- Email: [email protected]
243 Antioxidant supplements for prevention of liver cancer
03. Liver tumors' (epidemiology, diagnosis', managemen0 were collected before therapeutic treatment. Serum assays were performed using Hepa-IC for SCCA IgM and Hepa AFP-IC for AFP IgM. Serum FAFP levels were determined in parallel on each sample. The amount of DCP IgM was determined by a standardized ELISA and expressed in arbitrary units per mL (AU/mL). Results: The cut-off level o f D C P IgM was set at 2807AU/mL as mean + 2 standard deviation of serum levels of healthy controls. In terms of sensitivity, DCP IgM was above the cut-off in 23 of 44 HCC patients (52%) with a median serum concentration of 2854.5 AU/mL. FAFP levels were above 20 ng/mL in 50% (22/44) of HCC group, SCCA IgM levels were above the cut-off (120 AU/mL) in 66% (29/44) and AFP IgM levels in 50% of patients (22/44; cut-off 120 AU/mL). By combining significantly elevated serum levels ofSCCA IgM, AFP IgM and DCP IgM sensitivity for HCC detection reached 79.5% (35/44) with 100% specificity over healthy subjects. Conclusions: The data presented here are the first evidence of the occurrence of DCP IgM immune complexes in HCC patients, confirming our previous findings on the occurrence and diagnostic relevance of SCCA IgM and AFP IgM complexes. By combining SCCA IgM, AFP IgM and DCP IgM measurement, HCC detection is significantly enhanced compared to AFP determination.
I•-•
IMPROVEMENT OF SENSITIVITY FOR LIVER C A N C E R DETECTION BY SIMULTANEOUS EVALUATION OF SCCA-IgM, A F P - I g M COMPLEXES AND FREE AFP
L. Beneduce, A. Gallotta, M. Marino, G. Fassina. XEPTAGEN Xp.A.,
Marghera Venezia, Italy B a c k g r o u n d and Aims: Detection of HCC at an early stage may significantly reduce mortality. However massive screening should be justified only when sensitive and specific diagnostic procedures are available. It has been recently demonstrated that hepatocellullar carcinoma (HCC) detection may be achieved by exploiting the assessment of serum levels of a-fetoprotein (AFP) IgM and squamous cell carcinoma antigen (SCCA) IgM complexes. Significant levels o f A F P IgM and SCCA IgM immune complexes have been found in 60 70% of HCC patients and in 18 28% of patients affected by non-malignant chronic liver diseases, but with lower levels. In the present study we investigated the relevance of ternary assessment of SCCA IgM, AFP IgM and AFP for improved HCC detection. Patients and Methods: Blood samples from 44 patients affected by HCC were collected before therapeutic treatment. The diagnosis of HCC was based on the presence of hepatic focal lesion >2 cm, detected by liver ultrasound (US) and confirmed by US-assisted fine-needle biopsy, computed tomography, and magnetic resonance imaging, when indicated. Serum assays were performed using Hepa-IC (Xeptagen, Italy) for SCCA IgM and Hepa AFP-IC (Xeptagen, Italy) for AFP IgM. Serum AFP levels were determined in parallel on each sample using standard reagents for automatic analyzer. Results: 29 out of 44 patients (66%) were positive for SCCA IgM test (median level: 239.3 AU/mL), 28 out of 44 patients (64%) were positive for AFP IgM assay (median level:176.65 AU/mL). AFP test (serological gold standard) was significantly higher (>20 ng/mL) only in 22 out of 44 patients (50%; median level: 19.8 ng/mL). Co-detection of both SCCA and AFP IgM complexes allowed to identify 70.5% of patients (31/44), while the overall positivity reached 91% (40/44) when also AFP measurements were included. Conclusions: Compared to AFP determination, improvement in diagnosis of primary liver cancer can be achieved by co-determination of SCCA IgM and AFP IgM complexes (70.5% sensitivity). Inclusion of AFP determination further increases the positive rate of correct diagnosis to 91%.
I•
$97
NATURAL HISTORY OF UNTREATED HEPATOCELLULAR C A R C I N O M A (HCC) ON CIRRHOSIS: SURVIVAL ANALYSIS AND PROGNOSTIC FACTORS IN 559 PATIENTS
L. Benvegnu'1 , M. Gios 1, E Pasin 1, A. Di Nolfo 2, R Del Poggio 3, G. Rapaccini 4, E Farinati 5, M. Zoli 6, E Borzio 7, E.G. Giannini 8, E. Caturelli 9, A. Alberti 1, M. Bernardi 6, E Trevisani6. 1Dpt. of Clinical
and Experimentale Medicine, University of Padova, Italy," 2Dpt. of Medicine, Hospital of Seriate, Italy," 3Dpt. of Medicine, Hospital of Treviglio, Italy," 4Dpt. of Medicine, University Cattolica of Roma, Italy," 5Dpt. of Surgical and Gastroenterological Science, University of Padova, Italy," 6Dpt. of Internal Medicine, Cardioangilogy and Hepatology, University of Bologna, Italy," 7Dpt. of Medicine, Hospital of Milano, Italy," aGastroenterology Unit, Department of Internal Medicine, University of Genova, Italy," 9 Gas'trointestinal Unit, "Beleolle" Hospital, Viterbo, Italy The natural history of untreated HCC is still partially understood, particularly at early stage, because the majority of patients are submitted to some treatment procedures. We have therefore evaluated outcome and prognostic factors in a large group of 559 patients with HCC and cirrhosis, included between 1988 and 2004, who were not treated or underwent only symptomatic therapy. There were 417 males (74.6%) and 142 females (25.4%), and mean age was 66.0• years. Chil&Pugh stage of cirrhosis was A in 249 (44.5%) patients, B in 205 (36.7%) and C in 105 (18.8%). At diagnosis tumor was unifocal in 182 (32.6%) patients (<5 cm in 126 cases), paucifocal (<3 nodules <3 cm) in 87 (15.6%), multifocal in 125 (22.3%) and diffuse or massive in 165 (29.5%). a-fetoprotein (AFP) was >400 ng/ml in 177 (31.6%) patients. Portal vein thrombosis was present in 148 (26.5%) cases and extra-hepatic metastasis in 29 (5.2%). During a median follow-up of 8 (1 126) months, 425 (76%) patients died, with 1- and 3-year survival rates of 44% and 27%, respectively. By univariate analysis (Cox model) male sex (p <0.001), AFP <400ng/ml (p <0.00001), Child@ugh stage (p <0.00001), tumor pattern (diffuse/ massive vs multifocal vs paucifocal vs single, p <0.00001), tumor diameter >5cm (p < 0.005), presence of portal vein thrombosis (p < 0.05) and of metastasis (p <0.01) were significantly associated with reduced survival. By multivariate analysis (Cox proportional hazards regression analysis) male sex (p < 0.05), AFP < 400 ng/ml (p < 0.00001), Child@ugh stage (p <0.00001), tumor pattern but not tumor size (p <0.00001) and metastasis (p <0.05) were the only independent variables significantly affecting outcome. According to these factors, the estimated 1-year and 3-year survival rates were 78% and 50%, respectively, in female patients with stage A cirrhosis, single HCC and A F P < 4 0 0 n g / m l , and of 15% and 1%, respectively, in male patients with stage B/C cirrhosis, multifocal HCC and AFP < 400ng/ml. Our results indicate that besides sex, stage of cirrhosis, AFP levels and presence of extra-hepatic spread, tumor multifocality, independently of the size of single nodules, is a major determinant in predicting the outcome of patients with untreated HCC and cirrhosis. These findings might be useful for the evaluation of current and future therapeutic procedures.
I•
ANTIOXIDANT S U P P L E M E N T S FOR PREVENTION OF LIVER C A N C E R
G. Bielakovic 1 , D. Nikolova 2, R.G. Simonetti 3, C. Gluud 2. 1Department
of Internal Medicine Gastroenterology and Hepatology, Medical Faculty, University of Nis, Nis, Serbia and Montenegro," 2The Coehrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Dept. 71.02, H.'S Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark," 3Divisione di Medicina Ospedale 1( Cervello, Palermo, Italy B a c k g r o u n d and Aim: Oxidative stress may cause liver cancer. Whether antioxidant supplements can prevent liver cancer is uncertain. Our aim
POSTERS
$98
was to assess benefits and harms of antioxidant supplements in preventing liver cancer. Methods: Using The Cochrane Collaboration methodology we reviewed all randomised trials comparing antioxidant supplements with placebo/ no intervention. We searched for trials, published by October 2005, in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL in The Cochrane Library, MEDLINE, EMBASE, LILACS, and SCIEXPANDED. We scanned references, and contacted authors and pharmaceutical companies. Results: We identified nine randomised trials (130,674 participants), assessing beta-carotene, vitamin A, C, E, and selenium, either singly or combined. In five low-bias risk trials (120,876) neither the fixed-effect (relative risk 1.37, 95%CI 0.89 2.13) nor random-effects (1.37, 0.88 2.12) meta-analyses showed significant effects of the antioxidant supplements on liver cancer incidence. The four high-bias risk trials (9798 participants) examined solely selenium. Selenium significantly decreased liver cancer incidence with both the fixed-effect and random-effects meta-analyses (0.56, 0.42~0.76). The intervention effect differed significantly between low- and high-bias risk trials (z=3.3, p=0.001) by test of interaction. Non-serious adverse effects were yellowing of the skin and gastrointestinal upset.
ZA~ET _-:.24
z:..~4=: ;.,~
1.al
[:.:e.
•
-D
"~
:;2
7a~l~..§ le~,~
c~l
was assessed by histopathological examination using thin sectioning of explanted livers with or without TIPS. Results: The two groups of patients (with vs without TIPS) were comparable when considering age (50• vs 50.9• gender (sex ratio 3.32 vs 2.89, OR 1.55) and aetiology of liver cirrhosis (alcohol: 56.9% vs 43.8%, OR 1.62; hepatitis C: 31.3% vs 34.2%, OR 0.85; hepatitis B: 5.9% vs 12.5%, OR 0.44). Child@ugh score was comparable between the two groups (9.75 vs 10). Overall, LGDN, HGDN and HCCi were found in 15.3%, 3.2% and 16.6% respectively in the 156 patients. The frequency of DN and/or HCCi was higher in patients with TIPS than in patients without TIPS (47% vs 29%, OR 2.12, p <0.05). When considering separately the frequency of HCCi no statistical difference was noted between the two groups of patients (19.6% vs 15.2%, OR 1.36, with and without TIPS respectively). Of note, in our population, chronic HCV infection was significantly associated with HCCi as compared with other aetiologies of cirrhosis (OR 2.82, p <0.05). Conclusions: In our population of liver transplanted patients, the risk of HCCi is not increased by TIPS. However, the overall increased risk of histopathological nodular lesions (DN and/or HCCi) cannot rule out an increased risk of HCC in patients with TIPS in case of a longer follow up in the absence of liver transplantation.
3,.=,
~
r==~ - = : I " i
.... :'2
[•
COMPARATIVE P R O T E O M I C ANALYSIS OF H E P A T O C E L L U L A R C A R C I N O M A S ON N O N - F I B R O T I C LIVER A N D H E P A T O C E L L U L A R A D E N O M A S
.=:%
eee:L_'=_'.-:. = = : ; : . / z
M.R Bralet 1, A. Dos Santos2, S. Sal2, V. Thiers2, C. Br~chot 2, D. Samuel 3, C. Guettier 1, E Demaugre 2. 1Department of Pathology, Figure 1. Relative risk, 95%CI (fixed). Intervention effect of different antioxidant supplements versus placebo/no intervention on the incidence of liver cancer stratifying trials according to risk of bias. Conclusions: We could not find convincing evidence that antioxidant supplements prevent liver cancer. We confirmed the significant influence of bias risk on estimation of intervention effects. The potential cancer preventive effect of selenium should be studied.
I•
D O E S T R A N S J U G U L A R INTRAHEPATIC PORTOSYSTEMIC SHUNT INCREASE HEPATOCELLULAR C A R C I N O M A RISK IN PATIENTS WITH C I R R H O S I S ? P A T H O L O G I C A L STUDY F R O M E X P L A N T E D LIVERS
P. Borentainl, R Ananian2, S. Garcia 3, S. Henrion 1, C. Barrantes 1, D. Botta-Fridlund 1, Y.R Letreut 2, R. Gerolami 1. 1Service
d 'H@atogastroentdrologie, 2Service de transplantation h@atique, Hdpital Conception, 3Service d'Anatomopathologie, H@ital Nord, Marseille, France Background and Aims: It has been recently reported that patients with cirrhosis and a Transjugular Intrahepatic Portosystemic Shunt (TIPS) may have an increased risk of hepatocellular carcinoma (HCC) development. The aim of our study was to assess the frequency of dysplastic nodules and incidental HCC in explanted cirrhotic livers with or without TIPS. Methods: Out of the 352 patients who underwent liver transplantation since 1993 in our liver transplantation center, 156 patients with end stage cirrhosis and who were without pretransplant evidence of HCC were selected. Among them 51 had a patent TIPS in their explanted liver that was placed at least 2 months (mean 11.1 months) before transplantation. The presence of dysplastic nodules (DN) including high-grade (HGDN) and low-grade (LGDN) dysplastic nodules and incidental HCC (HCCi)
APHP, 2INSERM U370, Centre H@ato-biliaire, 3Centre H@ato-biliaire, EA3541, H@ital Paul Brousse, Villejuif, France Background and Aims: Hepatocellular carcinomas (HCC) occurring on non-fibrotic liver are a rare subgroup of HCC for which mechanisms of carcinogenesis are unclear. Moreover, differential diagnosis between well differentiated HCC on non-fibrotic liver and hepatocellular adenoma (Ad) is difficult using histological criteria. The aim of this study was to identify markers differentially expressed between HCC on non-fibrotic liver and Ad by proteomic analysis. Methods: Proteins were extracted from 5 HCC on non-fibrotic liver, 5 Ad, and 10 normal livers. Isoelectrofocalisation was performed with 200 gg of protein extracts immobilized on pH 4 to 7 IPG strips at 80000Vh. SDSPAGE gels (10% polyacrylamide) were stained with silver nitrate solution, scanned and analysed with Image 2D Master Software. Proteins of interest were identified by mass spectroscopy (Maldi-Tof). Each experiment was performed in triplicate. Results: 42 protein spots were differentially expressed between HCC and Ad, 27 with an expression ratio of more than 2; 15 proteins were identified by Maldi-Tof including heterogeneous nuclear ribonucleoproteins K and E hsp 60, alcohol sulfotransferase, chloride intracellular channel protein 1, proteasome activator complex subunit 1, proteasome subunit beta type 4 precursor, ubiquinol cytochrome c reductase complex core protein 1, endoplasmin precursor, annexin A4 and 1, alphal antitrypsine precursor, nicotinamide N methyltransferase, tubulin alpha, protein-glutamine gamma-glutamyltransferase. Western blots confirmed that these 3 latter proteins were down-regulated in HCC compared to Ad and that annexinl was up-regulated in HCC compared to Ad. Conclusions: Proteomic profiles of HCC on non-fibrotic liver are different from those of Ad. 2D-electrophoresis and Maldi-Tof should allow the identification of new diagnosis markers of hepatocellular tumors and potential therapeutic targets.
I•-•
IMPROVEMENT OF SENSITIVITY FOR LIVER C A N C E R DETECTION BY SIMULTANEOUS EVALUATION OF SCCA-IgM, A F P - I g M COMPLEXES AND FREE AFP
L. Beneduce, A. Gallotta, M. Marino, G. Fassina. XEPTAGEN Xp.A.,
Marghera Venezia, Italy B a c k g r o u n d and Aims: Detection of HCC at an early stage may significantly reduce mortality. However massive screening should be justified only when sensitive and specific diagnostic procedures are available. It has been recently demonstrated that hepatocellullar carcinoma (HCC) detection may be achieved by exploiting the assessment of serum levels of a-fetoprotein (AFP) IgM and squamous cell carcinoma antigen (SCCA) IgM complexes. Significant levels o f A F P IgM and SCCA IgM immune complexes have been found in 60 70% of HCC patients and in 18 28% of patients affected by non-malignant chronic liver diseases, but with lower levels. In the present study we investigated the relevance of ternary assessment of SCCA IgM, AFP IgM and AFP for improved HCC detection. Patients and Methods: Blood samples from 44 patients affected by HCC were collected before therapeutic treatment. The diagnosis of HCC was based on the presence of hepatic focal lesion >2 cm, detected by liver ultrasound (US) and confirmed by US-assisted fine-needle biopsy, computed tomography, and magnetic resonance imaging, when indicated. Serum assays were performed using Hepa-IC (Xeptagen, Italy) for SCCA IgM and Hepa AFP-IC (Xeptagen, Italy) for AFP IgM. Serum AFP levels were determined in parallel on each sample using standard reagents for automatic analyzer. Results: 29 out of 44 patients (66%) were positive for SCCA IgM test (median level: 239.3 AU/mL), 28 out of 44 patients (64%) were positive for AFP IgM assay (median level:176.65 AU/mL). AFP test (serological gold standard) was significantly higher (>20 ng/mL) only in 22 out of 44 patients (50%; median level: 19.8 ng/mL). Co-detection of both SCCA and AFP IgM complexes allowed to identify 70.5% of patients (31/44), while the overall positivity reached 91% (40/44) when also AFP measurements were included. Conclusions: Compared to AFP determination, improvement in diagnosis of primary liver cancer can be achieved by co-determination of SCCA IgM and AFP IgM complexes (70.5% sensitivity). Inclusion of AFP determination further increases the positive rate of correct diagnosis to 91%.
I•
$97
NATURAL HISTORY OF UNTREATED HEPATOCELLULAR C A R C I N O M A (HCC) ON CIRRHOSIS: SURVIVAL ANALYSIS AND PROGNOSTIC FACTORS IN 559 PATIENTS
L. Benvegnu'1 , M. Gios 1, E Pasin 1, A. Di Nolfo 2, R Del Poggio 3, G. Rapaccini 4, E Farinati 5, M. Zoli 6, E Borzio 7, E.G. Giannini 8, E. Caturelli 9, A. Alberti 1, M. Bernardi 6, E Trevisani6. 1Dpt. of Clinical
and Experimentale Medicine, University of Padova, Italy," 2Dpt. of Medicine, Hospital of Seriate, Italy," 3Dpt. of Medicine, Hospital of Treviglio, Italy," 4Dpt. of Medicine, University Cattolica of Roma, Italy," 5Dpt. of Surgical and Gastroenterological Science, University of Padova, Italy," 6Dpt. of Internal Medicine, Cardioangilogy and Hepatology, University of Bologna, Italy," 7Dpt. of Medicine, Hospital of Milano, Italy," aGastroenterology Unit, Department of Internal Medicine, University of Genova, Italy," 9 Gas'trointestinal Unit, "Beleolle" Hospital, Viterbo, Italy The natural history of untreated HCC is still partially understood, particularly at early stage, because the majority of patients are submitted to some treatment procedures. We have therefore evaluated outcome and prognostic factors in a large group of 559 patients with HCC and cirrhosis, included between 1988 and 2004, who were not treated or underwent only symptomatic therapy. There were 417 males (74.6%) and 142 females (25.4%), and mean age was 66.0• years. Chil&Pugh stage of cirrhosis was A in 249 (44.5%) patients, B in 205 (36.7%) and C in 105 (18.8%). At diagnosis tumor was unifocal in 182 (32.6%) patients (<5 cm in 126 cases), paucifocal (<3 nodules <3 cm) in 87 (15.6%), multifocal in 125 (22.3%) and diffuse or massive in 165 (29.5%). a-fetoprotein (AFP) was >400 ng/ml in 177 (31.6%) patients. Portal vein thrombosis was present in 148 (26.5%) cases and extra-hepatic metastasis in 29 (5.2%). During a median follow-up of 8 (1 126) months, 425 (76%) patients died, with 1- and 3-year survival rates of 44% and 27%, respectively. By univariate analysis (Cox model) male sex (p <0.001), AFP <400ng/ml (p <0.00001), Child@ugh stage (p <0.00001), tumor pattern (diffuse/ massive vs multifocal vs paucifocal vs single, p <0.00001), tumor diameter >5cm (p < 0.005), presence of portal vein thrombosis (p < 0.05) and of metastasis (p <0.01) were significantly associated with reduced survival. By multivariate analysis (Cox proportional hazards regression analysis) male sex (p < 0.05), AFP < 400 ng/ml (p < 0.00001), Child@ugh stage (p <0.00001), tumor pattern but not tumor size (p <0.00001) and metastasis (p <0.05) were the only independent variables significantly affecting outcome. According to these factors, the estimated 1-year and 3-year survival rates were 78% and 50%, respectively, in female patients with stage A cirrhosis, single HCC and A F P < 4 0 0 n g / m l , and of 15% and 1%, respectively, in male patients with stage B/C cirrhosis, multifocal HCC and AFP < 400ng/ml. Our results indicate that besides sex, stage of cirrhosis, AFP levels and presence of extra-hepatic spread, tumor multifocality, independently of the size of single nodules, is a major determinant in predicting the outcome of patients with untreated HCC and cirrhosis. These findings might be useful for the evaluation of current and future therapeutic procedures.
I•
ANTIOXIDANT S U P P L E M E N T S FOR PREVENTION OF LIVER C A N C E R
G. Bielakovic 1 , D. Nikolova 2, R.G. Simonetti 3, C. Gluud 2. 1Department
of Internal Medicine Gastroenterology and Hepatology, Medical Faculty, University of Nis, Nis, Serbia and Montenegro," 2The Coehrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Dept. 71.02, H.'S Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark," 3Divisione di Medicina Ospedale 1( Cervello, Palermo, Italy B a c k g r o u n d and Aim: Oxidative stress may cause liver cancer. Whether antioxidant supplements can prevent liver cancer is uncertain. Our aim
POSTERS
$98
was to assess benefits and harms of antioxidant supplements in preventing liver cancer. Methods: Using The Cochrane Collaboration methodology we reviewed all randomised trials comparing antioxidant supplements with placebo/ no intervention. We searched for trials, published by October 2005, in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL in The Cochrane Library, MEDLINE, EMBASE, LILACS, and SCIEXPANDED. We scanned references, and contacted authors and pharmaceutical companies. Results: We identified nine randomised trials (130,674 participants), assessing beta-carotene, vitamin A, C, E, and selenium, either singly or combined. In five low-bias risk trials (120,876) neither the fixed-effect (relative risk 1.37, 95%CI 0.89 2.13) nor random-effects (1.37, 0.88 2.12) meta-analyses showed significant effects of the antioxidant supplements on liver cancer incidence. The four high-bias risk trials (9798 participants) examined solely selenium. Selenium significantly decreased liver cancer incidence with both the fixed-effect and random-effects meta-analyses (0.56, 0.42~0.76). The intervention effect differed significantly between low- and high-bias risk trials (z=3.3, p=0.001) by test of interaction. Non-serious adverse effects were yellowing of the skin and gastrointestinal upset.
ZA~ET _-:.24
z:..~4=: ;.,~
1.al
[:.:e.
•
-D
"~
:;2
7a~l~..§ le~,~
c~l
was assessed by histopathological examination using thin sectioning of explanted livers with or without TIPS. Results: The two groups of patients (with vs without TIPS) were comparable when considering age (50• vs 50.9• gender (sex ratio 3.32 vs 2.89, OR 1.55) and aetiology of liver cirrhosis (alcohol: 56.9% vs 43.8%, OR 1.62; hepatitis C: 31.3% vs 34.2%, OR 0.85; hepatitis B: 5.9% vs 12.5%, OR 0.44). Child@ugh score was comparable between the two groups (9.75 vs 10). Overall, LGDN, HGDN and HCCi were found in 15.3%, 3.2% and 16.6% respectively in the 156 patients. The frequency of DN and/or HCCi was higher in patients with TIPS than in patients without TIPS (47% vs 29%, OR 2.12, p <0.05). When considering separately the frequency of HCCi no statistical difference was noted between the two groups of patients (19.6% vs 15.2%, OR 1.36, with and without TIPS respectively). Of note, in our population, chronic HCV infection was significantly associated with HCCi as compared with other aetiologies of cirrhosis (OR 2.82, p <0.05). Conclusions: In our population of liver transplanted patients, the risk of HCCi is not increased by TIPS. However, the overall increased risk of histopathological nodular lesions (DN and/or HCCi) cannot rule out an increased risk of HCC in patients with TIPS in case of a longer follow up in the absence of liver transplantation.
3,.=,
~
r==~ - = : I " i
.... :'2
[•
COMPARATIVE P R O T E O M I C ANALYSIS OF H E P A T O C E L L U L A R C A R C I N O M A S ON N O N - F I B R O T I C LIVER A N D H E P A T O C E L L U L A R A D E N O M A S
.=:%
eee:L_'=_'.-:. = = : ; : . / z
M.R Bralet 1, A. Dos Santos2, S. Sal2, V. Thiers2, C. Br~chot 2, D. Samuel 3, C. Guettier 1, E Demaugre 2. 1Department of Pathology, Figure 1. Relative risk, 95%CI (fixed). Intervention effect of different antioxidant supplements versus placebo/no intervention on the incidence of liver cancer stratifying trials according to risk of bias. Conclusions: We could not find convincing evidence that antioxidant supplements prevent liver cancer. We confirmed the significant influence of bias risk on estimation of intervention effects. The potential cancer preventive effect of selenium should be studied.
I•
D O E S T R A N S J U G U L A R INTRAHEPATIC PORTOSYSTEMIC SHUNT INCREASE HEPATOCELLULAR C A R C I N O M A RISK IN PATIENTS WITH C I R R H O S I S ? P A T H O L O G I C A L STUDY F R O M E X P L A N T E D LIVERS
P. Borentainl, R Ananian2, S. Garcia 3, S. Henrion 1, C. Barrantes 1, D. Botta-Fridlund 1, Y.R Letreut 2, R. Gerolami 1. 1Service
d 'H@atogastroentdrologie, 2Service de transplantation h@atique, Hdpital Conception, 3Service d'Anatomopathologie, H@ital Nord, Marseille, France Background and Aims: It has been recently reported that patients with cirrhosis and a Transjugular Intrahepatic Portosystemic Shunt (TIPS) may have an increased risk of hepatocellular carcinoma (HCC) development. The aim of our study was to assess the frequency of dysplastic nodules and incidental HCC in explanted cirrhotic livers with or without TIPS. Methods: Out of the 352 patients who underwent liver transplantation since 1993 in our liver transplantation center, 156 patients with end stage cirrhosis and who were without pretransplant evidence of HCC were selected. Among them 51 had a patent TIPS in their explanted liver that was placed at least 2 months (mean 11.1 months) before transplantation. The presence of dysplastic nodules (DN) including high-grade (HGDN) and low-grade (LGDN) dysplastic nodules and incidental HCC (HCCi)
APHP, 2INSERM U370, Centre H@ato-biliaire, 3Centre H@ato-biliaire, EA3541, H@ital Paul Brousse, Villejuif, France Background and Aims: Hepatocellular carcinomas (HCC) occurring on non-fibrotic liver are a rare subgroup of HCC for which mechanisms of carcinogenesis are unclear. Moreover, differential diagnosis between well differentiated HCC on non-fibrotic liver and hepatocellular adenoma (Ad) is difficult using histological criteria. The aim of this study was to identify markers differentially expressed between HCC on non-fibrotic liver and Ad by proteomic analysis. Methods: Proteins were extracted from 5 HCC on non-fibrotic liver, 5 Ad, and 10 normal livers. Isoelectrofocalisation was performed with 200 gg of protein extracts immobilized on pH 4 to 7 IPG strips at 80000Vh. SDSPAGE gels (10% polyacrylamide) were stained with silver nitrate solution, scanned and analysed with Image 2D Master Software. Proteins of interest were identified by mass spectroscopy (Maldi-Tof). Each experiment was performed in triplicate. Results: 42 protein spots were differentially expressed between HCC and Ad, 27 with an expression ratio of more than 2; 15 proteins were identified by Maldi-Tof including heterogeneous nuclear ribonucleoproteins K and E hsp 60, alcohol sulfotransferase, chloride intracellular channel protein 1, proteasome activator complex subunit 1, proteasome subunit beta type 4 precursor, ubiquinol cytochrome c reductase complex core protein 1, endoplasmin precursor, annexin A4 and 1, alphal antitrypsine precursor, nicotinamide N methyltransferase, tubulin alpha, protein-glutamine gamma-glutamyltransferase. Western blots confirmed that these 3 latter proteins were down-regulated in HCC compared to Ad and that annexinl was up-regulated in HCC compared to Ad. Conclusions: Proteomic profiles of HCC on non-fibrotic liver are different from those of Ad. 2D-electrophoresis and Maldi-Tof should allow the identification of new diagnosis markers of hepatocellular tumors and potential therapeutic targets.