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.

Hepatic spleen nodules (HSN).

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.

Early and very early hepatocellular carcinoma: when and how much do staging and choice of treatment really matter? A multi-center study.

BACKGROUND: A consensus on the most reliable staging system for hepatocellular carcinoma (HCC) is still lacking but the most used is a revised Barcelona Clinic Liver Cancer (BCLC) system, adopted by the American Association for the Study of Liver Diseases (AASLD). We investigated how many patients are diagnosed in "very early" and "early" stage, follow the AASLD guidelines for treatment and whether their survival depends on treatment. METHODS: Data were collected in 530 "very early" and "early" HCC patients recruited by a multicentric Italian collaborative group (ITA.LI.CA). The Kaplan-Meier method was used to estimate overall survival and the log rank to test the statistical significance of difference between groups. Cox's multivariate stepwise regression analysis was used to pinpoint independent prognostic factors and the adjusted relative risks (hazard ratios) were calculated as well. A statistical analysis based on the chi-square test was used to identify significant differences in clinical or pathological features between patients. A P-value < 0.05 was considered statistically significant. RESULTS: "Very early" HCC were 3%; Cox multivariate analysis did not identify variables independently associated with survival. The patients following AASLD recommendations (20%) did not show longer survival. In "early" HCC patients (25%), treatment significantly modulated survival (p = 0.0001); the 28% patients treated according to the AASLD criteria survived longer (p = 0,004). The Cox analysis however identified only age, gender, number of lesions and Child class as independent predictors of survival. CONCLUSION: patients with very early" HCC were very few in this analysis. In most instances they were not treated with the treatment suggested as the most appropriate by the AASLD guidelines and the type of treatment had no impact on survival, even though the number of patients was relatively low and part of the patients were diagnosed before the introduction of the guidelines: this analysis, therefore, might not be considered as conclusive and should be validated. The "early" stage group involved more patients, rarely treated according to the guidelines, both overall and also in those diagnosed after their publication; the survival was in part predicted by the type of treatment, with better results in those treated according to AASLD indications.

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-Cys(326). 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.

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.

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.

Hepatitis B virus-related hepatocellular carcinoma: primary, secondary, and tertiary prevention.

With respect to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), primary, secondary, and tertiary prevention measures have been or should be adopted. In primary prevention, behavioral patterns represent an important risk factor for HBV infection and should be controlled, discouraging those favoring infection. Interferon treatment shows a modest effect in reducing HCC risk in treated patients, but the data obtained cannot be converted in clinical practice. Nucleoside analogs significantly reduce, but do not abolish, HCC risk in patients with cirrhosis, and should therefore be used in patients with cirrhosis and also to diminish the risk of the other potential complications. With respect to secondary prevention, surveillance with semiannual ultrasound examination is indicated in patients with HBV-related cirrhosis as well as in other subgroups of patients, depending on racial and geographical pattern. Finally, the role of interferon in tertiary prevention of HCC relapse after radical treatment is still under debate; some evidence in favor of the treatment is present, but side effects due to toxicity are frequent and severe enough to limit patients' compliance substantially. As there is definitely no agreement on the efficacy and cost-effectiveness of antiviral treatment in HCC prevention, there is still a need for well-constructed, large size, and randomized prospective trials to confirm what is still required based on expert opinion rather than on sound scientific evidence.

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. METHODS: This study was an open label phase III randomized trial comparing Synchro-Levels (Alphrema, Varese, Italy) and megestrol, with a 2:1 design, in patients with advanced HCC, planned before the sorafenib registration. End-points were objective response and impact on performance status (primary) and biochemical response (secondary). RESULTS: The patients enrolled were 61 (43 men, 18 women; Child A in 28 [48%] and B in 33 [52%]). Forty-three were assigned to Synchro-Levels, 18 to megestrol. Most patients had multifocal disease (75% in megestrol and 59% in Synchro-Levels) and there was a significant difference in tumor burden, with more advanced disease in the megestrol arm (P = 0.0002). At 3 months, tumor burden was more frequently stable with megestrol, while performance status was significantly better in patients treated with Synchro-Levels. At 6 months, alpha-fetoprotein was more frequently stable or reduced with megestrol. An objective response was observed in a megestrol-treated patient. Mortality was significantly lower and long-term survival significantly more frequent with megestrol. CONCLUSION: Megestrol treatment shows good results in advanced HCC and could become part of best supportive care in patients not suitable for other treatments, that, despite sorafenib, remain an important share.

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, alpha-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 alpha-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.