Roberto Virdone

Screening for hepatocellular carcinoma in patients with Child's A cirrhosis: an 8-year prospective study by ultrasound and alphafetoprotein

One hundred and forty-seven patients with Childs A cirrhosis and no evidence of hepatocellular carcinoma were followed up in an 8-year prospective surveillance program with testing by ultrasound and alphafetoprotein every 6 months. Eighteen of 147 patients were HBsAg positive. Anti-hepatitis C virus antibodies were found in 103 out of 133 cases tested. Sixteen patients had a history of heavy drinking. Thirty hepatocellular carcinomas were detected during follow up. At the time of diagnosis, ultrasound detected focal lesions in all the patients whereas alphafetoprotein was below diagnostic levels. The hepatocellular carcinoma was single in 26 patients and multiple in four. The overall 8-year cumulative tumor-free rate was 69% (95% confidence interval = 58-73). The yearly hepatocellular carcinoma incidence from 1985 to 1992 was respectively 2%, 1.5%, 2%, 3%, 5%, 4.8%, 7% and 10%. The initial value of AFP > 50 ng/ml and < 400 ng/ml was significantly related to the development of hepatocellular carcinoma. This series shows that the cumulative incidence of hepatocellular carcinoma in cirrhosis in Italy is higher than previously reported, but lower than that observed in Asiatic areas. A 6-month interval for ultrasound is reasonable to detect treatable tumors. Alphafetoprotein has no value for early diagnosis, although its intermediate values (> 50 and < 400 ng/ml) may indicate the presence of undetectable cancer which will appear during the follow up, and suggests that ultrasound should be employed more frequently in patients with these values.

Competing risks and prognostic stages of cirrhosis: a 25‐year inception cohort study of 494 patients

Morphological, haemodynamic and clinical stages of cirrhosis have been proposed, although no definite staging system is yet accepted for clinical practice.

Crohn's disease: A comparative prospective study of transabdominal ultrasonography, small intestine contrast ultrasonography, and small bowel enema

Background: Small intestine contrast ultrasonography (SICUS), when performed after distention of the small bowel lumen with an iso‐osmolar polyethylene glycol electrolyte‐balanced solution, shows high sensitivity (100%) and specificity (97%) in detecting small bowel abnormalities in patients who have not received a diagnosis but in whom there is a suspicion of intestinal diseases. The diagnostic yield of SICUS remains to be established in detecting small bowel lesions in patients with proven Crohns disease (CD) in comparison with transabdominal ultrasonography (TUS), and in relationship to the experience of the operator, using small bowel enema (SBE) as the “gold standard.” Aim: The aim of this study was to evaluate the diagnostic value of SICUS, when performed by a sonologist with 1 year of experience, and TUS, when performed by a sonologist with 10 years of experience, compared to SBE in the assessment of the site, extension, and stenosis of small intestinal lesions in CD patients. Patients and Methods: A total of 28 consecutive patients (men, 16; women, 12; age range, 21 to 60 yr) with a diagnosis of CD underwent TUS and SICUS, which were performed by 2 sonologists who were unaware of the radiologic findings, on the same day. SICUS was performed after the ingestion of 375 mL of a polyethylene glycol contrast solution. A standard SBE was performed on a different day by an expert radiologist who was unaware of the sonographic findings. Results: Sensitivities in the detection of small bowel lesions were 96% for TUS and 100% for SICUS. Compared with SBE, SICUS detected the presence of 4 lesions in the jejunum that had been missed by TUS. The mean (±SD) extent of the ileal disease was 22 ± 12.5 cm when measured during SBE, 14.5 ± 8.6 cm when measured during TUS, and 19.5 ± 12.5 cm when measured during SICUS [P = 0.05 (SICUS versus SBE)]. The correlation of the extension of the lesions between SICUS and SBE (r = 0.88) was better than that between TUS and SBE (r = 0.64). The sensitivities of TUS and SICUS in the detection of at least 1 stricture were 76% and 94%, respectively. Sensitivity and specificity in assessing prestenotic dilatation were 50% and 100%, respectively, at TUS, and 100% and 90%, respectively, at SICUS. Conclusion: In inexperienced hands, SICUS is a more accurate technique for assessing CD lesions, and the accuracy is better than that of TUS performed by an expert sonologist. The use of SICUS, instead of SBE, could be indicated for the follow‐up of patients with CD.

Asymptomatic hepatocellular carcinoma in Child's A cirrhosis

The present study deals with the natural history of 37 asymptomatic patients with cirrhosis and hepatocellular carcinoma, 25 with 2-9-cm tumors who were not surgically treated (first group) and 12 with tumors smaller than 4 cm who underwent resection (second group). All patients were in Childs A class. Two-year survival (according to life-table analysis by the Kaplan-Meier method) was 50% in the first group and 39% in the second group. This difference was not significant. In the first group no relation was found between survival and initial tumor size or alpha-fetoprotein levels. Ultrasound examinations at 3-mo intervals revealed the following patterns of tumor growth: (a) no significant growth during the follow-up (9 patients); (b) significant growth (tumor size at least doubling) only in the final stage of the disease (11 patients); (c) initial significant growth followed by a period of no increase in size (5 patients). These findings show that in our geographical area (a) 2-yr survival of untreated asymptomatic patients with hepatocellular carcinoma associated with cirrhosis does not differ from that of similar patients undergoing resection and (b) the tumor can exhibit long periods of no growth alternating with periods of exponential growth.

Estimation of lead-time bias and its impact on the outcome of surveillance for the early diagnosis of hepatocellular carcinoma

BACKGROUND & AIMS Lead-time is the time by which diagnosis is anticipated by screening/surveillance with respect to the symptomatic detection of a disease. Any screening program, including surveillance for hepatocellular carcinoma (HCC), is subject to lead-time bias. Data regarding lead-time for HCC are lacking. Aims of the present study were to calculate lead-time and to assess its impact on the benefit obtainable from the surveillance of cirrhotic patients. METHODS One-thousand three-hundred and eighty Child-Pugh class A/B patients from the ITA.LI.CA database, in whom HCC was detected during semiannual surveillance (n = 850), annual surveillance (n = 234) or when patients came when symptomatic (n = 296), were selected. Lead-time was estimated by means of appropriate formulas and Monte Carlo simulation, including 1000 patients for each arm. RESULTS The 5-year overall survival after HCC diagnosis was 32.7% in semiannually surveilled patients, 25.2% in annually surveilled patients, and 12.2% in symptomatic patients (p<0.001). In a 10-year follow-up perspective, the median lead-time calculated for all surveilled patients was 6.5 months (7.2 for semiannual and 4.1 for annual surveillance). Lead-time bias accounted for most of the surveillance benefit until the third year of follow-up after HCC diagnosis. However, even after lead-time adjustment, semiannual surveillance maintained a survival benefit over symptomatic diagnosis (number of patients needed to screen = 13), as did annual surveillance (18 patients). CONCLUSIONS Lead-time bias is the main determinant of the short-term benefit provided by surveillance for HCC, but this benefit becomes factual in a long-term perspective, confirming the clinical utility of an anticipated diagnosis of HCC.

Can the serological status of anti-HBc alone be considered a sentinel marker for detection of occult HBV infection?

Some individuals have “occult” infection with hepatitis B virus (HBV), defined as presence of HBV genome in the serum or liver tissue without HBV surface antigen (HBsAg) in the serum. The aim of this study was to investigate whether serum antibodies against HBV core antigen in isolation (“anti‐HBc alone”) are a useful marker of “occult” HBV in patients with or without hepatitis C virus (HCV) infection. “Anti‐HBc alone” was detected in the sera of 119/6,544 (1.8%) asymptomatic outpatients referred to the diagnostic laboratory for routine testing for viral hepatitis, 62/607 (10.2%) drug users, and 42/195 (21.5%) patients with hepatocellular carcinoma. Using three in‐house nested‐PCR amplification assays to detect HBV preS‐S (S), precore‐core (C), and Pol viral regions, respectively, “occult” HBV sequences were found in 9 of the 223 sera (4.0%) with “anti‐HBc alone.” The highest prevalence of “occult” HBV sequences (5.9%) was detected in “anti‐HBV alone” sera of individuals referred to the diagnostic laboratory without HCV antibodies. Direct sequencing of all PCR products confirmed the specificity of the PCR reactions and revealed the predominance of HBV genotype D. The data presented in this study suggest that detection of “anti‐HBc alone” could reflect unrecognized “occult” HBV infection and that physicians should consider investigating such patients with HBV molecular tests. J. Med. Virol. 80:577–582, 2008.

Survival benefit of liver resection for patients with hepatocellular carcinoma across different Barcelona Clinic Liver Cancer stages: A multicentre study

BACKGROUND & AIMS The role of hepatic resection for hepatocellular carcinoma (HCC) in different Barcelona Clinic Liver Cancer (BCLC) stages is controversial. We aimed at measuring the survival benefit of resection vs. non-surgical-therapies in each BCLC stage. METHODS Using the ITA.LI.CA database, we identified 2090 BCLC A, B, and C HCC patients observed between 2000 and 2012: 550 underwent resection, 1046 loco-regional therapy (LRT), and 494 best supportive care (BSC). A multivariate log-logistic model was chosen to predict median survival (MS) after resection vs. MS after LRT or BSC. The results were expressed as net survival benefit of resection: (MS resection-MS LRT)/MS BSC. RESULTS After stratifying for BCLC stage, the median net survival benefit of resection over LRT was: BCLC 0=62% (40%, 82%), A=45% (13%, 65%), B=46% (9%, 76%), C=-16% (-55%, 33%). Model for end-stage liver disease (MELD) score>9, Child B class, and performance status (PST)=2 were the main risk factors for liver resection. 1181 Child A patients (57%) with MELD⩽9 and PST<2 had always a large positive net survival benefit of resection over LRT, independently of BCLC stage: BCLC 0=64% (44%, 85%), A=59% (45%, 74%), B=71% (52%, 90%), C=56% (36%, 78%). Among the 909 (43%) patients with at least one risk factor (MELD>9 or PST=2 or Child B class), resection did not prove any survival benefit over LRT. CONCLUSIONS Resection could result in survival benefit over LRT for HCC patients regardless of their BCLC stage, provided that liver dysfunction (Child B or MELD>9) and PST>1 are absent.

Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon

In HCV‐infected cirrhotic patients with successfully treated early hepatocellular carcinoma (HCC), the time to HCC recurrence and the effects of sustained viral eradication (SVR) by interferon (IFN)‐based or IFN‐free regimens on HCC recurrence remain unclear.

A meta-analysis of single HCV-untreated arm of studies evaluating outcomes after curative treatments of HCV-related hepatocellular carcinoma

Determining risk for recurrence or survival after curative resection or ablation in patients with hepatitis C virus (HCV)‐related hepatocellular carcinoma (HCC) is important for stratifying patients according to expected outcomes in future studies of adjuvant therapy in the era of direct‐acting antivirals (DAAs). The aims of this meta‐analysis were to estimate the recurrence and survival probabilities of HCV‐related early HCC following complete response after potentially curative treatment and to identify predictors of recurrence and survival.

Treatment of Small Hepatocellular Carcinoma Associated with Cirrhosis by Percutaneous Ethanol Injection: A Trial with a Comparison Group

BACKGROUND Ethanol injection has been reported to be effective in the treatment of hepatocellular carcinoma, but no controlled randomized trials have been performed. We therefore performed a trial comparing ethanol injection with an untreated, matched historical comparison group in the treatment of hepatocellular carcinoma. METHODS From 1992 to 1993, 35 patients (14 Childs A and 21 Childs B cirrhosis) with small (< 4 cm) hepatocellular carcinoma associated with cirrhosis were treated by ethanol injection. Each patient was matched with an untreated case (followed up during the period 1984-89) for variables known to have independent prognostic value (age, Childs classification, number of lesions, alpha-fetoprotein, and modality of diagnosis). RESULTS The 1-, 2-, and 3-year survival rates of ethanol-treated patients were 86% (95% confidence interval (CI), 69-94), 53% (95% CI, 34-68), and 33% (95% CI, 15-52), whereas the survival rates of the comparison group were 75% (95% CI, 56-85), 26% (95% CI, 13-41), and 14% (95% CI, 5-27) (P = 0.01). The 1-, 2-, and 3-year survival rates of Childs A were 100%. 87% (95% CI, 30-97), 71% (95 CI, 33-90), 71% (95% CI, 33-90) in the ethanol-treated patients and 92 (95% CI, 59-99), 43% (95% CI, 23-73), and 21% (95% CI, 23-72) in untreated patients. The 1-, 2-, and 3-year survival of Childs B patients were 76% (95% CI, 59-97), 32% (95% CI, 13-53), and 9% (95% CI, 0.8-33) in the treated group and 61% (95% CI, 40-83), 14% (95% CI, 3-32), and 9% (95% CI, 1-26) in the treated group. CONCLUSIONS These data suggest that ethanol injection prolongs the life of patients with hepatocellular carcinoma associated with Childs A cirrhosis but seems not to influence the survival of Childs B patients.