Massimo Attanasio

A meta‐analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma

Knowing the spontaneous outcome of hepatocellular carcinoma (HCC) is important for designing randomized controlled trials (RCTs) of new therapeutic approaches; however, survival of patients in the absence of treatment is highly variable, and prognostic factors influencing outcomes are incompletely defined. The aims of this meta‐analysis were to estimate the 1‐year and 2‐year survival rates of untreated HCC patients enrolled in RCTs of palliative treatments, and to identify prognostic factors. RCTs evaluating therapies for HCC with placebo or no‐treatment arms were identified on MEDLINE through April 2009. Data were combined in a random effect model. Primary outcomes were 1‐year and 2‐year survival. Thirty studies met the inclusion criteria. The pooled estimates of the survival rates were 17.5% at 1 year (95% confidence interval [95%CI], 11%‐27%; range, 0%‐75%) and 7.3% at 2 years (95%CI, 3.9%‐13%; range, 0%‐50%). Heterogeneity among studies was highly significant (P < 0.0001) both for 1‐year and 2‐year survival, and persisted when RCTs were stratified according to all patient and study features. Through meta‐regression, impaired performance status, Child‐Pugh B‐C class, and presence of portal vein thrombosis were all independently associated with shorter survival. Ascites was strongly linked to a worse outcome in intermediate/advanced Barcelona Clinic Liver Cancer stages. Conclusion: This meta‐analysis confirms the heterogeneity of behavior of untreated HCC and provides a sound basis for stratifying patients with HCC according to expected survival in future trials of new anti‐cancer agents. (HEPATOLOGY 2010.)

Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis C.

OBJECTIVES:Transient elastography (TE) is adequate for a diagnosis of cirrhosis, but its accuracy for milder stages of fibrosis is much less satisfactory. The objective of this study was to compare the performance and the discordance rate of acoustic radiation force impulse (ARFI) and TE with liver biopsy in a cohort of chronic hepatitis C (CHC) patients.METHODS:One hundred thirty-nine consecutive patients with CHC were enrolled in two tertiary centers, and evaluated for histological (Metavir score) and biochemical features. All patients underwent TE and ARFI.RESULTS:TE was unreliable in nine patients (6.5%), while in no cases (0%) were ARFI invalid measurements recorded (P=0.029). By area under receiver operating characteristic curve (AUROC), the best cutoff values for TE and ARFI for significant fibrosis (≥F2) were ≥6.5 kPa (AUROC: 0.78) and ≥1.3 m/s (AUROC: 0.86), respectively. For severe fibrosis (F3–F4), these cutoff values were 8.8 kPa (AUROC: 0.83) for TE and 1.7 m/s (AUROC: 0.94) for ARFI. For cirrhosis, TE had its best cutoff at ≥11 kPa (AUROC: 0.80) and ARFI at ≥2.0 m/s (AUROC: 0.89). By pairwise comparison of AUROC, ARFI was significantly more accurate than TE for a diagnosis of significant and severe fibrosis (P=0.024 and P=0.002, respectively), while this difference was only marginal for cirrhosis (P=0.09). By partial AUROC analysis, ARFI performance results significantly higher for all three stages of fibrosis. The average concordance rates of TE and ARFI vs. liver biopsy were 45.4 and 54.7%, respectively. By multivariate analysis, ARFI was not associated with alanine aminotransferase (ALT), body mass index, Metavir grade, and liver steatosis, while TE was significantly correlated with the ALT value (P=0.027).CONCLUSIONS:In a cohort of patients with CHC, ARFI imaging was more accurate than TE for the non-invasive staging of both significant and severe classes of liver fibrosis.

Slower Progression of HIV-1 Infection in Persons with GB Virus C Co-Infection Correlates with an Intact T-Helper 1 Cytokine Profile

Context Patients infected with HIV-1 progress to AIDS more slowly if they are co-infected with hepatitis G virus, also called GB virus C (GBV-C), than if they are not. The mechanism of this effect of GBV-C infection is not known. Contribution Among 80 asymptomatic HIV-1infected patients, T-helper 1 cytokine profiles changed unfavorably in those without GBV-C infection and remained stable in those with GBV-C infection. Implications Co-infection with GBV-C may slow progression of HIV-1 infection through a mechanism related to T-helper 1 cytokines. The Editors Hepatitis G virus, also called GB virus C (GBV-C), is a recently identified RNA virus belonging to the Flaviviridae family (1, 2). It is usually transmitted parenterally (2, 3). The prevalence of GBV-C viremia ranges from 20% to 24% among persons who use intravenous drugs (4, 5). Higher rates have been seen in patients with HIV-1 infection, regardless of intravenous drug use (4, 6). In recent surveys, HIV-1infected persons with GBV-C co-infection had better AIDS-free survival rates and higher CD4+ cell counts than HIV-1infected patients who were GBV-C negative (7-10). It has also been shown that GBV-C inhibits HIV-1 replication in vitro (11). Our objective was to evaluate AIDS-free survival rates, plasma HIV-1 viral load, and selected immunologic variables in 80 HIV-1seropositive patients with and without GBV-C co-infection. We sought to determine possible immunologic mechanisms involved in these co-infection scenarios. Methods The study was initiated between January and March 1989 at the Institute of Infectious Diseases, University of Catania, Catania, Italy. Institutional review boards at the Institute of Infectious Diseases, University of Catania, approved the follow-up protocol. Signed informed consent was obtained from each patient. Among 319 HIV-1seropositive patients, 240 used intravenous drugs, 60 were homosexual men, and 19 had received many blood transfusions. Eighty of these 319 patients (25%), all of whom used intravenous drugs, were asymptomatic and were enrolled in a prospective follow-up study to evaluate the progression of HIV-1related disease. All 80 patients underwent physical examination and routine blood biochemistry examinations every 6 months. Blood samples were obtained annually from each patient, and serum was stored at 80 C until use. The analyses for the current study were begun in January 1997. Quantitative plasma HIV-1 RNA levels and circulating levels of specific interleukins (ILs)IL-2, IL-4, IL-10, and IL-12were retrospectively determined in all serum samples. We determined GBV-C RNA levels in all serum specimens collected at the beginning of the study and at the end of follow-up. Analyses were repeated in January 2001. Anti-E2 antibodies were detected by using the Enzymun-Test Anti-HGenv (Boehringer Mannheim Corp., Indianapolis, Indiana). Plasma HIV-1 RNA copy numbers were determined by using the nucleic acid sequence-based amplification method (NASBA, Organon Teknika, Boxtel, the Netherlands). The sensitivity limit of the assay was 400 copies/mL. Interleukin-2 was analyzed by using a quantitative enzyme immunoassay (Predicta, Genzyme Diagnostics, Cambridge, Massachusetts) with a sensitivity limit of 4 pg/mL. Interleukin-4 was tested by using a quantitative enzyme immunoassay (InterTest, Genzyme Diagnostics) with a sensitivity limit of 0.045 ng/mL. Interleukin-10 was measured by using a competitive enzyme immunoassay (Cytokit Red 10, Genzyme Diagnostics), which had a range of detection between 0.195 and 200 ng/mL. Interleukin-12 levels were determined by using an enzyme immunoassay provided by R&D Systems (Oxon, United Kingdom) that had a lower sensitivity limit of 5 pg/mL. We measured GBV-C RNA level by using reverse transcriptase polymerase chain reaction, as described elsewhere (12). Statistical Analysis Plasma HIV-1 RNA levels were logarithmically transformed to normalize their distribution. Categorical variables were analyzed by using the Fisher exact test. The group means were compared by using the Student t-test. Variations of all interim values of plasma HIV-1 RNA level, CD4+ cell count, and IL levels were analyzed within each group by using two-way analysis of variance. We compared GBV-C RNApositive and GBV-C RNAnegative groups by using the MannWhitney U test to examine percentage variations from baseline values to values at the end of follow-up. Curves reflecting variations by time in immunologic and virologic variables were compared by using univariate repeated-measures analysis that followed an analysis-of-variance structure (13). Progression to AIDS was defined as the development of an opportunistic infection or malignant condition. We used the Kaplan-Meier method to evaluate the effect of GBV-C infection on AIDS-free survival by assuming that GBV-C and HIV-1 infection status was fixed at the beginning of follow-up. A P value less than 0.05 was considered statistically significant. Statistical analyses were performed by using SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Sources The funding sources had no direct control over the analysis of the study. Results The mean age of the study patients (SD) was 24.6 2.2 years. Fifty-two patients were men, and 28 were women. Mean duration of intravenous drug use (SD) was 24.2 1.8 months, and mean duration of known HIV-1 seropositivity (SD) was 9.2 1.6 months. The mean baseline CD4+ cell count (SD) was 471 55 109 cells/L. Fifty-eight patients declined to take any antiretroviral drug, and 6 were treated with zidovudine alone throughout the follow-up period. In 16 patients, didanosine was added to zidovudine, starting in 1993. In January 1997, follow-up was interrupted and all 80 patients began to receive different highly active antiretroviral therapy (HAART). At this time, 6 patients were asymptomatic, 24 had stage B disease, and 50 had stage C disease, according to stages defined by the U.S. Centers for Disease Control and Prevention. At the end of follow-up, the mean CD4+ cell count (SD) was 77 33 109 cells/L. Seventeen of the 80 serum specimens collected at the beginning of follow-up (21%) were positive for GBV-C RNA. All of these 17 patients maintained GBV-C viremia to the end of the follow-up period, and none of the 63 patients who were GBV-C RNA negative acquired the infection. Patients who were GBV-C negative and those who were GBV-C positive did not significantly differ in age, sex, duration of intravenous drug use and HIV-1 seropositivity, or rate of hepatitis C virus and hepatitis B virus infection (Table). Table. Epidemiologic and Virologic Variables Measured at Baseline and at the End of Follow-up Clinical Outcomes At the end of the 8-year follow-up, 3 of 17 GBV-Cpositive patients (18%) remained asymptomatic (stage A), 7 (41%) had stage B disease, and 7 (41%) had stage C disease. In the 7 patients with stage C disease, the following AIDS-defining diseases were observed: AIDS dementia complex (n = 7 [100%]), Pneumocystis carinii pneumonia (n = 4 [57%]), esophageal candidiasis (n = 3 [43%]), and Toxoplasma encephalitis infection (n = 1 [14%]). Three of 63 GBV-C RNAnegative patients (5%) had stage A disease, 17 (27%) had stage B disease, and 43 (68%) had stage C disease. Among those with stage C disease, the following diseases were observed: P. carinii pneumonia (n = 18 [42%]), esophageal candidiasis (n = 11 [26%]), Toxoplasma encephalitis infection (n = 5 [12%]), cryptococcal meningitis (n = 4 [9%]), intestinal cryptosporidiosis (n = 3 [7%]), Kaposi sarcoma (n = 2 [5%]), AIDS dementia complex (n = 2 [5%]), and disseminated cytomegalovirus disease (n = 1 [2%]). According to Kaplan-Meier curves showing progression to AIDS in HIV-1infected persons, cumulative AIDS-free survival rates at 24 and 48 months, respectively, were 0.5 (95% CI, 0.3 to 0.6) and 0.4 (CI, 0.3 to 0.5) in the GBV-Cnegative group and 0.9 (CI, 0.7 to 1.0) and 0.7 (CI, 0.5 to 0.9) in the GBV-Cpositive group (P = 0.02 for between-group comparisons). Mean AIDS-free survival time was 73 months (CI, 59 to 87 months) among GBV-Cpositive persons and 45 months (CI, 35 to 54 months) among GBV-Cnegative persons. Immunologic and Virologic Evaluations The Figure shows the cross-sectional averages of IL levels, CD4+ cell counts, and HIV RNA levels during the follow-up period. Annual plasma HIV-1 RNA levels significantly increased during follow-up in both the GBV-Cnegative and GBV-Cpositive groups, whereas CD4+ cell counts significantly decreased (P < 0.01 for all comparisons). In the GBV-Cnegative group, IL-4 and IL-10 levels increased significantly from baseline (P = 0.01 and P = 0.004, respectively) but IL-2 and IL-12 concentrations decreased significantly throughout the entire follow-up period (P = 0.005 and P = 0.01, respectively). In contrast, in the GBV-Cpositive group, none of the measured cytokine levels changed significantly during follow-up. The Table shows the percentage variation from baseline to the end of follow-up in plasma HIV-1 RNA levels, CD4+ cell counts, and cytokine concentrations between the two groups. Figure. Cross-sectional averages of interleukin ( IL ) levels, CD4+ cell counts, and HIV-1 RNA levels in GB virus C ( GBV-C )-positive and GBV-Cnegative patients during 8 years of follow-up. P P Response to HAART In January 1997, all 80 patients began taking HAART. Among the 17 GBV-Cpositive patients, 10 received zidovudine, lamivudine, and saquinavir and 7 received zidovudine, lamivudine, and indinavir. Among the 63 GBV-Cnegative patients, 20 were treated with zidovudine, lamivudine, and saquinavir; 20 were treated with zidovudine, lamivudine, and indinavir; 13 were treated with zidovudine, didanosine, and indinavir; and 10 were treated with zidovudine, lamivudine, and ritonavir. Fourteen patients, 2 in the GBV-Cpositive group and 12 in the GBV-Cnegative group, stopped taking HAART between 1997 and 2001 because of personal preference, lack of adh

Survival of patients with hepatocellular carcinoma in cirrhosis: a comparison of BCLC, CLIP and GRETCH staging systems

Background  A major problem in assessing the likelihood of survival of patients with hepatocellular carcinoma (HCC) arises from a lack of models capable of predicting outcome accurately.

Long-term interferon-β treatment for multiple sclerosis

Abstract.The aim of our study was to analyze the dropout rate in patients with relapsing-remitting multiple sclerosis (RRMS) under long-term treatment with the three commercially available interferon beta (IFNβ) preparations. According to the drug taken, we divided 122 RRMS patients into 4 groups: Betaferon group, 56 patients taking INFβ-1b (24 MIU weekly, subcutaneous injections); Avonex group, 38 patients taking IFNβ-1a (6 MIU weekly, intramuscularly); Rebif group, 18 patients taking INFβ-1b (18 MIU subcutaneously). Ten patients who shifted from Betaferon to Avonex were included in a fourth group. Dropouts were registered every trimester with the related cause. Data were evaluated using Kaplan-Meier survival analysis and log-rank test. During the observation period of five years, 48 patients (39.9%) dropped out: 48% of the patients in Betaferon group withdrew at a median of 758 days, 26% of the Avonex group at 356 days; 38% of the Rebif group at 421 days, and 40% of those who shifted from Betaferon to Avonex at 259 days. The differences between groups were not significant on survival analysis. Patients receiving higher dose treatment (Betaferon and Rebif groups) dropped out mainly for clinical adverse events; conversely, patients receiving lower dose therapy (Avonex group) dropped out most often for inefficacy. Patients who shifted to a lower dose treatment (fourth group) had a dropout rate similar to that of the initial treatment. Our data showed that one-third of the patients stopped the therapy, mostly for adverse events and then for inefficacy, while the remaining two-thirds were still on treatment without problems up to 5 years of follow-up. Compliance seems related to the dose of the drug, but further analysis is needed to confirm our data.

Fibrosis staging in chronic hepatitis C: analysis of discordance between transient elastography and liver biopsy

Summary.  In chronic hepatitis C, transient elastography (TE) accurately identifies cirrhosis, but its ability to assess significant fibrosis (Metavir ≥ F2) is variable. Constitutional and liver disease‐related factors may influence TE and here we examined the variables associated with differences. Three hundred consecutive hepatitis C virus (HCV)‐RNA positive patients had biochemical tests, TE and a biopsy performed on the same day. The Dale model was used to identify the variables associated with discordance between biopsy and elastography results. In 97 patients (34.2%), TE and histological assessment were discordant. Seventy‐six of 286 (26.6%) had stage ≥F2 and TE < 7.1 kPa (false negative); 21 of 286 (7.3%) had stage

Retreatment with pegylated interferon plus ribavirin of chronic hepatitis C non-responders to interferon plus ribavirin: A meta-analysis

BACKGROUND/AIMS Efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin of non-responders to standard or pegylated IFN plus ribavirin has been assessed in various studies, but sustained virologic response (SVR) rates are variable and factors influencing efficacy and tolerability still remain incompletely defined. We aimed to focus on SVR rates and to identify factors influencing them in this meta-analysis. METHODS MEDLINE as well as a manual search were used. Studies were included if they were controlled or uncontrolled trials, if they had been published as full-length papers and if they included non-responders to standard or pegylated IFN and ribavirin therapy. Fourteen trials were included in the meta-analysis. Data on study populations, interventions, and outcomes were extracted from trials using a random-effects model. Primary outcome was the SVR rate. RESULTS The pooled estimate of SVR rate was 16.3% (95% Confidence Interval - 95% CI, 8.3-29.6%). There was a significant heterogeneity among studies (p<0.0001). Heterogeneity was less apparent in studies that included fewer patients with cirrhosis or overweight. By meta-regression, higher SVR rate was observed in trials with a lower prevalence of subjects with genotype 1 infection and with fewer overweight patients. The use of a 24-week retreatment stopping rule did not affect SVR rate. CONCLUSIONS The overall modest efficacy argues against an indiscriminate retreatment with PEG-IFN and ribavirin of all non-responders. Restricting retreatment to non-overweight patients or to those with genotype 2 or 3 infection, using a 24-week retreatment stopping rule, would optimize the potential benefit with a scarce likelihood of missing a curative response.

A New Sampling Method for Spleen Stiffness Measurement Based on Quantitative Acoustic Radiation Force Impulse Elastography for Noninvasive Assessment of Esophageal Varices in Newly Diagnosed HCV-Related Cirrhosis

In our study, we evaluated the feasibility of a new sampling method for splenic stiffness (SS) measurement by Quantitative Acoustic Radiation Force Impulse Elastography (Virtual Touch Tissue Quantification (VTTQ)).We measured SS in 54 patients with HCV-related cirrhosis of whom 28 with esophageal varices (EV), 27 with Chronic Hepatitis C (CHC) F1–F3, and 63 healthy controls. VTTQ-SS was significantly higher among cirrhotic patients with EV (3.37 m/s) in comparison with controls (2.19 m/s, P < 0.001), CHC patients (2.37 m/s, P < 0.001), and cirrhotic patients without EV (2.7 m/s, P < 0.001). Moreover, VTTQ-SS was significantly higher among cirrhotic patients without EV in comparison with both controls (P < 0.001) and CHC patients (P < 0.01). The optimal VTTQ-SS cut-off value for predicting EV was 3.1 m/s (AUROC = 0.96, sensitivity 96.4%, specificity 88.5%, positive predictive value 90%, negative predictive value 96%, positive likelihood ratio 8.36, and negative likelihood ratio 0.04). In conclusion, VTTQ-SS is a promising noninvasive and reliable diagnostic tool to screen cirrhotic patients for EV and reduce the need for upper gastrointestinal endoscopy. By using our cut-off value of 3.1 m/s, we would avoid endoscopy in around 45% of cirrhotic subjects, with significant time and cost savings.

Statistical methods for the evaluation of university systems

Part I - Introduction: Different Perspectives of the Evaluation of the Italian University System.- Part II - The Evaluation in the Italian Universities. Student Teaching Evaluation.- Part III - The Evaluation in the Italian Universities. Statistical Methods for Careers and Services Evaluation.- Part IV - Research Design and data for Evaluation: University between the High School and the Labour Market.

Statistics in Education

During the last few decades, educational systems have attracted a great deal of interest because they are closely related to economic and social systems. For example, ‘higher education has been aff...