Flt3 agonist enhances immunogenicity of arenavirus vector-based simian immunodeficiency virus vaccine in macaques.

Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens are capable of inducing efficacious humoral and cellular immune responses in nonhuman primates. Several studies have evaluated the use of immune modulators to further enhance vaccine-induced T-cell responses. The hematopoietic growth factor Flt3L drives the expansion of various bone marrow progenitor populations, and administration of Flt3L was shown to promote expansion of dendritic cell populations in spleen and blood, which are targets of arenaviral vectors. Therefore, we evaluated the potential of Flt3 signaling to enhance the immunogenicity of arenaviral vaccines encoding SIV immunogens (SIVSME543 Gag, Env, and Pol) in rhesus macaques, with a rhesus-specific engineered Flt3L-Fc fusion protein. In healthy animals, administration of Flt3L-Fc led to a 10- to 100-fold increase in type 1 dendritic cells 7 days after dosing, with no antidrug antibody (ADA) generation after repeated dosing. We observed that administration of Flt3L-Fc fusion protein 7 days before arenaviral vaccine increased the frequency and activation of innate immune cells and enhanced T-cell activation with no treatment-related adverse events. Flt3L-Fc administration induced early innate immune activation, leading to a significant enhancement in magnitude, breadth, and polyfunctionality of vaccine-induced T-cell responses. The Flt3L-Fc enhancement in vaccine immunogenicity was comparable to a combination with αCTLA-4 and supports the use of safe and effective variants of Flt3L to augment therapeutic vaccine-induced T-cell responses.IMPORTANCEInduction of a robust human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T-cell response through therapeutic vaccination is considered essential for HIV cure. Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens have demonstrated strong immunogenicity and efficacy in nonhuman primates. Here, we demonstrate that the immunogenicity of arenaviral vectors encoding SIV immunogens can be enhanced by administration of Flt3L-Fc fusion protein 7 days before vaccination. Flt3L-Fc-mediated increase in dendritic cells led to robust improvements in vaccine-induced T- and B-cell responses compared with vaccine alone, and Flt3L-Fc dosing was not associated with any treatment-related adverse events. Importantly, immune modulation by either Flt3L-Fc or αCTLA-4 led to comparable enhancement in vaccine response. These results indicate that the addition of Flt3L-Fc fusion protein before vaccine administration can significantly enhance vaccine immunogenicity. Thus, safe and effective Flt3L variants could be utilized as part of a combination therapy for HIV cure.

HIV envelope antibodies and TLR7 agonist partially prevent viral rebound in chronically SHIV-infected monkeys.

A key challenge for the development of a cure to HIV-1 infection is the persistent viral reservoir established during early infection. Previous studies using Toll-like receptor 7 (TLR7) agonists and broadly neutralizing antibodies (bNAbs) have shown delay or prevention of viral rebound following antiretroviral therapy (ART) discontinuation in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques. In these prior studies, ART was initiated early during acute infection, which limited the size and diversity of the viral reservoir. Here we evaluated in SHIV-infected rhesus macaques that did not initiate ART until 1 year into chronic infection whether the TLR7 agonist vesatolimod in combination with the bNAb PGT121, formatted either as a human IgG1, an effector enhanced IgG1, or an anti-CD3 bispecific antibody, would delay or prevent viral rebound following ART discontinuation. We found that all 3 antibody formats in combination with vesatolimod were able to prevent viral rebound following ART discontinuation in a subset of animals. These data indicate that a TLR7 agonist combined with antibodies may be a promising strategy to achieve long-term ART-free HIV remission in humans.

Serum Inflammation Parameters and Survival in Hepatocellular Carcinoma Patients: Importance of Albumin and Gamma-Glutamyltranspeptidase.

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.

Critical overview of resection for Bismuth-Corlette type IV perihilar cholangiocarcinoma.

BACKGROUND: Current standard treatment for perihilar cholangiocarcinoma (pCCA) is surgical resection. Bismuth-Corlette (BC) type IV pCCA is accepted as an unresectable disease. In the present study, the results of non-transplant surgical approaches in patients with BC type IV pCCA were examined. METHODS: Medical records of consecutive patients with BC type IV pCCA between 2010 and 2021 were retrospectively reviewed. Patients were subdivided according to operation type. Postoperative survival rates were compared. RESULTS: Hemihepatectomy with caudate lobe and extrahepatic bile duct (EHBD) resection was performed in 15 patients and only EHBD resection was performed in 10 patients. Ten of the cases were found to be unresectable at the stage of laparotomy. Median follow-up was 41.3 (24.8-57.9) months. Overall survival rate for all 35 patients was 56.4% at 1 year, 32.2% at 2 years, and 16.1% at 3 years. When survivals were compared according to operation type, 1, 2, and 3-year survivals were 80%, 57.1% and 42.9% for the hepatectomy group; 55.6%, 44.4% and 11.1% for the EHBD resection group; 75%, 0% and 0% in laparotomy-only group, respectively (p = 0.13). The best survival rates were obtained in patients with pCCA who underwent hepatectomy and were lymph node negative, 100% for 1 year, 66.7 for 2 years and 50% for 3 years. CONCLUSION: It is difficult to achieve high survival rates in BC type IV pCCA. However, these patients mostly benefit from resective treatments. Acceptable survival rates can be achieved, especially in the R0N0 patient group.

The Cost of Surgically Treated Severe Odontogenic Infections: A Retrospective Study Using Severity Scores.

PURPOSE: Hospital treatment of odontogenic infections can be costly, and often these infections present with varying degrees of severity that can be quantified with odontogenic infection severity scores (OISSs). The purposes of this study were (1) to measure the association between OISSs and hospital bills and (2) to identify risk factors associated with OISSs. METHODS: This retrospective cohort study assessed subjects from January 1, 2016, to December 31, 2020, with severe odontogenic infections treated in the operating room and admitted to the University of Texas Southwestern Medical Center/Parkland Memorial Hospital for >1 hospital day. OISSs were assigned based on the risk to the airway and vital structures. OISSs ≥ 5 were designated group A and < OISSs 5 group B. The primary predictor variable was OISSs, and the primary outcome variable was the mean billed cost of the stay. Analysis to identify associated variables for OISS ≥ 5 was also conducted. Secondary predictor variables were age, gender, smoking status, HIV diagnosis, diabetes mellitus diagnosis, blood glucose at admission, and white blood cell count (WBC) at admission. The secondary outcome variable was OISS. Comparisons between Group A and Group B were conducted using t-tests. Analysis to identify associated variables for OISS ≥ 5 was conducted using univariate and multivariate analysis. Values of P < .05 were considered statistically significant. RESULTS: There were 144 subjects that met inclusion criteria. There were 65 subjects in Group A and 69 in Group B. Group A had a significantly larger mean billed cost of stay (95% CI 8937.7 to 48,225.74; P = .001). Analysis of secondary predictor variables revealed that male sex (OR 2.07; 95% CI 1.06 to 4.07; P = .03), blood glucose ≥ 100 at presentation (OR 3.05; 95% CI 1.46 to 6.38; P = .002), and WBC of > 11,000/mL at presentation (OR 3.17; 95% CI 1.44 to 6.98; P = .003) resulted in an increased likelihood of OISS ≥ 5. CONCLUSIONS: Patients with OISSs ≥ 5 have higher mean billed costs when compared to patients with OISSs < 5. Male sex, blood glucose ≥ 100, and WBC >11,000/mL at presentation is associated with increased likelihood of OISS >5.

Low Insertional Torque and Early Dental Implant Failure.

PURPOSE: There is lack of uniformity regarding the ideal insertional torque with which dental implants need to be placed. The purpose of this retrospective analysis is to compare the incidence of early dental implant failures with an insertional torque less than 30 N-cm to implants placed with an insertional torque 30 N-cm or greater. METHODS: A retrospective cohort study was conducted to evaluate dental implants placed between 2015 and 2016 at the Veterans Affairs North Texas Health Care System in Dallas. The primary predictor variable was dental implant insertional torque, measured at the time of implant placement as either greater than or equal to 30 N-cm or less than 30 N-cm. The primary outcome variable was early implant failure, defined as implant exfoliation noted by the patient or failure due to implant movement or pain necessitating explantation before prosthesis loading. The study conducted a time-to-event analysis to examine a group difference in time to implant failure between insertional torque group greater than or equal to 30 N-cm and less than 30 N-cm using Kaplan-Meir curves and a frailty model. The time to follow-up was censored at 6 months. RESULTS: One hundred three patients had 214 implants placed, with early failures occurring in 14 implants (6.5%). Implants placed with an insertional torque less than 30 N-cm were nearly 14 times more likely to have an early failure compared to implants placed with an insertional torque 30 N-cm or greater (hazard ratio = 13.909; 95% confidence interval, 1.835 to 105.416), which was statistically significant (P = .0108). CONCLUSIONS: The results of this retrospective cohort study suggest that insertional torque values less than 30 N-cm are associated with early dental implant failures. Future, prospective studies will be performed to further elucidate the association between insertional torque and early dental implant failure.

Incidental Hepatocellular Carcinoma after Liver Transplantation: Clinicopathologic Features and Prognosis.

Background: The prognostic impact and clinicopathologic features of incidental hepatocellular carcinoma (iHCC) detected in explanted livers of patients undergoing liver transplantation (LT) has been a controversial issue in previous studies when compared with patients who are diagnosed with hepatocellular carcinoma (pdHCC) before LT. We aimed to review and compare these patient groups in a high-volume LT center. Methods: The present study involves a retrospective analysis of 406 HCC patients who received LT between January 2002 and April 2022. Among these patients, demographic data, histopathologic features and prognosis for iHCC and pdHCC were evaluated. Results: In our series, 406 patients' final diagnosis was HCC after they had received LT, nevertheless 54 patients in this HCC group were diagnosed incidentally after the pathological evaluation of the explanted livers. The etiology of the underlying liver disease between pdHCC (n = 352) and iHCC (n = 54) groups had some differences in our study population. Most of the patients in the pdHCC group had moderately differentiated tumors (45.7%). On the other hand, most of the patients in the iHCC group had well differentiated tumors (79.6%). There were 158 (44%) patients who met the Milan criteria in the pdHCC group while there were 48 (92%) patients in the iHCC group (p < 0.001). IHCC patients had statistically better 1, 3, 5 and 10 years disease-free and overall survival rates when compared with pdHCC patients. There was only 1 (1.8%) patient who had tumor recurrence in the iHCC group while 76 (21%) patients had tumor recurrence in the pdHCC group (p = 0.001). There is no disease free and overall survival difference when iHCC patients are compared with pdHCC patients who met the Milan criteria. Conclusion: It is the first study to show that iHCC patients may differ from pdHCC patients in terms of etiological features. IHCC tumors show better histopathologic features than pdHCC with low recurrence rate and iHCC patients have better survival rates than pdHCC patients.

Serum levels of inflammatory markers CRP, ESR and albumin in relation to survival for patients with hepatocellular carcinoma.

INTRODUCTION: 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.

Hygiene Recall in Diabetic and Nondiabetic Patients: A Periodic Prognostic Factor in the Protection Against Peri-Implantitis?

PURPOSE: Diabetes mellitus is associated with an increased risk of poor outcomes with dental implant placement. This study aims to identify if frequency of hygiene visits is a protective factor for the development of peri-implantitis in diabetic patients. METHODS: A retrospective cohort design was conducted on patients presenting for dental implant placement at the Philadelphia Veterans Affairs (VA) Medical Center from 2006 to 2012. The primary predictor variable was hygiene frequency, recorded as either infrequent, annual (7-12 month recall), or biannual (≤6-month recall). The number of months between implant placement and the presence of peri-implantitis was the primary outcome (time-to-peri-implantitis) variable, which was assessed on a subject level and adjusted for clustered, correlated multiple implants on the same subject. Additional variables were greater than or equal to 60 years of age, male gender, smokers, short implant length, diabetes, uncontrolled diabetes, and removable prostheses. Descriptive, univariate, and Cox proportional hazards regression statistics were computed to measure associations with peri-implantitis with P ≤ .05 used to define statistical significance. RESULTS: The study sample was composed of 286 patients. In total, 748 implants were placed. Subjects greater than or equal to 60 years of age were 2 times more likely to develop peri-implantitis (hazards ratio (HR) = 2.015, 95% Cl (0.985-4.119), P = .0549). Subjects receiving implant-supported removable prostheses were 2.3 times more likely to develop peri-implantitis (HR = 2.315, 95% CI (1.006-5.327), P = .0485). With each hygiene visit, patients' risk of developing peri-implantitis decreased 20% (HR = 0.805, 95% Cl (0.394-1.647), P = .5528). In addition, diabetic patients were 49% more likely to develop peri-implantitis (HR = 1.491, 95% CI (0.758-2.936), P = .2475) than nondiabetic patients. CONCLUSIONS: Diabetic patients may be at increased risk for the development of peri-implantitis and an increased frequency of hygiene visits may reduce peri-implant diseases.

Is Alcohol Consumption Associated With Protection Against Peri-Implantitis? A Retrospective Cohort Analysis.

PURPOSE: Recent studies have pointed to the effects of social factors on the health of dental implants. We investigated whether varying levels of alcohol consumption will influence the health of dental implants and associated peri-implant inflammation. PATIENTS AND METHODS: A retrospective cohort study was performed to evaluate implants placed from 2006 to 2012 at the Philadelphia Veteran's Affairs Medical Center. Alcohol consumption was gathered from the health maintenance records within 3 months of implant placement and served as the predictor variable. Analysis was performed at follow-up visits for the presence of the outcome variable, peri-implantitis, which was assessed at an implant level. A multivariable generalized estimating equation logistic regression model was constructed, and a Wald test was used to analyze the statistical significance of each parameter. The results were interpreted as an odds ratio estimate, including the 95% confidence interval. Descriptive statistics were used to compute and analyze the data, with P < .05 used to define statistical significance. RESULTS: Demographically, our cohort consisted mainly of male patients (92%), with an average age of 60 years at implant placement. The mean interval to peri-implantitis was 30 ± 25 months. Peri-implantitis occurred most frequently within 2 years of implant placement. The incidence of peri-implantitis was greatest among heavy alcohol consumers (42%) and lowest among mild and moderate consumers (12 and 6%, respectively). Compared with no consumption, mild alcohol consumption was associated with a 47% decrease in peri-implantitis (P < .0223) and moderate consumption was associated with a 75% decrease (P < .0250). Heavy consumption was associated with a nearly threefold increase in peri-implantitis (P < .0001). CONCLUSIONS: The results from our retrospective cohort analysis revealed that mild to moderate alcohol consumption is associated with a lower rate of peri-implantitis. However, heavy consumption was associated with an increase in the incidence of peri-implantitis among patients with dental implants.

PD-1 Blockade and TLR7 Activation Lack Therapeutic Benefit in Chronic Simian Immunodeficiency Virus-Infected Macaques on Antiretroviral Therapy.

Antiretroviral therapy (ART) limits human immunodeficiency virus 1 (HIV-1) replication but does not eliminate the long-lived reservoir established shortly after viral acquisition. A successful HIV cure intervention necessitates either elimination or generation of long-term immune control of the persistent viral reservoir. Immune modulating strategies in conjunction with ART hold promise for achieving cure by inducing viral antigen expression and augmenting infected cell killing. Programmed death-1 (PD-1) blockade is a potential means to both activate and eliminate the latent reservoir by restoring exhausted T cell function. We assessed the therapeutic efficacy of PD-1 blockade, Toll-like receptor 7 (TLR7) activation with the agonist vesatolimod, or a combination of the two agents in chronically simian immunodeficiency virus (SIV)-infected macaques suppressed with ART for more than 2 years. Despite achieving extended anti-PD-1 antibody plasma exposure and TLR7-dependent immune activation after multiple administrations, neither individual treatment nor the combination resulted in changes to viral rebound kinetics following ART interruption or reduction in the SIV reservoir size. Our data in the context of other reports demonstrating improved viral control upon PD-1 blockade suggest that its therapeutic utility may be restricted to specific experimental conditions or treatment times during viral pathogenesis.

C-Reactive Protein and Platelet-Lymphocyte Ratio as Potential Tumor Markers in Low-Alpha-Fetoprotein Hepatocellular Carcinoma.

The 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.

Trainee Contribution Is Not Associated With Citation Frequency: A Retrospective Study.

PURPOSE: Publication citation frequency is a measure of scientific influence. The purpose of this study was to measure the association between trainee involvement in publications and citation frequency. MATERIALS AND METHODS: A retrospective cohort study of the Journal of Oral and Maxillofacial Surgery from January to December 2010 was conducted. For each included publication, the study topic and design were recorded. The primary predictor variable was trainee involvement (yes or no). For the purpose of our study, the term "trainee" encompassed dental students, graduate (non-dental) students, oral and maxillofacial surgery residents, and non-oral and maxillofacial surgery residents, as indicated by author affiliations listed in each article. The outcome variable was the number of citations accumulated between 2010 and 2017. Descriptive statistics were computed. Analyses of variance were performed to compare citation distribution among study types and designs. Student t tests and χ2 tests were performed. RESULTS: The sample consisted of 111 publications, of which 85 (76.6%) had at least 1 trainee author. Among all publications, the mean number of citations was significantly different across study designs (P = .03), with case reports earning the lowest number of citations on average (mean, 14.9 citations). Trainee publications had significantly different distributions of study topics (P = .02) and designs (P < .01). Among publications with a trainee author, the most common topic was pathology (37%) and the most common study design was a case report (45%). Despite the higher proportion of case reports, the mean number of citations between trainee (mean, 30.4 citations) and non-trainee (mean, 30.5 citations) publications was not significantly different (P = .99). CONCLUSIONS: Including trainees does not alter the citation frequency of the articles published in the Journal of Oral and Maxillofacial Surgery. This finding is encouraging to both academic surgeons and their trainees, as a higher volume of students and residents can be engaged in research while preserving the influence of the published works.

Characteristics of Hepatocellular Carcinoma Aggressiveness Factors in Turkish Patients.

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.

The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma.

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.

Role of Albumin in Growth Inhibition in Hepatocellular Carcinoma.

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.

A Hepatocellular Carcinoma Aggressiveness Index and Its Relationship to Liver Enzyme Levels.

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.

Hepatocellular Carcinoma Extrahepatic Metastasis in Relation to Tumor Size and Alkaline Phosphatase Levels.

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.

Low Alpha-Fetoprotein Levels Are Associated with Improved Survival in Hepatocellular Carcinoma Patients with Portal Vein Thrombosis.

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.