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Öğe C-reactive protein and platelet-lymphocyte ratio as potential tumor markers in low-alpha-fetoprotein hepatocellular carcinoma(KARGER, ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND, 2018) Carr, Brian I.; Karakülah, GökhanThe hepatocellular carcinoma (HCC) tumor marker alpha-fetoprotein (AFP) is only elevated in about half of the HCC patients, limiting its usefulness in following the effects of therapy or screening. New markers are needed. It has been previously noted that the inflammation markers C-reactive protein (CRP) and platelet-lymphocyte ratio (PLR) are prognostically important and may reflect HCC aggressiveness. We therefore examined these 2 markers in a low-AFP HCC cohort and found that for HCCs > 2 cm, both markers significantly rise with an increasing maximum tumor diameter (MTD). We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Youden index value for each marker, and their area-under-the-curve values for each MTD group. Patients were dichotomized into 2 groups based on the CRP and PLR from the receiver-operating characteristic curve analysis. In the logistic regression models of the 4 different MTD patient groups, CRP and PLR levels were statistically significant to estimate MTD in univariate logistic regression models of MTD groups > 2 cm. CRP and PLR were then combined, and the combination was statistically significant to estimate MTD groups of 3-, 4-, and 5-cm cutoffs. CRP and PLR thus have potential as tumor markers for low-AFP HCC patients, and possibly for screening. (C) 2018 S. Karger AG, BaselÖğe C-Reactive Protein and Platelet-Lymphocyte Ratio as Potential Tumor Markers in Low-Alpha-Fetoprotein Hepatocellular Carcinoma(Karger, 2019) Suner, Asli; Carr, Brian I.; Akkiz, Hikmet; Karakulah, Gokhan; Uskudar, Oguz; Yalcin, Kendal; Kuran, SedefThe hepatocellular carcinoma (HCC) tumor marker alpha-fetoprotein (AFP) is only elevated in about half of the HCC patients, limiting its usefulness in following the effects of therapy or screening. New markers are needed. It has been previously noted that the inflammation markers C-reactive protein (CRP) and platelet-lymphocyte ratio (PLR) are prognostically important and may reflect HCC aggressiveness. We therefore examined these 2 markers in a low-AFP HCC cohort and found that for HCCs > 2 cm, both markers significantly rise with an increasing maximum tumor diameter (MTD). We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Youden index value for each marker, and their area-under-the-curve values for each MTD group. Patients were dichotomized into 2 groups based on the CRP and PLR from the receiver-operating characteristic curve analysis. In the logistic regression models of the 4 different MTD patient groups, CRP and PLR levels were statistically significant to estimate MTD in univariate logistic regression models of MTD groups > 2 cm. CRP and PLR were then combined, and the combination was statistically significant to estimate MTD groups of 3-, 4-, and 5-cm cutoffs. CRP and PLR thus have potential as tumor markers for low-AFP HCC patients, and possibly for screening. (C) 2018 S. Karger AG, BaselÖğe 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 LudovicoBackground: 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.Öğe Clinical and Basic Research on Hepatocellular Carcinoma in Turkey(Springer, 2021) Carr, Brian I.[Abstract Not Available]Öğe 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, SezaiBackground 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/).Öğe THE EFFECT OF PRE-TRANSPLANT LIPID PROFILE ON POST-TRANSPLANT HCC RECURRENCE(Wiley, 2021) Ince, Volkan; Carr, Brian I.; Usta, Sertac; Ersan, Veysel; Bag, Harika G.; Yilmaz, Sezai[Abstract Not Available]Öğe Gamma glutamyl transpeptidase as a prognostic biomarker in hepatocellular cancer patients especially with >5 cm tumors, treated by liver transplantation(Sage Publications Ltd, 2020) Ince, Volkan; Carr, Brian I.; Bag, Harika Gozukara; Koc, Cemalettin; Usta, Sertac; Ersan, Veysel; Baskiran, AdilBackground Serum AFP levels are typically elevated in less than 50% of hepatocellular cancer (HCC) patients. Gamma-glutamyl transpeptidase (GGT) levels have been suggested to be a potentially useful HCC biomarker. Aims To assess in a cohort of prospectively evaluated HCC patients who underwent liver transplant and whose survival was known; the occurrence, prognosis, and clinical characteristics of patients with elevated serum GGT levels. Results Serum GGT levels were found to be elevated in a higher proportion in patients with either small or large HCC than alpha-fetoprotein (AFP) levels, and were significantly related to prognosis in patients with large size HCCs. There was no clear correlation between GGT and AFP levels, likely reflecting different HCC characteristics or HCC cell lineages associated with these two markers. Furthermore, elevated GGT was found in 24% of low-AFP patients with small tumors and 46% with large tumors. Elevated GGT levels were also significantly associated with microvascular invasion and tumor diameter. Conclusions Elevated serum GGT levels were associated with HCC size and worse survival, and were unrelated to AFP levels. GGT may be a useful prognostic tumor marker, especially for low-AFP HCC patients.Öğe 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 LudovicoSimple 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.Öğe Introduction to Special Issue on Liver Transplant and HCC at Inonu University, Turkey(Springer, 2020) Yilmaz, Sezai; Carr, Brian I.[Abstract Not Available]Öğe Liver Transplantation for Hepatocellular Carcinoma in Patients with Inherited Metabolic Liver Diseases: A Single-Center Analysis(Aves, 2023) Garzali, Ibrahim Umar; Hargura, Abdirahman Sakulen; Ince, Volkan; Varol, Fatma Ilknur; Carr, Brian I.; Yilmaz, SezaiBackground/Aims: Liver transplantation is an acceptable treatment for some selected hepatocellular carcinoma. We report our experi-ence of 6 patients with liver transplantation for hepatocellular carcinoma with background inherited metabolic disease. Materials and Methods: This is a single-center retrospective, descriptive study. Consecutive patients who underwent liver transplanta-tion for hepatocellular carcinoma with background inherited metabolic disease were included in the study. The record of the patients was accessed, and the following data were extracted: sociodemographic variables, type of metabolic disease, date of liver transplan-tation, tumor characteristics, laboratory parameters, Model for End-Stage Liver Disease score, immediate-and long-term outcome after transplantation, disease-free survival, and overall survival. Data were analyzed using Statistical Package for the Social Sciences version 25.0. Results: Six patients received liver transplantation for hepatocellular carcinoma with background inherited metabolic liver disease. The median age was 4.5 years. The median Model for End-Stage Liver Disease score was 29.30. The median maximum tumor diameter was 2.15 cm. Three patients had multiple tumor nodules. Half of the patients had microvascular invasion. Four of the patients had a mod-erately differentiated tumor. Progressive familial intrahepatic cholestasis type II is the commonest inherited metabolic disease seen in 3 patients. Median follow-up is 46.1 months. Half of the patients are currently more than 5 years post liver transplantation with no features of recurrence. The estimated survival rates at 1, 3, and 5 years are 100%, 83.3%, and 83.3%, respectively. Conclusion: Liver transplant for these categories of patients is associated with good disease-free and overall survival, even in the pres-ence of some seemingly poor prognostic features.Öğe Macroscopic Portal Vein Thrombosis in HCC Patients(Hindawi Ltd, 2018) Akkiz, Hikmet; Carr, Brian I.; Kuran, Sedef; Karaogullarindan, Umit; Uskudar, Oguz; Tokmak, Salih; Arslan, BurcuMacroscopic portal vein invasion (PVT) by hepatocellular carcinoma (HCC) in the liver is one of the most important negative prognostic factors for HCC patients. The characteristics of a large cohort of such patients were examined. We found that the percent of patients with PVT significantly increased with increasing maximum tumor diameter (MTD), from 13.7% with tumors of MTD <5cm to 56.4% with tumors of MTD >10cm. There were similar numbers of HCC patients with very large tumors with and without PVT. Thus, MTD alone was insufficient to explain the presence of PVT, as were high AFP levels, since less than 50% of high AFP patients had PVT. However, the percent of patients with PVT was also found to significantly increase with increasing blood alpha-fetoprotein (AFP) levels and tumormultifocality. A logistic regressionmodel that included these 3 factors together showed an odds ratio of 17.9 for the combination of MTD >5.0cm plus tumor multifocality plus elevated AFP, compared to low levels of these 3 parameters. The presence or absence of macroscopic PVT may therefore represent different HCC aggressiveness phenotypes, as judged by a significant increase in tumor multifocality and AFP levels in the PVT positive patients. Factors in addition to MTD and AFP must also contribute to PVT development.Öğe Microvascular Invasion in Hepatocellular Carcinoma: Some Puzzling Facets(Aves, 2024) Garzali, Ibrahim Umar; Carr, Brian I.; Ince, Volkan; Isik, Burak; Akatli, Ayse Nur; Yilmaz, SezaiBackground/Aims: Hepatocellular carcinoma is the main type of primary liver cancer. Macroscopic vascular invasion is usually identified during imaging, whereas microvascular invasion is usually determined by histopathological evaluation. We aim to identify the association between microvascular invasion and other markers of tumor aggressiveness and to identify the role of microvascular invasion in the prognosis of patients who were treated by liver transplantation for hepatocellular carcinoma. Materials and Methods: This is a single -center retrospective analysis of prospectively collected data. Patients who received liver transplantation for hepatocellular carcinoma were included in the study. Data were collected regarding sociodemographic variables, criteria of selection for liver transplantation, pretransplant alpha-fetoprotein, presence or absence of microvascular invasion, presence or absence of recurrence, overall survival, and disease -free survival. Data were analyzed using Statistical Package for the Social Sciences. Results: Sociodemographic laboratory values and radiologic tumor characteristics were found to be similar infconclu patients with or without microvascular invasion. Our study revealed that microvascular invasion is associated with increased recurrence, decreased diseasedfree survival, and decreased overall survival, only for patients with hepatocellular carcinoma beyond Milan criteria at the time of liver transplantation. Conclusion: For patients beyond Milan criteria, but not within Milan criteria, microvascular invasion plays a significant role in predicting recurrence and shorter survival after liver transplantation.Öğe Parameters Predicting Microvascular Invasion and Poor Differentiation in Hepatocellular Carcinoma Patients with Normal Alpha-fetoprotein Level Before Liver Transplantation(Aves, 2023) Kilci, Burak M.; Ince, Volkan; Carr, Brian I.; Usta, Sertac; Bag, Harika G.; Samdanci, Emine; Isik, BurakBackground/Aims: The aim of this study is to evaluate the parameters that might be associated with pathologically diagnosed microvascular invasion and poor differentiation, using complete blood count and routine clinical biochemistry test results, in hepatocellular carcinoma patients before liver transplantation. Materials and Methods: The data of patients who underwent liver transplantation for hepatocellular carcinoma at our institute, between March 2006 and November 2021, was researched retrospectively. Results: The incidence of microvascular invasion was 28.6%, poor differentiation rate was 9.3%, hepatocellular carcinoma recurrence rate after liver transplantation was 12.1%, and median time to recurrence was 13 months, in the patients with normal alpha-fetoprotein levels. After univariate and multivariate analysis, maximum tumor diameter >4.5 cm and the number of nodules (n > 5) were found to be independent risk factors for microvascular invasion, and number of nodules >4 and mean platelet volume =8.6 fL were found to be independent risk factors for poor differentiation. Serum alpha-fetoprotein levels were still within the normal range at the recurrence time, in 53% of the patients who had recurrence after liver transplantation, but surprisingly were elevated in 47% of the patients at time of hepatocellular carcinoma recurrence. Conclusion: In hepatocellular carcinoma patients with normal alpha-fetoprotein levels before liver transplantation, independent risk factors of the presence of microvascular invasion were maximum tumor diameter and number of nodules, and independent risk factors of poor differentiation were mean platelet volume and number of nodules. Furthermore, serum alpha-fetoprotein levels were still normal at time of recurrence in 53% of hepatocellular carcinoma patients whose alpha-fetoprotein levels were normal before liver transplantation but were elevated in 47% of the patients at recurrence time, despite having normal levels before liver transplantation.Öğe Prognostic role of platelet lymphocyte ratio (PLR) among patients with hepatocellular carcinoma undergoing liver transplantation(2023) Garzali, Ibrahim Umar; Hargura, Abdirahman Sakulen; İnce, Volkan; Usta, Sertaç; Aloun, Ali; Carr, Brian I.; Yılmaz, SezaiAim: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, but it is so aggressive that is the third most common cause of cancer related death. We aim to study the role of PLR in prognosis of HCC and to see if it can be a predictor of overall survival and disease-free survival among HCC patients that received liver transplantation in our center. Materials and Methods: This is a single center retrospective analysis of prospectively collected data. The study was carried out in liver transplant institute of Inonu University, Malatya, Turkey. Consecutive patients that received liver transplantation for HCC and survive for at least 90 days post transplantation were included in the study. Data was collected regarding age, gender, presence or absence of cirrhosis, cause of cirrhosis, number of nodules, maximum size of the tumor, preoperative PLR, pre-transplant GGT, type of transplant, presence or absence of microvascular invasion, overall survival and disease-free survival. The study was censored on June 2022. Data was analyzed using SPSS version 25. Results: Platelet lymphocyte ratio was found to be significantly associated with some poor prognostic factors of HCC in our patients. We found that PLR is significantly associated with maximum tumor diameter (MTD) and total tumor diameter (TTD) with p= <0.0001 and 0.0016 respectively. Univariate analysis revealed that PLR is a predictor of worse DFS or OS but when subjected to multivariate analysis, we found that PLR is not an independent predictor of OS and DFS. Conclusion: Platelet lymphocyte ratio is associated with poor prognostics feature of hepatocellular carcinoma.Öğe Relationships Between Indices of Tumor Aggressiveness in Hepatocellular Carcinoma(Springer, 2021) Carr, Brian I.; Guerra, Vito; Donghia, Rossella; Yilmaz, SeaiBackground 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.Öğe Serum levels of inflammatory markers CRP, ESR and albumin in relation to survival for patients with hepatocellular carcinoma(Wiley, 2021) Akkiz, Hikmet; Carr, Brian I.; Bag, Harika G.; Karaogullarindan, Umit; Yalcin, Kendal; Ekin, Nazim; Ozakyol, AysegulIntroduction Hepatocellular carcinoma is associated with several chronic inflammatory conditions. It is increasingly understood that the inflammation may be part of the carcinogenic process and prognostically important. Objective To evaluate the serum levels of three inflammation markers in relation to survival in HCC patients. Methods We retrospectively examined the serum levels of CRP, albumin and ESR, both singly and in combination, in relation to patient survival. Results Survival worsened with increase in CRP or ESR or decrease in albumin levels. Combinations of CRP plus albumin or CRP plus ESR were associated with an even greater range of survival (3-fold), together with significant differences in maximum tumor diameter (PVT) and percent of patients with portal vein thrombosis (PVT). The triplet of CRP plus albumin plus ESR was associated with a sevenfold difference in survival, comparing low vs high parameter levels. These significant differences were found in patients with small or large tumors. Conclusions Combinations of CRP with albumin or ESR or all three parameters together significantly related to differences in survival and to differences in MTD and percent PVT, in patients with both small and large size HCCs.Öğe Transplant and non-transplant HCC patients at a single institution(Kare Publ, 2024) Carr, Brian I.; Bag, Harika; Ince, Volkan; Isik, Burak; Baskiran, Adil; Yilmaz, SezaiBackground and Aim: Patients with hepatocellular carcinoma (HCC) are managed in various hospital departments, which complicates the assessment of the overall picture. In our large liver transplant institute, we evaluate all HCC patients in a weekly multi -disciplinary liver tumor board, and their data are prospectively collected in an institutional HCC database to evaluate HCC causes, tumor features, treatments, and survival. Materials and Methods: Baseline data for patients (n=1322) were prospectively recorded, including hepatitis status, routine clinical serum parameters, radiological assessment of maximum tumor diameter (MTD), tumor number, presence of macroscopic portal vein thrombosis (PVT), and serum alpha-fetoprotein (AFP) levels. Results: Cirrhosis was found in 81.1% of patients; 58.5% had hepatitis B virus (HBV), 14.9% hepatitis C virus (HCV), 8.9% cryptogenic cirrhosis, and less than 2% had alcoholism. MTD was <5 cm in 61.95% of patients, and 31.9% had PVT. The median overall survival was more than six -fold greater for the 444 liver transplant patients than for those without surgery. Transplanted patients had smaller tumors, whereas larger tumors (MTD >10 cm) were primarily in the no -surgery group. Parallel differences were found for AFP levels (highest in the no -surgery group). PVT was present in similar proportions (25.0% for transplant, 28.0% for no -surgery). The presence of cirrhosis was higher in the transplant group. MTD and levels of serum AFP, gamma-glutamyl transferase (GGT), and blood platelets were prognostic parameters for transplant. Furthermore, AFP and GGT levels were prognostic for transplanted PVT patients. Only albumin was prognostic in the no -surgery patients. Conclusion: Transplanted HCC patients have longer survival, smaller tumors, and more severe liver damage than no -surgery patients. Prognostic subsets were identified within the surgery and the PVT groups.Öğe Trends in Tumor Indices in Relation to Increased Hepatocellular Carcinoma Size: Evidence for Tumor Evolution as a Function of Growth(Springer, 2020) Carr, Brian I.; Guerra, V.; Donghia, R.; Yilmaz, S.Background The prognosis of HCC depends in large measure on maximum tumor diameter (MTD). Aims To examine characteristics of tumor aggressiveness over an MTD range of< 2 to 8 cm. Methods A large HCC database was examined retrospectively for trends in serum alpha-fetoprotein (AFP), and percent of patients with macroscopic portal vein thrombosis (PVT) or tumor multifocality. Results There was a significant trend to increased serum AFP levels and percent of patients with PVT, for each,p < 0.001. Within those trends, there were clearly identifiable sub-trends for variations of AFP or percent PVT patients, associated with specific MTD ranges. Calculation of the fold increase for either AFP or percent PVT patients over distinct MTD ranges showed a greater increase of AFP or percent PVT patients compared with the related MTD increase. Interestingly, the increase in percent PVT was mainly independent of AFP. Conclusions Patterns of AFP and PVT increase can be discerned with increasing MTD, which are nonlinear. The greater fold increase in tumor aggressiveness factors compared with MTD suggests that HCCs may change with increasing size to a more aggressive phenotype. Baseline HCC biopsies might therefore be insufficient in future rational HCC management, and repeated liquid biopsies have potential in following HCC evolution and thus choices of therapies.Öğe Understanding the Drawbacks of the Current Tumor Staging Systems: How to Improve?(Mdpi, 2023) Giacomelli, Luca; Sacco, Rodolfo; Papa, Simonetta; Carr, Brian I.[Abstract Not Available]