Fabio Piscaglia

The EFSUMB guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (CEUS): Update 2011 on non-hepatic applications

Authors F. Piscaglia1, C. Nolsøe2, C. F. Dietrich3, D. O. Cosgrove4, O. H. Gilja5, M. Bachmann Nielsen6, T. Albrecht7, L. Barozzi8, M. Bertolotto9, O. Catalano10, M. Claudon11, D. A. Clevert12, J. M. Correas13, M. D’Onofrio14, F. M. Drudi15, J. Eyding16, M. Giovannini17, M. Hocke18, A. Ignee19, E. M. Jung20, A. S. Klauser21, N. Lassau22, E. Leen23, G. Mathis24, A. Saftoiu25, G. Seidel26, P. S. Sidhu27, G. ter. Haar28, D. Timmerman29, H. P. Weskott30

The impact of vascular and nonvascular findings on the noninvasive diagnosis of small hepatocellular carcinoma based on the EASL and AASLD criteria.

OBJECTIVES:Noninvasive criteria for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis, recommended by the European Association for the Study of Liver (EASL) in 2001 and by the American Association for the Study of Liver Diseases (AASLD) in 2005, have left a number of small liver neoplastic nodules undefined. We designed this prospective study in 2003 with the aims of assessing the diagnostic contribution of vascular contrast-enhanced techniques and investigating the possible additional contribution of superparamagnetic iron oxide magnetic resonance (SPIO-MR) in this setting.METHODS:Between 2003 and 2005, 75 consecutive small (10–30u2009mm) liver nodules detected at ultrasonography in 60 patients with cirrhosis were prospectively submitted to contrast-enhanced ultrasound (CEUS), helical-computed tomography (helical-CT), and gadolinium magnetic resonance (gad-MR), each blinded to the other. A total of 68 nodules were also studied with SPIO-MR at the same time as gad-MR.RESULTS:Using the EASL noninvasive criteria, the diagnosis of HCC was established in 44 of 55 (80%) nodules with a final diagnosis of HCC. Gad-MR was the most sensitive technique for detecting the typical vascular pattern. SPIO-MR showed a pattern consistent with HCC in 5 of 10 HCCs, not satisfying the EASL noninvasive criteria, and was negative in 17 of 18 (94.4%) nonmalignant nodules. The review of the present case series according to the AASLD criteria for the noninvasive diagnosis of HCC yielded a sensitivity rate of 81.8%.DISCUSSION:This study shows that both EASL and AASLD noninvasive recall strategies for nodules of 10–30u2009mm in the cirrhotic liver, based on the vascular pattern of nodules, have a false-negative rate of ∼20%. SPIO-MR may increase the diagnostic potential of noninvasive techniques, contributing to the diagnosis of HCC lacking a typical vascular pattern.

Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma

BACKGROUND & AIMSnBoth hepatic resection and radiofrequency ablation (RFA) are considered curative treatments for hepatocellular carcinoma (HCC), but their economic impact still remains not determined. Aim of the present study was to analyze the cost-effectiveness (CE) of these two strategies in early stage HCC (Milan criteria).nnnMETHODSnAs first step, a meta-analysis of the pertinent literature of the last decade was performed. Seventeen studies fulfilled the inclusion criteria: 3996 patients underwent resection and 4424 underwent RFA for early HCC. Data obtained from the meta-analysis were used to construct a Markov model. Costs were assessed from the health care provider perspective. A Monte Carlo probabilistic sensitivity analysis was used to estimate outcomes with distribution samples of 1000 patients for each treatment arm.nnnRESULTSnIn a 10-year perspective, for very early HCC (single nodule <2 cm) in Child-Pugh class A patients, RFA provided similar life-expectancy and quality-adjusted life-expectancy at a lower cost than resection and was the most cost-effective therapeutic strategy. For single HCCs of 3-5 cm, resection provided better life-expectancy and was more cost-effective than RFA, at a willingness-to-pay above €4200 per quality-adjusted life-year. In the presence of two or three nodules ≤3 cm, life-expectancy and quality-adjusted life-expectancy were very similar between the two treatments, but cost-effectiveness was again in favour of RFA.nnnCONCLUSIONSnFor very early HCC and in the presence of two or three nodules ≤3 cm, RFA is more cost-effective than resection; for single larger early stage HCCs, surgical resection remains the best strategy to adopt as a result of better survival rates at an acceptable increase in cost.

Comparison of recurrence of hepatocellular carcinoma after resection in patients with cirrhosis to its occurrence in a surveilled cirrhotic population.

The presence of cirrhosis is the only risk factor that is advocated for recurrence of hepatocellular carcinoma (HCC) 2xa0years after hepatic resection compared with noncirrhotic control subjects; however, data for cohorts of exclusively patients with cirrhosis are lacking. This study was designed to assess risk factors and annual incidence of early (<2xa0years) and late (>2xa0years) recurrence after resection of cirrhosis and to compare these findings with those of patients with cirrhosis enrolled in HCC surveillance programs (HCC occurrence). Data from 204 patients with cirrhosis resected for HCC and 150 surveilled for cirrhosis were retrospectively collected and compared using propensity score matching to overcome biases of nonrandomized study. Risk factors for early recurrence (incidencexa0=xa021.8%/year) were higher serum alpha-fetoprotein (AFP) levels, poorly differentiated tumor, and presence of microvascular invasion (Pxa0<xa00.05). Risk factors for both late recurrence (18.4%/year) and HCC occurrence (3.3%/year) were male gender, older age, and higher serum transaminase levels; multiple primary tumors and higher AFP were additional risk factors for late recurrence and HCC occurrence respectively (Pxa0<xa00.05). After propensity adjustment, resected patients with less than two risk factors for late recurrence showed an annual incidence of HCC (6.2%/year) similar to that of surveilled patients withxa0≥2 risk factors (5.8%/year; Pxa0=xa00.898). Early and late recurrence of HCC for patients with cirrhosis after resection have distinct risk factors. Annual incidence of HCC 2xa0years or more after resection may be similar to that of general patients because the same risk factors are involved; assessment of these characteristics could be useful in tailoring clinical management.

Accuracy of VirtualTouch Acoustic Radiation Force Impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography.

PURPOSEnVirtualTouch is a new technique recently proposed to evaluate liver stiffness during B-mode ultrasonography. The goal of the present study was to analyze the diagnostic accuracy of VirtualTouch in the diagnosis of cirrhosis and its correlation with transient elastography (Fibroscan).nnnMATERIALS AND METHODSnA total of 133 patients with chronic liver disease were enrolled. 90 of 133 underwent VirtualTouch and transient elastography and 70 patients assessed with VirtualTouch were submitted to liver biopsy. Stiffness was assessed by both techniques in the right liver lobe. The diagnostic accuracy for cirrhosis was first assessed in the 90 patients submitted to transient elastography with > 13 kPa (47 % of patients) as diagnostic for cirrhosis values. The best cut-off for cirrhosis with VirtualTouch was then tested in the 70 patients with biopsy (cirrhosis in 38 % of patients). 41 patients were assessed by VirtualTouch by two different operators.nnnRESULTSnThe VirtualTouch values in controls, chronic hepatitis and cirrhosis were respectively 113, 147 and 255 cm/sec. The AUROC of liver VirtualTouch for the diagnosis of cirrhosis (reference Fibroscan) was 0.941 with 175 cm/sec as the best cut-off (sensitivity 93.0 %; specificity 85.1 %). VirtualTouch confirmed good performance also in patients with bioptic diagnosis of cirrhosis (AUROC 0.908, sensitivity 81.5 %, specificity 88.4 %,). The correlation of VirtualTouch with transient elastography was strict (r = 0.891) and the correlation in VirtualTouch measurements between two operators was also good (r = 0.874).nnnCONCLUSIONnVirtualTouch is able to identify the presence of cirrhosis with good accuracy, shows good interobserver reproducibility and the correlation of its values with those obtained by transient elastography with Fibroscan is good.

Criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation

Malignant portal vein thrombosis is a contraindication for liver transplantation. Patients with cirrhosis and early hepatocellular carcinoma (HCC) may have either malignant or benign (fibrin clot) portal vein thrombosis. The aim of this study was to assess prospectively whether well‐defined diagnostic criteria would enable the nature of portal vein thrombosis to be established in patients with HCC under consideration for liver transplantation. Benign portal vein thrombosis was diagnosed by the application of the following criteria: lack of vascularization of the thrombus on contrast‐enhanced ultrasound and on computed tomography or magnetic resonance imaging, absence of mass‐forming features of the thrombus, absence of disruption of the walls of veins, and, if uncertainty persisted, biopsy of the thrombus for histological examination. Patients who did not fulfill the criteria for benign thrombosis were not placed on the transplantation list. In this study, all patients evaluated at our center during 2001‐2007 with a diagnosis of HCC in whom portal vein thrombosis was concurrently or subsequently diagnosed were discussed by a multidisciplinary group to determine their suitability for liver transplantation. The outcomes for 33 patients who met the entry criteria of the study were as follows: in 14 patients who were placed on the transplantation list and underwent liver transplantation, no malignant thrombosis was detected when liver explants were examined histologically; 5 patients who were placed on the transplantation list either remained on the list or died from causes unrelated to HCC; in 9 patients, liver transplantation was contraindicated on account of a strong suspicion, or confirmation, of the presence of malignant portal vein thrombosis; and 5 patients who were initially placed on the transplantation list were subsequently removed from it on account of progression of HCC in the absence of evidence of neoplastic involvement of thrombosis. In conclusion, for a patient with HCC and portal vein thrombosis, appropriate investigations can establish whether the thrombosis is benign; patients with HCC and benign portal vein thrombosis are candidates for liver transplantation. Liver Transpl 16:658‐667, 2010.

Priority of candidates with hepatocellular carcinoma awaiting liver transplantation can be reduced after successful bridge therapy

The allocation rules for patients with hepatocellular carcinoma (HCC) who are awaiting liver transplantation (LT) are a difficult issue and are continually evolving. To reduce tumor progression or down‐stage advanced disease, most transplant centers have adopted the practice of treating HCC candidates with resection or locoregional therapies. This study was designed to assess the effectiveness of bridge therapy in preventing removal from the waiting list for death/sickness severity or tumor progression beyond the Milan criteria and in determining posttransplant outcomes. The removal rates for 315 adult patients with HCC who were listed for LT were analyzed and were correlated to responses to bridge therapy with a competing risk analysis. The 3‐, 6‐, and 12‐month dropout rates were 3.5%, 6.5%, and 19.9%, respectively, and they were significantly affected by the Model for End‐Stage Liver Disease score (P = 0.032), the tumor stage at diagnosis (P = 0.041), and the response to bridge therapy (P < 0.001). The stratification of candidates by the tumor stage and the response to bridge therapy showed that patients with T2 tumors who achieved only a partial response or no response to bridge therapy had the highest dropout rates, and they were followed by patients with successfully down‐staged T3‐T4a tumors (P = 0.037). Patients with T2 tumors who had a complete response and patients with T1 tumors had similar dropout rates (P = 0.964). The response to bridge therapy significantly affected both the recurrence rate of 176 transplant patients (P = 0.017) and the overall intention‐to‐treat survival rate (P = 0.001). In conclusion, the response to therapy is a potentially effective tool for prioritizing HCC patients for LT as well as select cases with different risks of tumor recurrence after transplantation. Liver Transpl 17:1344–1354, 2011.

Practice guidelines for the treatment of hepatitis C: Recommendations from an AISF/SIMIT/SIMAST expert opinion meeting

It is increasingly clear that a tailored therapeutic approach to patients with hepatitis C virus infection is needed. Success rates in difficult to treat and low-responsive hepatitis C virus patients are not completely satisfactory, and there is the need to optimise treatment duration and intensity in patients with the highest likelihood of response. In addition, the management of special patient categories originally excluded from phase III registration trials needs to be critically re-evaluated. This article reports the recommendations for the treatment of hepatitis C virus infection on an individual basis, drafted by experts of three scientific societies.

The intermediate hepatocellular carcinoma stage: Should treatment be expanded?

The most utilized staging system for establishing the prognosis of patients with hepatocellular carcinoma (HCC) and concurrently supporting the choice of best treatment strategy is the Barcelona Clinic Liver Cancer (BCLC), which includes 4 disease stages (early, intermediate, advanced, terminal). The BCLC intermediate stage (BCLC-B) consists of patients in Child-Pugh A or B with multinodular large HCC and preserved performance status. This definition is rather broad and includes a heterogeneous patient population, according to either tumor extension (from bifocal HCC to subtotal tumor replacement of liver parenchyma) or liver function (from Child-Pugh compensated A5 to decompensated B9). The recommended treatment modality for this HCC stage is, in general, transarterial chemoembolization (TACE). However, according to the heterogeneity of the intermediate population, patients are best served when the treatment decision is individualized and taken within a multidisciplinary team. For instance, patients in Child-Pugh B may not benefit at all from TACE or even suffer detrimental effects. TACE achieves complete radiological necrosis in about 35-60% of cases (after 2-3 courses). Patients not achieving complete necrosis and patients with early large recurrence should be managed individually, taking into consideration systemic treatments, which usually are reserved for advanced cases.

Validation of noninvasive methods for the assessment of liver fibrosis in patients with recurrent hepatitis C after transplantation

Much effort is being devoted to finding noninvasive methods for assessing fibrosis in transplant patients with recurrent hepatitis C virus (HCV) infections. This would help us to avoid some biopsy procedures, monitor fibrosis progression more strictly during posttransplant follow-up, and better predict graft prognosis and the right time for starting antiviral therapies. A prospective validation of a noninvasive index based on laboratory data [the Hospital Universitario La Fe (HULF) index] failed to reproduce the high accuracy in identifying significant fibrosis found in the initial retrospective analysis from which the HULF index was initially developed [the area under the receiver operating characteristic curve (AUROC) was 0.68 in the new validation study versus 0.80 and 0.84 in the training and testing groups, respectively, in the initial study]. Previously, we prospectively tested various noninvasive indexes for the detection of significant fibrosis, including the HULF index, and transient elastography. Our findings showed good results with the HULF index [AUROC 1⁄4 0.799, 95% confidence interval (CI) 1⁄4 0.626-0.973] but significantly better results with transient elastography (AUROC 1⁄4 0.943, 95% CI 1⁄4 0.846-0.987). Recently, an English collaborative group proposed a new noninvasive index based on laboratory variables, the London Transplant Centres (LTC) score, that easily estimates the presence of significant fibrosis in patients with recurrent HCV infections. This index was derived retrospectively from their patient series and provided an AUROC of 0.86 for METAVIR fibrosis F2. Because all variables required to calculate the LTC score were available in our prospectively collected database, we calculated the AUROC of the LTC score for the diagnosis of METAVIR fibrosis F2 in patients included in our recent work. The AUROC calculation and comparison with other indexes were made with MedCalc 9 (MedCalc Software, Mariakerke, Belgium). The LTC score showed an AUROC of 0.761 (95% CI 1⁄4 0.587-0.888) with a best cutoff of 8.25 (not very dissimilar to the value of 6.40 found by Cross and coworkers), a sensitivity of 83.3%, a specificity of 60.9%, positive and negative likelihood ratios of 2.13 and 0.27, respectively, and positive and negative predictive values of 52.6% and 87.5%, respectively. The AUROC of the LTC score was not statistically significantly different from the AUROC of the HULF index but was significantly inferior to that of transient elastography (P < 0.02), as the AUROC of the HULF index also was (P < 0.05). Poynard and coworkers recommended that, when AUROCs derived from different populations are being compared, they should be adjusted for the prevalence and extent of fibrosis with the difference between the mean fibrosis stage of advanced fibrosis and the mean fibrosis stage of nonadvanced fibrosis (DANA). Our DANA was 1.46, and all AUROCs can be adjusted for this, but this adjustment would not affect the comparison of different AUROC values calculated in the same series, as in the present case; thus, we reported only the original AUROC values. In conclusion, the LTC score performs well, but it does not seem to improve the accuracy of the HULF index in this Italian series of liver transplant patients with recurrent HCV infections. Transient elastography, already shown to be a very valid technique in this setting, appears to perform better at identifying significant liver fibrosis than indexes derived from laboratory variables.