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    Alpha-fetoprotein and albumin inversely relate to each other and to tumor parameters in patients with hepatocellular carcinoma
    (Kare Publ, 2024) Carr, Brian; Guerra, Vito; Ince, Volkan; Isik, Burak; Yilmaz, Sezai
    Background and Aim: Alpha-fetoprotein (AFP), an oncofetal protein and biomarker in hepatocellular carcinoma (HCC), has unclear roles and ac-tions.To evaluate the relationships between AFP, liver function tests, and HCC aggressiveness. Materials and Methods: A retrospective analysis of an HCC patient data-base was conducted to examine the relationships between baseline serum AFP values, liver function tests, and tumor characteristics. Results: Statistically significant positive trends were observed between AFP levels and both AST and bilirubin, along with negative trends between AFP and albumin. Significant correlations were also found between AFP and MTD, multifocality, and PVT. Increases in MTD, multifocality, and PVT were noted even at low AFP levels, indicating both AFP-independent and AFP-dependent processes. However, these parameter changes were minimal compared to the substantial changes in AFP levels. Relationships between AFP-related liver and tumor characteristics were found to be sim-ilar but inverse to those for albumin, with normal albumin levels associated with more favorable tumor characteristics. Additionally, serum levels of albumin and AFP were inversely related. Conclusion: AFP and albumin levels significantly, but inversely, correlate with tumor parameters, suggesting that albumin may suppress HCC func-tions and could serve as a potential prognostic marker.
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    Changes in hepatocellular carcinoma aggressiveness characteristics with an increase in tumor diameter
    (Sage Publications Ltd, 2021) Carr, Brian I.; Guerra, Vito; Donghia, Rossella; Farinati, Fabio; Giannini, Edoardo G.; Piscaglia, Fabio; Rapaccini, Gian Ludovico
    Background: Hepatocellular carcinoma prognosis depends on both liver and tumor determinants, especially on maximum tumor diameter, multifocality, and presence of portal vein thrombosis, despite apparently complete tumor removal by resection or liver transplantation. Aims: To examine parameters of hepatocellular carcinoma aggressiveness as tumor size increases. Methods: A large hepatocellular carcinoma database was examined for trends in serum alpha-fetoprotein and the percentage of patients with macroscopic portal vein thrombosis or tumor multifocality. Results: A total of 13,016 hepatocellular carcinoma patients were identified having full tumor and survival data. Of these, 76.56% were male and 23.44% were female, with a median age of 64.4 years. We found that as the maximum tumor diameter increased, there was a significant trend for increased alpha-fetoprotein levels (P<0.001) and an increased percentage of patients with either portal vein thrombosis or tumor multifocality, each P<0.0001. Furthermore, the increases of both alpha-fetoprotein and portal vein thrombosis were proportionately greater than the related maximum tumor diameter increases. These trends of increased alpha-fetoprotein, portal vein thrombosis, and multifocality with increasing maximum tumor diameter had non-linear patterns. Within alpha-fetoprotein and multifocality trends, there were identifiable sub-trends associated with specific maximum tumor diameter ranges. Conclusions: The greater fold-increases in alpha-fetoprotein and portal vein thrombosis compared with increases in maximum tumor diameter imply that hepatocellular carcinoma characteristics may change with increasing size to a more aggressive phenotype, suggesting that follow-up tumor sampling might be useful, in addition to baseline tumor sampling, for optimal therapeutic choices to be made.
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    Discordance among aggressiveness characteristics of hepatocellular carcinoma: Portal vein thrombosis and multifocality, related to tumor size, but not to serum alpha-fetoprotein level
    (Keai Publishing Ltd, 2023) Carr, Brian I.; Guerra, Vito; Ince, Volkan; Isik, Burak; Yilmaz, Sezai
    Background and aims: Hepatocellular carcinoma (HCC) is characterized by several clinically important prognostic parameters, including portal vein thrombosis (PVT), tumor multifocality, and serum alpha-fetoprotein (AFP) levels, in addition to maximum tumor diameter (MTD). However, associations among these parameters have not been thoroughly examined. Thus, the study aimed to investigate the correlations among these HCC characteristics in a prospectively collected database.Methods: An 8080 HCC patient database derived from our weekly HCC council meeting was examined with respect to the correlations at baseline patient presentation between increases in MTD and changes in the percentage of patients with PVT, multifocality, or AFP levels.Results: The percentage of patients with PVT and with multifocality (tumor nodule numbers >= 3) significantly increased with enlarging MTD, regardless of the serum AFP level, showing the indepen-dence of PVT and multifocality on AFP. The percentage of patients with multifocality increased with enlarging MTD, in the presence or absence of PVT, showing the independence of multifocality from PVT. Therefore, discordance was found between different tumor parameters.Conclusions: A statistically significant association was found between PVT and MTD and between mul-tifocality and MTD, all three of which are independent of AFP. PVT and multifocality appeared to be independent of each other. Although PVT and multifocality were independent of AFP, they were also augmented with high serum AFP levels. The results suggest the possibility of multiple pathways of tumor progression in the later stages of HCC development.(c) 2023 The Third Affiliated Hospital of Sun Yat-sen University. Publishing services by Elsevier B. V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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    Identification of Clinical Phenotypes and Related Survival in Patients with Large HCCs
    (Mdpi, 2021) Carr, Brian I.; Guerra, Vito; Donghia, Rossella; Farinati, Fabio; Giannini, Edoardo G.; Muratori, Luca; Rapaccini, Gian Ludovico
    Simple Summary Factors influencing the survival of hepatocellular carcinoma (HCC) patients include portal vein thrombosis (PVT), tumor numbers (multifocality), blood alpha-fetoprotein (AFP) levels, and the degree of liver damage (levels of blood bilirubin and albumin). However, the role of tumor size can be ambiguous. We therefore examined multiple clinical characteristics for their relationship with patient death and combined the three parameters with the greatest impact to create a tool to examine the characteristics and survival of patients with normal and abnormal levels of this three-parameter tool. In patients with large tumors, we found that normal levels of these three parameters-no PVT or multifocality plus normal blood albumin levels-were associated with longer survival than any group containing patients with PVT. This good-survival group could also be divided into two subgroups, differing in survival, based on blood AFP levels. This three-parameter tool might be prognostically useful in stratifying patients and management decisions. Background. Hepatocellular carcinoma (HCC) factors, especially maximum tumor diameter (MTD), tumor multifocality, portal vein thrombosis (PVT), and serum alpha-fetoprotein (AFP), influence survival. Aim. To examine patterns of tumor factors in large HCC patients. Methods. A database of large HCC patients was examined. Results. A multiple Cox proportional hazard model on death identified low serum albumin levels and the presence of PVT and multifocality, with each having a hazard ratio >= 2.0. All combinations of these three parameters were examined in relation to survival. Using univariate Cox analysis, the combination of albumin >3.5 g/dL and the absence of both PVT and multifocality had the best survival rate, while all combinations that included the presence of PVT had poor survival and hazard ratios. We identified four clinical phenotypes, each with a distinct median survival: patients with or without PVT or multifocality plus serum albumin >= 3.5 (g/dL), with each subgroup displaying high (>= 100 IU/mL) or low (<100 IU/mL) blood AFP levels. Across a range of MTDs, we identified only two significant trends, blood AFP and platelets. Conclusions. Patients with large HCCs have distinct phenotypes and survival, as identified by the combination of PVT, multifocality, and blood albumin levels.
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    Inflammatory Mechanisms of HCC Development
    (Mdpi, 2020) Refolo, Maria Grazia; Messa, Caterina; Guerra, Vito; Carr, Brian Irving; D'Alessandro, Rosalba
    HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents.
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    Microscopic Portal Vein Invasion in Relation to Tumor Focality and Dimension in Patients with Hepatocellular Carcinoma
    (Springer, 2022) Carr, Brian, I; Guerra, Vito; Donghia, Rossella; Ince, Volkan; Akbulut, Sami; Ersan, Veysel; Usta, Sertac
    Background Microscopic portal vein invasion (microPVI) and tumor multifocality are hepatocellular carcinoma (HCC) prognosis factors. To investigate whether microPVI and multifocality are directly related to each other. Methods We retrospectively analyzed the relationships between microPVI, multifocality, and maximum tumor diameter (MTD) in prospectively collected transplanted HCC patients. Results HCCs with 1, 2, or >= 3 foci had more microPVI in larger than in smaller HCCs, with microPVI being present in 52.24% of single large foci. Conversely, microPVI patients had similar percentages of single and multifocal lesions. A linear regression model of MTD, showed microPVI best associated with MTD, with 2.49 as coefficient, whereas multifocality had a 0.83 coefficient. A logistic regression model of microPVI showed significant association with tumor multifocality, especially for small HCCs. Trends for microPVI and multifocality in relation to MTD revealed that both increased with MTD but more significantly for microPVI. Survival was similar in patients with small HCCs, with or without microPVI, but was significantly worse in microPVI patients with larger HCCs. No patient survival differences were found in relation to focality. Conclusions MTD had stronger associations with microPVI than with multifocality. microPVI was associated with worse survival in patients with large HCCs, but survival was not impacted by number of tumor foci. microPVI and multifocality appear weakly related, having different behavior in relation to MTD and survival.
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    Relationships Between Indices of Tumor Aggressiveness in Hepatocellular Carcinoma
    (Springer, 2021) Carr, Brian I.; Guerra, Vito; Donghia, Rossella; Yilmaz, Seai
    Background Hepatocellular carcinoma (HCC) aggressiveness factors include serum levels of alpha-fetoprotein (AFP), maximum tumor diameter (MTD), tumor multifocality, and presence of portal vein thrombosis (PVT). Aims The interdependence of these factors has not been closely studied. Methods A large HCC database was examined for the presence of patients with PVT and multifocality and was analyzed retrospectively for the relationship of these 2 parameters to each other and to MTD and survival. Results Multifocality was found to increase with increase in MTD in the whole cohort and especially in patients with PVT. PVT also increased with increasing MTD. Neither increases in multifocality nor in PVT depended on elevated serum AFP levels, although they each increased with higher AFP levels. PVT increased in monofocal tumors as MTD increased but increased further in multifocal tumors. Conclusions Multifocality and PVT appear to be separate processes, each increasing with increase in MTD and AFP levels. The data support the hypothesis that in hepatocarcinogenesis, various factors cause increase in MTD, that in turn causes increased multifocality and PVT, which are non-co-dependent. However, both multifocality and PVT mechanisms involve both HCC cell growth and invasiveness, multifocality in liver parenchyma, and PVT in the portal vein.
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    Serum Inflammation Parameters and Survival in Hepatocellular Carcinoma Patients: Importance of Albumin and Gamma-Glutamyltranspeptidase
    (Karger, 2023) Carr, Brian I. I.; Guerra, Vito
    Introduction: Many single and combination blood tests that reflect local or systemic inflammation have been shown to be useful prognosticators in patients with a variety of tumor types. To try to clarify, this issue in patients with nonsurgically treatable hepatocellular carcinoma, multiple serum parameters were evaluated for their relationship to survival. Methods: A prospectively collected database was interrogated of 487 patients with known hepatocellular carcinoma and documented survival and having all the inflammation parameters of interest in this study, together with baseline tumor characteristics from CT scans. Serum parameters included NLR, PLR, CRP, ESR, albumin, and GGT. Results: All the parameters had significant hazard ratios on Cox regression model. Combination double parameters with hazard ratios >2.0 were: ESR plus GGT, albumin plus GGT, albumin plus ESR. The triplet combination of albumin plus GGT plus ESR had a hazard ratio of 6.33. Using Harrell's concordance index (C-index), the highest inflammation-based 2-parameter prognostic score was for albumin plus GGT. When clinical characteristics of patients with high values for albumin plus low values for GGT were compared to low values for albumin plus high values for GGT (worse prognosis), statistically significant differences were found for tumor size, tumor focality, macroscopic portal vein invasion, and serum alpha-fetoprotein levels. Addition of ESR did not provide additional tumor information. Conclusion: The combination of serum albumin plus GGT levels was the most prognostically useful among the inflammation parameters that were tested, and reflected significant differences in tumor aggressiveness characteristics.