• The day I learned how to be a doctor.

• Presence of filterable and nonfilterable mRNA in the plasma of cancer patients and healthy individuals.

• The promoting molecular mechanism of alpha-fetoprotein on the growth of human hepatoma Bel7402 cell line.

• The point mutation of p53 gene exon7 in hepatocellular carcinoma from Anhui Province, a non HCC prevalent area in China.

• [Regulation of p53 and bcl-2 proteins to apoptosis and cell proliferation in liver cirrhosis and hepatocellular carcinoma]

• Transforming growth factor-beta1 triggers hepatocellular carcinoma invasiveness via alpha3beta1 integrin.

• Zinc depletion reduced Egr-1 and HNF-3beta expression and apolipoprotein A-I promoter activity in Hep G2 cells.

• Impact of aging on the development of hepatocellular carcinoma in patients with posttransfusion chronic hepatitis C.

• Platelets promote the adhesion of human hepatoma cells with a highly metastatic potential to extracellular matrix protein: involvement of

• Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas.

• Optimal pulse sequence for ferumoxides-enhanced MR imaging used in the detection of hepatocellular carcinoma: a comparative study using seven

• [Plasma cell infiltration of the liver in multiple myeloma]

• Magnetic resonance of focal liver lesions in hepatic cirrhosis and chronic hepatitis.

• A distinct repertoire of autoantibodies in hepatocellular carcinoma identified by proteomic analysis.

• Impact of hepatitis C virus infection on the aetiology of cirrhosis and hepatocarcinoma in three affiliated hospitals in southern Belgium.

• Hepatitis C virus: the burden of the disease.

• Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.

• Is hepatocellular carcinoma part of the natural history of nonalcoholic steatohepatitis?

• Primary sclerosing cholangitis: a premalignant condition.

• Analysis of tumor characteristics and survival in liver transplant recipients with incidentally diagnosed hepatocellular carcinoma.

• Octreotide scans are positive in a subset of patients with hepatocellular carcinoma.

• Advances in liver disease. Highlights from the 51st Annual Meeting of the American Association for the Study of Liver Diseases, October 27-31,

• Multimodality diagnosis of liver tumors: feature analysis with CT, liver-specific and contrast-enhanced MR, and a computer model.

• Augmentation effect of postprandial hyperinsulinaemia on growth of human hepatocellular carcinoma.

• Prospective comparative study of spiral computer tomography and magnetic resonance imaging for detection of hepatocellular carcinoma.

• Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis.

• Underexpression of mRNA in human hepatocellular carcinoma focusing on eight loci.

• Large scale identification of human hepatocellular carcinoma-associated antigens by autoantibodies.

• Survival benefit of cirrhotic patients with hepatocellular carcinoma treated by percutaneous ethanol injection as a salvage therapy.

• Mutation of the DR5/TRAIL receptor 2 gene is infrequent in hepatocellular carcinoma.

• Viral load is a significant prognostic factor for hepatitis B virus-associated hepatocellular carcinoma.

• Hepatocyte antigen as a marker of hepatocellular carcinoma: an immunohistochemical comparison to carcinoembryonic antigen, CD10, and

• Combined hepatocellular-cholangiocarcinoma: a histopathologic, immunohistochemical, and in situ hybridization study.

1
UI - 11913176
AU - Greenberg B
TI - The day I learned how to be a doctor.
SO - Med Econ 2002 Mar 8;79(5):93-4, 97

2
UI - 12142376
AU - Ng EK; Tsui NB; Lam NY; Chiu RW; Yu SC; Wong SC; Lo ES; Rainer TH;
TI - Johnson PJ; Lo YM Presence of filterable and nonfilterable mRNA in the plasma of cancer patients and healthy individuals.
SO - Clin Chem 2002 Aug;48(8):1212-7
AD - Institute of Molecular Oncology and Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region.
BACKGROUND: As RNA is labile, we investigated whether circulating RNA in human plasma may be present in a particle-associated form. METHODS: Blood was collected from 27 healthy individuals and 16 hepatocellular carcinoma (HCC) patients. The plasma from each individual was processed by two means: filtration through filters with different pore sizes (from 5 microm to 0.22 microm) and ultracentrifugation. We assessed plasma RNA content by a real-time quantitative reverse transcription-PCR assay for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) transcripts and plasma DNA by a real-time quantitative PCR assay for the beta-globin gene. RESULTS: The plasma GAPDH mRNA concentrations in the healthy individuals were significantly different in every pair of these filter sizes (P <0.05 for each pair). Overall, the plasma GAPDH mRNA concentration was higher by a median of 15-fold (interquartile range, 10- to 24-fold) in the paired unfiltered sample than in the sample filtered through a 0.22 microm filter. In contrast, no significant difference was seen in beta-globin DNA concentrations among different pore-size-filtered plasma samples (P = 0.455). Similarly, a significant difference was observed for RNA, but not DNA, between unfiltered plasma and ultracentrifuged plasma (P <0.05). No significant difference in GAPDH mRNA concentrations was seen between the 0.22-microm-filtered plasma samples and the ultracentrifuged plasma samples (P >0.05). In HCC patients, filtration with a 0.22 microm filter produced a median 9.3-fold (interquartile range, 6.9- to 311-fold) reduction in GAPDH mRNA concentration in plasma. Plasma GAPDH mRNA concentrations in HCC patients were significantly higher than those in healthy individuals, both with or without filtration (P <0.0 5 for filtered plasma samples; P <0.005 for unfiltered plasma samples). CONCLUSIONS: A substantial proportion of plasma mRNA species is particle-associated. In HCC patients, both circulating particle- and non-particle-associated plasma RNA are increased.

3
UI - 12046072
AU - Li MS; Li PF; He SP; Du GG; Li G
TI - The promoting molecular mechanism of alpha-fetoprotein on the growth of human hepatoma Bel7402 cell line.
SO - World J Gastroenterol 2002 Jun;8(3):469-75
AD - Department of Biochemistry, Hainan Medical College, Hainan, China.
AIM: The goal of this study was to characterize the AFP receptor, its possible signal transduction pathway and its proliferative functions in human hepatoma cell line Bel 7402. METHODS: Cell proliferation enhanced by AFP was detected by MTT assay, 3H-thymidine incorporation and S-stage percentage of cell cycle analysis. With radioactive labeled 125I-AFP for receptor binding assay; cAMP accumulation, protein kinase A activity were detected by radioactive immunosorbent assay and the change of intracellular free calcium (Ca2+i) was monitored by scanning fluorescence intensity under TCS-NT confocal microscope. The expression of oncogenes N- ras, p 53, and p21( ras ) in the cultured cells in vitro were detected by Northern blotting and Western blotting respectively. RESULTS: It was demonstrated that AFP enhanced the proliferation of human hepatoma Bel 7402 cell in a dose dependent fashion as shown in MTT assay, (3)H-thymidine incorporation and S-phase percentage up to 2-fold. Two subtypes of AFP receptors were identified in the cells with Kds of 1.3 x 10(-9)mol.L(-1) and 9.9 x10(-8)mol. (-1)L respectively. Pretreatment of cells with AFP resulted in a significant increase (625%) in cAMP accumulation. The activity of protein kinase A activity were increased up to 37.5, 122.6, 73.7 and 61.2% at treatment time point 2, 6, 12 and 24 hours. The level of intracellular calcium were elevated after the treatment of alpha-fetoprotein and achieved to 204% at 4 min. The results also showed that AFP(20mg.L(-1)) could upregulate the expression of N- ras oncogenes and p 53 and p21( ras ) in Bel 7402 cells. In the later case,the alteration were 81.1%(12h) and 97.3%(12h) respectively compared with control. CONCLUSION: These results demonstrate that AFP is a potential growth factor to promote the proliferation of human hepatoma Bel 7402 cells. Its growth-regulatory effects are mediated by its specific plasma membrane receptors coupled with its transmembrane signaling transduction through the pathway of cAMP-PKA and intracellular calcium to regulate the expression of oncogenes.

4
UI - 12046074
AU - Liu H; Wang Y; Zhou Q; Gui SY; Li X
TI - The point mutation of p53 gene exon7 in hepatocellular carcinoma from Anhui Province, a non HCC prevalent area in China.
SO - World J Gastroenterol 2002 Jun;8(3):480-2
AD - Laboratory of Molecular Biology and Department of biochemistry, Anhui Medical University, Hefei 230032, Anhui Province, China.
AIM: In hepatocellular carcinoma (HCC) prevalent areas of China, the point mutation of p53 exon7 is highly correlated with Hepatitis B virus(HBV) infection and aflatoxin B intake. While in non-HCC-prevalent areas of China, these factors are not so important in the etiology of HCC. Therefore, the point mutation of p53 exon7 may also be different than that in HCC-prevalent areas of China. The aim of this study is to investigate the status and carcinogenic role of the point mutation of p53 gene exon7 in hepatocellular carcinoma from Anhui Province, a non-HCC-prevalent area in China. METHODS: PCR PCR-SSCP and PCR-RFLP were applied to analyze the homozygous deletion and point mutation of p53 exon7 in HCC samples from Anhui, which were confirmed by DNA sequencing and Genbank comparison. RESULTS: In the 38 samples of hepatocellular carcinoma, no homozygous deletion of p53 exon7 was detected and point mutations of p53 exon7 were found in 4 cases, which were found to be heterozygous mutation of codon 249 with a mutation rate of 10.53%(4/38). The third base mutation(G-T) of p53 codon 249 was found by DNA sequencing and Genbank comparison. CONCLUSION: The incidence of point mutation of p53 codon 249 is lower in hepatocellular carcinoma and the heterozygous mutation of p53 exon7 found in these patients only indicate that they have genetic susceptibility to HCC. p53 codon 249 is a hotspot of p53 exon7 point mutation, suggesting that the point mutation of p53 exon 7 may not play a major role in the carcinogenesis of HCC in Anhui Province, a non-HCC-prevalent area in China.

5
UI - 12080637
AU - Feng D; Zheng H; Shen M; Cheng R; Yan Y
TI - [Regulation of p53 and bcl-2 proteins to apoptosis and cell proliferation in liver cirrhosis and hepatocellular carcinoma]
SO - Hunan Yi Ke Da Xue Xue Bao 1999;24(4):325-8
AD - Department of Pathology, Hunan Medical University, Changsha 410078.
In situ apoptosis labelling was used for detecting apoptotic cells, and immunohistochemistry for p53, bcl-2 proteins and proliferation cell nuclear antigen(PCNA) in hepatocellular carcinoma(HCC) and liver cirrhosis tissues. The results were that in HCC, the number of apoptotic cells was higher, the density of proliferation cells lower, and expressions of p53 and bcl-2 protein were stronger than that in liver cirrhosis, and they were related to differentiation degree of HCC. The data indicate that overexpression of bcl-2 and mutant p53 proteins, which causes imbalance between cell proliferation and apoptosis, may bring about genesis and development of HCC by selecting proliferation of cells.

6
UI - 12107103
AU - Giannelli G; Fransvea E; Marinosci F; Bergamini C; Colucci S; Schiraldi
TI - O; Antonaci S Transforming growth factor-beta1 triggers hepatocellular carcinoma invasiveness via alpha3beta1 integrin.
SO - Am J Pathol 2002 Jul;161(1):183-93
AD - Department of Internal Medicine, Immunology, and Infectious Diseases, University of Bari Medical School, Bari, Italy. g.giannelli@intmed.uniba.it
Metastasis occurrence in the course of hepatocellular carcinoma (HCC) severely affects prognosis and survival. We have shown that HCC invasive cells express alpha3beta1-integrin whereas noninvasive cells do not. Here we show that transforming growth factor (TGF)-beta1 stimulates alpha3-integrin expression at a transcriptional level in noninvasive HCC cells, causing transformation into a motile and invasive phenotype. Such activities are inhibited by neutralizing anti-alpha3- but not anti-alpha6-integrin monoclonal antibodies. HCC invasive cells secrete abundant levels of active TGF-beta1 in comparison with noninvasive cells, but in the latter, addition of active matrix metalloproteinases-2 increases the concentration of active TGF-beta1. In this way, the cells express alpha3-integrin at a transcriptional level and acquire motility on Ln-5. By contrast, an anti-TGF-beta1-neutralizing antibody reduces alpha3-integrin expression and the invasive ability of HCC invading cells. In HCC patients, TGF-beta1 serum concentrations and alpha3-integrin expression are strongly correlated. The integrin, absent in normal and peritumoral liver parenchyma, is abundantly expressed in HCC primary and metastatic tissue. In particular, patients with metastasis show higher levels of TGF-beta1 serum concentrations and stronger expression of TGF-beta1 and alpha3-integrin in HCC tissues. In conclusion, TGF-beta1 may play an important role in HCC invasiveness by stimulating alpha3-integrin expression, and could therefore be an important target for new therapies.

7
UI - 12107072
AU - Cui L; Schoene NW; Zhu L; Fanzo JC; Alshatwi A; Lei KY
TI - Zinc depletion reduced Egr-1 and HNF-3beta expression and apolipoprotein A-I promoter activity in Hep G2 cells.
SO - Am J Physiol Cell Physiol 2002 Aug;283(2):C623-30
AD - Department of Nutrition and Food Science, University of Maryland, College Park 20742, USA.
We examined the influence of zinc status on expression of certain transcription factors involved in regulation of apolipoprotein A-I (apoAI) expression in human hepatoblastoma Hep G2 cells. A low zinc basal medium (zinc deficient, ZD) consisting of DMEM and 10% Chelex100-treated fetal bovine serum was used to deplete cellular zinc over one passage. Cells were also cultured for one passage in medium supplemented with 0.4 (ZD0.4), 4.0 (zinc normal, ZN), 16.0 (zinc adequate, ZA), or 32.0 microM zinc (zinc supplemented, ZS). Compared with ZN cells, cellular zinc levels were 43 and 31% lower in ZD and ZD0.4 cells but 70 and 146% higher in ZA and ZS cells, respectively. Supplementation of 0.4 microM zinc significantly increased DNA contents per plate, from 65% in ZD cells to 83% in ZD0.4 cells compared with ZN cells. Addition of >4 microM zinc in medium did not further increase DNA contents. The proportion of cells in G(1)/S and S phase was about fourfold higher and threefold lower, respectively, in ZD cells compared with ZN and other groups. Nuclear Egr-1 protein was markedly decreased in ZD and ZD0.4 cells. Moreover, hepatocyte nuclear factor (HNF)-3beta was severely degraded in ZD and ZD0.4 cells. In contrast, HNF-4alpha remained stable in all groups and was not significantly lower in ZD and ZD0.4 cells. Furthermore, downregulation of trans-acting factor Egr-1 and cleavage of HNF-3beta were associated with reduction of apoAI promoter activity in zinc-deficient Hep G2 cells. Thus zinc is critical in transcriptional regulation of apoAI gene expression in hepatocytes.

8
UI - 12124834
AU - Hamada H; Yatsuhashi H; Yano K; Daikoku M; Arisawa K; Inoue O; Koga M;
TI - Nakata K; Eguchi K; Yano M Impact of aging on the development of hepatocellular carcinoma in patients with posttransfusion chronic hepatitis C.
SO - Cancer 2002 Jul 15;95(2):331-9
AD - Institute for Clinical Research, World Health Organization Collaborating Center for Reference and Research on Viral Hepatitis, National Nagasaki Medical Center, Nagasaki, Japan.
BACKGROUND: Hepatitis C virus (HCV) infection is a heterogeneous disease, the natural history of which remains controversial. There is solid evidence that chronic HCV infection is responsible for the occurrence of hepatocellular carcinoma (HCC). The aim of the current cohort study was to determine the rate of the development of HCC from the time of primary HCV infection and to assess the risk factors for the development of HCC in chronic posttransfusion hepatitis C patients. METHODS: Four hundred sixty-nine patients with clinically compensated HCV, who had undergone a single blood transfusion comprised the current study cohort. Patients with other risk factors for chronic liver disease were excluded. All patients were referred to the liver center at the and were followed prospectively until the end of the analysis (June 2000). RESULTS: Follow-up data were obtained for 445 patients. The mean duration from HCV infection to the end of the observation was 28 years. Fifty-two patients (11.1%) progressed to HCC. The mean duration from the time of blood transfusion to the diagnosis of HCC was 31 years. Multivariate Cox regression analyses revealed age, fibrosis, duration from HCV infection to study entry, and alcohol consumption to be the independent factors affecting the development of HCC. The risk of developing HCC in patients age > or = 56 years was increased 7.8-fold compared with that in patients age < 56 years. The mean age of patients at the time of HCC diagnosis was 65 years (range, 58-79 years). CONCLUSIONS: At the time of diagnosis, 92% of the 52 HCC patients were age > 60 years and 38 of the HCC patients (73%) were in their 60s. There was a significantly negative correlation between the duration from HCV infection to the development of HCC and the age of the patient at the time of infection (correlation coefficient = 0.702; P < 0.0001; Y = 61.1-0.82X), indicating that the age of patients, rather than the duration of HCV infection, is more significant for HCC development in patients with posttransfusion HCV. Moreover, these data may contribute to the design of an optimal follow-up schedule for patients with posttransfusion HCV. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10662

9
UI - 12029445
AU - Yu Y; Zhou XD; Liu YK; Ren N; Chen J; Zhao Y
TI - Platelets promote the adhesion of human hepatoma cells with a highly metastatic potential to extracellular matrix protein: involvement of platelet P-selectin and GP IIb-IIIa.
SO - J Cancer Res Clin Oncol 2002 May;128(5):283-7
AD - Liver Cancer Institute, Zhong Shan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China. shiningyu@hotmail.com
PURPOSE: To investigate the role and possible mechanisms of platelets in liver cancer metastasis. METHODS: The optimum conditions of hepatoma cell adhesion to the extracellular matrix (ECM) were determined. The ability of cells to adhere to the ECM was compared between human hepatoma cell lines with a highly metastatic potential (MHCC97) and human hepatoma cell lines with a lower metastatic potential (SMMC7721). By using adhesion assays and inhibition studies in vitro, the effects of platelets and their specific adhesive molecules were compared via the ability of MHCC97 and SMMC7721 to adhere to ECM protein. RESULTS: The SMMC7721 cell adhesion rate to vitronectin, fibronectin, and fibrinogen, respectively, was significantly lower than that of MHCC97 cells (44.9% vs 73.6%, 47.4% vs 76.4%, and 59.3% vs 80.6%, P<0.05). Both hepatoma cell adhesion to the ECM-bound platelets was unchanged whether the platelets were activated or not. SMMC7721 cell adhesion to the ECM was not affected by platelets, but MHCC97 cell adhesion to the ECM was significantly enhanced by platelets ( P<0.01). In addition, this effect was significantly reduced when either P-selectin or GP IIb-IIIa was blocked by monoclonal antibodies ( P<0.05, P<0.01). In the inhibition studies, the ability of SMMC7721 to adhere to the ECM-bound activated platelets was also lower than that of MHCC97 ( P<0.05). However, when GP IIb was blocked by antibody, the adhesion ability of both cells was similar ( P >0.05). CONCLUSIONS: Human hepatoma cells with a highly metastatic potential proved to have a highly adhesive ability. MHCC97 cell adhesion to the ECM was significantly enhanced by platelets. The interaction of MHCC97 cells with the ECM-bound activated platelets may be mediated by platelet P-selectin and GP IIb-IIIa.

10
UI - 11948118
AU - Zhong S; Tang MW; Yeo W; Liu C; Lo YM; Johnson PJ
TI - Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas.
SO - Clin Cancer Res 2002 Apr;8(4):1087-92
AD - Department of Clinical Oncology, Sir Y. K. Pao Centre for Cancer, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N. T., Hong Kong SAR, China.
PURPOSE AND EXPERIMENTAL DESIGN: Glutathione S-transferases, enzymes that defend cells against damage mediated by oxidant and electrophilic carcinogens, may be critical determinants of cancer pathogenesis. In this report, we assess the role of epigenetic silencing of the GSTP1 gene, a gene encoding the pi-class glutathione S-transferase, in the pathogenesis of hepatitis B virus (HBV)-associated hepatocellular carcinomas (HCC). The cell lines Hep3B, HepG2, and a cohort of 43 HBV-associated HCC tissue specimens and corresponding nontumor tissues were subjected to analysis for GSTP1 epigenetic alteration and expression. GSTP1 "CpG" island DNA hypermethylation in the liver cell lines, and the tissue specimens were determined by methylation-specific PCR and correlated with expression of the gene using reverse-transcription PCR, immunoblotting, and immunohistochemistry. RESULTS: GSTP1 CpG island DNA hypermethylation was detected in 28 of 43 (65.1%) HCC tissues and 4 of 40 (10%) corresponding nontumor tissues. GSTP1 protein was absent in those cases showing hypermethylation of the gene. Similarly, DNA from Hep3B and HepG2 cell lines displayed complete GSTP1 hypermethylation in the CpG island, and they failed to express GSTP1 mRNA and the corresponding protein product. Treatment of the cell lines with the DNA methyltransferase inhibitor 5-aza-deoxycytidine reversed the hypermethylation, and restored GSTP1 mRNA and polypeptide expression. CONCLUSIONS: These data indicate that epigenetic silencing of GSTP1 gene expression by CpG island DNA hypermethylation is common in human HBV-associated HCC. In addition, somatic GSTP1 inactivation via CpG island hypermethylation may contribute to the pathogenesis of this malignancy.

11
UI - 12087198
AU - Kim SH; Choi D; Lim JH; Lee WJ; Jang HJ; Lim HK; Lee SJ; Cho JM; Kim SK;
TI - Kim GC Optimal pulse sequence for ferumoxides-enhanced MR imaging used in the detection of hepatocellular carcinoma: a comparative study using seven pulse sequences.
SO - Korean J Radiol 2002 Apr-Jun;3(2):87-97
AD - Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. shkim@smc.samsung.co.kr
OBJECTIVE: To identify the optimal pulse sequence for ferumoxides-enhanced magnetic resonance (MR) imaging in the detection of hepatocelluar carcinomas (HCCs). MATERIALS AND METHODS: Sixteen patients with 25 HCCs underwent MR imaging following intravenous infusion of ferumoxides. All MR studies were performed on a 1.5-T MR system, using a phased-array coil. Ferumoxides (Feridex IV) at a dose of 15 micromol/Kg was slowly infused intravenously, and axial images of seven sequences were obtained 30 minutes after the end of infusion. The MR protocol included fast spin-echo (FSE) with two echo times (TR3333-8571/TE18 and 90-117), singleshot FSE (SSFSE) with two echo times (TRinfinity/TE39 and 98), T2*-weighted gradient- recalled acquisition in the steady state (GRASS) (TR216/TE20), T2*-weighted fast multiplanar GRASS (FMPGR) (TR130/TE8.4-9.5), and T2*-weighted fast multiplanar spoiled GRASS (FMPSPGR) (TR130/TE8.4-9.5). Contrast-to-noise ratios (CNRs) of HCCs determined during the imaging sequences formed the basis of quantitative analysis, and images were qualitatively assessed in terms of lesion conspicuity and image artifacts. The diagnostic accuracy of all sequences was assessed using receiver operating characteristic (ROC) analysis. RESULTS: Quantitative analysis revealed that the CNRs of T2*-weighted FMPGR and T2*-weighted FMPSPGR were significantly higher than those of the other sequences, while qualitative analysis showed that image artifacts were prominent at T2*-weighted GRASS imaging. Lesion conspicuity was statistically significantly less clear at SSFSE imaging. In term of lesion detection, T2*-weighted FMPGR, T2*- weighted FMPSPGR, and proton density FSE imaging were statistically superior to the others. CONCLUSION: T2*-weighted FMPGR, T2*- weighted FMPSPGR, and proton density FSE appear to be the optimal pulse sequences for ferumoxidesenhanced MR imaging in the detection of HCCs.

12
UI - 12098098
AU - Sucker C; Dolken G; Preuss J; Schwesinger G; Stockschlader M
TI - [Plasma cell infiltration of the liver in multiple myeloma]
SO - Dtsch Med Wochenschr 2002 Jul 5;127(27):1469-72
AD - Klinik und Poliklinik fur Innere Medizin C, Germany. sucker@uni-greifswald.de

13
UI - 11866223
AU - Martin J; Puig J; Darnell A; Donoso L
TI - Magnetic resonance of focal liver lesions in hepatic cirrhosis and chronic hepatitis.
SO - Semin Ultrasound CT MR 2002 Feb;23(1):62-78
AD - Unitat de Diagnostic d'Alta Tecnologia-Centre Diagnostic, Corporacio Sanitaria del Parc Tauli, Sabadell, Spain. Jmartinm@cspt.es
Detection of focal liver nodules in patients with cirrhosis continues to be a radiologic challenge despite progressive advances in liver imaging in the past 2 decades. Patients with hepatic cirrhosis have a high predisposition to develop hepatocellular carcinoma (HCC), and the early detection and diagnosis of this tumor is very important because the most effective treatment is surgical resection, transplantation, or local ablation therapy when the tumor is small. Cirrhotic livers are mainly composed of fibrosis, together with a broad spectrum of focal nodular lesions ranging from regenerative nodules to premalignant dysplastic nodules to overt HCC. Awareness of such lesions and interpretation of imaging studies in these patients requires a critical review to detect subtle tumors, and a thorough understanding of the imaging appearance of the malignant and benign masses that can occur in the cirrhotic liver. Although the recent advances in liver imaging techniques, especially computed tomography (CT) and magnetic resonance (MR), have facilitated the detection and characterization of focal liver nodules in cirrhotic patients, discriminating between HCC and precancerous nodules remains problematic with all available imaging techniques. Nevertheless, MR imaging appears to have more potential than other imaging techniques in the study of cirrhotic patients and MR may be more appropriate than the other imaging modalities for the detection of small HCCs. In this article we review the imaging characteristics of nodular focal lesions that arise in cirrhotic livers, with special attention to MR imaging features.

14
UI - 12096119
AU - Le Naour F; Brichory F; Misek DE; Brechot C; Hanash SM; Beretta L
TI - A distinct repertoire of autoantibodies in hepatocellular carcinoma identified by proteomic analysis.
SO - Mol Cell Proteomics 2002 Mar;1(3):197-203
AD - Departments of Microbiology and Immunology, University of Michigan, ann Arbor, Michigan 48109-0666, USA.
Chronic infections with hepatitis B (HBV) and hepatitis C (HCV) viruses are major risk factors for hepatocellular carcinoma (HCC). We have utilized a proteomic approach to determine whether a distinct repertoire of autoantibodies can be identified in HCC. Sera from 37 patients with HCC and 31 subjects chronically infected with HBV or HCV without HCC were investigated. Sera from 116 patients with other cancers, three patients with systemic lupus erythematosus, and 24 healthy subjects were utilized as controls. We report the identification of eight proteins, for each of which autoantibodies were detected in sera from more than 10% of patients with HCC but not in sera from healthy individuals (p < 0.05). Autoantibodies to four of these proteins were detected at a comparable frequency in sera from patients with chronic hepatitis. The other four proteins, which consisted of calreticulin isoforms, cytokeratin 8, nucleoside diphosphate kinase A, and F(1)-ATP synthase beta-subunit, induced autoantibodies among patients with HCC, independently of their HBV/HCV status. Calreticulin, and a novel truncated form of calreticulin (Crt32) we have identified, most commonly elicited autoantibodies among patients with HCC (27%). We conclude that a distinct repertoire of autoantibodies is associated with HCC that may have utility in early diagnosis of HCC among high risk subjects with chronic hepatitis.

15
UI - 12148443
AU - Henrion J; De Maeght S; Deltenre P; Ghilain JM; Maisin JM; Schapira M;
TI - Heller F Impact of hepatitis C virus infection on the aetiology of cirrhosis and hepatocarcinoma in three affiliated hospitals in southern Belgium.
SO - Acta Gastroenterol Belg 2002 Apr-Jun;65(2):80-2
AD - Hopital de Jolimont, B-7100 Haine St Paul, Belgium.
In a consecutive series of 411 patients with cirrhosis attending the outpatient liver clinics of 3 general hospitals located in the southern part of Belgium, hepatitis C virus infection accounted for 20% of the cases, far behind alcohol (63%). However, in a consecutive series of 57 hepatocarcinoma superimposed on cirrhosis, hepatitis C virus infection was the main aetiological factor accounting for 44% of the cases.

16
UI - 12148444
AU - Adler M; Goubau P; Nevens F; Van Vlierberghe H
TI - Hepatitis C virus: the burden of the disease.
SO - Acta Gastroenterol Belg 2002 Apr-Jun;65(2):83-6
AD - Department of Gastroenterology and Hepatopancreatology, Hopital Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgique.
Chronic hepatitis C infection affects approximately 3% of the world population and is responsible for a large proportion of patients with cirrhosis, end-stage liver diseases, hepatocellular carcinoma and for those who are candidates for liver transplantation or die of liver-related complications. The health care burden of this infection, whose epidemic peaked in the 1980s, is expected to significantly increase in the next 15 years in the absence of an organized national strategy. On the other hand, hepatitis C infection can be easily diagnosed with third generation enzyme immunoassay and indications for molecular biology-based assay are well defined. Composite scores and non-invasive markers of fibrosis may in the future replace liver biopsy which is still recommended in the presence of chronically elevated transaminases and indications for antiviral treatment.

17
UI - 12105842
AU - Bugianesi E; Leone N; Vanni E; Marchesini G; Brunello F; Carucci P;
TI - Musso A; De Paolis P; Capussotti L; Salizzoni M; Rizzetto M Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
SO - Gastroenterology 2002 Jul;123(1):134-40
AD - Department of Gastroenterology, Ospedale S. Giovanni Battista, University of Turin, Turin, Italy. ebugianesi@contacta.it
BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) may progress to cirrhosis; whether NASH plays also a role in the development of hepatocellular carcinoma (HCC) is unknown. METHODS: Among 641 cirrhosis-associated HCCs, we retrospectively identified 44 patients with cryptogenic cirrhosis (CC). Of these, 23 were actively followed up and were compared in a case-control study with viral- and alcohol-associated HCC. Family and personal history of diabetes, hypertension, coronary heart disease, dyslipidemia, obesity, and biochemical data were compared between groups. Iron status and presence of mutations in the HFE gene of familiar hemochromatosis were also determined. RESULTS: Family history was not different in relation to etiology. The prevalence of obesity and diabetes was significantly higher in patients with CC. Although liver function was similar, CC patients had higher glucose, cholesterol, and triglyceride plasma levels, increased parameters of insulin resistance, and lower aminotransferase levels. Iron status and prevalence of mutations in the HFE gene did not differ. Logistic regression analysis identified in sequence hypertriglyceridemia, diabetes, and normal aminotransferases as independent factors associated with HCC arising in CC. CONCLUSIONS: Features suggestive of NASH are more frequently observed in HCC arising in patients with CC than in age- and sex-matched HCC patients of well-defined viral or alcoholic etiology. HCC may represent a late complication of NASH-related cirrhosis.

18
UI - 12105866
AU - Ong JP; Younossi ZM
TI - Is hepatocellular carcinoma part of the natural history of nonalcoholic steatohepatitis?
SO - Gastroenterology 2002 Jul;123(1):375-8

19
UI - 12145822
AU - Blendis L; Lurie Y
TI - Primary sclerosing cholangitis: a premalignant condition.
SO - Gastroenterology 2002 Aug;123(2):647-8

20
UI - 12086897
AU - Cho CS; Knechtle SJ; Heisey DM; Hermina M; Armbrust M; D'Alessandro AM;
TI - Musat AI; Kalayoglu M Analysis of tumor characteristics and survival in liver transplant recipients with incidentally diagnosed hepatocellular carcinoma.
SO - J Gastrointest Surg 2001 Nov-Dec;5(6):594-601; discussion 601-2
AD - Division of Transplantation, Department of Surgery, University of Wisconsin Hospital and Clinics, Madison, Wis. 53792, USA.
The use of orthotopic liver transplantation (OLTX) for the treatment of hepatocellular carcinoma (HCC) has generally become restricted to carefully selected cases of small oligocentric tumors. However, it is not uncommon to find previously undetected HCC within recipient cirrhotic livers at the time of hepatectomy. The impact of unsuspected HCC on patient outcomes remains unclear. A retrospective analysis of our institutional experience with adult primary OLTX was performed comparing recipients with incidental HCC (group 1), recipients with known or suspected HCC (group 2), and recipients confirmed by pathologic examination to be tumor free (group 3). Between 1984 and 2000, 27 patients in group 1, 12 patients in group 2, and 612 patients in group 3 underwent primary OLTX. Tumors were smaller (P = 0.0172) in group 1 than in group 2; however, the number of tumors and the histologic findings were similar in the groups. Incidence of bilobar involvement, vascular invasion, portal vein tumor thrombus, lymphatic involvement, and distant metastasis at the time of OLTX did not differ significantly between these groups. Four-year patient survival appeared to be lower in group 1 (70.0%) than in group 3 (79.0%) (P = 0.0546); 4-year patient survival was significantly worse in group 2 (31.0%) compared to group 3 (P = 0.0106). Thus, in our experience, incidentally diagnosed cases of HCC possess many of the same features of malignancy as preoperatively diagnosed HCC. Indeed, patient survival after OLTX appears to be adversely affected by the presence of incidental HCC.

21
UI - 12072777
AU - Rabinowitz I; Telepak R; Lee FC
TI - Octreotide scans are positive in a subset of patients with hepatocellular carcinoma.
SO - Clin Nucl Med 2002 Jul;27(7):499-502
AD - Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico. irabinowitz@salud.unm.edu
PURPOSE: In vitro data suggest that a proportion of hepatocellular carcinomas express the somatostatin receptor. However, in vivo data are lacking. There has been little reported use of octreotide scans in hepatocellular carcinomas. This study was performed to determine the percentage of positive results of octreotide scanning in patients with hepatocellular carcinoma. MATERIALS AND METHODS: In-111 octreotide scans were performed in the standard manner in eight patients with unresectable hepatocellular carcinoma. Computer fusion imaging of the nuclear medicine and computed tomographic scans was performed in selected patients. RESULTS: Five of eight (63%) patients tested had hepatocellular carcinomas that displayed focal tracer uptake. CONCLUSIONS: This is the first report of positive uptake of octreotide scans in patients with hepatocellular carcinoma. These findings may have implications for the treatment of hepatocellular carcinoma with octreotide. Furthermore, these results may broaden the differential diagnosis in patients with positive results of octreotide scanning.

22
UI - 12120119
AU - Davis GL; Keeffe EB
TI - Advances in liver disease. Highlights from the 51st Annual Meeting of the American Association for the Study of Liver Diseases, October 27-31, 2000, Dallas, TX.
SO - Rev Gastroenterol Disord 2001;1(1):42-7
AD - University of Florida College of Medicine, Gainesville, FL, USA.

23
UI - 11887942
AU - Seltzer SE; Getty DJ; Pickett RM; Swets JA; Sica G; Brown J; Saini S;
TI - Mattrey RF; Harmon B; Francis IR; Chezmar J; Schnall MO; Siegelman ES; Ballerini R; Bhat S Multimodality diagnosis of liver tumors: feature analysis with CT, liver-specific and contrast-enhanced MR, and a computer model.
SO - Acad Radiol 2002 Mar;9(3):256-69
AD - Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
RATIONALE AND OBJECTIVES: The purpose of this study was to measure and to clarify the diagnostic contributions of image-based features in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions. MATERIALS AND METHODS: Six experienced abdominal radiologists each read images from 146 cases (including a contrast material-enhanced computed tomographic [CT] scan and contrast-enhanced and unenhanced magnetic resonance [MR] images) following a checklist-questionnaire requiring them to rate quantitatively each of as many as 131 image features and then reported on each of the two differentiations. The diagnostic value of each feature was assessed, and linear discriminant analysis was used to develop statistical prediction rules (SPRs) for merging feature data into computerized "second opinions." For the two differentiations, accuracy (area under the receiver operating characteristic curve [Az]) was then determined for the radiologists' readings by themselves and for each of three SPRs. RESULTS: Thirty-seven candidate features had diagnostic value for each of the two differentiations (a slightly different feature set for each). Radiologists' performance at both differentiations was excellent (Az = 0.929 [benign vs malignant] and 0.926 [hepatocyte-containing vs non-hepatocyte-containing]). Performance of the SPR that operated on the features from all modalities together was better than that of radiologists (Az = 0.936 [benign vs malignant] and 0.951 [hepatocyte-containing vs non-hepatocyte-containing]), but this difference was of marginal statistical significance (P = .11). Contrast-enhanced MR imaging and contrast-enhanced CT each made significant adjunctive contributions to accuracy compared with unenhanced MR imaging alone. CONCLUSION: Many CT- and MR imaging-based features have diagnostic value in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions. Radiologists could also benefit from the fully informed SPR's "second opinions."

24
UI - 12077100
AU - Saito K; Inoue S; Saito T; Kiso S; Ito N; Tamura S; Watanabe H; Takeda
TI - H; Misawa H; Togashi H; Matsuzawa Y; Kawata S Augmentation effect of postprandial hyperinsulinaemia on growth of human hepatocellular carcinoma.
SO - Gut 2002 Jul;51(1):100-4
AD - Second Department of Internal Medicine, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
BACKGROUND: Cirrhotic patients with hepatocellular carcinoma (HCC) frequently have impaired glucose metabolism. AIMS: To investigate whether impaired glucose metabolism affects the growth rate of the tumour. PATIENTS AND METHODS: Tumour doubling time (DT), assessed by ultrasound imaging analysis, was measured in 60 patients with single small HCC (diameter <30 mm). DT was compared with plasma insulin and glucose concentrations following the oral glucose tolerance test (OGTT). The effect of continuous infusion of octreotide (a somatostatin analogue 200 microg/day) for three months on DT in five cases was assessed. RESULTS: The 60 patients were divided into two groups because the median DT was 140 days: rapid growth group (DT 140 days, n=30). Fasting plasma insulin concentration and area under the plasma insulin curve (AUC(ins)) of the OGTT (10.4 (6.2) microU/ml and 262 (152) microU/ml/h, respectively; mean (SD)) in the rapid growth group were significantly higher than those in the slow growth group (7.6 (4.3) and 146 (140), respectively) (p=0.041 and p=0.0006, respectively). In contrast, fasting plasma glucose concentration and area under the plasma glucose curve (AUC(gluc)) in the rapid growth group were significantly lower than those in the slow growth group (p=0.0003 and p=0.0012, respectively). Univariate and multivariate analyses of logistic regression models demonstrated that AUC(ins) was a significant factor contributing to the growth rate of HCC (p=0.001 and p=0.016, respectively). AUC(ins) significantly decreased after octreotide treatment (p<0.02) but AUC(gluc) did not significantly change. DT after treatment increased in three of the five patients and could not be calculated in the remaining two patients because of no change in the diameter of the tumour. CONCLUSIONS: These data suggest that postprandial hyperinsulinaemia is associated with accelerated HCC growth.

25
UI - 12077101
AU - Stoker J; Romijn MG; de Man RA; Brouwer JT; Weverling GJ; van Muiswinkel
TI - JM; Zondervan PE; Lameris JS; Ijzermans JN Prospective comparative study of spiral computer tomography and magnetic resonance imaging for detection of hepatocellular carcinoma.
SO - Gut 2002 Jul;51(1):105-7
AD - Department of Radiology, Erasmus Medical Centre Rotterdam, University of Amsterdam, The Netherlands. j.stoker@amc.uva.nl
BACKGROUND: Hepatocellular carcinoma (HCC) is often detected at a relatively late stage when tumour size prohibits curative surgery. Screening to detect HCC at an early stage is performed for patients at risk. AIM: The aim of this study was to compare prospectively the diagnostic accuracy and classification for management of the two state of the art secondline imaging techniques: triphasic spiral computer tomography (CT) and super paramagnetic iron oxide (SPIO) enhanced magnetic resonance imaging (MRI). PATIENTS: Sixty one patients were and MRI within a mean interval of 6.75 days. METHODS: CT and MRI were evaluated blindly for the presence and number of lesions, characterisation of these lesions, and classification for management. For comparison of the data on characterisation, the CT and MRI findings were compared with histopathological studies of the surgical specimens and/or follow up imaging. Data of patients not lost to follow up were lesions and overall smaller lesions than triphasic spiral CT (number of lesions 189 v 124; median diameter 1.0 v 1.8 cm; Spearman rank's correlation coefficient 0.63, p<0.001). There was no significant difference in accuracy between CT and MRI for lesion characterisation. The agreement in classification for management was very good (weighted kappa 0.91, 95% CI 0.83-0.99). CONCLUSION: SPIO enhanced MRI detects more and smaller lesions, but both techniques are comparable in terms of classification for management. SPIO enhanced MRI may be preferred as there is no exposure to ionising radiation.

26
UI - 12143050
AU - Nguyen MH; Garcia RT; Simpson PW; Wright TL; Keeffe EB
TI - Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis.
SO - Hepatology 2002 Aug;36(2):410-7
AD - Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304-1509, USA.
alpha-Fetoprotein (AFP) is frequently used as a diagnostic marker for hepatocellular carcinoma (HCC). Most available data concerning AFP come from studies of patients with chronic hepatitis B or other chronic liver diseases of mixed etiologies. Limited data concerning the diagnostic value of AFP for hepatitis C virus (HCV)-related HCC have to date come only from Asian and European studies, and results are conflicting. There may be significant differences in AFP levels depending on racial backgrounds and etiologies of primary liver disease. We conducted a multicenter, retrospective, case-control study of 163 HCC patients with HCV infection and 149 control patients with HCV-related cirrhosis. The positive likelihood ratios for AFP at 0 to 20, 21 to 50, 51 to 100, and 101 to 200 ng/mL were 0.46, 1.31, 1.15, and 6.90, respectively. No controls had AFP greater than 200 ng/mL. The sensitivity of AFP for the diagnosis of HCC in African Americans with HCV infection was lower than that of patients of all other ethnic groups combined (57.1% vs. 81.6% for AFP > 10 ng/mL, P =.02, and 42.9% vs. 66.0% for AFP > 20 ng/mL, P =.05). The area under the receiver operating characteristics curve was 0.81 for non-African Americans but only 0.56 for African Americans. In conclusion, AFP greater than 200 ng/mL can be used to confirm HCC in patients with HCV-related cirrhosis and a hepatic mass. However, AFP is insensitive for the diagnosis of HCC in African Americans.

27
UI - 12143053
AU - Kinoshita M; Miyata M
TI - Underexpression of mRNA in human hepatocellular carcinoma focusing on eight loci.
SO - Hepatology 2002 Aug;36(2):433-8
AD - Gene Analysis Center, Otsuka Assay Laboratories, Otsuka Life Science Initiative, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan. kinoshitamo@assay.otsuka.co.jp
Genetic alterations associated with human hepatocellular carcinoma (HCC) have been reported previously, but are not sufficient to specify differences of HCCs from precancerous diseases of the liver, such as hepatitis, hepatic fibrosis, and cirrhosis. In the present study, we performed differential gene display analysis (DGDA) to clarify the specific genetic alterations associated with gene expression changes in the course of development of HCC from chronic viral hepatitis. Four pairs of surgically resected HCCs and hepatitis tissues were investigated. We found 1,028 expression sequence tags (ESTs) that were decreased or increased in HCC tissues compared with hepatitis tissues in the same patient. Nucleotide sequencing showed that they included 55 EST clones in the GenBank database, which were considered candidates for specific messenger RNA (mRNA) expression alterations in HCCs. After excluding 9 ESTs that code mitochondrial DNA, we performed quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) for the 46 remaining EST clones. We found 8 mRNAs underexpressed in primary HCC tissues in 20 patients in higher percentages than found in previous studies, including 18 cases (90%) for aldolase B (ALDOB), 15 cases (75%) for carbamyl phosphate synthetase 1 (CPS1), albumin (ALB), plasminogen (PLG), and EST 51549, 13 cases (65%) for cytochrome P450 subfamily 2E1 (CYP2E1), 12 cases (60%) for human retinol-binding protein 4 (RBP4), and 11 cases (55%) for human organic anion transporter C (OATP-C) gene. In conclusion, underexpression of key gene products may be important in the development and/or progression of HCC.

28
UI - 12097419
AU - Wang Y; Han KJ; Pang XW; Vaughan HA; Qu W; Dong XY; Peng JR; Zhao HT;
TI - Rui JA; Leng XS; Cebon J; Burgess AW; Chen WF Large scale identification of human hepatocellular carcinoma-associated antigens by autoantibodies.
SO - J Immunol 2002 Jul 15;169(2):1102-9
AD - Immunology Department, School of Basic Medical Science, Peking University Health Science Center, Beijing, China.
Autoantibodies are often detected in hepatocellular carcinoma (HCC), and these responses may represent recognition of tumor Ags that are associated with transformation events. The identities of these Ags, however, are less well known. Using serological analysis of recombinant cDNA expression libraries (SEREX) from four HCC patients, we identified 55 independent cDNA sequences potentially encoding HCC tumor Ags. Of these genes, 15 are novel. Two such proteins, HCA587 and HCA661, were predominantly detected in testis, but not in other normal tissues, except for a weak expression in normal pancreas. In addition to HCC, these two Ags can be found in cancers of other histological types. Therefore, they can be categorized as cancer-testis (CT) Ags. Two other Ags (HCA519 and HCA90) were highly overexpressed in HCC and also expressed in cancer cell lines of lung, prostate, and pancreas, but not in the respective normal tissues. Four other Ags were identified to be expressed in particular types of cancer cell lines (HCA520 in an ovarian cancer cell line, HCA59 and HCA67 in a colon cancer cell line, HCA58 in colon and ovarian cancer cell lines), but not in the normal tissue counterpart(s). In addition, abundant expression of complement inactivation factors was found in HCC. These results indicate a broad range expression of autoantigens in HCC patients. Our findings open an avenue for the study of autoantigens in the transformation, metastasis, and immune evasion in HCC.

29
UI - 11916199
AU - Huo TI; Huang YH; Wu JC; Lee PC; Chang FY; Lee SD
TI - Survival benefit of cirrhotic patients with hepatocellular carcinoma treated by percutaneous ethanol injection as a salvage therapy.
SO - Scand J Gastroenterol 2002 Mar;37(3):350-5
AD - Dept. of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taiwan, Republic of China. tihuo@vghtpe.gov.tw
BACKGROUND: The therapeutic strategy for cirrhotic patients with hepatocellular carcinoma (HCC) who cannot tolerate surgery or transcatheter arterial chemoembolization (TACE) is uncertain. The safety and efficacy of percutaneous ethanol injection (PEI) as a salvage therapy in such patients is not clear. METHODS: A total of 63 (49 men) HCC patients (mean age 67 +/- 11 years), for whom surgery or TACE was not indicated because of the coexistence of various medical conditions, were enrolled and prospectively studied. Fifty-six (89%) were treated with PEI and 7 were treated with conservative measures. The outcome and the factors that may affect survival were evaluated.

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