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Dendritic cell function in patients with hepatocellular carcinoma
Poster Sessions
78
~265-] ROYAL FREE (RFH) SCORING SYSTEM FOR UNIFOCAL HEPATOCELLULAR CARCINOMA (HCC) <5 cm DIAMETER: A VALUABLE PROGNOSTIC TOOL Romano Colombari 1, Roberto Togni 2, Alberto Furlanetto 3, Alberto Quaglia 4, Arjun Dhillon 4, Francesca Demicbelis 5, A. Spinoso 6, E Capelli 6, L. Marchiori 7, N. Nicoli 7, Paulette Bioulac-Sage 8, Charles Balabaud s , Amar Paul Dhillon 4. lServizio di Anatomia
Patologica, Arzignano; 2Servizio di Anatomia Patologica, Trento; 3Servizio di Anatomia Patologica, Treviso; 5IRST, Trento; 61stituto di Anatomia Patologica Policlinico Universitario, Verona; 71stituto di Chrirugia Generale B Policlinico Universitario, Verona, Italy; 4Department of Histopathology Royal Free Campus, London, UK; SLab Pathology INSERM/E9917, Bordeaux, France Baekground: Prognostic assessment for hepatocellular carcinoma (HCC) patients is a difficult task. We formulated a histological scoring system for RFH-scoring system (J Hepatol 34 (Suppll); 105: 2001). The system was primarily designed to render systematic the individual features that contribute to the pathological diagnosis of HCC. We tested the HCC scoring system against patient survival data to judge its potential utility in prognostic assessment. Materials and Methods: 315 surgical resections of HCC were performed at the University Hospital in Verona, between 1978 and 2001.28 of these were unifocal; less than 5 cm diameter; from cirrhotic patients and were Child-Pugh Class A. Each lesion was reviewed (RC) with systematic documentation of the following histological features: nodule size, nodule heterogeneity, reticulin loss, trabecular thickness, capillarisation, number of solitary arterioles, cellular atypia, mitotic activity, necrosis, vascular invasion, capsular invasion. Survival curves were estimated using the KaplanMeier method and compared by means of the log rank test. Results: The median survival time was 71 months after surgery. The overall HCC score ranged between 13 and 35, with a median score of 28. A statistically significant difference (P = 0.042) in survival of patients with a RFH score for HCC less than 28 (median survival time 108 months) was obtained as compared with the survival time of patients with a score more than 28 (median survival time 35 months). Candusion: The RFH scoring system for HCC is a valuable prognostic tool for surgically resected, unifocal, <5 cm, HCC in cirrhotic (Child-Pugh Class A) patients.
•6]
DENDRITIC CELL FUNCTION IN PATIENTS WITH HEPATOCELLULAR CARCINOMA
Helena Daniels i, Joti Hannoe 1, Sinead CosteUoe 1, Vinod Patel 1, Farzin Farzaneh 2, Phillip Harrison I . llnstitute of Liver Studies, GKT
School of Medicine, London; 2Department of Molecular Medicine, GKT School of Medicine, London, UK Previous reports of defective dendritic cell (DC) function in hepatocellular carcinoma (HCC) included a majority of patients with hepatitis C virus infection (HCV), itself associated with impaired DC function. We investigated monocyte-derived DC function in five groups of patients, cirrhosis (n = 17) or HCC (n = 11) of non-virai origin, HCC + HCV (n = 5), HCV alone (n = 23) and controls (n = 17). In allogeneic mixed lymphocyte reaction (MLR), DC from patients with HCC (11166 cpm 4- 4091), cirrhosis (9661 4- 8625) and controls (11959 4- 7032) were similar but DC from patients with HCV (6784 4- 4854 p = 0.03) or HCC + HCV (5959 45807) were less stimulatory. However, T cell responses to autologous DC loaded with PPD (a recall antigen, 20 ug/ml) or KLH (a neo-antigen, 80 ug/ml) were not impaired in any patient group (see table). DC phenotype investigated by flow cytometry showed that in HCV CD14 and CDla were higher (14.1%, 38.2%) compared to controls (5.5% p = 0.031 and 8.7%, p = 0.011), whereas CD83 was lower (12.3% vs 60.1%, p = 0.001), indicating a less mature phenotype. After pulsing with KLH, DC from HCV expressed more CD83 (58.6% vs 10.0%, p = 0.02, n = 6), indicating antigen induced maturation. DC from patients with non-viral HCC have a normal pheno-
Antigen
Stimulation Index HCC N o r m a l Cirrhotic HCV (±SD) HCC-HCVPPD 22.2±22.1 8.94-7.3 27.34-31.7 34±48.5 29.04-36.5 KLH 2.5±1.7 4.44-5.0 4.4±5.2 16.44-16.9 7.14-9.8 type and T-cell stimulation capacity. DC from patients with HCV 4- HCC have an immature phenotype and reduced stimulatory capacity in MLR but they mature when pulsed with soluble antigens.
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7HIP/PAP ]A C-TYPE LECTIN OVEREXPRESSED IN HEPATOCELLULAR CARClNOMABINDS THE RII ALPHA REGULATORY SUBUNIT OF PKA
France Demaugre 1, Yannick Philippe 1, Bernard Pileire 2, Sokavuth Sar l, Laurence Chfista 1, Christian Brechot I . l Demaugre F INSERM U370,
Paris; 2Biochemical Laboratory, CHU Point ?*Pitre Guadeloupe, France HIP/PAP is a Ctype lectin overexpressed in hepatocellular carcinoma. Pleiotropic biological activities have been ascribed to this protein. However, nothing is known about the function of HIP/PAP in the liver during hepatic carcinogenesis. Thus we sought for proteins interacting with HIP/PAP by screening a hepatocellular eDNA expression library. Using that approach we identified the RII alpha regulatory subunit of PKA as a partner of HIP/PAP. The interaction between the two proteins was further established in HIP/PAP expressing cells. HIP/PAP expression increased native PKA activity, suggesting that HIP/PAP may be involved in modulating PKA dependent signalling. Overall, our findings lead us to propose PKA as a target for a C-type lectin. They also offer a mechanism which may of importance to account for certain steps of liver carcinogenesis. TUMOR SIZE THE ONLY FACTOR THAT DETERMINES THE •8"7 ISEFFICACY OF PERCUTANEOUS ETHANOL INJECTION (PEI) FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA (HCC)? Giovan Giuseppe Di Costanzo, Massimo de Luca, Antonio Ascione.
Hepatology, Cardarelli Hospital, Naples, Italy PEI is the standard percutaneous technique to cure HCC, but predictive factors of efficacy have been investigated only in few studies. Aim: To identify factors predicting complete tumor necrosis after PEI. Patients and Methods: 177 HCC nodules in 142 consecutive cirrhotics (males 107; mean age 65 4- 8 years; etiology: virus-related 80%, non-viral 9%, mixed 11%; Child-Pugh A = 58.5%, B = 41.5%) were considered. PEI was performed by a single operator and efficacy was assessed by spiralCT. Nodule characteristics: SIZE = <20 mm: 34.4%, 20-30 mm: 29.4%, >30 mm: 36.2% (range 10--68 mm); US PATTERN = hypoechoic 68%, hyperechoic 18%, complex 14%; OUTLINE = regular 85%, irregular 15%; HALO SIGN+ = 15%. AFP was <20 ng/mi in 59.3%, 20-200 ng/ml in 29.4% and >200 ng/ml in 11.3%. All listed factors were evaluated by Mann-Whitney, Chi-square and multivariate logistic regression analysis. Results: Complete necrosis of nodule was observed in 69% of cases. At univariate as at multivariate analysis, only size (p = 0.001, OR 3.6, C195% 1.6-8.2) and regularity of nodule margins (p < 0.001, OR 7.5, C195% 2.621.5) were associated with necrosis. In particular, a regular nodule outline resulted the factor more related to complete necrosis, occurring in 77% of regular and 22% of irregular shaped HCCs. Conclusions" Nodule outline at ultrasonography is another parameter in predicting PEI success and this sign should be sistematically evaluated in selecting the appropriate locoregional treatment.
78
~265-] ROYAL FREE (RFH) SCORING SYSTEM FOR UNIFOCAL HEPATOCELLULAR CARCINOMA (HCC) <5 cm DIAMETER: A VALUABLE PROGNOSTIC TOOL Romano Colombari 1, Roberto Togni 2, Alberto Furlanetto 3, Alberto Quaglia 4, Arjun Dhillon 4, Francesca Demicbelis 5, A. Spinoso 6, E Capelli 6, L. Marchiori 7, N. Nicoli 7, Paulette Bioulac-Sage 8, Charles Balabaud s , Amar Paul Dhillon 4. lServizio di Anatomia
Patologica, Arzignano; 2Servizio di Anatomia Patologica, Trento; 3Servizio di Anatomia Patologica, Treviso; 5IRST, Trento; 61stituto di Anatomia Patologica Policlinico Universitario, Verona; 71stituto di Chrirugia Generale B Policlinico Universitario, Verona, Italy; 4Department of Histopathology Royal Free Campus, London, UK; SLab Pathology INSERM/E9917, Bordeaux, France Baekground: Prognostic assessment for hepatocellular carcinoma (HCC) patients is a difficult task. We formulated a histological scoring system for RFH-scoring system (J Hepatol 34 (Suppll); 105: 2001). The system was primarily designed to render systematic the individual features that contribute to the pathological diagnosis of HCC. We tested the HCC scoring system against patient survival data to judge its potential utility in prognostic assessment. Materials and Methods: 315 surgical resections of HCC were performed at the University Hospital in Verona, between 1978 and 2001.28 of these were unifocal; less than 5 cm diameter; from cirrhotic patients and were Child-Pugh Class A. Each lesion was reviewed (RC) with systematic documentation of the following histological features: nodule size, nodule heterogeneity, reticulin loss, trabecular thickness, capillarisation, number of solitary arterioles, cellular atypia, mitotic activity, necrosis, vascular invasion, capsular invasion. Survival curves were estimated using the KaplanMeier method and compared by means of the log rank test. Results: The median survival time was 71 months after surgery. The overall HCC score ranged between 13 and 35, with a median score of 28. A statistically significant difference (P = 0.042) in survival of patients with a RFH score for HCC less than 28 (median survival time 108 months) was obtained as compared with the survival time of patients with a score more than 28 (median survival time 35 months). Candusion: The RFH scoring system for HCC is a valuable prognostic tool for surgically resected, unifocal, <5 cm, HCC in cirrhotic (Child-Pugh Class A) patients.
•6]
DENDRITIC CELL FUNCTION IN PATIENTS WITH HEPATOCELLULAR CARCINOMA
Helena Daniels i, Joti Hannoe 1, Sinead CosteUoe 1, Vinod Patel 1, Farzin Farzaneh 2, Phillip Harrison I . llnstitute of Liver Studies, GKT
School of Medicine, London; 2Department of Molecular Medicine, GKT School of Medicine, London, UK Previous reports of defective dendritic cell (DC) function in hepatocellular carcinoma (HCC) included a majority of patients with hepatitis C virus infection (HCV), itself associated with impaired DC function. We investigated monocyte-derived DC function in five groups of patients, cirrhosis (n = 17) or HCC (n = 11) of non-virai origin, HCC + HCV (n = 5), HCV alone (n = 23) and controls (n = 17). In allogeneic mixed lymphocyte reaction (MLR), DC from patients with HCC (11166 cpm 4- 4091), cirrhosis (9661 4- 8625) and controls (11959 4- 7032) were similar but DC from patients with HCV (6784 4- 4854 p = 0.03) or HCC + HCV (5959 45807) were less stimulatory. However, T cell responses to autologous DC loaded with PPD (a recall antigen, 20 ug/ml) or KLH (a neo-antigen, 80 ug/ml) were not impaired in any patient group (see table). DC phenotype investigated by flow cytometry showed that in HCV CD14 and CDla were higher (14.1%, 38.2%) compared to controls (5.5% p = 0.031 and 8.7%, p = 0.011), whereas CD83 was lower (12.3% vs 60.1%, p = 0.001), indicating a less mature phenotype. After pulsing with KLH, DC from HCV expressed more CD83 (58.6% vs 10.0%, p = 0.02, n = 6), indicating antigen induced maturation. DC from patients with non-viral HCC have a normal pheno-
Antigen
Stimulation Index HCC N o r m a l Cirrhotic HCV (±SD) HCC-HCVPPD 22.2±22.1 8.94-7.3 27.34-31.7 34±48.5 29.04-36.5 KLH 2.5±1.7 4.44-5.0 4.4±5.2 16.44-16.9 7.14-9.8 type and T-cell stimulation capacity. DC from patients with HCV 4- HCC have an immature phenotype and reduced stimulatory capacity in MLR but they mature when pulsed with soluble antigens.
•
7HIP/PAP ]A C-TYPE LECTIN OVEREXPRESSED IN HEPATOCELLULAR CARClNOMABINDS THE RII ALPHA REGULATORY SUBUNIT OF PKA
France Demaugre 1, Yannick Philippe 1, Bernard Pileire 2, Sokavuth Sar l, Laurence Chfista 1, Christian Brechot I . l Demaugre F INSERM U370,
Paris; 2Biochemical Laboratory, CHU Point ?*Pitre Guadeloupe, France HIP/PAP is a Ctype lectin overexpressed in hepatocellular carcinoma. Pleiotropic biological activities have been ascribed to this protein. However, nothing is known about the function of HIP/PAP in the liver during hepatic carcinogenesis. Thus we sought for proteins interacting with HIP/PAP by screening a hepatocellular eDNA expression library. Using that approach we identified the RII alpha regulatory subunit of PKA as a partner of HIP/PAP. The interaction between the two proteins was further established in HIP/PAP expressing cells. HIP/PAP expression increased native PKA activity, suggesting that HIP/PAP may be involved in modulating PKA dependent signalling. Overall, our findings lead us to propose PKA as a target for a C-type lectin. They also offer a mechanism which may of importance to account for certain steps of liver carcinogenesis. TUMOR SIZE THE ONLY FACTOR THAT DETERMINES THE •8"7 ISEFFICACY OF PERCUTANEOUS ETHANOL INJECTION (PEI) FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA (HCC)? Giovan Giuseppe Di Costanzo, Massimo de Luca, Antonio Ascione.
Hepatology, Cardarelli Hospital, Naples, Italy PEI is the standard percutaneous technique to cure HCC, but predictive factors of efficacy have been investigated only in few studies. Aim: To identify factors predicting complete tumor necrosis after PEI. Patients and Methods: 177 HCC nodules in 142 consecutive cirrhotics (males 107; mean age 65 4- 8 years; etiology: virus-related 80%, non-viral 9%, mixed 11%; Child-Pugh A = 58.5%, B = 41.5%) were considered. PEI was performed by a single operator and efficacy was assessed by spiralCT. Nodule characteristics: SIZE = <20 mm: 34.4%, 20-30 mm: 29.4%, >30 mm: 36.2% (range 10--68 mm); US PATTERN = hypoechoic 68%, hyperechoic 18%, complex 14%; OUTLINE = regular 85%, irregular 15%; HALO SIGN+ = 15%. AFP was <20 ng/mi in 59.3%, 20-200 ng/ml in 29.4% and >200 ng/ml in 11.3%. All listed factors were evaluated by Mann-Whitney, Chi-square and multivariate logistic regression analysis. Results: Complete necrosis of nodule was observed in 69% of cases. At univariate as at multivariate analysis, only size (p = 0.001, OR 3.6, C195% 1.6-8.2) and regularity of nodule margins (p < 0.001, OR 7.5, C195% 2.621.5) were associated with necrosis. In particular, a regular nodule outline resulted the factor more related to complete necrosis, occurring in 77% of regular and 22% of irregular shaped HCCs. Conclusions" Nodule outline at ultrasonography is another parameter in predicting PEI success and this sign should be sistematically evaluated in selecting the appropriate locoregional treatment.