)</isbn><accession-num>11493326</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11493326</url></related-urls></urls><electronic-resource-num>his1188 [pii]</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Rahman El-Zayadi</Author><Year>2001</Year><RecNum>1384</RecNum><record><rec-number>1384</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1384</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rahman El-Zayadi, A.</author><author>Abaza, H.</author><author>Shawky, S.</author><author>Mohamed, M. 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Precursors/*blood</keyword><keyword>Prothrombin</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2002</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0366-6999 (Print)&#xD;0366-6999 (Linking)</isbn><accession-num>11930656</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11930656</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Toyoda</Author><Year>2006</Year><RecNum>1260</RecNum><record><rec-number>1260</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1260</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Toyoda, H.</author><author>Kumada, T.</author><author>Kiriyama, S.</author><author>Sone, Y.</author><author>Tanikawa, M.</author><author>Hisanaga, Y.</author><author>Yamaguchi, 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I.</author><author>Kanke, F.</author><author>Wise, M.</author><author>Satomura, S.</author></authors></contributors><auth-address>Liver Cancer Center, Starzl Transplantation Institute, University of Pittsburgh Medical Center, E1552 BST, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA. carrbi@upmc.edu</auth-address><titles><title>Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States</title><secondary-title>Dig Dis Sci</secondary-title></titles><pages>776-82</pages><volume>52</volume><number>3</number><edition>2007/01/27</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Biological Markers/*blood</keyword><keyword>Carcinoma, Hepatocellular/*blood/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lens Plant/*immunology</keyword><keyword>Liver 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Studies</keyword><keyword>Hepacivirus/immunology</keyword><keyword>Hepatitis/blood</keyword><keyword>Hepatitis Antibodies/blood</keyword><keyword>Hepatitis B Surface Antigens/blood</keyword><keyword>Humans</keyword><keyword>Immunoenzyme Techniques</keyword><keyword>Liver Cirrhosis/blood</keyword><keyword>Liver Neoplasms/*blood/pathology/therapy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Protein Precursors</keyword><keyword>Prothrombin/*analogs &amp; derivatives/analysis</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>1994</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>0008-543X (Print)&#xD;0008-543X (Linking)</isbn><accession-num>7525036</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=7525036</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Sassa</Author><Year>1999</Year><RecNum>1255</RecNum><record><rec-number>1255</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1255</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sassa, T.</author><author>Kumada, T.</author><author>Nakano, S.</author><author>Uematsu, T.</author></authors></contributors><auth-address>Department of Pharmacology, Gifu University School of Medicine, Japan.</auth-address><titles><title>Clinical utility of simultaneous measurement of serum high-sensitivity des-gamma-carboxy prothrombin and Lens culinaris agglutinin A-reactive alpha-fetoprotein in patients with small hepatocellular 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M.</author></authors></contributors><auth-address>Second Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.</auth-address><titles><title>A simultaneous monitoring of Lens culinaris agglutinin A-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin as an early diagnosis of hepatocellular carcinoma in the follow-up of cirrhotic patients</title><secondary-title>Oncol Rep</secondary-title></titles><pages>249-56</pages><volume>7</volume><number>2</number><edition>2000/02/15</edition><keywords><keyword>Aged</keyword><keyword>Agglutinins</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/*diagnosis/etiology/*metabolism</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/complications/*metabolism</keyword><keyword>Liver Neoplasms/*diagnosis/etiology/*metabolism</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of 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Article">17</ref-type><contributors><authors><author>Ishii, M.</author><author>Gama, H.</author><author>Chida, N.</author><author>Ueno, Y.</author><author>Shinzawa, H.</author><author>Takagi, T.</author><author>Toyota, T.</author><author>Takahashi, T.</author><author>Kasukawa, R.</author></authors></contributors><auth-address>Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.</auth-address><titles><title>Simultaneous measurements of serum alpha-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma. South Tohoku District Study Group</title><secondary-title>Am J Gastroenterol</secondary-title></titles><pages>1036-40</pages><volume>95</volume><number>4</number><edition>2000/04/14</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/blood/*diagnosis</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Hepatitis B, Chronic/blood/diagnosis</keyword><keyword>Hepatitis C, Chronic/blood/diagnosis</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/blood/diagnosis</keyword><keyword>Liver Neoplasms/blood/*diagnosis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Prospective Studies</keyword><keyword>Protein Precursors/*metabolism</keyword><keyword>Prothrombin</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/*metabolism</keyword></keywords><dates><year>2000</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0002-9270 (Print)&#xD;0002-9270 (Linking)</isbn><accession-num>10763956</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=10763956</url></related-urls></urls><electronic-resource-num>S000292700000770X [pii]&#xD;10.1111/j.1572-0241.2000.01978.x</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Cui</Author><Year>2002</Year><RecNum>1363</RecNum><record><rec-number>1363</rec-number><foreign-keys><key app='EN' db-id='s0xwzw0atx009mef90o5sfpzafsw5vtdwzpr'>1363</key></foreign-keys><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Cui, R.</author><author>Wang, B.</author><author>Ding, H.</author><author>Shen, H.</author><author>Li, Y.</author><author>Chen, X.</author></authors></contributors><auth-address>Liver Research Center, Beijing Friendship Hospital, Capital University of Medical Sciences, Beijing 100050, China. cuirutao@sina.com</auth-address><titles><title>Usefulness of determining a protein induced by vitamin K absence in detection of hepatocellular carcinoma</title><secondary-title>Chin Med J (Engl)</secondary-title></titles><periodical><full-title>Chin Med J (Engl)</full-title></periodical><pages>42-5</pages><volume>115</volume><number>1</number><edition>2002/04/05</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/blood/*diagnosis/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/blood</keyword><keyword>Liver Neoplasms/blood/*diagnosis/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Protein Precursors/*blood</keyword><keyword>Prothrombin</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2002</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0366-6999 (Print)&#xD;0366-6999 (Linking)</isbn><accession-num>11930656</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11930656</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Fujiyama</Author><Year>2002</Year><RecNum>1304</RecNum><record><rec-number>1304</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1304</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fujiyama, S.</author><author>Tanaka, M.</author><author>Maeda, S.</author><author>Ashihara, H.</author><author>Hirata, R.</author><author>Tomita, K.</author></authors></contributors><auth-address>Third Department of Internal Medicine, Kumamoto University School of Medicine, Japan.</auth-address><titles><title>Tumor markers in early diagnosis, follow-up and management of patients with hepatocellular carcinoma</title><secondary-title>Oncology</secondary-title></titles><pages>57-63</pages><volume>62 Suppl 1</volume><edition>2002/03/01</edition><keywords><keyword>Animals</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/*diagnosis/metabolism/therapy</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*diagnosis/metabolism/therapy</keyword><keyword>Protein Precursors/analysis</keyword><keyword>Prothrombin/analysis</keyword><keyword>Tumor Markers, Biological/*analysis</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2002</year></dates><isbn>0030-2414 (Print)&#xD;0030-2414 (Linking)</isbn><accession-num>11868787</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11868787</url></related-urls></urls><electronic-resource-num>ocl2a057 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>.'D<EndNote><Cite><Author>Fujiyama</Author><Year>1986</Year><RecNum>1235</RecNum><record><rec-number>1235</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1235</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fujiyama, S.</author><author>Morishita, T.</author><author>Sagara, K.</author><author>Sato, T.</author><author>Motohara, K.</author><author>Matsuda, I.</author></authors></contributors><titles><title>Clinical evaluation of plasma abnormal prothrombin (PIVKA-II) in patients with hepatocellular carcinoma</title><secondary-title>Hepatogastroenterology</secondary-title></titles><pages>201-5</pages><volume>33</volume><number>5</number><edition>1986/10/01</edition><keywords><keyword>Adenoma, Bile Duct/blood</keyword><keyword>Antibodies, Monoclonal/diagnostic use</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/*blood/surgery</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Female</keyword><keyword>Hepatitis, Chronic/blood</keyword><keyword>Humans</keyword><keyword>Liver Diseases/blood</keyword><keyword>Liver Neoplasms/*blood/secondary/surgery</keyword><keyword>Male</keyword><keyword>*Protein Precursors</keyword><keyword>Prothrombin/*analogs &amp; derivatives/analysis</keyword><keyword>Vitamin K/administration &amp; dosage/pharmacology</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>1986</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0172-6390 (Print)&#xD;0172-6390 (Linking)</isbn><accession-num>2433199</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=2433199</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Saitoh</Author><Year>1994</Year><RecNum>1276</RecNum><record><rec-number>1276</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1276</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saitoh, S.</author><author>Ikeda, K.</author><author>Koida, I.</author><author>Tsubota, A.</author><author>Arase, Y.</author><author>Chayama, K.</author><author>Kumada, H.</author></authors></contributors><auth-address>Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan.</auth-address><titles><title>Serum des-gamma-carboxyprothrombin concentration determined by the avidin-biotin complex method in small hepatocellular carcinomas</title><secondary-title>Cancer</secondary-title></titles><pages>2918-23</pages><volume>74</volume><number>11</number><edition>1994/12/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/*blood/pathology/therapy</keyword><keyword>Case-Control Studies</keyword><keyword>Chronic Disease</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Hepacivirus/immunology</keyword><keyword>Hepatitis/blood</keyword><keyword>Hepatitis Antibodies/blood</keyword><keyword>Hepatitis B Surface Antigens/blood</keyword><keyword>Humans</keyword><keyword>Immunoenzyme Techniques</keyword><keyword>Liver Cirrhosis/blood</keyword><keyword>Liver Neoplasms/*blood/pathology/therapy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Protein Precursors</keyword><keyword>Prothrombin/*analogs &amp; derivatives/analysis</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>1994</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>0008-543X (Print)&#xD;0008-543X (Linking)</isbn><accession-num>7525036</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=7525036</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Ishii</Author><Year>2000</Year><RecNum>1242</RecNum><record><rec-number>1242</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1242</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ishii, M.</author><author>Gama, H.</author><author>Chida, N.</author><author>Ueno, Y.</author><author>Shinzawa, H.</author><author>Takagi, T.</author><author>Toyota, T.</author><author>Takahashi, T.</author><author>Kasukawa, R.</author></authors></contributors><auth-address>Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.</auth-address><titles><title>Simultaneous measurements of serum alpha-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma. South Tohoku District Study Group</title><secondary-title>Am J Gastroenterol</secondary-title></titles><pages>1036-40</pages><volume>95</volume><number>4</number><edition>2000/04/14</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/blood/*diagnosis</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Hepatitis B, Chronic/blood/diagnosis</keyword><keyword>Hepatitis C, Chronic/blood/diagnosis</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/blood/diagnosis</keyword><keyword>Liver Neoplasms/blood/*diagnosis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Prospective Studies</keyword><keyword>Protein Precursors/*metabolism</keyword><keyword>Prothrombin</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/*metabolism</keyword></keywords><dates><year>2000</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0002-9270 (Print)&#xD;0002-9270 (Linking)</isbn><accession-num>10763956</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=10763956</url></related-urls></urls><electronic-resource-num>S000292700000770X [pii]&#xD;10.1111/j.1572-0241.2000.01978.x</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Cui</Author><Year>2002</Year><RecNum>1363</RecNum><record><rec-number>1363</rec-number><foreign-keys><key app='EN' db-id='s0xwzw0atx009mef90o5sfpzafsw5vtdwzpr'>1363</key></foreign-keys><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Cui, R.</author><author>Wang, B.</author><author>Ding, H.</author><author>Shen, H.</author><author>Li, Y.</author><author>Chen, X.</author></authors></contributors><auth-address>Liver Research Center, Beijing Friendship Hospital, Capital University of Medical Sciences, Beijing 100050, China. cuirutao@sina.com</auth-address><titles><title>Usefulness of determining a protein induced by vitamin K absence in detection of hepatocellular carcinoma</title><secondary-title>Chin Med J (Engl)</secondary-title></titles><periodical><full-title>Chin Med J (Engl)</full-title></periodical><pages>42-5</pages><volume>115</volume><number>1</number><edition>2002/04/05</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/blood/*diagnosis/pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Liver Cirrhosis/blood</keyword><keyword>Liver Neoplasms/blood/*diagnosis/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Protein Precursors/*blood</keyword><keyword>Prothrombin</keyword><keyword>Tumor Markers, Biological/*blood</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2002</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0366-6999 (Print)&#xD;0366-6999 (Linking)</isbn><accession-num>11930656</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=11930656</url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Fujiyama</Author><Year>2002</Year><RecNum>1304</RecNum><record><rec-number>1304</rec-number><foreign-keys><key app="EN" db-id="0pfdtxtw0xx2e0e0225xxdxxt0fewfwap0f2">1304</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fujiyama, S.</author><author>Tanaka, M.</author><author>Maeda, S.</author><author>Ashihara, H.</author><author>Hirata, R.</author><author>Tomita, K.</author></authors></contributors><auth-address>Third Department of Internal Medicine, Kumamoto University School of Medicine, Japan.</auth-address><titles><title>Tumor markers in early diagnosis, follow-up and management of patients with hepatocellular carcinoma</title><secondary-title>Oncology</secondary-title></titles><pages>57-63</pages><volume>62 Suppl 1</volume><edition>2002/03/01</edition><keywords><keyword>Animals</keyword><keyword>*Biological Markers</keyword><keyword>Carcinoma, Hepatocellular/*diagnosis/metabolism/therapy</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms/*diagnosis/metabolism/therapy</keyword><keyword>Protein Precursors/analysis</keyword><keyword>Prothrombin/analysis</keyword><keyword>Tumor Markers, Biological/*analysis</keyword><keyword>alpha-Fetoproteins/analysis</keyword></keywords><dates><year>2002</year></dates><isbn>0030-2414 (Print)&#xD;0030-2414 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