A. Sangiovanni

Hepatocellular carcinoma in Italian patients with cirrhosis.

BACKGROUND AND METHODS Patients with cirrhosis of the liver are recognized as being at risk for hepatocellular carcinoma. The magnitude of the risk, the natural history of this disease, and the possibilities for detecting potentially curable tumors in patients in the Western world are unknown. To address these questions, we examined 447 Italian patients with well-compensated cirrhosis (which was of viral origin in 62 percent of them) from 1985 through 1990, performing serum alpha-fetoprotein assays and real-time ultrasonography every 3 to 12 months. RESULTS Hepatocellular carcinoma was found in 30 patients (7 percent) at base line and in another 29 patients (7 percent of 417 patients free of tumor at base line) during follow-up periods averaging 33 months (range, 1 to 48). The cumulative hazard of the development of hepatocellular carcinoma during follow-up was higher among patients with persistently elevated serum alpha-fetoprotein levels (12 with tumors among 42 with such levels) than among those with fluctuating levels (11 among 82) or those with consistently normal levels (6 among 255). Only 17 patients had potentially operable tumors. The proportion of potentially operable tumors among those detected during follow-up was significantly lower than the proportion at enrollment (4 of 29 vs. 13 of 30, P = 0.027). The survival at one year of the 12 patients who underwent surgery was 67 percent, and the tumor-recurrence rate was 60 percent. Outcome was not appreciably different for the five patients who refused surgery. CONCLUSIONS In the West, as in Asia, patients with cirrhosis of the liver are at substantial risk for hepatocellular carcinoma, with a yearly incidence rate of 3 percent. Our screening program did not appreciably increase the rate of detection of potentially curable tumors.

The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients†

Large databases of consecutive patients followed for sufficiently long periods are needed to establish the rates, chronology, and hierarchy of complications of cirrhosis as well as the importance of other potential causes of liver disease. In accordance with this goal, a cohort of patients with compensated cirrhosis due to hepatitis C virus (HCV) was followed for 17 years. Two hundred and fourteen HCV RNA–seropositive patients with Child‐Pugh class A cirrhosis who had no previous clinical decompensation were prospectively recruited and followed up with periodic clinical and abdominal ultrasound examinations. During 114 months (range 1–199), hepatocellular carcinoma (HCC) developed in 68 (32%), ascites in 50 (23%), jaundice in 36 (17%), upper gastrointestinal bleeding in 13 (6%), and encephalopathy in 2 (1%), with annual incidence rates of 3.9%, 2.9%, 2.0%, 0.7%, and 0.1%, respectively. Clinical status remained unchanged in 154 (72%) and progressed to Child‐Pugh class B in 45 (21%) and class C in 15 (7%). HCC was the main cause of death (44%) and the first complication to develop in 58 (27%) patients, followed by ascites in 29 (14%), jaundice in 20 (9%), and upper gastrointestinal bleeding in 3 (1%). The annual mortality rate was 4.0% per year and was higher in patients with other potential causes of liver disease than in those without them (5.7% vs. 3.6%; P = .04). In conclusion, hepatitis C–related cirrhosis is a slowly progressive disease that may be accelerated by other potential causes of liver disease. HCC was the first complication to develop and the dominant cause for increased mortality. (HEPATOLOGY 2006;43:1303–1310.)

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial.

BACKGROUND & AIMS The Sorafenib Hepatocellular Carcinoma (HCC) Assessment Randomized Protocol (SHARP) trial demonstrated that sorafenib improves overall survival and is safe for patients with advanced HCC. In this trial, 602 patients with well-preserved liver function (>95% Child-Pugh A) were randomized to receive either sorafenib 400mg or matching placebo orally b.i.d. on a continuous basis. Because HCC is a heterogeneous disease, baseline patient characteristics may affect individual responses to treatment. In a comprehensive series of exploratory subgroup analyses, data from the SHARP trial were analyzed to discern if baseline patient characteristics influenced the efficacy and safety of sorafenib. METHODS Five subgroup domains were assessed: disease etiology, tumor burden, performance status, tumor stage, and prior therapy. Overall survival (OS), time to progression (TTP), disease control rate (DCR), and safety were assessed for subgroups within each domain. RESULTS Subgroup analyses showed that sorafenib consistently improved median OS compared with placebo, as reflected by hazard ratios (HRs) of 0.50-0.85, similar to the complete cohort (HR=0.69). Sorafenib also consistently improved median TTP (HR, 0.40-0.64), except in HBV-positive patients (HR, 1.03), and DCR. Results are limited by small patient numbers in some subsets. The most common grade 3/4 adverse events included diarrhea, hand-foot skin reaction, and fatigue; the incidence of which did not differ appreciably among subgroups. CONCLUSIONS These exploratory subgroup analyses showed that sorafenib consistently improved median OS and DCR compared with placebo in patients with advanced HCC, irrespective of disease etiology, baseline tumor burden, performance status, tumor stage, and prior therapy.

Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study

AIMS To evaluate the prevalence, incidence and clinical relevance of bacterial infection in predominantly non-alcoholic cirrhotic patients hospitalised for decompensation. PATIENTS/METHODS A total of 405 consecutive admissions in 361 patients (249 males and 112 females; 66 Child-Pugh class B and 295 class C) were analysed. Blood, urine, ascitic and pleural fluid cultures were performed within the first 24 hours, during hospitalisation whenever infection was suspected, and again before discharge. RESULTS Over a one year period, 150 (34%) bacterial infections (89 community- and 61 hospital-acquired) involving urinary tract (41%), ascites (23%), blood (21%) and respiratory tract (17%) were diagnosed. The prevalence of bacterial peritonitis was 12%. Infections were asymptomatic in 69 cases (46%) and 130 (87%) involved a single site. Enteric flora accounted for 62% of infections, Escherichia Coli being the most frequent pathogen (25%). Community-acquired infections were associated with more advanced liver disease (Child-Pugh mean score 10.2+/-2.1 versus 9.5+/-1.9, p<0.05), renal failure (p<0.05), and high white blood cell count (p<0.01). Hospital-acquired infections occurred more frequently in patients admitted for gastrointestinal bleeding (p<0.05). The in-hospital mortality was significantly higher in infected than in non-infected patients (15% versus 7%, p<0.05), and infection emerged as an independent variable affecting survival. Moreover bacterial infection accounted for a significantly prolonged hospital stay. CONCLUSIONS Bacterial infection, regardless of the aetiology, is a severe complication of decompensated cirrhosis, and, although frequently asymptomatic, accounts for both longer hospital stay and increased mortality.

The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis

Background Contrast-enhanced ultrasound (CE-US), contrast CT scan and gadolinium dynamic MRI are recommended for the characterisation of liver nodules detected during surveillance of patients with cirrhosis with US. Aim To assess the sensitivity, specificity, diagnostic accuracy and economic impact of all possible sequential combinations of contrast imaging techniques in patients with cirrhosis with 1–2 cm liver nodules undergoing US surveillance. Patients/methods 64 patients with 67 de novo liver nodules (55 with a size of 1–2 cm) were consecutively examined by CE-US, CT, MRI, and a fine-needle biopsy (FNB) as diagnostic standard. Undiagnosed nodules were re-biopsied; non-malignant nodules underwent enhanced imaging follow-up. The typical radiological feature of hepatocellular carcinoma (HCC) was arterial phase hypervascularisation followed by portal/venous phase washout. Results HCC was diagnosed in 44 (66%) nodules (2, <1 cm; 34, 1–2 cm; 8, >2 cm). The sensitivity of CE-US, CT and MRI for 1–2 cm HCC was 26, 44 and 44%, with 100% specificity, the typical vascular pattern of HCC being identified in 22 (65%) by a single technique versus 12 (35%) by at least two techniques carried out at the same time point (p=0.028). Compared with the cheapest dual examination (CE-US+CT), the cheapest single technique of stepwise imaging diagnosis of HCC was equally expensive (€26 440 vs €28 667), but led to a 23% reduction of FNB procedures (p=0.031). Conclusions In patients with cirrhosis with a 1–2 cm nodule detected during surveillance, a single imaging technique showing a typical contrast pattern confidently permits the diagnosis of HCC, thereby reducing the need for FNB examinations.

The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma.

BACKGROUND/AIMS Liver biopsy for hepatocellular carcinoma (HCC) detection is largely restricted to small hepatocellular lesions, which are often morphologically challenging, requiring careful distinction between dysplastic nodules (high-grade) and well-differentiated HCC. METHODS We investigated the diagnostic accuracy of a panel of markers (HSP70 GPC3 and GS), previously tested in resection specimens, in a series of liver biopsies of large regenerative nodules (n=13), low-grade dysplastic nodules (n=21), high-grade dysplastic nodules (n=50), very well-differentiated (VWD) (n=17), well-differentiated (WD-G1) (n=40) and G2-3 (n=35) HCC. RESULTS Almost all cases of large regenerative and low-grade dysplastic nodules did not stain while high-grade dysplastic nodules showed 1 marker (22%) but never 2 or 3. For HCC detection the overall accuracy of marker combination was 60.8% (3 markers) and 78.4% (2 markers) with 100% specificity. When restricted to VWD+WD-G1 HCC the accuracy was 57% (3 markers) and 72.9% (2 markers) with 100% specificity. CONCLUSIONS This panel proved useful to detect well-differentiated HCC in biopsy. Two immunoreactive markers (out of 3) are recommended as the most valuable diagnostic combination for HCC detection. The diagnostic accuracy of the panel could be improved using additional markers, as suggested by studies of expression profiling in other human models.

A 28-Year Study of the Course of Hepatitis Δ Infection: A Risk Factor for Cirrhosis and Hepatocellular Carcinoma

BACKGROUND & AIMS Chronic infection with hepatitis Delta virus (HDV) is a risk factor for cirrhosis and hepatocellular carcinoma (HCC); predictors of disease outcome are, however, poorly defined. We tracked the course of HDV infection in 299 patients over a mean period of 233 months. METHODS We analyzed data from patients who had been HDV positive for at least 6 months (230 males; mean age, 30 years) admitted from 1978 to 2006 to Maggiore Hospital, Milan. HDV infection was defined by the presence of HDV antigen in liver tissue or serum HDV RNA in anti-HDV/hepatitis B surface antigen seropositive patients. At enrollment, 7 patients had acute hepatitis, 101 had mild-moderate chronic hepatitis, 76 had severe chronic hepatitis, and 104 had histologic or clinical cirrhosis. Ninety patients were treated with interferon, 62 with corticosteroids, and 12 with nucleoside analogues; 135 received no therapy. RESULTS Over a mean period of 233 months, 82 patients developed cirrhosis. Among the 186 total patients with cirrhosis, 46 developed HCC, 43 ascites, 44 jaundice, and 1 encephalopathy. Female sex, alcohol abuse, and HDV replication were associated with liver decompensation; HBV replication and interferon were associated with HCC development. By the end of the study, 186 patients were still alive, 63 had died, and 29 had received liver transplants. The main cause of death was liver failure (n = 37, 59%); HDV replication was the only independent predictor of mortality. CONCLUSIONS Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8%, respectively, and is the only predictor of liver-related mortality.

Computed tomographic colonography and conventional colonoscopy for colon diseases : A prospective, blinded study

OBJECTIVES: Computed tomographic (CT) colonography or virtual colonoscopy is a new diagnostic method for the colon and rectum, developed on the basis of spiral computed axial tomography and employing virtual reality technology. The aim of this study was to determine the sensitivity, specificity, and diagnostic accuracy of CT colonography compared with colonoscopy in a prospective, blinded study in one single institution in Italy. METHODS: Ninety-nine patients randomly selected among those attending the open-access endoscopy unit for diagnostic colonoscopy underwent colonoscopy and spiral CT. The images obtained were transmitted to generate the virtual colonoscopy pictures. A supervisor compared the results with the findings of conventional colonoscopy. RESULTS: CT colonography diagnosed seven of eight tumors, one being missed because the patient had been inadequately prepared. In 28 patients, CT colonography identified 26 polyps of 45 (57.8% sensitivity, 92.6% specificity, 86.7% positive predictive value), regardless of their size. The sensitivity in detecting colonic polyps was 31.8% (7/22) in the first 25 cases and 91.6% (11/12) in the last 20 patients. CT colonography missed one flat adenoma, some angioectasias and colonic lesions because of portal hypertension in one patient, Crohns disease ulcers in two patients, and ulcerative colitis lesions in three. CONCLUSIONS: CT colonography shows poor sensitivity for identifying colonic polyps and does not always detect neoplastic lesions. Flat lesions are impossible to see by this method.

Transarterial chemoembolization with epirubicin-eluting beads versus transarterial embolization before liver transplantation for hepatocellular carcinoma.

PURPOSE To retrospectively compare radiologic tumor response and degree of necrosis in explanted livers after chemoembolization with epirubicin-loaded DC Bead versus bland embolization in patients on a transplant waiting list. MATERIALS AND METHODS From 2003 to 2007, 49 patients with hepatocellular carcinoma (HCC) underwent transplantation at a single center. Sixteen patients were treated with bland embolization (n = 8) with 100-300-microm Embosphere particles or chemoembolization with epirubicin-loaded 100-300-microm DC Bead particles (n = 8) every other month until complete tumor devascularization. Computed tomography was performed every 3 months until recurrence. Explanted livers were analyzed to evaluate the degree of necrosis in the nodules. After orthotopic liver transplantation (OLT), patients were followed up for survival and disease status. RESULTS The groups were comparable for baseline characteristics. Most patients had Child-Pugh class A disease. Solitary HCC was found in 75% of patients. Mean target lesion size was 32 mm +/- 15.4. Chemoembolization with drug-eluting beads achieved complete necrosis in 77% of lesions whereas bland embolization achieved complete necrosis in 27.2% of lesions. There was a significant difference between bland embolization and chemoembolization with DC Bead with regard to histologic necrosis (P = .043). No significant treatment-related complications were observed for either group. Fifteen patients are alive with no tumor recurrence. CONCLUSIONS Chemoembolization with drug-eluting beads before OLT achieved higher rates of complete histologic response than bland embolization, with no serious adverse events observed. Because of the retrospective data analyses and small sample size, further studies are warranted to confirm these promising results.

Prognostic Gene Expression Signature for Patients With Hepatitis C–Related Early-Stage Cirrhosis

BACKGROUND & AIMS Cirrhosis affects 1% to 2% of the world population and is the major risk factor for hepatocellular carcinoma (HCC). Hepatitis C cirrhosis-related HCC is the most rapidly increasing cause of cancer death in the United States. Noninvasive methods have been developed to identify patients with asymptomatic early-stage cirrhosis, increasing the burden of HCC surveillance, but biomarkers are needed to identify patients with cirrhosis who are most in need of surveillance. We investigated whether a liver-derived 186-gene signature previously associated with outcomes of patients with HCC is prognostic for patients with newly diagnosed cirrhosis but without HCC. METHODS We performed gene expression profile analysis of formalin-fixed needle biopsy specimens from the livers of 216 patients with hepatitis C-related early-stage (Child-Pugh class A) cirrhosis who were prospectively followed up for a median of 10 years at an Italian center. We evaluated whether the 186-gene signature was associated with death, progression of cirrhosis, and development of HCC. RESULTS Fifty-five (25%), 101 (47%), and 60 (28%) patients were classified as having poor-, intermediate-, and good-prognosis signatures, respectively. In multivariable Cox regression modeling, the poor-prognosis signature was significantly associated with death (P = .004), progression to advanced cirrhosis (P < .001), and development of HCC (P = .009). The 10-year rates of survival were 63%, 74%, and 85% and the annual incidence of HCC was 5.8%, 2.2%, and 1.5% for patients with poor-, intermediate-, and good-prognosis signatures, respectively. CONCLUSIONS A 186-gene signature used to predict outcomes of patients with HCC is also associated with outcomes of patients with hepatitis C-related early-stage cirrhosis. This signature might be used to identify patients with cirrhosis in most need of surveillance and strategies to prevent the development of HCC.