Radiological diagnosis of hepatocellular carcinoma

Treatment of hepatocellular carcinomas (HCC) is often complicated by the fact that early HCCs are mostly asymptomatic and the carcinoma is often discovered at an advanced stage. The aim of diagnostic imaging is to detect HCC at an early stage, when curative options are available. In recent years, there have been many efforts to improve early detection of small HCC. The purpose of this article is to describe the pertinent findings of HCCs in non-invasive, diagnostic imaging, including ultrasound, computed tomography, as well as modern magnetic resonance imaging techniques. Special emphasis is given to the frequently addressed difficulties of differentiation of precancerous lesions and small HCCs. A non-invasive diagnostic approach is considered with a review of the literature.

Non-selective beta-blockers may reduce risk of hepatocellular carcinoma: a meta-analysis of randomized trials

BACKGROUND & AIMS Non-selective beta-blockers (NSBB) are used in patients with cirrhosis and oesophageal varices. Experimental data suggest that NSBB inhibit angiogenesis and reduce bacterial translocation, which may prevent hepatocellular carcinoma (HCC). We therefore assessed the effect of NSBB on HCC by performing a systematic review with meta-analyses of randomized trials. METHODS Electronic and manual searches were combined. Authors were contacted for unpublished data. Included trials assessed NSBB for patients with cirrhosis; the control group could receive any other intervention than NSBB. Fixed and random effects meta-analyses were performed with I(2) as a measure of heterogeneity. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate heterogeneity, bias and the robustness of the results after adjusting for multiple testing. RESULTS Twenty-three randomized trials on 2618 patients with cirrhosis were included, of which 12 reported HCC incidence and 23 reported HCC mortality. The mean duration of follow-up was 26 months (range 8-82). In total, 47 of 694 patients randomized to NSBB developed HCC vs 65 of 697 controls (risk difference -0.026; 95% CI-0.052 to -0.001; number needed to treat 38 patients). There was no heterogeneity (I(2) = 7%) or evidence of small study effects (Eggers P = 0.402). The result was not confirmed in sequential analysis, which suggested that 3719 patients were needed to achieve the required information size. NSBB did not reduce HCC-related mortality (RD -0.011; 95% CI -0.040 to 0.017). CONCLUSIONS Non-selective beta-blockers may prevent HCC in patients with cirrhosis.

Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study

It is unknown whether sorafenib can be combined with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma. This study assesses the safety and tolerability of a continuous regimen of sorafenib combined with TACE.

Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06)

Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC).

Hepatocellular carcinoma and regenerating nodule in a 3-year-old child with Alagille syndrome

In Alagille syndrome, routine follow-up imaging of the liver plays an important role in detecting early parenchymal changes and to evaluate portal hypertension. Modern contrast-enhanced imaging methods not only allow early detection of focal liver lesions, but also enable further characterization of their nature and guide biopsy procedures. We present the US and MR imaging findings of hepatocellular carcinoma and a regenerating nodule in a 3-year-old child with Alagille syndrome.

Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib.

Aberrant lipid metabolism in hepatocellular carcinoma revealed by plasma metabolomics and lipid profiling

There has been limited analysis of the effects of hepatocellular carcinoma (HCC) on liver metabolism and circulating endogenous metabolites. Here, we report the findings of a plasma metabolomic investigation of HCC patients by ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS), random forests machine learning algorithm, and multivariate data analysis. Control subjects included healthy individuals as well as patients with liver cirrhosis or acute myeloid leukemia. We found that HCC was associated with increased plasma levels of glycodeoxycholate, deoxycholate 3-sulfate, and bilirubin. Accurate mass measurement also indicated upregulation of biliverdin and the fetal bile acids 7α-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochol-4,6-dien-24-oic acid in HCC patients. A quantitative lipid profiling of patient plasma was also conducted by ultraperformance liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (UPLC-ESI-TQMS). By this method, we found that HCC was also associated with reduced levels of lysophosphocholines and in 4 of 20 patients with increased levels of lysophosphatidic acid [LPA(16:0)], where it correlated with plasma α-fetoprotein levels. Interestingly, when fatty acids were quantitatively profiled by gas chromatography-mass spectrometry (GC-MS), we found that lignoceric acid (24:0) and nervonic acid (24:1) were virtually absent from HCC plasma. Overall, this investigation illustrates the power of the new discovery technologies represented in the UPLC-ESI-QTOFMS platform combined with the targeted, quantitative platforms of UPLC-ESI-TQMS and GC-MS for conducting metabolomic investigations that can engender new insights into cancer pathobiology.

The homeobox gene HLXB9 is upregulated in a morphological subset of poorly differentiated hepatocellular carcinoma

The prognostic outcome for hepatocellular carcinoma (HCC) remains poor. Disease progression is accompanied by dedifferentiation of the carcinoma, a process that is not well understood. The aim of this study was to get more insight into the molecular characteristics of dedifferentiated carcinomas using high throughput techniques. Microarray-based global gene expression analysis was performed on five poorly differentiated HCC cell lines compared with non-neoplastic hepatic controls and a set of three cholangiolar carcinoma (CC) cell lines. The gene with the highest upregulation was HLXB9. HLXB9 is a gene of the homeobox genfamily important for the development of the pancreas. RT-PCR confirmed the upregulation of HLXB9 in surgical specimens of carcinoma tissue, suggesting its biological significance. Interestingly, HLXB9 upregulation was primary observed in poorly differentiated HCC with a pseudoglandular pattern compared with a solid pattern HCC or in moderate or well-differentiated HCC. Additional the expression of translated HLXB9, the protein HB9 (NCBI: NP_001158727), was analyzed by western blotting. Expression of HB9 was only detected in the cytoplasm but not in the nuclei of the HCC cells. For validation CC were also investigated. Again, we found an upregulation of HLXB9 in CC cells accompanied by an expression of HB9 in the cytoplasms of these tumor cells, respectively. In conclusion, homeobox HLXB9 is upregulated in poorly differentiated HCC with a pseudoglandular pattern. The translated HB9 protein is found in the cytoplasm of these HCC and CC. We therefore assume HLXB9 as a possible link in the understanding of the development of HCC and CC, respectively.

Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions

The intermediate stage of hepatocellular carcinoma (HCC) comprises a highly heterogeneous patient population and therefore poses unique challenges for therapeutic management, different from the early and advanced stages. Patients classified as having intermediate HCC by the Barcelona Clinic Liver Cancer (BCLC) staging system present with varying tumor burden and liver function. Transarterial chemoembolization (TACE) is currently recommended as the standard of care in this setting, but there is considerable variation in the clinical benefit patients derive from this treatment.In April 2012, a panel of experts convened to discuss unresolved issues surrounding the application of current guidelines when managing patients with intermediate HCC. The meeting explored the applicability of a subclassification system for intermediate HCC patients to tailor therapeutic interventions based on the evidence available to date and expert opinion. The present report summarizes the proposal of the expert panel: four substages of intermediate HCC patients, B1 to B4.