Adriana Sergio

Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness.

OBJECTIVE:Although transcatheter arterial chemoembolization (TACE) is effective in hepatocellular carcinoma (HCC), it is not considered a curative procedure. Among the factors potentially interfering with its effectiveness is a hypothetical neoangiogenic reaction due to ischemia. In our study, we evaluated the changes in the levels of two angiogenic factors (vascular endothelial growth factor [VEGF] and basic fibroblast growth factor [b-FGF]) and one parameter of invasiveness (urokinase-type plasminogen activator [uPA]) in patients treated with TACE.METHODS:Three blood samples were provided from 71 HCC patients undergoing TACE: before TACE (t0), after 3 days (t1), and after 4 wk, when they had spiral computed tomography (sCT) scanning (t2). The referring radiologists blindly evaluated tumor burden and vascularization at t0 and residual activity at t2. The choice of TACE as treatment was based on the American Association for the Study of Liver Diseases (AASLD) guidelines.RESULTS:Complete response at sCT was recorded in 27% of patients; mean survival was 35 months (confidence interval [CI] 31–40) and the 4-yr survival was 57%. VEGF levels were significantly correlated with the number of nodes and were higher in nonresponders at t2 (P = 0.01); below-median VEGF levels predicted a longer survival (P = 0.008). b-FGF correlated with VEGF, tumor size, vascularization, and residual activity, showing a borderline correlation with survival. uPA correlated with tumor size and VEGF. VEGF was singled out in the Cox multivariate analysis as an independent predictor of survival.CONCLUSIONS:When TACE is not totally effective, it may induce a significant neoangiogenetic reaction, as suggested by an increase in VEGF and b-FGF following treatment; this affects patient survival. VEGF emerges as the most reliable prognostic parameter, so it could be measured for judging TACE efficacy. Finally, antiangiogenic drugs may be indicated in TACE-treated HCC.

Hepatitis C virus: from oxygen free radicals to hepatocellular carcinoma

Summary.  Epidemiological evidence clearly identifies chronic infection with hepatitis C virus (HCV) as a major risk factor for the development of hepatocellular carcinoma (HCC). Among the mechanisms that have been implicated in the pro‐carcinogenic effect of HCV infection, an increased production of reactive oxygen species in the liver seems to have a major pathogenetic role in leading from chronic inflammation to cancer. Recent data have also demonstrated that HCV is capable of inducing this active production of free radicals per se, not just through inflammation, a feature peculiar to this virus and the specific activity of its core protein. This paper provides an overview of the inter‐relationships between HCV, liver damage, free radical production and HCC, describing at least in part the complex network involving DNA oxidative damage, cytokine synthesis, proto‐oncogene activation and oestrogen receptor expression, that may all be deeply involved in liver carcinogenesis.

Squamous cell carcinoma antigen in human liver carcinogenesis

Background: Squamous cell carcinoma antigen (SCCA) is a serine protease inhibitor that can be overexpressed in hepatocellular carcinoma (HCC) at both molecular and protein level, but no data are available on its expression in pre-malignant stages. Aim: To assess SCCA expression by immunohistochemistry in HCC and its nodular precursors in cirrhotic livers. Methods: 55 nodules from 42 explanted livers were evaluated: 7 large regenerative nodules (LRNs), 7 low-grade dysplastic nodules (LG-DNs), 10 high-grade DNs (HG-DNs), and 31 HCC. SCCA expression was semiquantitatively scored on a four-tiered scale. Results: SCCA hepatocyte immunostaining was always restricted to the cytoplasm, mainly exhibiting a granular pattern. Stain intensity varied, ranging from weak to very strong. Within the nodules, positive cells were unevenly distributed, either scattered or in irregular clusters. The prevalence of SCCA expression was 29% in LRNs, 100% in DNs and 93% in HCC. A significant difference emerged in both prevalence and score for LRNs versus LG-DNs (p<0.039), HG-DNs (p = 0.001), and HCC (p = 0.000). A barely significant difference (p = 0.49) was observed between LG-DNs and HG-DNs, while no difference in SCCA expression was detected between HG-DNs and HCC. Cirrhotic tissue adjacent to the nodules was positive in 96% of cases, with a significant difference in the score (p = 0.000) between hepatocytes adjacent to HCC and those surrounding LRNs. Discussion: This study provides the first evidence that aberrant SCCA expression is an early event in liver cell carcinomatous transformation.

Oxidative DNA damage in gastric cancer : cagA status and OGG1 gene polymorphism

Oxidative DNA damage is thought to play an important part in the pathogenesis of H. pylori‐induced mucosal damage. 8‐OHdG is a sensitive marker of DNA oxidation and is repaired by a polymorphic glycosylase (OGG1) more effectively than by OGG1‐Cys326. The aims of this study were to ascertain the respective roles of H. pylori, cagA status and OGG1 polymorphism in determining 8‐OHdG levels in benign and premalignant stomach diseases and in gastric cancer (GC). The study involved 50 GC patients (for whom both neoplastic tissue and surrounding mucosa were available), 35 with intestinal metaplasia and atrophy (IMA) and 43 controls. H. pylori and cagA status were determined by histology and polymerase chain reaction for urease and cagA. 8‐OHdG was assayed using HPLC with an electrochemical detector (HPLC‐ED). The OGG1 1245C→G transversion was identified using RFLP analyses. 8‐OHdG levels were significantly higher in GC, with no differences in relation to H. pylori or cagA status. OGG1 polymorphism was documented in 34% of GC (15 Ser/Cys, 2 Cys/Cys). OGG1 1245C→G polymorphism was detected in 54% of IMA patients, but only 16% of controls (p = 0.0004) and coincided with significantly higher 8‐OHdG levels. In the multivariate analysis, 8‐OHdG levels were predicted by histotype and OGG1 status. OGG1 1245C→G polymorphism was common in both GC and IMA, but very rare in controls, and correlated more closely with 8‐OHdG levels than do H. pylori infection or cagA status.

Is female sex a significant favorable prognostic factor in hepatocellular carcinoma

Objective As sex favorably modulates the natural history of chronic liver diseases and the risk for neoplastic evolution, our study aimed to ascertain whether female hepatocellular carcinoma (HCC) patients are also characterized by better prognosis. Methods The ITA.LI.CA (Italian Liver Cancer) database was used, including 1834 HCC patients (482 females, 1352 males) that were consecutively diagnosed. The following variables were considered: age, etiology, modality of diagnosis, earlier interferon treatment, bilirubin, &agr;-fetoprotein levels, constitutional syndrome, portal thrombosis, metastasis, number and size of nodules, grading, Child–Pugh class, tumor–nodes–metastases and Cancer of the Liver Italian Program staging, and treatment. Results Female HCC patients were characterized by older age (P=0.0001), higher prevalence of HCV infection (P=0.0001), diagnosis more frequently by surveillance (P=0.003), higher &agr;-fetoprotein levels (P=0.0055), lower prevalence of constitutional syndrome (P=0.03), portal thrombosis (P=0.04), and metastasis (P=0.0001). HCC in females was more frequently unifocal (P=0.0001), smaller (P=0.001), well differentiated (P=0.001), and of lower Cancer of the Liver Italian Program and tumor–nodes–metastases stage (P=0.0001 and 0.0001). However, females underwent curative treatments (transplantation, resection, percutaneous ablation) in the same percentage of cases as males. Finally, females had a significantly longer survival (median 29 [95% confidence interval (CI): 24–33] vs. 24 (22–25) months, P=0.0001). The difference was sharper [median 36 (CI: 31–41] vs. 17 (CI: 15–19)] when females undergoing surveillance were compared with males diagnosed incidentally or for symptoms. The Cox model also identified sex as an independent predictor of survival. When only patients undergoing surveillance were considered, no significant difference was observed. Conclusion HCC in females has better prognosis, but this is possibly more because of higher compliance with surveillance than to real biological differences.

Liver transplantation for hepatocellular carcinoma in clinical practice: the lesson from a 20-year multicentre experience in Italy.

Introduction Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT), but the selection criteria and priority are still debated. Aims To ascertain the number and features of patients with HCC who undergo transplantation in a Western country, the number of patients eligible for LT according to the American Association for the Study of Liver Diseases (AASLD) guidelines, the number of patients who actually undergo transplantation and whether adherence affects survival. Methods This is a retrospective analysis from a multicentre Italian database of 2042 cases of HCC, recruited prospectively and consecutively. Kaplan–Meier (log rank) and Cox multivariate analysis estimated survival. Results Patients who had undergone transplantation (50, 2.5%, with no change over time) had a median survival of 133 months, significantly influenced by the number of lesions and alpha-fetoprotein levels, which were found to be independent predictors of survival on multivariate analysis. Milan criteria were fulfilled in 68%, impacting on survival, whereas 48% fulfilled AASLD guidelines, without such an impact. Two hundred and twenty-eight (11%) patients were eligible for LT according to AASLD; in this group, alpha-fetoprotein levels and Child–Pugh class were independent predictors of survival. Conclusion Among patients with HCC, those undergoing LT represent a small minority; even fewer (1%) are those who undergo transplantation according to AASLD guidelines, adherence to which only marginally affects survival. Overall, LT impact on HCC patients’ treatment is very limited.

Hepatic spleen nodules (HSN)

Abstract Hepatic splenosis is a nodular implant of normal spleen tissue in the liver. This innocent liver nodule is frequently misinterpreted as a malignancy. Almost all hepatic splenoses have been associated with a clinical history of splenic trauma or prior surgery. This report describes two cases of hepatic splenosis. In both patients, the nodular lesions were initially thought to be liver malignancies and they were ultimately assessed by histology. The clinico-pathological findings of all published cases of liver splenosis underwent critical review. Although they are rare, hepatic spleen nodules should always be included in the diagnostic spectrum of nodular liver lesions because of their impact on treatment decisions.

Megestrol and embryonic extracts in the treatment of advanced hepatocellular carcinoma : A prospective randomized trial in the pre-sorafenib era

Background:  Patients with advanced hepatocellular carcinoma (HCC) achieved significant results by the new treatment with sorafenib (a multi‐tyrosine kinase inhibitor), but, because it has been tested mainly in Child A cirrhosis, patients with impaired liver function are not eligible for the treatment.

Molecular Targeted Therapy in Hepatocellular Carcinoma: Present Achievements and Future Challenges

Therapeutic options in advanced stage hepatocellular carcinoma have been very poor until the discovery of new therapeutic agents that target the molecular pathways involved in hepatocarcinogenesis. In this paper we try to review the most important molecular agents in development, with a specific focus on sorafenib’s role and safety profile, especially in the treatment of patients with suboptimal liver function.

244 DIAGNOSTIC AND PROGNOSTIC ROLE OF SCCA-IGM IN HEPATOCELLULAR CARCINOMA (HCC)

generation of reactive oxygen species (ROS), phosphorylation/ inactivation of GSK-3b as well as phosphorylation of PI-3K, ERK1/2, JNK1/2, p38MAPK and STAT3. Invasiveness of cancer cells was prevented either by inhibiting ERK1/2, PI3K or JNK1/2 as well as by preventing ROS generation. Finally, OSM was expressed “in vivo” in tumor cells of HCC in areas also positive for hypoxia-related antigens. Conclusions: OSM, which is expressed in human HCC cells and peritumoral cirrhotic tissue, can induce EMT in human hepatic cancer cell lines and stimulate their increased invasiveness through the involvement of redox-dependent activation of EMT-related critical kinases and transcription factors.