A4 Abstracts / Digestive and Liver Disease 39 (2007) A1–A28
PROGNOSIS OF HEPATOCELLULAR CARCINOMA: COMPARI-SON OF CLIP, TNM, AND BCLC IN A COHORT OF PATIENTS FOLLOWED PROSPECTIVELY AT A SINGLE REFERRAL CEN-TER
M. De Giorgioa,b, R. Bezzob, U. Govindarajuluc, J. Dziurac, M.G. Luc`aa, G. Vergaa, D. Pinellia, G. Boninia, A. Sonzognia, M. Colledana, S. Fagiuolia, M. Strazzaboscob,c
aOspedali Riuniti di Bergamo, Italy bCeLiVer
cYale University, USA
Background. Staging systems for HCC are essential to assess prognosis, to guide the therapeutic approach and to design clinical trials. So far, no con-sensus is achieved on which of the several proposed staging system performs better.
Aim. To compare the three main staging systems (TNM, CLIP and BCLC) for which external validation data are present, using a large cohort of HCC patients followed prospectively at a single referral centre.
Methods. Demographic, clinical and histological data were prospectively collected, together with liver imaging, at baseline and at 3-month intervals after enrolment, in 327 consecutive HCC patients referred to our Unit from January 2000 to June 2005. HCC was diagnosed according with EASL crite-ria (histologically confirmed in 69%). Median follow-up was 2 years. 71 pts were resected, 46 pts underwent liver transplantation inside Milan Criteria (age <65 years); 96 pts received ablative treatments (PEI or RFTA) and 49 pts were treated with TACE. 66 pts remained untreated, because of advanced dis-ease, refusal of therapy or co-morbidities. The Kaplan–Meyer method and Cox regression models were used to analyse survival and prognosis factors for each staging system.
Results. Median age of the cohort was 64,5± 9.8 years, range 34–87, M:F ratio was 3, 6:1; 84.7% of the HCC arose on cirrhotic liver, 61.1% were monofocal at diagnosis. Overall probability of survival at 1, 3 and 5 years was 73.2% 53.9%, 28%, respectively, while for disease-free survival, they were 50.2% 20.7%, 11.5%. Univariate Cox models were run for each staging system and the likelihood ratio tests (p < 0.001) for each model indicated there were significant differences in overall survival and disease-free survival among categories for each system. The Akaike’s (AIC) information criteria (a measure of the overall goodness of fit) and the c-statistic are reported in the table.
Staging system AIC c-statistic
Overall survival Disease-free survival Overall survival Disease-free survival
1 year 3 years 5 years 0.5 years 1 year 3 years
TNM 57.47 37.50 0.721 0.634 0.559 0.657 0.606 –
BCLC 62.44 33.38 0.740 0.637 0.561 0.636 0.595 –
CLIP 90.71 55.20 0.782 0.679 0.614 0.680 0.638 –
Conclusion. All three staging systems effectively predict overall survival in a cohort of consecutive HCC patients prospectively followed and treated according to current guidelines. Disease-free survival can also be predicted by these models, for which we calculate the c-statistic at earlier time points due to greater number of events in the first year for this analysis. The TNM and the BCLC perform better than CLIP according to the AIC and c-statistic. BCLC is of peculiar interest because it establishes a link between staging and treatment.
doi:10.1016/j.dld.2006.12.028
PDGF-BB AS MITOGENIC AND CHEMOTACTIC STIMULUS FOR BONE MARROW-DERIVED HUMAN MESENCHYMAL STEM CELLS, PUTATIVE PRECURSORS OF PROFIBROGENIC MYOFIBROBLAST-LIKE CELLS
L. Valfr`e di Bonzoa, E. Novoa, E. Zamaraa, S. Cannitoa, I. Ferrerob, D. Rustichellib, S. Colombattoa, M. Pinzanic, S.J. Forbesd, F. Fagiolib, M. Parolaa
aDip. Medicina e Oncol. Sperimentale, Italy bDepartment of Pediatrics, University of Torino, Italy
cDip. Medicina Interna-Centro di Ricerca, Trasferimento e Alta Formazione
“DENOThe”, University of Florence, Italy
dTissue Fibrosis and Remodeling Laboratory, MRC/University of Edinburgh
Centre for Inflammation Research, Edimburgh, UK
Background and aims. Myofibroblast-like cells (MFs), key pro-fibrogenic effectors in chronic liver diseases (CLDs), can originate from activated hepatic stellate cells (HSC/MFs), portal (myo)fibroblasts and, as recently proposed, from bone marrow-derived stem cells. Here we investigated the ability of bone marrow-derived human mesenchymal stem cells (hMSC) to respond to key pro-fibrogenic mediators known to affect HSC/MFs prolif-eration and/or migration.
Methods. hMSC (CD34/CD45 negative; CD90, CD29, CD44 and CD105 positive) were isolated, purified and expanded “ex vivo”, morphologically characterized for antigen repertoire and tested for proliferation, chemotaxis (modified Boyden’s chamber assay) and/or non-oriented migration (wound healing assay, WHA) when exposed to PDGF-BB, bFGF, AT-II, thrombin, SDF-1, HGF, MCP-1, IP-10 and superoxide anion. PDGF-BB signaling was also investigated.
Results. hMSC used in this study expressed markers of “in vivo” activated HSC/MFs (␣-SMA, GFAP, vimentin, PDGF-receptor) but, differently from human HSC/MFs that proliferate with bFGF, thrombin and AT-II, they replicated significantly only in the presence of PDGF-BB. PDGF-BB, that was much more effective than MCP-1 in inducing chemokinesis (WHA), also stimulated significantly chemotaxis, although hMSC also consistently responded to SDF-1 and VEGF (hMSC being CXCR4, Flt-1 and Flk-1 posi-tive cells). For both hMSC and human HSC/MFs migration/chemotaxis were crucially involving activation of c-Jun N-terminal kinase isoforms (JNK1, 2), as also confirmed by using the specific JNK pharmacological inhibitor SP-600125.
Conclusions. PDGF-BB, the only effective stimulus for both chemotaxis and proliferation of human MSC, putative precursors of HSC/MFs, may favour hMSC liver engraftment and replication in CLDs.
doi:10.1016/j.dld.2006.12.029
EXPRESSION OF ANGIOGENIC CYTOKINES BY LEPTIN REQUIRES THE TSC/M-TOR PATHWAY AND GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IN HUMAN HEPATIC STEL-LATE CELLS
S. Aleffi, N. Navari, F. Marra
Dipartimento di Medicina Interna, Universit`a di Firenze, Italy
Leptin has recently emerged as an important mediator of liver angiogene-sis. Its actions include the induction of vascular endothelial growth factor
