The performance of circulating biomarkers for the diagnosis of hepatocellular carcinoma (HCC) is sub-optimal. In this study we tested circulating microRNAs as biomarkers for HCC in cirrhotic patients by performing a two stage study: a discovery phase conducted by microarray and a validation phase performed by qRT-PCR in an independent series of 118 patients. Beside miRNAs emerged from the discovery phase, miR-21, miR-221, miR-519d were also tested in the validation setting on the basis of literary and tissue findings. Deregulated microRNAs were assayed in HCC-derived cells in the intracellular compartment, cell culture supernatant and exosomal fraction. Serum and tissue microRNA levels were compared in 14 patients surgically treated for HCC. From the discovery study, it emerged that seven circulating microRNAs were differentially expressed in cirrhotic patients with and without HCC. In the validation set, miR-939, miR-595 and miR-519d were shown to differentiate cirrhotic patients with and without HCC. MiR-939 and miR-595 are independent factors for HCC. ROC curves of miR-939, miR-595 and miR-519d displayed that AUC was higher than AFP. An exosomal secretion of miR-519d, miR-21, miR-221 and miR-1228 and a correlation between circulating and tissue levels of miR-519d, miR-494 and miR-21 were found in HCC patients. Therefore, we show that circulating microRNAs deserve attention as non-invasive biomarkers in the diagnostic setting of HCC and that exosomal secretion contributes to discharging a subset of microRNAs into the extracellular compartment.

Immune inflammation indicators and implication for immune modulation strategies in advanced hepatocellular carcinoma patients receiving sorafenib Immune inflammation indicators and implication for immune modulation strategies in advanced hepatocellular carcinoma patients receiving sorafenib

BACKGROUND: α‐Fetoprotein (AFP) is a biomarker commonly used in the management of patients with hepatocellular carcinoma (HCC), although the possible determinants of its serum levels in these patients have not been adequately explored. For this study, the authors evaluated the relevance of demographic, clinical, and oncologic factors to the presence of elevated AFP levels in large cohort of patients with HCC.METHODS: In 4123 patients with HCC who were managed by the Italian Liver Cancer Group, AFP levels were assessed along with their association with demographic, biochemical, clinical, and oncologic characteristics. Patients were subdivided according to the presence of elevated AFP (ie, >10 ng/mL).RESULTS: AFP levels were elevated in 62.4% of patients with HCC. Multivariate logistic regression analysis indicated that being a woman (odds ratio [OR], 1.497; 95% confidence interval [95%CI], 1.250‐1.793; P < .0001), the presence of cirrhosis (OR, 1.538; 95% CI, 1.050‐2.254; P = .027), liver disease with viral etiology (OR, 1.900; 95% CI, 1.589‐2.272; P < .0001), an elevated alanine aminotransferase level (OR, 1.878; 95% CI, 1.602‐2.202; P < .0001), a low albumin level (OR, 1.301; 95% CI, 1.110‐1.525; P = .012), an HCC tumor size >2 cm (OR, 1.346; 95% CI, 1.135‐2.596; P = .001), multinodular HCC (OR, 1.641; 95% CI, 1.403‐1.920; P < .0001), and the presence of vascular invasion (OR, 1.774; 95% CI, 1.361‐2.311; P < .0001) were associated independently with elevated levels of AFP. Both the median AFP level and the proportion of patients who had elevated levels increased with decreasing degrees of HCC differentiation (P < .0001).CONCLUSIONS: Sex and features of chronic liver disease were identified as nontumor characteristics that influence serum AFP levels in patients with HCC. These findings should be taken into account as limitations in interpreting the oncologic meaning of this biomarker in clinical practice. Cancer 2014;120:2150–2157. © 2014 American Cancer Society.

Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells’ extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet–tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC.

Objective. Ultrasonography is the first examination performed for screening of hepatocellular carcinoma (HCC); contrast‐enhanced ultrasonography (CEUS) can help discriminate between HCC and other lesions. Primary hepatic lymphoma (PHL), even if rare, should be considered in the differential diagnosis of focal liver lesions (FLLs). Few data are available in the literature about the role of CEUS in the diagnosis of PHL; we tried to determine whether CEUS could have a role in this setting. Methods. we describe 2 cases of primary non‐Hodgkin lymphoma of the liver associated with hepatitis B virus (HBV) infection. The first patient was a 62‐year‐old man who was an HBV‐inactive carrier, and the second was a 58‐year‐old man with type 2 diabetes and chronic HBV hepatitis. Results. in both cases, ultrasonography showed a hypoechoic liver lesion (4 and 3 cm, respectively) with irregular margins in segment 4 of the liver. On CEUS, these lesions were inhomogeneously hyperenhanced in the arterial phase and hypoenhanced in the portal and late phases. Contrast‐enhanced computed tomography (CT) in both patients showed slight hyperenhancement in the arterial phase and hypoenhancement in the remaining phases. Needle biopsy showed marginal zone B‐cell lymphoma of the mucosa‐associated lymphoid tissue type in both patients. Conclusions. Contrast‐enhanced ultrasonography and CT did not help us differentiate PHL from HCC; in fact, in both cases we saw the characteristic findings of primary HCC. Primary hepatic lymphoma is a rare condition, but it should always be considered in the differential diagnosis of FLLs. We stress the important role of liver biopsy when imaging indicates HCC in patients without underlying cirrhosis.