Plasma cholesterol and lipoprotein levels in relation to tumor aggressiveness and survival in HCC patients

open13Hepatocellular carcinoma is associated with several chronic liver diseases, especially chronic hepatitis B virus, hepatitis C virus, and alcoholism. It is increasingly appreciated that obesity/metabolic syndrome is also associated with chronic liver disease and subsequent hepatocellular carcinoma.openCarr, Brian I; Giannelli, Gianluigi; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Rapaccini, Gian Ludovico; Marco, Maria Di; Zoli, Marco; Caturelli, Eugenio; Masotto, Alberto; Virdone, Roberto; Sacco, Rodolfo; Trevisani, FrancoCarr, Brian I; Giannelli, Gianluigi; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Rapaccini, Gian Ludovico; Marco, Maria Di; Zoli, Marco; Caturelli, Eugenio; Masotto, Alberto; Virdone, Roberto; Sacco, Rodolfo; Trevisani, Franc

A Liver Index and its Relationship to Indices of HCC Aggressiveness

A Hepatocellular (HCC) Aggressiveness Index was recently constructed, consisting of the sum of the scores for the 4 clinical parameters of maximum tumor size, multifocality, presence of portal vein thrombus and blood alphafetoprotein levels. It was observed that there was an association with several liver function tests. We have now formed a Liver Index from the 4 liver parameters with the highest hazard ratios with respect to HCC aggressiveness, namely: blood total bilirubin, gamma glutamyl transpeptidase (GGTP), albumin and platelet levels (cirrhosis surrogate). We found that the scores for the Liver Index related significantly to survival, but also to the Aggressiveness Index and to its individual HCC components as well as showing significant trends with the components. These results support the hypothesis that liver function is not only an important prognostic factor in HCC patients, but may also be involved in HCC biology and aggressiveness. Blood albumin, GGTP, albumin and platelet levels were used to create a Liver Index that related significantly to parameters of HCC aggressiveness

Transarterial Chemoembolization for Hepatocellular Carcinoma in Clinical Practice: Temporal Trends and Survival Outcomes of an Iterative Treatment

BACKGROUND: Transarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE application and repetition, as well as the related outcome, have changed over the last three decades in Italy. METHODS: Data of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988–1993), P2 (1994–1998), P3 (1999–2004), P4 (2005–2009), P5 (2010–2014), and P6 (2015–2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment. RESULTS: The proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p < 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p < 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC). CONCLUSIONS: Despite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis

The influence of HIV infection on the natural history of hepatocellular carcinoma: results from a global multi-cohort study

Purpose. Conflicting evidence indicates HIV-seropositivity to influence the outcome of patients with hepatocellular carcinoma (HCC), a leading cause of mortality in people with HIV. We aimed to verify whether HIV affected the overall survival (OS) of patients with HCC independent of treatment and geographic origin. Patients and Methods: We designed an international multi-cohort study of HCC patients who did not receive any anticancer treatment accrued from four continents. We estimated the effect of HIV-seropositivity on patients’ OS while accounting for common prognostic factors and demographic characteristics in uni- and multi-variable models. Results: A total of 1588 patients were recruited, 132 of whom were HIV-positive. Most patients clustered within Barcelona Clinic Liver Cancer (BCLC) C/D criteria (n=1168, 74%), Child-Turcotte-Pugh (CTP) Class B (median score 7, IQR 3). At HCC diagnosis the majority of HIV-positive patients (n=65, 64%) had been on anti-retrovirals for a median duration of 8.3 years (IQR 8.59) and had median CD4+ cell counts of 256 (IQR 284) with undetectable HIV RNA (n=68, 52%). OS significantly reduced throughout BCLC stages 0-D (16, 12, 7.5, 3.1 and 3 months, p<0.001). Median OS of HIV-positive patients was half that of HIV-uninfected counterparts: 2.2 months, (bootstrap 95%CI 1.2-3.1) versus 4.1 months (95%CI 3.6-4.4). In adjusted analyses HIV-seropositivity increased the hazard of death by 24% (p=0.0333) independent of BCLC (p<0.0001), CTP (p<0.0001), alpha-fetoprotein (AFP) (p<0.0001), geographical origin (p<0.0001) and male gender (p=0.0016). Predictors of worse OS in HIV-positive patients included CTP (p=0.0071) and AFP (p<0.0001). Conclusions. Despite adequate antiretroviral treatment, HIV-seropositivity is associated with decreased survival in HCC independent of stage, anti-cancer treatment and geographical origin. Mechanistic studies investigating the immuno-biology of HIV-associated HCC are urgently required

Bridge treatments of hepatocellular carcinoma in cirrhotic patients submitted to liver transplantation

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Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters.

none14Previous work has shown that two general processes contribute to hepatocellular cancer (HCC) prognosis: liver damage, monitored by indices such as blood bilirubin, prothrombin time (PT), and aspartate aminostransferase (AST); and tumor biology, monitored by indices such as tumor size, tumor number, presence of portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels. These processes may affect one another, with prognostically significant interactions between multiple tumor and host parameters. These interactions form a context that provide personalization of the prognostic meaning of these factors for every patient. Thus, a given level of bilirubin or tumor diameter might have a different significance in different personal contexts. We previously applied network phenotyping strategy (NPS) to characterize interactions between liver function indices of Asian HCC patients and recognized two clinical phenotypes, S and L, differing in tumor size and tumor nodule numbers. Our aim was to validate the applicability of the NPS-based HCC S/L classification on an independent European HCC cohort, for which survival information was additionally available. Four sets of peripheral blood parameters, including AFP-platelets, derived from routine blood parameter levels and tumor indices from the ITA.LI.CA database, were analyzed using NPS, a graph-theory-based approach that compares personal patterns of complete relationships between clinical data values to reference patterns with significant association to disease outcomes. Without reference to the actual tumor sizes, patients were classified by NPS into two subgroups with S and L phenotypes. These two phenotypes were recognized using solely the HCC screening test results, consisting of eight common blood parameters, paired by their significant correlations, including an AFP-platelets relationship. These trends were combined with patient age, gender, and self-reported alcoholism into NPS personal patient profiles. We subsequently validated (using actual scan data) that patients in L phenotype group had 1.5× larger mean tumor masses relative to S, P = 6 × 10(-16). Importantly, with the new data, liver test pattern-identified S-phenotype patients had typically 1.7× longer survival compared to L-phenotype patients. NPS integrated the liver, tumor, and basic demographic factors. Cirrhosis-associated thrombocytopenia was typical for smaller S tumors. In L tumor phenotype, typical platelet levels increased with the tumor mass. Hepatic inflammation and tumor factors contributed to more aggressive L tumors, with parenchymal destruction and shorter survival. NPS provides integrative interpretation for HCC behavior, identifying two tumor and survival phenotypes by clinical parameter patterns. The NPS classifier is provided as an Excel tool. The NPS system shows the importance of considering each tumor marker and parameter in the total context of all the other parameters of an individual patient.restrictedCarr BI;Pancoska P;Giannini EG;Farinati F;Ciccarese F;Ludovico Rapaccini G;Di Marco M;Benvegnu L;Zoli M;Borzio F;Caturelli E;Chiaramonte M;Trevisani F;Italian Liver Cancer GroupCarr, Bi; Pancoska, P; Giannini, Eg; Farinati, Fabio; Ciccarese, F; Ludovico Rapaccini, G; Di Marco, M; Benvegnu', Luisa; Zoli, M; Borzio, F; Caturelli, E; Chiaramonte, M; Trevisani, F; Italian Liver Cancer, Grou

Association of abnormal plasma bilirubin with aggressive hepatocellular carcinoma phenotype

Cirrhosis-related abnormal liver function is associated with predisposition to hepatocellular carcinoma (HCC). It features in several HCC classification systems and is an HCC prognostic factor. The aim of the present study was to examine the phenotypic tumor differences in HCC patients with normal or abnormal plasma bilirubin levels. A 2,416-patient HCC cohort was studied and dichotomized into normal and abnormal plasma bilirubin groups. Their HCC characteristics were compared for tumor aggressiveness features, namely, blood alpha-fetoprotein (AFP) levels, tumor size, presence of portal vein thrombosis (PVT) and tumor multifocality. In the total cohort, elevated bilirubin levels were associated with higher AFP levels, increased PVT and multifocality, and lower survival, despite similar tumor sizes. When different tumor size terciles were compared, similar results were found, even among patients with small tumors. A multiple logistic regression model for PVT or tumor multifocality showed increased odds ratios for elevated levels of gamma glutamyl transpeptidase (GGTP), bilirubin, and AFP and for larger tumor sizes. We conclude that HCC patients with abnormal bilirubin levels had worse prognosis than patients with normal bilirubin. They also had an increased incidence of PVT and tumor multifocality, and higher AFP levels, in patients with both small and larger tumors. The results show an association between bilirubin levels and indices of HCC aggressiveness