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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., (© 2023 S. Karger AG, Basel.)

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., (© 2021. The Society for Surgery of the Alimentary Tract.)

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., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

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.

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.

Background: Macroscopic portal vein thrombosis (PVT) is a major poor prognosis factor in patients with hepatocellular carcinoma (HCC). Inflammation is increasingly recognized to be part of the hepatocarcinogenic process and its markers are also prognostically useful., Aims: To examine the relationship of inflammation biomarkers to the presence of PVT and to survival in PVT patients with HCC., Methods: A large HCC cohort was examined for the presence of PVT and analyzed retrospectively., Results: Blood levels of NLR, PLR, ESR, CRP, AFP and GGTP were significantly related to the presence of PVT, but not the Glasgow Index. For patients with low alpha-fetoprotein levels, blood ESR and GGTP levels were also significantly increased in patients with PVT compared with those in patients without PVT. In a Cox regression model, serum GGTP levels had a significantly increased hazard ratio on death (1.52, p = 0.008). Kaplan-Meier analysis showed that PVT patients with low serum GGTP levels had significantly longer survival than PVT patients with high GGTP levels (p = 0.0041)., Conclusions: Indices of inflammation, especially serum GGTP levels, related significantly to the presence of PVT and to survival in HCC patients with PVT.

In randomized clinical trials, no survival benefit has been observed for selective internal radiation therapy (SIRT) over sorafenib in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess, through a metaanalysis, whether overall survival (OS) with SIRT, as monotherapy or followed by sorafenib, is noninferior to sorafenib and to compare safety profiles for patients with advanced HCC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library up to February 2019 to identify randomized clinical trials comparing SIRT, as monotherapy or followed by sorafenib, with sorafenib monotherapy among patients with advanced HCC. The main outcomes were OS and frequency of treatment-related severe adverse events (≥grade 3). The per-protocol population was the primary analysis population. A noninferiority margin of 1.08 in terms of hazard ratio was prespecified for the upper boundary of 95% confidence interval for OS. Prespecified subgroup analyses were performed. Results: Three randomized clinical trials, involving 1,243 patients, comparing sorafenib with SIRT (SIRveNIB and SARAH) or SIRT followed by sorafenib (SORAMIC), were included. After randomization, 411 of 635 (64.7%) patients allocated to SIRT and 522 of 608 (85.8%) allocated to sorafenib completed the studies without major protocol deviations. Median OS with SIRT, whether or not followed by sorafenib, was noninferior to sorafenib (10.2 and 9.2 mo [hazard ratio, 0.91; 95% confidence interval, 0.78-1.05]). Treatment-related severe adverse events were reported in 149 of 515 patients (28.9%) who received SIRT and 249 of 575 (43.3%) who received sorafenib only ( P < 0.01). Conclusion: SIRT as initial therapy for advanced HCC is noninferior to sorafenib in terms of OS and offers a better safety profile., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Aims:: Hepatocellular 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., Methods:: We retrospectively investigated the serum lipid profiles in a large hepatocellular carcinoma cohort, associated predominantly with the hepatitis B virus, hepatitis C virus, alcohol or nonalcoholic steatohepatitis. The cohort was examined both as a whole, as well as stratified by etiology., Results:: We found significant associations between parameters of hepatocellular carcinoma biology such as maximum tumor diameter, portal vein thrombosis, tumor multifocality or alpha-fetoprotein levels and individual lipid components, including total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and body mass index. In a final multiple linear regression model considering all lipid variables together, only high-density lipoprotein cholesterol was significantly associated with the tumor Tumor Aggressiveness Index. High-density lipoprotein cholesterol was found to have a statistically higher hazard ratio for death than low high-density lipoprotein cholesterol levels (Cox). On examination by etiological group, alpha-fetoprotein levels were significantly higher in patients with hepatitis C virus compared to those with alcohol or nonalcoholic steatohepatitis, but maximum tumor diameter, tumor multifocality and portal vein thrombosis were similar across etiological groups. Nonalcoholic steatohepatitis patients had significantly less cirrhosis than other groups and hepatitis B virus patients had significantly higher cholesterol and low-density lipoprotein cholesterol levels than hepatitis C virus patients., Conclusions:: This is the first report, to our knowledge, of a relationship between serum lipid parameters and indices of hepatocellular carcinoma growth, invasion and aggressiveness, as well as with survival.

Macroscopic 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 tumor multifocality. A logistic regression model 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.

Aim: To investigate novel predictors of survival in hepatocellular carcinoma (HCC) patients following transarterial chemoembolization (TACE)., Methods: One hundred sixty seven patients with un-resectable HCC were retrospectively analyzed to identify factors that might contribute to their HCC biology and aggressiveness. We correlated routine laboratory results (total bilirubin, AST, ALKP, GGTP, albumin etc .) to maximum tumor diameter, number of tumor nodules, portal vein thrombosis and blood alpha-fetoprotein levels. These 4 parameters were previously combined to form an aggressiveness index (AgI). We used The Wilcoxon rank-sum (Mann-Whitney), to test the correlation between the AgI categories and liver function parameters. The Cox proportional hazards model was applied to evaluate the categories of AgI associated with overall survival., Results: The AgI was strongly correlated with survival in this novel patient population. Three year survival probability for AgI > or < 4 was 42.4% vs 61.8%; P < 0.0863 respectively. Several factors independently correlated with AgI using univariate multiple logistic regression of AgI with 8 laboratory parameters. Lower albumin levels had an OR of 2.56 (95%CI: 1.120-5.863 P < 0.026), elevated Alkaline phosphatase and gamma glutamyl transpeptidase (GGTP) had ORs of 1.01 (95%CI: 1.003-1.026, P < 0.017) and 0.99 (95%CI: 0.99-1.00, P < 0.053) respectively. In a Cox proportional hazard model combining mortality for AgI score and liver function parameters, only GGTP levels and the AgI were independently associated with survival. An AgI > 4 had HR for mortality of 2.18 (95%CI: 1.108-4.310, P < 0.024). GGTP's single unit change had a HR for mortality of 1.003 (95%CI: 1.001-1.006, P < 0.016). These were considered in the final multivariate model with the total cohort. An AgI > 4 had a HR for mortality of 2.26 (95%CI: 1.184-4.327, P < 0.016). GGTP had a HR of 1.003 (95%CI: 1.001-1.004, P < 0.001)., Conclusion: Our study validates the AgI in a new population with un-resectable HCC patients undergoing TACE. The analysis establishes a correlation between GGTP and the AgI., Competing Interests: Conflict-of-interest statement: Professor Shibolet has nothing to disclose.

A large cohort of hepatocellular carcinoma (HCC) patients from several collaborating Turkish institutions were examined for the tumor parameters of maximum diameter (MTD), portal vein thrombosis (PVT), and α-fetoprotein (AFP) levels. A relationship was found between MTD and blood platelet levels. Patients with large ≥5 cm tumors who had normal platelet levels had significantly larger tumors, higher percent of PVT, and significantly lower blood total bilirubin and liver cirrhosis than similar ≥5 cm tumor patients having thrombocytopenia. A comparison of patients with and without PVT showed significantly larger tumors, greater multifocality, blood AFP, and C-reactive protein levels, and, interestingly, lower HDL levels in the patients with PVT. Fifty-eight percent of the total cohort had AFP levels ≤100 IU/mL (and 42.1% had values ≤20 IU/mL). These patients had significantly smaller tumors, less tumor multifocality and percent PVT, lower total bilirubin, and less cirrhosis. There was considerable geographic heterogeneity within Turkey in the patterns of HCC presentation, with areas of higher and lower hepatitis B virus, hepatitis D virus, cirrhosis, and tumor aggressiveness parameters. Turkish patients thus have distinct patterns of presentation, but the biological relationships between MTD and both platelets and bilirubin levels are similar to the relationships that have been reported in other ethnic patient groups., (© 2017 S. Karger AG, Basel.)

Background: Serum albumin levels have been shown to have prognostic significance in hepatocellular carcinoma (HCC), as part of an inflammatory index. The aim of this study was to examine the possible relationship of serum albumin levels to parameters of HCC aggressiveness., Methods: A large HCC patient cohort was retrospectively examined, and the possible relationships of albumin levels to tumor diameter, multifocality, portal vein thrombosis (PVT) and α-fetoprotein levels were examined., Results: HCC patients with lower serum albumin levels had significantly larger maximum tumor diameters, greater prevalence of PVT, increased tumor multifocality and higher α-fetoprotein levels, than HCC patients with higher albumin levels. A correlation was found between levels of these tumor parameters and serum albumin levels., Conclusions: These results indicate that low serum albumin levels correlate with increased parameter measures of HCC aggressiveness, in addition to their role as a monitor of systemic inflammation. Decreased serum albumin might have a role in HCC aggressiveness.

Background & Aims: Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patient's mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross-validation, especially in intermediate stage HCC, where OS is highly heterogeneous., Methods: We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n=1461) accrued from Europe, the United States and Asia., Results: Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection (p<0.001), transarterial chemoembolization (p<0.001) and sorafenib (p<0.001). Stratification by Barcelona Clinic Liver Cancer stage confirmed the independent prognostic value of the ALBI across the diverse stages of the disease, geographical regions of origin and time of recruitment to the study (p<0.001)., Conclusions: In this large, multi-centre retrospective study, the ALBI grade satisfied the criteria for accuracy and reproducibility following statistical validation in Eastern and Western HCC patients, including those treated with chemoembolization. Consideration should be given to the ALBI grade as a stratifying biomarker of liver reserve in routine clinical practice., Lay Summary: Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: Levels of serum albumin have recently emerged, together with C-reactive protein, as an important prognostic indicator for hepatocellular carcinoma (HCC). It has recently been reported that larger HCCs are associated with lower albumin levels. However, the albumin-mediated growth decrease has yet to be determined., Methods: We examined a large HCC cohort and then by direct exposure of HCC cells in vitro, the relationship of albumin levels to HCC growth., Results: We found that patients with lower albumin levels had significantly larger maximum tumor diameters, more portal vein thrombosis, more tumor multifocality, higher α-fetoprotein levels, and a lower survival than patients with higher albumin levels. Direct addition of exogenous albumin at physiological concentrations resulted in decreased growth in several HCC cell lines in vitro. We found a decrease in MAP kinase levels and in levels of Cdk2 and Cdk4, cyclinE, as well as in α-fetoprotein., Conclusion: These results indicate that in addition to its role as a monitor of systemic inflammation, albumin may have a direct role in HCC growth inhibition, either through modulation of α-fetoprotein or through its actions on growth-controlling kinases., (© 2017 S. Karger AG, Basel.)

Background: Macroscopic portal vein thrombosis (PVT) is a common and dire prognostic feature of patients with hepatocellular carcinoma (HCC) and often precludes many treatments as a result. Little is known about its causes or mechanisms or clinical associations., Aims: To examine patients with PVT in order to possibly identify prognostically different subsets., Methods: A large cohort of non-curable patients with advanced and biopsy-proven HCC in which survival was documented, were retrospectively examined., Results: We analyzed a large HCC cohort containing 366 (63.3%) PVT-positive patients and found that PVT is associated with patients having larger tumors and higher levels of alpha-fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP). We identified in patients with normal bilirubin levels (≤ 2.0 mg/dl) two PVT-positive patients, having higher and lower AFP levels, respectively. They differed in the significantly better prognosis of the low AFP patients, which may be useful for patient management decisions., Conclusions: Patients with PVT are heterogeneous with respect to AFP levels. AFP-negative patients have a significantly better survival than those who have elevated AFP.

Background: Hepatocellular carcinoma (HCC) is known to metastasize. However, there are few reports on patients with metastasis at the time of HCC diagnosis., Aims: To evaluate the incidence and characteristics of extrahepatic metastasis patients presenting at baseline with noncurable, advanced HCC., Results: The total HCC cohort was initially dichotomized into 2 subcohorts, with (n = 214) and without (n = 719) extrahepatic metastasis ('metastasis'), and patient baseline characteristics were compared. The main findings for patients with metastasis (22.9% of total cohort) compared with other, nonmetastatic patients were: more advanced tumors, as judged by larger tumor diameters, more tumor multifocality and percent with portal vein thrombosis, higher blood α-fetoprotein and des x03B3;-carboxy prothrombin levels and alkaline phosphatase (ALKP), but not bilirubin levels, and a lower incidence of cirrhosis. There was a strong correlation between increases in tumor size and percent of patients with metastasis. A subset of patients with larger tumors was identified with low blood ALKP levels and better survival. Survival in the total metastasis cohort was lower than in the non-metastasis cohort, as expected, but only in patients with smaller tumors. In patients with larger tumors, survival with or without metastasis was similar and poor., Conclusions: There was a lower incidence of cirrhosis in HCC patients with metastasis, and they had larger and more aggressive primary tumors. Patients with smaller, but not larger, tumors and metastasis had worse prognosis than patients without metastasis. A distinct subset of metastatic patients was identified that had better prognosis and low ALKP levels., (© 2016 S. Karger AG, Basel.)

Background: Prognosis in hepatocellular carcinoma (HCC) is influenced by both liver and tumor factors, which have been considered independent influences. However, recent evidence has shown that the underlying liver also has prognostic information., Aims: To investigate possible relationships between liver function parameters and HCC aggressiveness indices., Methods: A large HCC patient database with baseline clinical information and survival data was retrospectively examined., Results: Data on 756 HCC patients with normal bilirubin were examined for a relationship between serum liver enzymes and 4 HCC aggressiveness indices of maximum tumor diameter, portal vein invasion, tumor multifocality or serum alpha-fetoprotein levels. An association was found between elevated enzyme levels and increased HCC aggressiveness. An aggressiveness index was constructed from the 4 indices and expressed as a sum of their scores, which in turn reflected 3 survival groups. In a Cox model, the hazard ratios for each of the groups were significantly different., Conclusions: Statistically significant correlations were found between standard liver function parameters and HCC aggressiveness. A composite aggressiveness index was constructed, yielding 3 groups with different survival probabilities. These findings support the concept of the importance of the underlying liver in relation to HCC biology., (© 2016 S. Karger AG, Basel.)

Hepatocellular carcinoma (HCC) is a leading cause of cancer death and has characteristic causes, epidemiology and clinical features. The leading causes include hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholism, and aflatoxin B1 dietary exposure, as well as combinations of these factors. Few cancers offer the opportunity to study the clinical and cancer phenotype that results from different causes, quite like HCC. Advantage was taken of a large cohort of advanced, unresectable and untransplantable HCCs to compare the phenotypes resulting from HBV-based compared with HCV-based HCC. The main findings were that HBV-based HCC patients were statistically significantly younger, had a higher percent of males, had larger maximum tumor sizes, and had higher blood alpha-fetoprotein (AFP) and albumin levels and platelet counts than HCV-based HCC patients. These differences partly reflect an earlier age of HBV infection and a lesser degree of cirrhosis-associated liver damage, as a result of the different biological consequences of chronic HBV compared with chronic HCV infection., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: HCC patients are heterogeneous in terms of both tumor and liver factors. Alpha-fetoprotein (AFP) is an important prognostic tumor marker for those patients with elevated AFP levels., Aims: To examine the differences in HCC patients with high or low AFP levels in blood and evaluate the prognostic parameters in low AFP patients., Methods: A cohort of 2,440 HCC patients from 11 Italian medical centers was studied. AFP-positive patients were compared to AFP-negative ones, and the blood and tumor parameters of AFP-negative patients were examined., Results: Low blood AFP levels were found in 58% of the total cohort, in 64% of patients with small HCCs, and in 51% of patients with large HCCs. In patients with large tumors, platelet and gamma glutamyl transpeptidase (GGTP) levels, tumor multifocality and portal vein thrombosis (PVT) incidence were all greater than in patients with small tumors, regardless of AFP status. Patients with higher AFP levels had worse survival rates than those with low AFP in each tumor size group. In patients with small tumors, the elevated AFP was associated with significantly increased PVT and worse survival. In patients with large tumors, the elevated AFP was associated with significantly higher GGTP, ALKP, and bilirubin levels, as well as with increased PVT and multifocality, and worse survival. Low-AFP patients with high GGTP levels had worse survival than patients with low GGTP levels., Conclusion: Patients with low AFP were the majority in this cohort, and patients with elevated GGTP had worse prognosis than those with low GGTP. GGTP may be a useful tumor and prognosis marker in low-AFP patients. AFP-negative patients are important to identify due to their enhanced survival.

Background: Hepatocellular carcinoma (HCC) is a heterogeneous disease with both tumor and liver factors being involved., Aims: To investigate HCC clinical phenotypes and factors related to HCC size., Methods: Prospectively-collected HCC patients' data from a large Italian database were arranged according to the maximum tumor diameter (MTD) and divided into tumor size terciles, which were then compared in terms of several common clinical parameters and patients' survival., Results: An higer MTD tercile was significantly associated with increased blood alpha-fetoprotein (AFP), gamma-glutamyl transpeptidase (GGTP), and platelet levels. Patients with higher platelet levels had larger tumors and higher GGTP levels, with lower bilirubin levels. However, patients with the highest AFP levels had larger tumors and higher bilirubin levels, reflecting an aggressive biology. AFP correlation analysis revealed the existence of 2 different groups of patients: those with higher and with lower AFP levels, each with different patient and tumor characteristics. The Cox proportional-hazard model showed that a higher risk of death was correlated with GGTP and bilirubin levels, tumor size and number, and portal vein thrombosis (PVT), but not with AFP or platelet levels., Conclusions: An increased tumor size was associated with increased blood platelet counts, AFP and GGTP levels. Platelet and AFP levels were important indicators of tumor size, but not of survival.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Massive hepatocellular carcinomas (HCCs) are uncommon and poorly characterized., Aim: To characterize a large cohort of HCC patients with massive tumors, with documented baseline characteristics and survival data., Methods: Records were examined of a cohort of 344 biopsy-proven and randomly presenting unresectable HCC patients with tumors of at least 10 cm diameter (massive), which were analyzed for their clinical characteristics and survival., Results: Massive HCC patients were significantly different from others, in having less severe cirrhosis and higher blood platelet counts, α-fetoprotein (AFP), alkaline phosphatase (ALKP), and γ-glutamyl transpeptidase (GGTP) levels. Platelets, ALKP, and GGTP correlated with tumor size. Within massive HCCs, ALKP levels related to tumor number, whereas platelet counts related to tumor size. AFP and GGTP related to neither. All four parameters related to survival. A multivariate Cox proportional hazard model showed that ALKP and AFP were significant for overall survival. Survival of massive tumors was not significantly worse than for other larger tumors., Conclusion: Massive HCCs were characterized by high blood platelets, AFP, ALKP, and GGTP levels. AFP levels were important for survival, but did not directly relate to tumor size or number, suggesting that AFP represents some other property of massive HCC biology. Patients with massive HCC should thus be considered for active therapeutic intervention, just as for other sizes of HCC.

Background/aims: Thrombocytopenia has been reported to be a surrogate for cirrhosis, but the HCC phenotypes associated with and without cirrhosis are not well studied. To compare characteristics of HCC patients with and without associated thrombocytosis., Methodology: Records were examined of a cohort of 668 biopsy-proven and randomly presenting unresectable HCC patients, who were dichotomized for presence (platelets <125 x 109/L) or absence (platelets 125-400 x 109/L) of thrombocytopenia., Results: Patients with normal platelets had larger tumors, more tumor nodules and longer survival than in the thrombocytopenia group. They also had more normal total plasma bilirubin, albumin and prothrombin times, yet had higher GGTP, ALKP and AFP levels., Conclusions: Thrombocytopenia in association with HCC occurs in patients with smaller tumor sizes, worse liver function and poorer survival, supporting the importance of host factors and liver micro-environment in HCC patients and the likelihood of two pathways for HCC development.

Purpose: Large hepatocellular carcinoma (HCC) presents on cirrhosis or in the absence of cirrhosis. Prognostic factors include both tumor and liver factors. Evaluate clinical and tumor characteristics of a group of large resected HCC in European patients., Methods: Data for patients with HCC >7 cm who underwent liver resection between 1992 and 2011 were analyzed. Patients were dichotomized into those with tumor diameters of 7-10 cm or >10 cm and their characteristics and outcomes were compared., Results: A total of 65 hepatectomies for HCC ≥7 cm were performed. Severe fibrosis or cirrhosis was present in 41.5 % of patients. Thirty-seven (56.9 %) patients had HCC ≥10 cm. Mortality and morbidity rates were 1.5 % and 37.5 %, respectively. Preoperative blood platelet levels and serum alkaline phosphatase (ALKP) levels showed significant differences between the groups. The 3-year survival was 43.5 % and 17.4 % for patients with tumors 7-10 and ≥10 cm, respectively., Conclusions: Patients with large size HCC and preserved liver function can be resected with low operative risk. ALKP levels and platelet counts were higher in the larger tumors. Given these patterns of clinical and biochemical characteristics, this group of tumors may be a selected subset of large HCCs and might potentially benefit from surgical resection.

Background: Thrombocytopenia has been reported to be both a risk factor for hepatocellular carcinoma (HCC) development as well as a prognostic factor. Many HCCs also occur in presence of normal platelets., Aim: To examine a cohort of HCC patients with associated thrombocytosis., Methods: Records were examined of a cohort of 634 biopsy-proven and randomly presenting HCC patients without thrombocytopenia., Results: In the total cohort, 52 patients were identified with thrombocytosis (platelet levels >400 × 10(9)/L) and compared with 582 patients with normal platelet values. The average tumor sizes were 13.1 versus 8.8 cm (p < 0.0001), and their total average bilirubin levels were 0.9 versus 1.5 (p = 0.02), comparing thrombocytosis patients versus normal platelet count HCC patients. These differences were even more pronounced in patients with HCC sizes >5 cm. Thrombocytosis patients were younger and had less cirrhosis, but similar percent with hepatitis B or C or alcohol consumption., Conclusion: Thrombocytosis in association with HCC occurs in patients with larger tumor sizes and better liver function.

Background: Thrombocytopenia is a cirrhosis surrogate which is associated with hepatocellular carcinoma (HCC) development., Aims: To compare the clinical characteristics of HCC in the presence and absence of thrombocytopenia., Methods: The baseline clinical data of a large cohort of randomly presenting, biopsy-proven HCC patients was examined for phenotypic patterns, after organizing the data by tumor size and subdivision into tumor size terciles., Results: Small tumor size tercile I patients had the lowest platelet counts. Patients with higher platelets within each size tercile had the lowest bilirubin and prothrombin time and higher γ-glutamyl transpeptidase (GGTP) and alkaline phosphatase (ALKP) levels. When patients with similar platelet and bilirubin levels were compared, α-fetoprotein, GGTP, and ALKP were significantly increased in patients with larger tumors and in the presence of portal vein thrombus. Large tumor size tercile III patients without thrombocytopenia had larger tumors, higher GGTP and ALKP, and lower bilirubin levels than did patients with thrombocytopenia., Conclusions: Thrombocytopenia occurred in 40.7% of patients with smaller tumors but only in 11.3% of patients with larger tumors. Patients without thrombocytopenia had elevated GGTP and ALKP and lower bilirubin levels, regardless of tumor size, but they also had larger tumors within the large tumor tercile., (© 2013 S. Karger AG, Basel.)

Background: Clinical phenotypes of small and large hepatocellular carcinomas (HCCs) are not well characterized., Aim: To evaluate the characteristics of small HCCs diagnosed by screening., Method: A cohort of 430 small HCCs that were diagnosed through screening, were dichotomized according to a size of ≤ 3 cm or >3 cm maximum tumor diameter and compared for radiological and blood-test parameters., Results: There were 330 males and 100 females. A higher percent of females had smaller tumors. The majority of patients had single tumors, but 15% of those with larger tumors had portal vein thrombosis (PVT) compared to 5% of those with smaller tumors. Significant differences between the tumor-size groups included alpha-fetoprotein (AFP) values and platelet counts, with thrombocytopenia and elevated bilirubin levels being associated with smaller tumors. In comparing PVT-positive and PVT-negative patients, AFP levels and platelet counts were also significantly different between the 2 groups. A mean multinomial multiple logistic regression model was developed for maximum tumor diameter plus PVT., Conclusions: The finding of larger tumors being associated with normal platelets and bilirubin levels in comparison to smaller tumors having thrombocytopenia reveals 2 different patterns of HCC presentation., (Copyright © 2012 S. Karger AG, Basel.)

Background: Hepatocellular carcinoma (HCC) size at diagnosis is important in management. Without screening programs, tumor size at diagnosis is heterogeneous., Aims: To examine the clinical parameters related to tumor size., Methods: Using prospectively collected data from a 1,100-patient biopsy-proven HCC cohort presenting in the absence of screening, tumor sizes were ordered and trichotomized and the resulting terciles were compared for tumor and blood parameters., Results: The terciles were significantly different with respect to portal hypertension and thrombocytopenia, which were present in a higher percent of tercile I patients with smaller tumors. Tercile III patients with larger HCCs had the highest serum α-fetoprotein (AFP), γ-glutamyl transpeptidase (GGTP), and alkaline phosphatase (ALKP) levels and the most portal vein (PV) thrombosis. Subclassification of tercile I patients by AFP showed that patients with high serum AFP had increased numbers of tumor nodules, more PV thrombosis, higher bilirubin, ALKP, and GGTP levels, and shorter survival., Conclusions: Smaller-tumor tercile I patients had more advanced portal hypertension with thrombocytopenia than did larger-tumor patients. Tercile I patients with higher AFP levels had more frequent PV thrombosis and worse survival than those with lower AFP levels. Elevated serum GGTP and ALKP levels appear to be associated with a more aggressive HCC phenotype. These differing patterns suggest more than one HCC pathway., (Copyright © 2012 S. Karger AG, Basel.)

Aims: To evaluate possible modifications in the manganese superoxide dismutase (MnSOD) activity during neoplastic transformation of a cirrhotic liver and to find out whether its assessment may have predictive value to identify cirrhotic patients at a higher risk of hepatocellular carcinoma (HCC)., Methods: Seventy-one consecutive subjects with Child-Pugh class A liver cirrhosis were recruited. At the time of enrolment, HCC was diagnosed in 20 cirrhotic patients. The 51 cirrhotic patients without HCC were followed up for the occurrence of tumour by 6-monthly screening for 7 years. During follow-up, 16 patients developed HCC. Seventy healthy subjects formed the control group. MnSOD activity was assayed spectrophotometrically., Results: Serum MnSOD activity was significantly lower in 70 healthy subjects compared with 51 cirrhotic patients and 20 cirrhotic patients with HCC. Cirrhotic patients who developed HCC during follow-up showed significantly higher values of MnSOD activity than HCC-free patients. The best cut-off of MnSOD activity was 0.40 U/ml. At this cut-off, chi2 analysis revealed that MnSOD activity was significantly different between the HCC-free cirrhotic patients and cirrhotic patients who developed HCC., Conclusion: The present findings suggest that during neoplastic transformation of cirrhotic liver, an increase in MnSOD activity may occur already during the precancerous phase, making this enzyme a probable malignancy-associated parameter.

In this study we assessed the prognostic significance of 90K/MAC-2BP serum levels in a group of 40 hepatocellular carcinoma patients. This glycoprotein is a new, interesting serum marker that reflects the immune reaction of the host against certain viral infections and tumors such as breast, ovarian and pancreatic cancer. Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world. AFP is currently the most useful marker for HCC, in spite of its poor diagnostic sensitivity. In this study 40 cirrhotic HCC patients were enrolled. The prevalence of viral hepatic infections in this group was 73% for HCV, 8% for HBV, and 8% for both viruses. Thirteen percent of the patients showed non-virus-related liver damage. 90K serum levels were assayed by an ELISA kit and AFP levels by a chemiluminescent enzyme immunometric system. The overall survival curves were estimated by the Kaplan-Meier method, taking into account age, sex, 90K and AFP serum levels. Statistical analysis showed a highly significant influence on overall survival of age below 70 years and 90K serum levels below the cutoff of 14 ng/mL. Serum AFP (< or = 20 ng/mL) had positive prognostic value only when it was associated with 90K levels (p < 0.02, log-rank).

Liver cirrhosis is the main risk factor for the development of human hepatocellular carcinoma (HCC). In this condition, the liver and plasma suffer a drastic depletion of retinoids. This study was conducted to investigate whether any relation exists between serum retinol levels and HCC development in cirrhotics. Seventy child-Pugh class A cirrhotic patients, 16 child-Pugh class A cirrhotic patients with HCC, and 140 age- and sex-matched subjects were included in this study. At the time of enrollment, fasting blood samples were taken to determine serum retinol levels. For the following 7 years, the 70 cirrhotic patients were also followed up for the occurrence of HCC by periodic screening with ultrasonography and serum alpha-fetoprotein assays. The serum retinol levels in both cirrhotic patients and HCC patients were significantly lower than those in healthy subjects. Among the 70 cirrhotic patients, 14 HCC were detected during follow-up. The prediagnostic retinol levels were significantly lower in cirrhotic patients who developed HCC compared with patients who did not. The odds ratio of cirrhotic patients who developed HCC in the lowest tertile to highest tertile of retinol status was 6.75 (95% CI=1.26--36.0; P=0.015). Our results suggest that a state of retinoid deficiency may promote hepatocarcinogenesis in patients at high risk such as cirrhotics.