Patient age and extent of liver resection influence outcome of liver resection for hepatocellular carcinoma in non-cirrhotic liver.

BACKGROUND/AIMS: Data about the clinical course after liver resection for HCC in non-cirrhotic liver (NCL) is rare in western countries. Although the patients with HCC in NCL tolerate major liver resections, it is less clear if an underlying steatosis or NASH increase the perioperative and postoperative risk. The purpose of this study was to characterize the clinical course after hepatic resection in patients with HCC in the absence of liver cirrhosis and in the absence of viral hepatitis. METHODOLOGY: The data of 148 patients with HCC in non-cirrhotic liver, who underwent curatively intented liver resection, were analyzed. Patients with hepatitis B or C infection were excluded. Patients with fibrolamellar HCC or liver cirrhosis or fibrosis higher than grade 2 according to the Desmet-Scheuer score were also excluded. RESULTS: The overall 1-, 3- and 5-year survival rates were 75.4%, 54.7% and 38.9%. Increased patient age (elder than 70 years) influenced the cumulative survival significantly. Especially the combination of increased patient age and major resection (>2 segments) at once influenced the cumulative survival. The overall postoperative morbidity was 37.8 %. No intraoperative death was observed. Postoperative increased leucocytes, urea and creatinin increased the postoperative complications. In the subgroup with major resection increased GGT correlated with steatosis, and raised AST correlated with elevated patient age. CONCLUSIONS: In Western countries HCC in non-cirrhotic liver is rare. Liver resection is safe and is the only curative therapy option for the time by HCC without liver cirrhosis. Further studies are necessary for identification of more prognostic factors and optionally special treatment

Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis.

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1's role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/ß-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.

Long-term results of liver resection for hepatocellular carcinoma in noncirrhotic liver.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common malignant neoplasms worldwide. Only few data on HCC in noncirrhotic livers without viral hepatitis in Western countries are available. The purpose of this study was to define the outcomes and potential prognostic factors associated with survival after hepatic resection in patients with HCC in the absence of liver cirrhosis and hepatitis B or C infection. PATIENTS AND METHODS: From January 2000 to September 2010, 148 patients without liver cirrhosis and without extrahepatic metastases underwent curative hepatic resection for HCC at the Surgical Department of the Charité, Campus Virchow Klinikum. The outcomes of these patients were retrospectively reviewed. Patients with cirrhosis or severe fibrosis, fibrolamellar HCC, and those positive for hepatitis B or C were excluded. RESULTS: The cumulative 1-, 3-, 5-, and 7-year survival rates were 75.4%, 54.7%, 38.9%, and 31.8%, respectively. The 1-, 3-, 5-, and 7-year disease-free survival rates were 60.3%, 38.0%, 29.1%, and 18.1%, respectively. In the multivariate analysis, cumulative survival was decreased by patient age, increased operative time, increased preoperative serum gamma-glutamyl transferase (GGT), and tumor stage. In the subgroup with unifocal neoplasms, N0 and R0 status, tumor size >10 cm, and tumor differentiation were highly predictive of lesser survival. Unfavorable survival was observed in patients with multifocal neoplasms, tumor size >10 cm, and/or poor tumor differentiation. CONCLUSION: The current TNM staging system is stratified for survival and recurrence. Extension of the current TNM staging system by grading and more exact differentiation of tumor size may increase its prognostic accuracy for predicting outcome. Preoperative increased serum GGT level could be a new poor prognostic factor.