Sara Marinelli

Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study.

Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD‐related HCC (NAFLD‐HCC) and to compare them to those of hepatitis C virus (HCV)‐related HCC. A total of 756 patients with either NAFLD (145) or HCV‐related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead‐time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD‐HCC patients, in contrast to the near totality of HCV‐HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD‐HCC, 25.5 months (95% confidence interval 21.9‐29.1), than in those with HCV‐HCC, 33.7 months (95% confidence interval 31.9‐35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD‐HCC and HCV‐HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) Conclusions: NAFLD‐HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment. (Hepatology 2016;63:827–838)

Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis.

Sorafenib and transarterial 90Y‐radioembolization (TARE) are possible treatments for Barcelona Clinic Liver Cancer (BCLC) intermediate‐advanced stage hepatocellular carcinoma (HCC). No study directly comparing sorafenib and TARE is currently available. This single‐centre retrospective study compares the outcomes achieved with sorafenib and TARE in HCC patients potentially amenable to either therapy.

VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: The ALICE‐1 study

Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF‐A, VEGF‐C and VEGFR‐1,2,3 single nucleotide polymorphisms (SNPs). Patients progression‐free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF‐A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF‐C alleles T of rs4604006, G of rs664393, VEGFR‐2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways.

Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma.

The aim of this review is to present the similarities and differences between the latest guidelines for noninvasive diagnosis of hepatocelullar carcinoma (HCC) of American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), Asian Pacific Association for the Study of the Liver (APASL), and Japanese Society of Hepatology. All the four guidelines defined a typical HCC vascular pattern as the homogeneous hyperenhancement (wash-in) in the arterial phase followed by wash-out in the venous or late phase. The AASLD and EASL guidelines accept only four-phase computed tomography and dynamic contrast magnetic resonance imaging (MRI) for HCC diagnosis, whereas the APASL and Japanese guidelines also accept contrast-enhanced ultrasound (CEUS). Regarding CEUS, the APASL guidelines accept the use of Levovist or Sonazoid as contrast agents, whereas the Japanese guidelines accept only the use of Sonazoid. The AASLD and EASL guidelines recommend using only extracellular contrast agents such as gadolinium for MRI, whereas the APASL guidelines also included the use of super paramagnetic iron oxid-MRI, and the Japanese guidelines recommended the use of gadolinium-ethoxybenzyl-diethylentriamine pentaacetic acid-MRI. The AASLD and EASL guidelines propos a diagnostic algorithm starting from the tumor size, whereas the APASL and Japanese guidelines recommend an algorithm starting from arterial tumor vascularity (hyper- or hypovascular in the arterial phase). In conclusion, important differences exist among the Western and Eastern guidelines for noninvasive HCC diagnosis.

The influence of aminotransferase levels on liver stiffness assessed by Acoustic Radiation Force Impulse Elastography: A retrospective multicentre study

BACKGROUNDnAcoustic Radiation Force Impulse Elastography is a new method for non-invasive evaluation of liver fibrosis.nnnAIMnTo evaluate the impact of elevated alanine aminotransferase levels on liver stiffness assessment by Acoustic Radiation Force Impulse Elastography.nnnMETHODSnA multicentre retrospective study including 1242 patients with chronic liver disease, who underwent liver biopsy and Acoustic Radiation Force Impulse. Transient Elastography was also performed in 512 patients.nnnRESULTSnThe best Acoustic Radiation Force Impulse cut-off for predicting significant fibrosis was 1.29 m/s in cases with normal alanine aminotransferase levels and 1.44 m/s in patients with alanine aminotransferase levels>5 × the upper limit of normal. The best cut-off for predicting liver cirrhosis were 1.59 and 1.75 m/s, respectively. Acoustic Radiation Force Impulse cut-off for predicting significant fibrosis and cirrhosis were relatively similar in patients with normal alanine aminotransferase and in those with alanine aminotransferase levels between 1.1 and 5 × the upper limit of normal: 1.29 m/s vs. 1.36 m/s and 1.59 m/s vs. 1.57 m/s, respectively. For predicting cirrhosis, the Transient Elastography cut-offs were significantly higher in patients with alanine aminotransferase levels between 1.1 and 5 × the upper limit of normal compared to those with normal alanine aminotransferase: 12.3 kPa vs. 9.1 kPa.nnnCONCLUSIONnLiver stiffness values assessed by Acoustic Radiation Force Impulse and Transient Elastography are influenced by high aminotransferase levels. Transient Elastography was also influenced by moderately elevated aminotransferase levels.

Patterns of appearance and risk of misdiagnosis of intrahepatic cholangiocarcinoma in cirrhosis at contrast enhanced ultrasound

Primary aim was to validate the percentage of intrahepatic cholangiocarcinomas (ICC) which have a contrast vascular pattern at contrast enhanced ultrasound (CEUS) at risk of misdiagnosis with hepatocellular carcinoma (HCC) and, secondary aim, to verify if any characteristics in the CEUS pattern helps to identify ICC.

The role of ultrasound elastographic techniques in chronic liver disease: Current status and future perspectives

This review illustrates the state of the art clinical applications and the future perspectives of ultrasound elastographic methods for the evaluation of chronic liver diseases, including the most widely used and validated technique, transient elastography, followed by shear wave elastography and strain imaging elastography. Liver ultrasound elastography allows the non-invasive evaluation of liver stiffness, providing information regarding the stage of fibrosis, comparable to liver biopsy which is still considered the gold standard; in this way, it can help physicians in managing patients, including the decision as to when to start antiviral treatment. The characterization of focal liver lesions and the prognostic role of the elastographic technique in the prediction of complications of cirrhosis are still under investigation.

Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, Identify Cirrhotic Patients with HCC

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.

Natural history of malignant bone disease in hepatocellular carcinoma: final results of a multicenter bone metastasis survey.

Background Bone is an uncommon site of metastasis in patients with advanced hepatocellular carcinoma (HCC). Therefore, there are few studies concerning the natural history of bone metastasis in patients with HCC. Patients and Methods Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 211 deceased HCC patients with evidence of bone metastasis were statistically analyzed. Results The median age was 70 years; 172 patients were male (81.5%). The median overall survival was 19 months. The median time to the onset of bone metastasis was 13 months (22.2% at HCC diagnosis); 64.9% patients had multiple bone metastases. Spine was the most common site of bone metastasis (59.7%). Most of these lesions were osteolytic (82.4%); 88.5% of them were treated with zoledronic acid. At multivariate analysis, only the Child Score was significantly correlated with a shorter time to diagnosis of bone metastases (pu200a=u200a0.001, HRu200a=u200a1.819). The median survival from bone metastasis was 7 months. At multivariate analysis, HCC etiology (pu200a=u200a0.005), ECOG performance status (pu200a=u200a0.002) and treatment with bisphosphonate (pu200a=u200a0.024) were associated with shorter survival after bone disease occurrence. The site of bone metastasis but not the number of bone lesions was associated with the survival from first skeletal related event (SRE) (pu200a=u200a0.021) and OS (pu200a=u200a0.001). Conclusions This study provides a significant improvement in the understanding the natural history of skeletal disease in HCC patients. An early and appropriate management of these patients is dramatically needed in order to avoid subsequent worsening of their quality of life.

Use of VEGFR-2 Targeted Ultrasound Contrast Agent for the Early Evaluation of Response to Sorafenib in a Mouse Model of Hepatocellular Carcinoma

PurposeThe aim of this study was to assess the early response to sorafenib using ultrasound molecular imaging in a murine model of hepatocellular carcinoma (HCC).ProceduresA xenograft model of HCC was established. Then, mice were divided in two groups and received treatment (sorafenib) or placebo for 14xa0days. The treatment group was further divided into non-responders and responders according to the degree of growth. Contrast enhanced ultrasound (CEUS) was performed using VEGFR-2 targeted microbubbles (BR55, Bracco Suisse SA, Geneva, Switzerland). Dedicated software was used to quantify the amount of bound microbubbles in the tumor as a numerical value (differential targeted enhancement (dTE)). Tumors were then excised and western blot analysis performed.ResultsThe dTE values decreased from day 0 to day +14 both in the treatment and control groups, but were lower in the former. The non-responder group had higher dTE levels at day 2 compared to responders (pu2009=u20090.019).ConclusionBR55 appears to be useful in the prediction of response to sorafenib in a xenograft model of HCC.