Prospective evaluation of the International Study Group for Liver Surgery definition of post hepatectomy liver failure after liver resection: an international multicentre study.

BACKGROUND: The International Study Group for Liver Surgery (ISGLS) definition of post hepatectomy liver failure (PHLF) was developed to be consistent, widely applicable, and to include severity stratification. This international multicentre collaborative study aimed to prospectively validate the ISGLS definition of PHLF. METHODS: 11 HPB centres from 7 countries developed a standardised reporting form. Prospectively acquired anonymised data on liver resections performed between 01 July 2010 and 30 June 2011 was collected. A multivariate analysis was undertaken of clinically important variables. RESULTS: Of the 949 patients included, 86 (9%) met PHLF requirements. On multivariate analyses, age ≥70 years, pre-operative chemotherapy, steatosis, resection of >3 segments, vascular reconstruction and intraoperative blood loss >300 ml significantly increased the risk of PHLF. Receiver operator curve (ROC) analysis of INR and serum bilirubin relationship with PHLF demonstrated post-operative day 3 and 5 INR performed equally in predicting PHLF, and day 5 bilirubin was the strongest predictor of PHLF. Combining ISGLS grades B and C groups resulted in a high sensitivity for predicting mortality compared to the 50-50 rule and Peak bilirubin >7 mg/dl. CONCLUSIONS: The ISGLS definition performed well in this prospective validation study, and may be the optimal definition for PHLF in future research to allow for comparability of data.

Predictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting.

BACKGROUND: In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ∼250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis. Genes that participate in tumorigenesis were defined using a gene-gene correlation meta-analysis procedure that compared AN versus TU tissues. Genes predictive of survival in AN (AN-survival genes) were found to be enriched in the differential gene-gene correlation gene set indicating that they directly participate in the process of tumorigenesis. Additionally the AN-survival genes were mostly not predictive after tumorigenesis in TU tissue and this transition was associated with and could largely be explained by the effect of somatic DNA copy number variation (sCNV) in cis and in trans. The data was consistent with the variance of AN-survival genes being rate-limiting steps in tumorigenesis and this was confirmed using a treatment that promotes HCC tumorigenesis that selectively altered AN-survival genes and genes differentially correlated between AN and TU. CONCLUSIONS/SIGNIFICANCE: This suggests that the process of tumor evolution involves rate-limiting steps related to the background from which the tumor evolved where these were frequently predictive of clinical outcome. Additionally treatments that alter the likelihood of tumorigenesis occurring may act by altering AN-survival genes, suggesting that the process can be manipulated. Further sCNV explains a substantial fraction of tumor specific expression and may therefore be a causal driver of tumor evolution in HCC and perhaps many solid tumor types.

Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis.

BACKGROUND AND AIMS: The peptidyl prolyl isomerase Pin1 frequently is overexpressed in hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) is the most common etiologic agent in HCC, and its encoded X-protein (HBx) is oncogenic and possesses a serine-proline motif that may bind Pin1. The role of Pin1 in hepatocarcinogenesis, particularly in HBV-related HCC, was investigated. METHODS: Immunohistochemical staining was performed to evaluate the prevalence of Pin1 overexpression in HCCs of different etiologies. Glutathione S-transferase pull-down and co-immunoprecipitation experiments were used to validate the physical interaction between Pin1 and HBx. Reporter assay, cell proliferation assay, and xenotransplantation experiments were used to show the functional consequence and importance of Pin1-HBx interaction in hepatocarcinogenesis. RESULTS: We showed preferential Pin1 overexpression in HBV-related tumors and confirmed the interaction between Pin1 and HBx at the specific serine-proline motif. Pin1 overexpression increased the protein stability of HBx. Furthermore, HBx-mediated transactivation was enhanced by co-expression of Pin1. HepG2 expressing Pin1 and HBx showed a synergistic increase in cellular proliferation, as compared with cells expressing Pin1 or HBx alone. Furthermore, concomitant expression of Pin1 and HBx in the nontumorigenic human hepatocyte cell line MIHA led to a synergistic increase in tumor growth. Finally, in Hep3B cells with suppressed Pin1 expression, HBx-enhanced tumor growth in nude mice was abrogated. CONCLUSIONS: Pin1 binds HBx to enhance hepatocarcinogenesis in HBV-infected hepatocytes. The discovery of an interaction between Pin1 and HBx will further our understanding of the molecular pathogenic mechanism of HBV-related HCC in human beings.

Overexpression of NDRG1 is an indicator of poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma is a highly lethal cancer that typically has poor prognosis. Prognostic markers can help in its clinical management and in understanding the biology of poor prognosis. Through an earlier gene expression study, we identified N-Myc downregulated gene 1 (NDRG1) to be significantly highly expressed in hepatocellular carcinoma compared to nontumor liver. As NDRG1 is a differentiation-related gene with putative metastasis suppressor activity, we investigated the clinical significance of its overexpression. Quantitative real-time polymerase chain reaction using an independent set of patient samples confirmed the significant overexpression of NDRG1 in hepatocellular carcinoma compared to nontumor liver samples (P<0.001). Additionally, high levels of NDRG1 transcript correlated with shorter overall survival (P<0.001), late tumor stage (P=0.001), vascular invasion (P=0.003), large tumor size (P=0.011), and high Edmondson-Steiner histological grade (P=0.005). Using immunohistochemistry, NDRG1 protein was found to be significantly overexpressed in hepatocellular carcinoma samples compared to nontumor liver or cirrhotic and benign liver lesions (P<0.001). Among the hepatocellular carcinoma samples, those which are moderately and poorly differentiated express higher levels of NDRG1 protein than those which are well-differentiated (P<0.005). Additionally, hepatocellular carcinomas with vascular invasion also express elevated levels of NDRG1 protein compared to those without vascular invasion (significant at P<0.005). Our results suggest NDRG1 to be a likely tumor marker for hepatocellular carcinoma, the overexpression of which is correlated with tumor differentiation, vascular invasion, and overall survival. Its significantly elevated expression in hepatocellular carcinoma could be a useful indicator of tumor aggressiveness and therefore patient prognosis.

Outcomes of patients with hepatocellular carcinoma presenting with variceal bleeding.

OBJECTIVE: Variceal bleeding is an important manifestation of hepatocellular carcinoma (HCC). However, little has been documented in the literature regarding the outcomes of HCC patients presenting with variceal bleeding. This study evaluated the clinical characteristics, management, and outcomes of this specific group of patients. METHODS: A retrospective analysis of a prospectively collected database comprising 2,928 HCC patients managed from January 1989 to December 2002 identified 78 patients who had presented with variceal bleeding. Their clinical outcomes were compared to those patients who did not present with variceal bleeding, and a multivariate analysis was performed to identify prognostic factors for their survival. RESULTS: HCC patients who presented with variceal bleeding had more severe cirrhosis than those who did not, with a significantly higher serum bilirubin level, lower albumin level, lower platelet count, and longer prothrombin time. They had significantly smaller HCCs but more frequent portal vein thrombosis. There was a significant difference in the overall survival between HCC patients who presented with variceal bleeding and those who did not (median 3.5 months vs 7.5 months, p < 0.001). In the variceal bleeding group, by multivariate analysis, treatment with transarterial chemoembolization was the only significant independent prognostic factor for survival (odds ratio 17.16, 95% CI: 2.81-104.91, p= 0.002). CONCLUSIONS: HCC patients who presented with variceal bleeding can be expected to have a significantly worse survival outcome than the general HCC patients. However, transarterial chemoembolization may offer some survival benefit to a selected group of HCC patients presenting with variceal bleeding.

Clinicopathologic and prognostic significance of the histologic activity of noncancerous liver tissue in hepatitis B virus-associated hepatocellular carcinoma.

We prospectively studied 66 patients infected with the hepatitis B virus who underwent liver resection for hepatocellular carcinoma (HCC) to evaluate the influence of the histologic activity of noncancerous liver tissue on clinicopathologic features and prognosis. Based on the histologic activity index (HAI) score of nontumorous liver tissue, patients were classified into 3 groups: mild, moderate, or severe hepatitis. Overall, higher HAI scores were more frequent in patients with poorer liver function: lower serum albumin levels and higher indocyanine green retention at 15 minutes. Moreover, patients with moderate hepatitis had more frequent venous invasion, and the tumor size decreased with increasing HAI scores. Similar results were observed when the fibrosis category was excluded in the calculation of HAI scores. The overall or disease-free survival rates did not differ significantly among the 3 groups of patients. However, higher fibrosis scores were associated significantly with shorter disease-free survival rates. HAI scores correlated significantly with certain clinicopathologic features. In patients with hepatitis B-related HCC, a higher fibrosis score in the nontumorous liver tissue, but not histologic hepatitic activity, seems to be a significant factor predisposing to shorter survival.