title: Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters.
abstract: Previous 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.
authors.affiliation: Department of Liver Tumor Biology IRCCS de Bellis, National Institute for Digestive Diseases, Castellana Grotte , BA, Italy.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Carr
authors.affiliation: Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Pancoska
authors.affiliation: Department of Internal Medicine, Gastroenterology Unit, University of Genoa.
authors.forename: Edoardo G
authors.initials: EG
authors.lastname: Giannini
authors.affiliation: Department of Surgical Science and Gastroenterology, Gastroenterology Unit, University of Padua.
authors.forename: Fabio
authors.initials: F
authors.lastname: Farinati
authors.affiliation: Division of Surgery, Policlinico San Marco, Zingonia.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ciccarese
authors.affiliation: Internal Medicine and Gastroenterology Unit, Catholic University of Rome, Rome.
authors.forename: Gian Ludovico
authors.initials: GL
authors.lastname: Rapaccini
authors.affiliation: Division of Medicine, Azienda Ospedaliera Bolognini, Seriate.
authors.forename: Maria Di
authors.initials: MD
authors.lastname: Marco
authors.affiliation: Departiment of Clinical and Experimental Medicine, Medical Unit, University of Padua.
authors.forename: Luisa
authors.initials: L
authors.lastname: Benvegnù
authors.affiliation: Department of Medical and Surgical Science, Internal Medicine Unit, Alma Mater Studiorum - University of Bologna.
authors.forename: Marco
authors.initials: M
authors.lastname: Zoli
authors.affiliation: Department of Medicine, Internal Medicine and Hepatology Unit, Ospedale Fatebenefratelli, Milan.
authors.forename: Franco
authors.initials: F
authors.lastname: Borzio
authors.affiliation: Gastroenterology Unit, Ospedale Belcolle, Viterbo.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Caturelli
authors.affiliation: Gastroenterology Unit, Ospedale Sacro Cuore Don Calabria, Negrar.
authors.forename: Maria
authors.initials: M
authors.lastname: Chiaramonte
authors.affiliation: Department of Medical Surgical Sciences, Medical Semiotics Unit, Alma Mater Studiorum - University of Bologna, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Trevisani
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D001792:Blood Platelets / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000145:classification / Q000401:mortality / Q000473:pathology*; D016208:Databases, Factual; D006801:Humans; D008113:Liver Neoplasms / Q000145:classification / Q000401:mortality / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D015996:Survival Rate; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D000509:alpha-Fetoproteins