Emanuela Bertolini

Safety and efficacy of laparoscopic radiofrequency of hepatocellular carcinoma in patients with liver cirrhosis

Background: The optimal treatment for hepatocellular carcinoma (HCC) is surgical resection. However, only a small percentage of patients are operative candidates. Percutaneous radiofrequency interstitial thermal ablation (RITA) has been shown to be efficacious in the treatment of unresectable HCC. Recent advances in laparoscopic ultrasound have greatly improved the accuracy in detecting intrahepatic HCC nodules, many of which were missed by computed tomography. Our objective was to introduce a novel operative combination of laparoscopic ultrasound with laparoscopic RITA in the treatment of HCC. Methods: Eighty-eight patients with HCC in liver cirrhosis were submitted to laparoscopic RITA under sonographic guide. Most patients were in Child’s A class of liver function. Patients with large tumors (> 5 cm), portal vein thrombosis, or severe liver disease (Child’s C class) were excluded. Results: The laparoscopic RITA procedure was completed in 86 of 88 patients (98% feasibility rate). Laparoscopy with laparoscopic ultrasound identified 23 new malignant lesions (27%) in comparison with the results of preoperative imaging. A total of 127 lesions were treated by RITA. There was no operative mortality. Sixty-one patients had no complication (71%). After a mean follow-up of 14.3 ± 11.6 months, a complete response with a 100% necrosis was achieved in 70 of 83 patients examined (86%). During follow-up, 9 patients (11%) locally recurred at the RITA site and 38 patients (46%) had new malignant nodules. Conclusions: Laparoscopic RITA of HCC proved to be a safe and effective technique in the short term. This technique may be indicated when the percutaneous approach to the lesion is very difficult or if the patient is too ill to undergo laparotomy.

Effect of Different Doses of Ursodeoxycholic Acid in Chronic Liver Disease

Recent clinical studies have indicated that ursodeoxycholic acid (ursodiol), administered at dosages ranging between 10 and 15 mg/kg/day, improves liver function indices in both cholestatic and inflammatory chronic liver diseases. These dosages would be considered high for the use of ursodiol in gallstone dissolution therapy. To investigate the dose-response relationship to ursodiol administration, we planned a few studies in patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and chronic hepatitis (CH). Patients with PBC were subdivided into two groups on the basis of their serum bilirubin values, with 2 mg/dl as the dividing line. Ursodiol was given at dosages of 250, 500, and 750 mg/day for consecutive periods of two months, the order of treatment being randomly assigned to each patient. The enrichment with ursodiol of biliary bile acids was similar in both PBC and CH and, within the PBC group, in both anicteric and icteric patients. Highly significant decreases in serum enzyme levels were observed in all groups with the 250 mg/day dose, corresponding to about 4–5 mg/kg/day. The two higher doses induced further improvements in serum enzyme levels, especially in patients with PBC, but no significant differences were found between the 500 and the 750 mg/day doses. The improvements were roughly proportional to the enrichment of conjugated biliary bile acids with ursodiol. Serum bilirubin levels, an important prognostic factor in PBC, were also significantly reduced by ursodiol administration in patients with initial serum levels higher than 2 mg/dl. The present study indicated that ursodiol is a potentially useful drug for chronic liver disease. Controlled trials on adequate numbers of patients assuming clinically meaningful endpoints are needed. The present investigation suggests that daily doses of 500–600 mg/day, corresponding to about 8 mg/kg/day, should be employed for such studies.

Radiofrequency interstitial thermal ablation of hepatocellular carcinoma in liver cirrhosis. Role of the laparoscopic approach.

BackgroundThe laparoscopic approach to radiofrequency interstitial thermal ablation (RITA) of hepatocellular carcinoma (HCC) with intraoperative ultrasound guidance has been proposed with the aim of obtainning additional information for a better neoplastic staging and a complete and effective treatment of the liver lesions in patients with a difficult percutaneous approach.MethodsIn this pilot study, 29 patients with HCC in liver cirrhosis were submitted to laparoscopic RITA under sonographic guide. Most of these patients were in Child’s A class of liver function. Patients with large tumors (>5 cm), portal vein thrombosis, or severe liver disease (Child’s C class) were excluded from the study.ResultsThe laparoscopic RITA procedure was completed in 27 of 29 patients (93% feasibility rate). The laparoscopic ultrasound examination identified new malignant liver nodules in five patients (18.5%). A total of 44 lesions were treated. The mean operative time was 75.8 ± 20.5 min (range, 45–120 min), and the mean RITA time was 18 ± 10 min (range, 10–56 min). There was no operative mortality, and postoperative morbidity was low (four cases) without any mortality. A complete tumor necrosis was observed in 90% of the patients via spiral computed tomography (CT) 1 month after treatment.ConclusionsLaparoscopic RITA of hepatocellular carcinoma proved to be a safe and effective technique, at least in the short term. Its role in the treatment of HCC needs to be defined in larger series.

Failure of ursodeoxycholic acid to dissolve radiolucent gallstones in patients with cystic fibrosis

Ursodeoxycholic acid has been used widely to dissolve cholesterol gallstones and more recently was shown to improve clinical symptoms and biochemical indices in different chronic liver diseases, including that associated with cystic fibrosis. We treated 10 cystic fibrosis patients (5 males, 5 females, age range 2–22 years) with pancreatic insufficiency and normal liver function with ursodeoxycholic acid 15–20 mg/kg/day. Seven patients had radiolucent gallstones (in 3 cases associated with biliary sludge) and 3 had sludge; all were asymptomatic. Before treatment, the gallbladder was well opacified in oral cholecystogram. The gallbladder was scanned by ultrasound in similar conditions and by the same operator before administration of ursodeoxycholic acid and after a median period of treatment of 16 months (range 11–32 months). During treatment, all patients remained asymptomatic and the relative proportion of ursodeoxycholic acid in duodenal bile increased from 4.7 ± 3.2% at baseline to 34.7 ± 8.6%. Complete or partial dissolution of gallstones was never observed and the maximum diameter of stones increased from a mean of 6.1 ± 3.4 to 8.0 ± 5.3 mm; in one case the development of biliary sludge occurred during bile acid therapy. Sludge disappeared in 1 of the 6 patients who initially had it, while in 2 cases its volume increased. We conclude that ursadeokycholic acid is not effective in most CF patients with gallstones, probably because cholesterol is not the main component of stone or sludge.

Comparison of Effects of Chenodeoxycholic and Ursodeoxycholic Acid and Their Combination on Biliary Lipids in Obese Patients with Gallstones

To study the effects of different bile acids on biliary lipids in obese patients with radiolucent gallstones, 12 subjects were given chenodeoxycholic acid (CDCA) at a dose of 15 mg/kg/day, ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg/day, and an equimolar combination of the two (7.5 + 7.5 mg/kg/day) in accordance with a double-blind crossover design. Mean molar percentage of cholesterol and cholesterol saturation index corrected for urso-rich bile (CSI) decreased significantly with all three treatments, but the combination was more effective in decreasing the CSI than either of the two bile acids given alone (p less than 0.05). Bile became desaturated in 10 of 12 patients receiving the combination, in 4 of 12 receiving CDCA, and 3 of 12 receiving UDCA alone. Combination treatment was well tolerated since mild diarrhea and slight increase in transaminases were observed only in a few patients. We conclude that the combined administration of CDCA and UDCA in equimolar doses is the treatment of choice for dissolution of gallstones in obese patients.

Hepatitis C virus testing in primary biliary cirrhosis

We retrospectively investigated anti-HCV prevalence in a series of 160 consecutive patients with primary biliary cirrhosis who presented between 1980 and 1989. Of these, 19 (12%) were positive for anti-HCV by C-100 ELISA. Serum IgG levels were significantly higher in anti-HCV-positive patients and correlated to optical density values. A serum sample was again collected from all the patients from the same series who were seen in 1990 for follow-up, after a median period of 32 months. Anti-HCV positivity was found to be substantially unchanged in this subgroup of patients when the freshly drawn blood samples were retested with C-100 ELISA, while it increased from 10% to 17% when second generation ELISA was used. Three of the C-100 ELISA positive samples were C-100 RIBA reactive, and six of the second generation ELISA positive samples were 4-RIBA reactive. The HCV genome was not detected in any of the seven anti-HCV C-100 ELISA and second generation ELISA positive sera which were studied by polymerase chain reaction, including four cases confirmed by 4-RIBA. Life expectancy, as determined by survival analysis, did not differ significantly between anti-HCV-positive and -negative patients. These findings suggest that anti-HCV positivity does not influence the clinical presentation and course of primary biliary cirrhosis.

External validation of the ITA.LI.CA prognostic system for patients with hepatocellular carcinoma: A multicenter cohort study

Several staging systems for hepatocellular carcinoma (HCC) have been developed. The Barcelona Clinic Liver Cancer staging system is considered the best in predicting survival, although limitations have emerged. Recently, the Italian Liver Cancer (ITA.LI.CA) prognostic system, integrating ITA.LI.CA tumor staging (stages 0, A, B1‐3, C) with the Child‐Turcotte‐Pugh score, Eastern Cooperative Oncology Group performance status, and alpha‐fetoprotein with a strong ability to predict survival, was proposed. The aim of our study was to provide an external validation of the ITA.LI.CA system in an independent real‐life occidental cohort of HCCs. From September 2008 to April 2016, 1,508 patients with cirrhosis and incident HCC were consecutively enrolled in 27 Italian institutions. Clinical, tumor, and treatment‐related variables were collected, and patients were stratified according to scores of the Barcelona Clinic Liver Cancer system, ITA.LI.CA prognostic system, Hong Kong Liver Cancer system, Cancer of the Liver Italian Program, Japanese Integrated System, and model to estimate survival in ambulatory patients with hepatocellular carcinoma. Harrells C‐index, Akaike information criterion, and likelihood‐ratio test were used to compare the predictive ability of the different systems. A subgroup analysis for treatment category (curative versus palliative) was performed. Median follow‐up was 44 months (interquartile range, 23‐63 months), and median overall survival was 34 months (interquartile range, 13‐82 months). Median age was 71 years, and patients were mainly male individuals and hepatitis C virus carriers. According to ITA.LI.CA tumor staging, 246 patients were in stage 0, 472 were in stage A, 657 were in stages B1/3, and 133 were in stage C. The ITA.LI.CA prognostic system showed the best discriminatory ability (C‐index = 0.77) and monotonicity of gradients compared to other systems, and its superiority was also confirmed after stratification for treatment strategy. Conclusion: This is the first study that independently validated the ITA.LI.CA prognostic system in a large cohort of Western patients with incident HCCs. The ITA.LI.CA system performed better than other multidimensional prognostic systems, even after stratification by curative or palliative treatment. This new system appears to be particularly useful for predicting individual HCC prognosis in clinical practice. (Hepatology 2018;67:2215‐2225)

Intraoperative ultrasound for prediction of hepatocellular carcinoma biological behaviour: Prospective comparison with pathology

Preoperative prediction of both microinvasive hepatocellular carcinoma and histological grade of hepatocellular carcinoma is pivotal to treatment planning and prognostication. The aim of this study was to evaluate whether some intraoperative ultrasound features correlate with both the presence of same histological patterns and differentiation grade of hepatocellular carcinoma on the histological features of the primary resected tumour.

Management and prognosis of hepatocellular carcinoma in the elderly: Results of an in-field multicenter cohort study

This multicentre cohort study evaluated the role of ageing on clinical characteristics, treatment allocation and outcome of new hepatocellular carcinomas (HCCs), in clinical practice.

Combination Therapy of Chenodeoxycholic Acid and Ursodeoxycholic Acid

Bile acid therapy has become well established as nonsurgical treatment in selected patients with cholesterol gallstones since chenodeoxycholic acid (cheno) and, later on, ursodeoxycholic acid (urso) were introduced in the early 1970s and 1980s, respectively.