The association of IL28B genotype with the histological features of chronic hepatitis C is HCV genotype dependent.

The interleukin 28B (IL28B) rs12979860 polymorphism is associated with treatment outcome in hepatitis C virus (HCV) genotype 1 and 4 patients. Its association with the histological features of chronic hepatitis C and disease severity needs further clarifications. To assess the correlation between IL28B genotype, HCV genotype and liver biopsy findings in untreated patients. MATERIALS AND METHODS: Pre-treatment liver biopsies from 335 HCV Caucasian patients (59% males, age 50 years) enrolled in the MIST study were staged for fibrosis and inflammation according to the METAVIR and the Ishak scoring systems; steatosis was dichotomized as <5% or ≥5%. IL28B was typed by Taqman Single Nucleotide Polymorphism (SNP) genotyping assay. HCV genotype was 1 in 151 (45%), 2 in 99 (30%), 3 in 50 (15%) and 4 in 35 (10%) patients. IL28B genotype was CC in 117 (34%), CT in 166 (49%) and TT in 52 (15%). At univariate analysis, the IL28B CC genotype was associated with severe portal inflammation in HCV-1 patients (CC vs. CT/TT: 86% vs. 63%, p = 0.005), severe lobular inflammation in HCV-2 patients (CC vs. CT/TT: 44% vs. 23%, p = 0.03), and less fatty infiltration in HCV-1 patients (CC vs. CT/TT: 72% vs. 51%, p = 0.02). Despite the lack of any association between IL28B and fibrosis stage, in HCV-3 patients IL28B CC correlated with METAVIR F3-F4 (CC vs. CT/TT: 74% vs. 26%, p = 0.05). At multivariate analysis, the genotype CC remained associated with severe portal inflammation in HCV-1, only (Odds Ratio (OR): 95% Confidence Interval (CI): 3.24 (1.23-8.51)). IL28B genotype is associated with the histological features of chronic hepatitis C in a HCV genotype dependent manner, with CC genotype being independently associated with severe portal inflammation.

A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.

UNLABELLED: Although annular fibrosis is the hallmark of cirrhosis, other microscopic changes that affect liver function such as sinusoid capillarization or loss of metabolic zonation are common. A sustained virological response (SVR) may halt fibrosis deposition in hepatitis C virus (HCV)-infected patients, but its impact on the other cirrhosis-associated lesions is unknown. The aim of this study was to assess the impact of an SVR on cirrhosis-related histopathological features. Paired pre- and posttreatment liver biopsies from 38 HCV patients with cirrhosis with an SVR were analyzed. Fibrosis was staged using the METAVIR scoring system, and the area of fibrosis was measured using morphometry. Ductular proliferation, metabolic zonation, sinusoid capillarization, and hepatic stellate cell activation were assessed by anti-cytokeratin-7, anti-glutamine synthetase (GS), anti-cytochrome P4502E1 (CYP2E1), anti-CD34, and anti α-smooth muscle actin (αSMA). After 61 months from an SVR, cirrhosis regression was observed in 61%, and the collagen content decreased in 89%. Although periportal and lobular necroinflammation vanished, portal inflammation persisted in 66%. Ductular proliferation decreased in 92%. Before treatment, metabolic zonation was lost, as shown by GS and CYP2E1, in 71% and 88%, respectively, with normalization in 79% and 73%, after an SVR. Conversely, no changes in sinusoidal capillarization were observed after treatment, as assessed by CD34 (P = 0.41) and αSMA (P = 0.95). Finally, no differences in all the immunohistochemical scores emerged whether or not cirrhosis persisted. CONCLUSION: Cirrhosis regression and decreased fibrosis are frequently observed among HCV patients with cirrhosis with an SVR. Despite ductular proliferation vanishing and lobular zonation restoration, portal inflammation and sinusoidal capillarization may not regress after viral eradication.

Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C.

BACKGROUND & AIMS: Transient elastography (TE) has gained popularity for the non-invasive assessment of severity of chronic viral hepatitis, but a comprehensive evaluation of the factors that might account for discrepancy in diagnostic accuracy between TE and the standard of care liver biopsy (LB) is still needed. METHODS: Patients with chronic hepatitis-B (HBV, n=104) or -C (HCV, n=453) underwent percutaneous LB concomitantly with TE (FibroScan®; Echosens, Paris, France). Liver cell necroinflammatory activity (A) and fibrosis (F) were assessed by METAVIR. Perisinusoidal fibrosis was rated with a 0-3 score. Determinants of TE results were investigated by a linear regression model whereas discordance between TE and LB results was assessed by logistic regression. RESULTS: Fibrosis (p<0.0001) and liver cell necroinflammatory activity (p<0.0001) were independently associated with TE results in both HBV and HCV patients, whereas steatosis (p<0.0001) was independently associated with TE in HCV only. Fibrosis overestimation was predicted by severe/moderate necroinflammatory activity in HBV and by older age (41-60 or>60years vs.<40), >2 UNL AST and>2 UNL GGT, as well as severe/moderate necroinflammatory activity and severe/moderate steatosis in HCV. In the latter patients, however, moderate/severe necroinflammatory activity and steatosis were the only independent predictors of fibrosis overestimation. CONCLUSIONS: Fibrosis and necroinflammatory activity are the main determinants of TE in chronic viral hepatitis. Since TE staging of fibrosis is influenced by necroinflammatory activity and steatosis, a diagnostic LB is deemed necessary for a reliable intra-patient TE monitoring of the course of viral hepatitis.

Diagnosis of hepatocellular carcinoma in cirrhosis by dynamic contrast imaging: the importance of tumor cell differentiation.

UNLABELLED: Dynamic contrast imaging techniques are considered the standard of care for the radiological diagnosis of hepatocellular carcinoma (HCC) in cirrhosis. However, the accuracy of radiological diagnosis depends largely on the degree of arterial hypervascularization, which increases with tumor size. Owing to the interplay and prognostic relevance of tumor vascularization and cell differentation, we asked ourselves whether tumor grade also affects the outcome of radiological diagnosis. Sixty-two HCCs (47 of which measured 1-2 cm) were consecutively detected in 59 patients with compensated cirrhosis under surveillance with ultrasound and confirmed by way of echo-guided biopsy and concurrent investigations with contrast-enhanced ultrasound (CE-US), computed tomography (CT), and gadolinium magnetic resonance imaging (MRI). Tumor cell differentiation was evaluated using Edmondson-Steiner criteria in liver cores of 0.9-5.0 cm (median 1.6 cm). Eighteen (29%) HCCs were grade I (1.5 cm), 28 (45%) were grade II (1.5 cm), 16 (26%) were grade III (1.8 cm), and none were grade IV. Contrast wash-in and wash-out were concurrently demonstrated in 21 (34%) tumors by way of CE-US, including three (16%) grade I and 18 (41%) grade II-III (P = 0.08); in 32 (52%) tumors by way of CT, including three (16%) grade I and 29 (66%) grade II-III (P = 0.0006); and 28 (47%) tumors by way of MRI, including three grade I (16%) and 25 (57%) grade II-III (P = 0.01). Among 1- to 2-cm tumors, the radiological diagnosis was achieved in two of 16 grade I and 17 of 31 grade II-III tumors (P = 0.006). CONCLUSION: Tumor grade, a relevant predictor of disease severity, influences the accuracy of dynamic contrast techniques in the diagnosis of HCC.

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 (euro 26 440 vs euro 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.

A 28-year study of the course of hepatitis Delta 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.

Lack of rapid virological response predicts interferon-alpha2b/ribavirin therapy failure in HCV genotype 2 patients: a single-centre study.

BACKGROUND: A minority of patients with HCV-2 chronic hepatitis does not attain a sustained virological response to interferon-based therapies. Registration trials have failed to identify the real proportion of HCV-2 non-responders, and predictors of non-response. The analysis of 'real-life' HCV-2 patients might help define the effectiveness of anti-HCV therapy and the role of response moderators. METHODS: A re-analysis of all treatment-naive HCV-2 patients who consecutively received weight-dosed ribavirin with either 3 MU three times a week standard interferon-alpha2b or 1.5 microg/kg/week pegylated interferon-alpha2b. RESULTS: The 94 interferon-treated patients and the 136 pegylated-interferon-treated patients were comparable for demography, prevalence of cirrhosis (25%) and adherence to therapy (74%). By intention-to-treat analysis, the overall sustained virological response rate was 80% (82% interferon versus 78% pegylated interferon). Overall, sustained virological rates were 83% for the 182 patients who cleared HCV RNA at week 4 (rapid virological response) and 52% for the 48 who did not (P < 0.001). The corresponding week 12 figures of HCV RNA clearance were 90% and 32%, respectively (P < 0.001). Sustained response was independent of gender, age, body mass index, modality of infection, duration and severity of liver disease, adherence to therapy and interferon type. After stratification for interferon type, the only treatment failure predictor was persistence of HCV RNA at week 4 and 12. CONCLUSIONS: Despite the prevalence of moderators of treatment outcome, HCV-2 patients showed as high sustained virological response rates as those reported in registration trials for HCV-2 and HCV-3 pooled patients; pegylated interferon therapy failure was predicted by lack of rapid virological response.

Impaired response to interferon-alpha2b plus ribavirin in cirrhotic patients with genotype 3a hepatitis C virus infection.

Patients with chronic infection with the 3a genotype of hepatitis C virus (HCV) are considered as 'easy-to-treat' with interferon/ribavirin (IFN/RBV), independent of liver disease severity. However, patients with extensive fibrosis or cirrhosis were under-represented in all the registration Phase III trials performed so far. To assess the influence of liver fibrosis on the outcome of anti-HCV therapy, all patients with genotype 3a hepatitis C who were naive to IFN-based therapies, and received RBV combined with standard IFN or pegylated IFN-(alpha2b (peg-IFN-alpha2b) as standard of care for their disease, were investigated at our centre. A sustained virological response (SVR) was achieved in 68 of 91 patients (75%) independent of IFN type, pretreatment viraemia, clearance of HCV RNA at week 4 and relevant co-morbidities. A SVR was less common in cirrhotics (6 of 17) than in non-cirrhotics (62 of 74; 35% vs 84%; P<0.0005). Compared to non-cirrhotics, the age and sex adjusted odds ratio (OR) of treatment failure for cirrhotics was 10.1 (95% confidence interval: 2.4-41.7). By multivariate analysis, cirrhosis was the only predictor of non-SVR. In conclusion, cirrhosis is an independent predictor of IFN/RBV treatment failure in patients chronically infected with HCV 3a and is associated with an increased risk of post-treatment hepatitis relapse. Evaluation of liver fibrosis is important in the management of patients with genotype 3a hepatitis C, since it helps to predict response to IFN/RBV therapy.

Contrast-enhanced computed tomography and ultrasound-guided liver biopsy to diagnose dysplastic liver nodules in cirrhosis.

BACKGROUND: Dysplastic nodules in cirrhosis herald a very high risk of transition to hepatocellular carcinoma. A better understanding of the relationships between dysplastic nodules and hepatocellular carcinoma development may help refining strategies of enhanced follow-up. METHODS: All consecutive cirrhotics with a histologically proven de novo dysplastic nodule, were retrospectively identified and underwent alternating abdominal ultrasound and contrast-computed tomography every 3 months. An ultrasound-guided liver biopsy was the diagnostic gold standard, whereas surveillance and recall policies were according to current guidelines. RESULTS: Among 36 patients with dysplastic nodule (21 low-grade, 15 high-grade, 17.4 ± 2.6mm), 17 (47%) showed arterial wash-in, 15 (42%) portal/venous hypodensity whereas 4 (11%) had neither pattern. During 6-128 (median 36) months, 21 patients developed a hepatocellular carcinoma at a rate of 13.8% per year, intranodular=8.7% vs extranodular=7.1% per year. Hepatocellular carcinoma occurred more frequently in high-grade than low-grade dysplastic nodules (32.2% vs 9.3% per year, p=0.0039); the maximum time to hepatocellular carcinoma transformation was 27 months for intranodular vs 67 months for extranodular tumours (p=0.025). No contrast-computed tomography pattern predicted neoplastic transformation of dysplastic nodules. CONCLUSION: The histological examination of liver nodules in cirrhosis lacking the imaging hallmark of hepatocellular carcinoma improves both prognostication and outcome of surveillance, since it dictates the intensity of the radiological follow-up.

A non-invasive algorithm accurately predicts advanced fibrosis in hepatitis C: a comparison using histology with internal-external validation.

BACKGROUND/AIMS: Biochemical tests and ultrasonography (US) are useful in the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C (CH-C); however histology remains the reference standard. This multicenter, cross-sectional cohort study evaluated the accuracy of APRI (AST-to-platelet-ratio-index) and liver surface ultrasound nodularity (LSN), singularly and sequentially combined in an algorithm, in diagnosing advanced fibrosis (i.e. METAVIR F3,F4), to derive a prediction rule to confirm or exclude F3,F4. METHODS: Four hundred and thirty consecutive CH-C patients with elevated ALT, grouped into a first cohort (training set), and an internal and an external validation cohort, were studied. APRI and LSN were compared to liver biopsy and sequentially combined in order to obtain a predictive rule for advanced fibrosis METAVIR F3,F4. RESULTS: LSN was negative and APRI < or = 1 in 185/430 patients, whereas LSN was positive and APRI>2 in 46/430 cases, with a 94% diagnostic accuracy for presence/absence of F3, F4, respectively. In a further 60/430 patients, F3,F4 was detected with an accuracy of 83%. In the remaining cases no classification was possible. CONCLUSIONS: An algorithm based on APRI and LSN confirms or excludes F3,F4 in 54% of CH-C patients with elevated ALT and suggests a highly probable diagnosis in a further one-sixth of patients, thus rendering liver biopsy unnecessary in these patients.

Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.

OBJECTIVE: Transient elastography (TE) is gaining popularity as a non-invasive method for predicting liver fibrosis, but intraobserver and interobserver agreement and factors influencing TE reproducibility have not been adequately assessed. This study investigated these aspects. SETTING: Tertiary referral liver unit. PATIENTS: Over a 4-month period, 200 patients with chronic liver disease (CLD) with varying aetiology consecutively underwent TE and liver biopsy. INTERVENTIONS: TE was performed twice by two different operators either concomitantly or within 3 days of the bioptic procedure (METAVIR classification). MAIN OUTCOME MEASURES: Intraobserver and interobserver agreement were analysed using the intraclass correlation coefficient (ICC) and correlated with different patient-related and liver disease-related covariates. RESULTS: 800 TE examinations were performed, with an indeterminate result rate of 2.4%. The overall interobserver agreement ICC was 0.98 (95% CI 0.977 to 0.987). Increased body mass index (>25 kg/m(2)), steatosis, and low staging grades (fibrosis (F) stage <2) were significantly associated with reduced ICC (p<0.05). Intraobserver agreement ICC was 0.98 for both raters. Using receiver operating characteristic curves, three diagnostic TE thresholds were identified: >7.9 kPa for F>/=2, >10.3 for F>/=3 and >11.9 for F = 4. TE values assessed by the two raters fell within the same cut-off of fibrosis in 88% of the cases for F>/=2, in 92% for F>/=3 and 91% for F = 4. CONCLUSIONS: TE is a highly reproducible and user-friendly technique for assessing liver fibrosis in patients with CLD. However, because TE reproducibility is significantly reduced (p<0.05) in patients with steatosis, increased BMI and lower degrees of hepatic fibrosis, caution is warranted in the clinical use of TE as a surrogate for liver biopsy.

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.

Serum levels of hepatitis C virus core antigen as a marker of infection and response to therapy.

OBJECTIVES: Hepatitis C virus (HCV) core antigen is a recently developed marker of hepatitis C infection. We compared the predictive power of HCV core antigen with reverse transcription polymerase chain reaction (RT-PCR) and branched DNA assay for HCV-RNA as markers of infection and response to interferon therapy. METHODS: Four hundred and forty-four sera from 111 patients (65 men, 52 yr) with chronic hepatitis C, receiving ribavirin together with standard interferon (n = 61) or pegylated interferon (n = 50) were retrospectively investigated. RESULTS: Pretreatment, RT-PCR, branched DNA (median 621,887 IU/ml), and HCV core antigen (median 57 pg/ml) gave positive results in 100%, 99%, and 94% of the sera; the correlation between HCV core antigen and branched DNA was 0.75. The median HCV RNA level among the 7 of 111 (6%) patients that had a negative core Ag result was 15,016 IU/ml. Pretreatment levels of HCV core antigen were significantly lower in the 41 patients with a sustained virological response than in the 39 relapsers and 31 nonresponders (17 pg/ml, 114 pg/ml, 58 pg/ml; p-value 0.005). Independently of treatment schedule, wk 12 more than 2 log(10) reduction of viremia or a negative result for HCV core antigen had 100% negative predictive value (NPV) for a response to therapy compared to 94% for negative RT-PCR. The positive predictive value (PPV) of HCV core antigen and branched DNA was only 47% and 48%. CONCLUSIONS: In conclusion, the HCV core antigen is a less sensitive test of HCV viremia than HCV-RNA assays and is competitive with the bDNA assay as an early predictor of a nonresponse.

The clinical and pathogenetic significance of estrogen receptor-beta expression in chronic liver diseases and liver carcinoma.

BACKGROUND: Estrogen receptor-alpha (ERalpha) is variably expressed in hepatocellular carcinoma (HCC) and is believed to be correlated with prognosis and survival. Recently, another estrogen receptor (ERbeta) has been identified, but its relevance in liver diseases is unknown. METHODS: The expression of ERbeta in the liver of 42 patients with HCC (10 with paired extratumoral tissues) and 26 with chronic liver disease without HCC was studied by a reverse transcriptase-polymerase chain reaction method, and correlated with the expression of ERalpha and severity of the liver disease. RESULTS: Both ERbeta and wild-type ERalpha were found to be expressed more often in patients with chronic liver disease compared with those with HCC (69% vs. 45% [P = 0.046] and 46% vs. 10% [P = 0.0008], respectively). ERs were similarly expressed in HCC and in the paired extratumoral tissue. Wild-type receptors, either alone or together with the deleted mutants ERdelta5, were more often coexpressed in chronic liver disease (58%) than in HCC (29%); in 13 tumors (31%), either ERdelta5 or no receptors at all were detected (P = 0.006). Hepatitis B virus (HBV)-related tumors either did not appear to express ERs or expressed ERdelta5 more often than hepatitis C virus (HCV)-related tumors (67% vs. 15%; P = 0.007). The same was true for multinodular compared with single nodular tumors (50% vs. 19%; P = 0.04). CONCLUSIONS: Both receptors were expressed in chronic liver disease and neoplastic livers demonstrating different patterns in relation to the etiology and clinical presentation of the tumor. These differences might underscore different pathogenetic mechanisms in HBV-related and HCV-related HCC and a different evolutionary course for the tumor.

Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance.

BACKGROUND & AIMS: Significant improvements in management of hepatocellular carcinoma (HCC) have occurred in the last years, but their impact on surveillance outcome is unknown. To clarify this, we compared survival of HCC patients identified along 3 consecutive quinquennia of surveillance. METHODS: A cohort of 417 HCC-free outpatients with compensated cirrhosis was prospectively followed for 148 months (range, 1-213 months) with periodic ultrasound examinations. RESULTS: HCC developed in 112 patients, at a 3.4% rate per year, and was the prime cause of death (n = 54). Forty-six (41%) patients had a single tumor, with a mean size of 3.7 cm, 3.0 cm, and 2.2 cm in the 3 quinquennia (first vs. second: ns; first vs. third: P = 0.017; second vs. third: P = 0.02), and 38 (44%) underwent radical therapy. Mortality rates in HCC patients fell from 45% in the first quinquennium to 37% in the second and 10% in the third (first vs. second: ns; first vs. third: P = 0.0009; second vs. third: P = 0.018) in parallel with a reduction in yearly mortality of treated patients (34%, 28%, and 5%, respectively; first vs. second: ns; second vs. third: P = 0.036; first vs. third: P = 0.0024). After stratification for quinquennium, tumor staging, according to Cancer of the Liver Italian Program (CLIP), was the only independent predictor of survival (P = 0.015). CONCLUSIONS: Cirrhotic patients developing a HCC during the last 5 years of surveillance survived longer than previously, as a consequence of improved management of the tumor and complications of cirrhosis.

Segmental transcatheter arterial chemoembolization treatment in patients with cirrhosis and inoperable hepatocellular carcinomas.

PURPOSE: To establish whether segmental transcatheter arterial chemoembolization (TACE) treatment may improve the rates of survival in patients with compensated cirrhosis and inoperable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Fifty-six patients with compensated cirrhosis and inoperable HCC were treated with segmental TACE. One hundred forty treatments (mean, 2.5 per patient; 30-60 mg Epirubicin, 4-10 mL Lipiodol, and Gelfoam particles) were administered. RESULTS: During the 69-month study, 25 patients (45%) died of tumor progression, 12 (21%) of liver failure, nine (16%) of gastrointestinal hemorrhage, and three (5%) of other causes; seven patients (13%) are still alive. The 3-year rate of survival was 32%. Intention-to-treat analysis determined that patients with Child-Pugh class A disease (n = 44; 79%) or a single <5-cm HCC (n = 21; 37%) had a higher rate of survival than those with Child-Pugh class B disease (n = 12; 21%; P <.002) or a larger HCC (n = 35; 63%; P <.02) and patients (n = 41) who were treated with more than one course of TACE had a higher rate of survival than those who were treated with a single TACE procedure (n = 15; P <.0003). Multivariate analysis was used to predict rates of survival by number of treatments (hazard ratio, 0.6; CI, 0.48-0.86; P <.004), Child-Pugh class (hazard ratio, 2.8; CI, 1.41-5.74; P <.003), and tumor size (hazard ratio, 3.8; CI, 1.81-8.01; P <.001). The 3-year rate of survival in patients with Child-Pugh class A disease and a < or =5-cm-HCC (n = 16) was 56%. This result was similar to the 50% 3-year rate of survival in untreated historic controls with similar characteristics. CONCLUSION: The rate of survival in patients with compensated cirrhosis and inoperable HCC did not appear to improve with use of TACE therapy.