The role and evolution of partial splenic embolization over three decades: A multicentric retrospective single cohort study of 90 patients from French nationwide experience.

BACKGROUND: Partial splenic embolization (PSE) has been proposed to treat the consequences of hypersplenism in the context of portal hypertension, especially thrombocytopenia. However, a high morbidity/mortality rate has made this technique unpopular. We conducted a multicenter retrospective nationwide French study to reevaluate efficacy and tolerance. METHODS: All consecutive patients who underwent PSE for hypersplenism and portal hypertension in 7 tertiary liver centers between 1998 and 2023 were included. RESULTS: The study population consisted of 91 procedures in 90 patients, with a median age of 55.5 years [range 18-83]. The main cause of portal hypertension was cirrhosis (84.6 %). The main indications for PSE were (1) an indication of medical treatment or radiological/surgical procedure in the context a severe thrombocytopenia (59.3 %), (2) a chronic hemorrhagic disorder associated with a severe thrombocytopenia (18.7 %), and (3) a chronic pain associated with a major splenomegaly (9.9 %). PSE was associated with a transjugular intrahepatic portosystemic shunt in 20 cases. Median follow-up after PSE was 41.9 months [0.5-270.5]. Platelet count increased from a median of 48.0 G/L [IQR 37.0; 60.0] to 100.0 G/L [75.0; 148]. Forty-eight patients (52.7 %) had complications after PSE; 25 cases were considered severe (including 7 deaths). A Child-Pugh B-C score (p < 0.02) was significantly associated with all complications, a history of portal vein thrombosis (p < 0.01), and the absence of prophylactic antibiotherapy (p < 0.05) with severe complications. CONCLUSION: Our results strongly confirm that PSE is very effective, for a long time, although a quarter of the patients experienced severe complications. Improved patient selection (exclusion of patients with portal vein thrombosis and decompensated cirrhosis) and systematic prophylactic antibiotherapy could reduce morbidity and early mortality in the future.

Long-term oncological results of percutaneous radiofrequency ablation for intrahepatic cholangiocarcinoma.

INTRODUCTION: The effectiveness of percutaneous radiofrequency ablation (RFA) in intrahepatic cholangiocarcinomas (iCCA) remains insufficiently studied. METHODS: We conducted a retrospective study including patients with histologically proven iCCA within Milan criteria treated by percutaneous RFA from 2000 to 2022. The primary outcome was overall survival in treatment-naive patients and secondary outcomes included ablation completeness, adverse events, local and distant recurrence. A total of 494 patients with hepatocellular carcinoma (HCC) on cirrhosis treated by RFA were included as a comparison group. Oncological events were analysed using Kaplan-Meier, log-rank and univariate/multivariate Cox models. RESULTS: The main population included 71 patients, mostly cirrhotic (80%) with solitary tumours (66%) of a median size of 24 mm. Local recurrence was 45% at 5 years, lower in multibipolar versus monopolar RFA (22% vs. 55%, p = .007). In treatment-naive patients (n = 45), median overall and recurrence-free survivals were 26 and 11 months, respectively. Tumour size (p = .01) and Child-Pugh B (p = .001) were associated with death. The rate of distant recurrence was 59% at 5 years significantly lower for single tumours of less than 2 (p = .002) or 3 cm (p = .02). In cirrhotic patients naïve of previous treatment (n = 40), overall survival was shorter than in HCC (26 vs 68 months, p < .0001), with more local recurrences (p < .0001). Among distant recurrences, 50% were extrahepatic metastases compared to 12% in HCC (p < .001). CONCLUSION: Multibipolar RFA provides better results in terms of tumour recurrence than monopolar RFA and could be used to treat small iCCA (<3 cm). Adjuvant chemotherapy should be discussed due to the frequent extra-hepatic metastasis at recurrence.

Percutaneous ablation for locally advanced hepatocellular carcinoma with tumor portal invasion.

INTRODUCTION: We aim to assess the outcomes of percutaneous ablation of locally advanced HCC in a tertiary center, which is usually not indicated. We compared to sorafenib or trans-arterial radioembolization (TARE). METHODS: We included 272 patients with HCC and tumor portal invasion treated by percutaneous ablation (n = 44) assessed retrospectively from one center compared to a control group from the SARAH trial including patients treated with sorafenib (n = 123) or TARE (n = 105). A propensity-score matching was performed in a subgroup of patients with similar baselines characteristics. RESULTS: 84% of patients treated by ablation were male with a unique nodule (median size 50 mm) in 72.7% of the case. Complete tumor ablation was achieved in 75% of the patients with 20% Dindo-Clavien III-V adverse events including 6.8% of 90-days mortality. Sum of tumor size ≥70 mm was associated with incomplete ablation (p = 0.0239) and a higher risk of death (p = 0.0375). Patients in control group had a higher tumor burden, and more Vp3/4 compared to ablation group. Median overall survival was similar in the ablation and in the control group (16.4 and 14.0 months respectively, p = 0.48). The median progression-free survival was 6.6 months in ablation group compared to 4.2 months in the control group (p = 0.12). CONCLUSION: Percutaneous ablation for locally advanced HCC was feasible and associated with similar long-term outcomes to sorafenib or TARE.

Prior surveillance and antiviral treatment improve the prognosis of HCC developed in HBV patients in the West.

BACKGROUND: In Western countries, hepatocellular carcinoma (HCC) in hepatitis B (HBV) patients without cirrhosis was poorly studied. The aim was to describe the characteristics and outcome of HBV-related HCC according to fibrosis stage. METHOD: All patients with chronic HBV infection and HCC discussed in a multidisciplinary tumor board between 2007 and 2017 were retrospectively included. RESULTS: A total of 152 out of 2,038 HCC patients had underlying HBV infection. HBV viral load>2000IU/ml, positive HBeAg and Hepatitis D coinfection were observed in 41%, 13% and 13% of cases, respectively. HCC was uninodular in 53%, associated with portal thrombosis in 16% and/or metastasis in 9% of cases. 130 patients (86%) had cirrhosis. No difference regarding HCC risk factors and viral characteristics was observed according to fibrosis stage. 5-year survival was 48%(47% on cirrhosis versus 57% without cirrhosis, P=0.26). At HCC diagnosis, 47% and 32% of cirrhotic and non-cirrhotic patients received an antiviral treatment (AVT), which was associated with less aggressive tumor and better survival (P=0.005). In cirrhosis, screening was associated with a lower tumor burden and patients were more amenable to curative treatment with better outcome (P<0.001). CONCLUSION: HBV represents 8% of HCC etiologies without differences of viral characteristics according to fibrosis stage. AVT and surveillance were associated with less aggressive tumors, better access to curative treatment and outcome.

Transient elastography predicts survival after radiofrequency ablation of hepatocellular carcinoma developing on cirrhosis.

BACKGROUND AND AIM: The prognostic value of transient elastography (TE) in cirrhotic patients with hepatocellular carcinoma (HCC) treated by percutaneous radiofrequency ablation (RFA) is currently unknown. METHOD(S): We included patients with histologically proven cirrhosis and with a first diagnosis of HCC inside Milan criteria treated by percutaneous RFA, and with TE available the year before treatment with 10 shots and interquartile range/median < 30%. Association between variables and clinical events was assessed by the Kaplan-Meier method with the log-rank test and using Cox univariate and multivariate analyses. RESULTS: One hundred fifty-nine patients were included, with a median age of 65 years; 77.4% were men. Causes of cirrhosis were alcohol consumption (48.1%), hepatitis C (43.7%), hepatitis B (12.7%), and non-alcoholic steatohepatitis (32.3%). Median value of TE was 26 kPa (4-75 kPa). Overall survival at 1, 2, and 5 years was, respectively, 93%, 81%, and 44%; overall recurrence was 28%, 49%, and 80%. The TE value was not associated with tumor recurrence (0.13). In contrast, in univariate analysis, TE value, age, Child-Pugh B, and alkaline phosphatase were predictive factors in overall survival. In multivariate analysis, TE value (hazards ratio [HR] = 1.02, 95% confidence interval (IC): 1.01-1.04, 0.001), age (HR = 1.05, 95% IC: 1.03-1.08, P = 0.00006), and Child-Pugh B score (HR = 2.78, 95% IC: 1.27-6.08, P = 0.01) were independently associated with higher risk of death. A TE value ≥ 40 kPa was associated with shorter median overall survival (34 months) compared to a TE value < 40 kPa (59 months, P = 0.0008). CONCLUSION(S): Transient elastography (TE) predicts overall survival but not tumor recurrence in cirrhotic patients with HCC treated by RFA.

Virologic control and severity of liver disease determine survival after radiofrequency ablation of hepatocellular carcinoma on cirrhosis.

BACKGROUND: We aimed to identify the main determinants of long-term overall survival (OS), including virologic control, and recurrence after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) on cirrhosis. METHODS: Cirrhotic patients treated by RFA for HCC within Milan criteria were included. Associations between patient features and events were estimated by the Kaplan-Meier method with the log rank test and using uni/multivariate Cox models. RESULTS: 389 cirrhotic patients (Child-Pugh A 86.6%, 473 tumors) were included. OS was 79.8%, 42.4% and 16%, and overall tumor recurrence 45%, 78% and 88% at 2, 5 and 10 years, respectively. In multivariate analysis, age, Child-Pugh, GGT, HCC near major vessels, esophageal varices, alkaline phosphatase and HBV predicted OS. Gender, ALT, AFP and alcohol intake were associated with tumor recurrence. Multinodular HCC (19.5%) was associated with risk of tumor recurrence outside Milan criteria. HBV patients had longer OS than other patients (P = 0.0059); negative HBV PCR at RFA was associated with decreased tumor recurrence (P = 0.0157). Using time-dependent analysis in HCV patients, a sustained virologic response was associated with increased OS (124.5 months) compared to other patients (49.2 months, P < 0.001). CONCLUSION: Virologic response and severity of underlying liver disease were the main determinants of long-term OS after RFA for HCC developing on cirrhosis.

A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.

BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).

Concomitant screening for liver fibrosis and steatosis in French type 2 diabetic patients using Fibroscan.

BACKGROUND: Type 2 diabetes is a risk factor for steatohepatitis and fibrosis. Non-invasive liver stiffness (LS) and controlled attenuation parameter (CAP) measurements by Fibroscan allow assessing liver fat and fibrosis. AIM: To determine the prevalence of steatosis and significant fibrosis in a community-based diabetic population. METHODS: LS and CAP were measured in 705 patients using the standard "M probe." A second "XL probe" was used, without CAP measurement, in case of failure with the "M probe." RESULTS: LS and CAP measurements were obtained in 437 patients (the M group), LS measurements (LSM) with the XL probe being available in additional 232 patients. After the combined use of both probes, LSM failure and unreliable result were 1.6% and 5.6% respectively. Overall, 12.7% (n=85), 7.3% and 2.1% exhibited significant or advanced fibrosis or cirrhosis (LSM≥8 kPa, ≥9.6 kPa, ≥13 kPa respectively), half of the patients with LSM≥8 kPa displayed normal liver tests. Significant and severe steatosis were measured in 75% and 24% of the M group patients. By multivariate analysis, factors associated with severe fibrosis were age, overweight, high GGT. Forty-seven patients with LSM≥8 kPa underwent liver biopsy; 93% had steatosis and 51% severe fibrosis. A significant correlation was found between LSM values and fibrosis score with an accuracy rate of 83%, 68% and 83% for LSM≥8 kPa, ≥9.6 kPa and ≥13 kPa respectively. CONCLUSIONS: The prevalence of significant steatosis is very high and significant fibrosis affect 12.7% of the patients. Fibroscan is an effective procedure to screen for fibrosis and steatosis in diabetic patients.

The CRP level and STATE score predict survival in cirrhotic patients with hepatocellular carcinoma treated by transarterial embolization.

BACKGROUND: Prognostic biomarkers are needed in a heterogeneous population of patients with intermediate hepatocellular carcinoma (HCC) treated by transarterial (chemo)embolization. We aimed to validate the prognostic value of serum CRP levels and the STATE score, combining CRP, albumin and tumor burden. METHODS: All cirrhotic patients with HCC treated by a first transarterial (chemo)embolization (2007-2013) in our institution were included. Overall survival was assessed using the Kaplan-Meier method, log rank, univariate and multivariate Cox analyses. RESULTS: Among 157 patients included, 87% were men, 86% had Child Pugh A. Etiologies of liver disease included alcohol (57%), hepatitis C (32%), hepatitis B (11%) and/or metabolic syndrome (32%); 89% of patients were classified BCLC B. 33% of the patients had a CRP >1mg/dl and 33% a STATE score conferring poor prognosis (<18). Patients with CRP <1mg/dl had better overall survival than patients with CRP >1mg/dl (20 vs. 8 months, P=0.00186). Median overall survival was 6.73 months for patients with a STATE score <18 vs. 22.23 months for patients with STATE-score ≥18 (P=0.0002). In multivariate analysis, a STATE score <18 was independently associated with increased mortality (HR: 2.06 (CI95%: 1.28-3.34), P=0.0031). CONCLUSION: In cirrhotic patients with HCC who underwent transarterial treatment, serum CRP level and STATE score at baseline can predict overall survival.

Percutaneous Treatment of Localized Infiltrative Hepatocellular Carcinoma Developing on Cirrhosis.

BACKGROUND: Infiltrating hepatocellular carcinoma (HCC) is characterized by a difficult diagnosis, dismal prognosis, and limited therapeutic options. We describe long-term results of percutaneous treatment of infiltrative HCC, i.e., multibipolar radiofrequency ablation (mbpRFA) and percutaneous intra-arterial ethanol injection (PIAEI). METHODS: All cirrhotic patients with localized (up to two segments) infiltrating HCC treated by mbpRFA or PIAEI between 2002 and 2012 were included. Survival was analyzed using the Kaplan-Meier method, log-rank test, and Cox univariate followed by multivariate analyses. RESULTS: Fifty-one patients were considered eligible for mbpRFA (n = 20) or PIAEI (n = 31). Cirrhosis etiologies were alcohol (67 %), hepatitis C (33 %), hepatitis B (16 %), and/or NASH (16 %). HCC were multinodular in 31 % of cases, with a median main tumor size of 60 mm (range 30-200) and macrovascular invasion in 59 % of cases. The median serum level of alphafetoprotein was 125 ng/ml (range 2-215,000). Treatment-related adverse events occurred in 58 %, mainly postablation syndrome (31 %), and one death (2 %). Median overall survival was 18.3 months, with 63, 35, 20, and 12 % survival at 1, 2, 3, and 4 years, respectively. Baseline serum bilirubin >normal [hazard ratio (HR) 2.98; 95 % confidence interval (CI) 1.38-6.50; P = 0.0057] and tumor burden >70 mm (HR 1.02; 95 % CI 1.003-1.04; P = 0.0221) were associated with poorer overall survival. The radiological response using mRECIST criteria and an alphafetoprotein decrease 1 month post-procedure was associated with increased overall survival (P = 0.0002 and P = 0.024, respectively). DISCUSSION: Despite its overall poor prognosis, localized infiltrating HCC can be safely treated using percutaneous approaches, with potential survival benefits for these difficult-to-treat patients.

Duplication of the V3 domain in hepatitis C virus (1b) NS5A protein: Clonal analysis and physicochemical properties related to hepatocellular carcinoma occurrence.

BACKGROUND: Hepatitis C virus non-structural protein 5A is known to play a role in development of hepatocellular carcinoma (HCC) via interactions with host cell pathways. OBJECTIVES: Hepatitis C virus genotype 1b strains presenting a wide insertion of 31 amino acids in the non-structural protein 5A V3 domain (V3 DI) were studied to determine whether this V3-like additional domain (V3 DII) was associated with HCC occurrence. STUDY DESIGN: Seventy-four patients' sera were screened for V3 DII presence regarding clinical status. RESULTS: Three strains with duplicated V3 were detected among patients with progression to HCC (n=28), two strains among patients with liver cirrhosis (Ci, n=27) and none among patients with chronic hepatitis (Chr, n=19). Phylogenetic trees built from V3 DI and V3 DII sequences indicated that the latter clustered separately. In between-group clonal analysis, V3 DII sequences from the HCC group were found to be more distant from HCV-J than V3 DI sequences (p<0.0001). Between-group comparisons showed significant differences in genetic distances from HCV-J, in HCC V3 DI and HCC V3 DII compared to Ci V3 DI and Ci V3 DII sequences (p<0.0001). HCC V3 DII domain and its junction with V3 DI exhibited higher Shannon entropy values and enrichment in disorder-promoting residues. CONCLUSIONS: Taken together, our results suggest that V3 DII evolution may differ in strains associated with HCC occurrence. The presence of an intrinsically "disordered" V3 duplicate may alter the NS5A protein network. Further investigations are necessary to elucidate the potential impact of V3 duplication in the context of carcinogenesis.

Peripheral intrahepatic cholangiocarcinoma occurring in patients without cirrhosis or chronic bile duct diseases: epidemiology and histopathology of distant nontumoral liver in 57 White patients.

BACKGROUND/AIM: Peripheral intrahepatic cholangiocarcinoma (ICC) occurring mainly in the absence of cirrhosis represents an increasing subgroup of primary liver tumors in Western countries. Histopathologic changes in the non-neoplastic liver in this context are not well characterized. PATIENTS AND METHODS: We assessed the clinical characteristics and histopathologic changes in the distant nontumoral liver of 57 consecutive White patients (34 men, mean age 59 years) referred to one medical and one surgical liver institution over a 16-year period who developed a peripheral ICC in the absence of cirrhosis or bile duct disease. RESULTS: High alcohol consumption was observed in 11 patients (20%), 38 patients (66%) had a BMI of 25 kg/m or more, 22 patients (40%) had diabetes, two patients had hepatitis B virus infection, two others had hepatitis C virus infection, three patients had genetic hemochromatosis, and two patients had cutaneous porphyria tarda. The distant nontumoral liver was normal in 10 patients (18%). The two main histopathologic changes observed were macrovesicular steatosis (>10% of hepatocytes) in 38 patients (66%), including 11 patients (19%) with steatohepatitis, and moderate or intense hepatocyte iron overload in 22 patients (38%). CONCLUSION: This study shows a high prevalence of macrovesicular steatosis associated or not with steatohepatitis and iron overload in patients who develop peripheral ICC in the absence of cirrhosis or bile duct disease.

Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCV-associated cirrhosis.

UNLABELLED: Propranolol bears antioxidant, anti-inflammatory, and antiangiogenic properties and antitumoral effects and therefore is potentially active in the prevention of hepatocellular carcinoma (HCC). We retrospectively assessed the impact of propranolol treatment on HCC occurrence in a cohort of 291 patients with compensated viral C (HCV) cirrhosis, prospectively followed and screened for HCC detection. Of the 291 patients included in the cohort, 93 patients [50 males: mean age, 59.5 ± 12 years; body mass index (BMI), 25.7 ± 4.4 kg/m(2); and platelet count, 111 ± 53 Giga/L] developed esophageal varices (OV) or had OV at inclusion and 198 patients (111 males: mean age, 55.8 ± 13 years; BMI, 25.7 ± 5 kg/m(2); platelet count, 137 ± 59 Giga/L) did not. Among patients with OV, 50 received treatment by propranolol. During a median follow-up of 54 months interquartile range (32-82), 61 patients developed an HCC. The 3- and 5-year HCC incidence was 4% and 4%, and 10% and 20% for patients treated and not treated by propranolol, respectively (Gray test, P = 0.03). In multivariate analysis, propranolol treatment was associated with a decrease risk of HCC occurrence [HR, 0.25; 95% confidence interval (CI), 0.09-0.65; P = 0.004], and was the only independent predictive factor of HCC occurrence in patients with OV (HR, 0.16; CI, 0.06-0.45; P = 0.0005). The benefit of propranolol was further supported by propensity scores analyses. CONCLUSION: This retrospective long-term observational study suggests that propranolol treatment may decrease HCC occurrence in patients with HCV cirrhosis. These findings need to be verified by prospective clinical trial.

Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients.

CONTEXT: Insulin resistance plays a role in hepatocarcinogenesis and is decreased by metformin treatment. OBJECTIVE: The aim of the study was to assess the influence of metformin treatment on the prognosis of compensated hepatitis C virus (HCV) cirrhosis in patients with type 2 diabetes. DESIGN AND SETTING: We studied an observational prospective cohort (1988-2007) at a university hospital referral center. PATIENTS: A total of 100 consecutive diabetic patients (53 men, age 61 ± 11 yr) with ongoing HCV cirrhosis and no contraindication for metformin were included in a screening program for hepatocellular carcinoma (HCC). MAIN OUTCOMES: The patients were prospectively followed up for HCC incidence, liver-related death, or hepatic transplantation. RESULTS: The level of platelet count was significantly lower in patients treated with metformin (n = 26) compared with those not treated with metformin (n = 74) [117 (interquartile range, 83-166) vs. 149 (105-192) Giga/liter, P = 0.045]. During a median follow-up of 5.7 (3.8-9.5) yr, one patient was lost to follow-up, 39 developed a HCC, and 33 died from liver causes or were transplanted. The 5-yr incidence of HCC was 9.5 and 31.2% (P = 0.001) and of liver-related death/transplantation, 5.9 and 17.4% (P = 0.013), in patients who received metformin treatment and in those who did not, respectively. In multivariate analysis, metformin treatment was independently associated with a decrease in HCC occurrence [hazard ratio, 0.19 (95% confidence interval, 0.04-0.79); P = 0.023] and liver-related death or transplantation [hazard ratio, 0.22 (95% confidence interval, 0.05-0.99); P = 0.049]. CONCLUSIONS: In patients with type 2 diabetes and HCV cirrhosis, use of metformin is independently associated with reduced incidence of HCC and liver-related death/transplantation.

Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis.

BACKGROUND & AIMS: Mechanisms linking obesity and unfavourable outcomes in patients with viral hepatitis C (HCV) cirrhosis are not well understood. Obesity is associated with insulin resistance, increased leptin, and decreased adiponectin serum levels. METHODS: We assessed the predictive value of those factors for the occurrence of hepatocellular carcinoma (HCC) and liver-related death or transplantation in a cohort of 248 patients (mean age 58 (12 years, BMI 25.4 ± 4.4 kg/m(2)) with compensated HCV cirrhosis and persistent infection prospectively followed and screened for HCC. RESULTS: The mean baseline serum levels of adiponectin and leptin were 16.8 ± 15 mg/L and 16.8 ± 19 ng/ml, respectively. The mean homeostasis model assessment of insulin resistance (HOMA) index was 3.8 ± 3; median 2.9. After a median follow-up of 72 months, 61 patients developed HCC, 58 died of liver causes, and 17 were transplanted. The incidences (Kaplan Meier) of HCC were 7%, 18%, and 27% at 5 years (p=0.017) and of liver-related death or transplantation 15%, 15% and 29% (p=0.002) according to the lowest, middle and highest tertile of HOMA, respectively. In multivariate analysis, the HOMA index was associated with HCC occurrence (HR=1.10, [1.01-1.21] p=0.026) and was a strong predictor of liver-related death or transplantation (HR=1.13, [1.07-1.21] p<0.0001). Serum levels of adiponectin and leptin were not associated with the outcome. CONCLUSIONS: In patients with compensated HCV cirrhosis, insulin resistance but not serum levels of adiponectin and leptin predicted the occurrence of HCC and of liver-related death or transplantation.

Clinical validation of combined serological biomarkers for improved hepatocellular carcinoma diagnosis in 961 patients.

BACKGROUND: Alpha-fetoprotein (AFP), the only serological marker currently available for the detection of hepatocellular carcinoma (HCC), is unsatisfactory because of its poor sensitivity, as are other recently proposed markers. Therefore new biomarkers are badly needed. Squamous cell carcinoma antigen (SCCA), a serine protease inhibitor physiologically present in the skin, has recently been reported to be present in HCC patients, as also the immunocomplexed (IC) forms of SCCA and AFP: SCCAIC and AFPIC, respectively. METHODS: To determine the diagnostic accuracy of new serum biomarkers for the diagnosis of HCC a rapid, simple ELISA test was applied in 961 patients. Sensitivity and specificity were determined for each marker and for all the markers combined in detecting smaller and larger HCC versus liver cirrhosis. RESULTS: In smaller HCC, receiver operating characteristics analysis yielded the following AUC: AFP 0.714 (CI 95% 0.679-0.748), AFPIC 0.691 (CI95% 0.655-0.748), SCCA 0.703 (CI95% 0.667-0.736), SCCAIC 0.694 (CI 95% 0.659-0.728). SCCA was inversely correlated with size. The combined use of AFPIC, SCCA and SCCAIC in patients displaying low levels of AFP (<20 IU/mL) identified 25.6% HCC (186/725). CONCLUSION: This study suggests that the use of a combination of all these markers in clinical practice provides a non invasive and simple test that could increase the accuracy of HCC diagnosis.