Purpose: Hemostatic activation is common in pancreatic cancer and may be linked to angiogenesis and venous thromboembolism.We investigated expression of tissue factor (TF), the prime initiator of coagulation, in noninvasive and invasive pancreatic neoplasia.We correlatedTF expression with vascular endothelial growth factor (VEGF) expression, microvessel density, and venous thromboembolism in resected pancreatic cancer. Experimental Design: Tissue cores from a tri-institutional retrospective series of patients were used to build tissue microarrays. TF expression was graded semiquantitatively using immunohistochemistry in normal pancreas (n = 10), intraductal papillary mucinous neoplasms (n = 70), pancreatic intraepithelial neoplasia (n = 40), and resected or metastatic pancreatic adenocarcinomas (n = 130). Results: TF expression was observedin a majority of noninvasive and invasive pancreatic neoplasia, including 77% of pancreatic intraepithelial neoplasias, 91% of intraductal papillary mucinous neoplasms, and 89% of pancreatic cancers, but not innormalpancreas. Sixty-six of122 resectedpancreatic cancers (54%) were found to have high TF expression (defined as grade z2, the median score). Carcinomas with high TF expression were more likely to also expressVEGF (80% versus 27% with low TF expression, P < 0.0001) and had a higher median MVD (8 versus 5 per tissue core with low TF expression, P = 0.01). Pancreatic cancer patients with high TF expression had a venous thromboembolism rate of 26.3% compared with 4.5% in patients with low TF expression (P = 0.04). Conclusions: TF expression occurs early in pancreatic neoplastic transformation and is associated with VEGF expression, increased microvessel density, and possibly clinical venous thromboembolism in pancreatic cancer. Prospective studies evaluating the role of TF in pancreatic cancer outcomes are warranted.
Living donor liver transplantation allows an increasing number of patients with end-stage liver disease the opportunity for effective treatment in the face of a critical shortage of cadaveric organs. Hepatic steatosis decreases functional graft mass and may contribute to graft dysfunction. Screening liver biopsy allows accurate quantitation of hepatic fat, but is an invasive procedure that is not universally employed in the evaluation of living donors. We studied 100 consecutive prospective right lobe living donors, all evaluated with liver biopsy, imaging studies, and various clinical parameters. The accuracy and predictive value of body mass index (BMI) and imaging were compared with biopsy in determining the amount of hepatic fat. There were no complications to biopsy, with 33% showing some degree of steatosis. BM1 correlated only weakly with biopsy, with 73% of overweight (BM1 > 25) donors having little or no hepatic fat. Imaging was only 12% sensitive to small amounts (5% to 10%) of fat, with increasing sensitivity to more severe steatosis. Imaging diagnosed steatosis in 2 donors without hepatic fat and failed to identify a candidate denied with biopsy-proven 30% steatosis. Conversely, 9% of candidates with BMIs of 25 or less had 10% or greater steatosis. Moreover, three candidates were denied surgery because biopsy detected occult liver disease. Accurate quantification of hepatic fat is not afTorded by BM1 and imaging studies alone. Screening liver biopsy has a low complication rate and may serve to increase donor safety. Biopsy is essential in identifying donor g r a f t s at risk for poor recipient outcome while maximizing the donor pool.
Hepatitis B virus (HBV)-induced hepatitis and carcinogen-induced hepatocellular carcinoma (HCC) are associated with serum androgen concentration. However, how androgen or the androgen receptor (AR) contributes to HBV-induced hepatocarcinogenesis remains unclear. We found that hepatic AR promotes HBV-induced hepatocarcinogenesis in HBV transgenic mice that lack AR only in the liver hepatocytes (HBV-L-AR −/y ). HBV-L-AR −/y mice that received a low dose of the carcinogen N′-N′-diethylnitrosamine (DEN) have a lower incidence of HCC and present with smaller tumor sizes, fewer foci formations, and less α-fetoprotein HCC marker than do their wild-type HBV-AR +/y littermates. We found that hepatic AR increases the HBV viral titer by enhancing HBV RNA transcription through direct binding to the androgen response element near the viral core promoter. This activity forms a positive feedback mechanism with cooperation with its downstream target gene HBx protein to promote hepatocarcinogenesis. Administration of a chemical compound that selectively degrades AR, ASC-J9, was able to suppress HCC tumor size in DEN-HBV-AR +/y mice. These results demonstrate that targeting the AR, rather than the androgen, could be developed as a new therapy to battle HBV-induced HCC.
Our findings indicate that VHL gene alterations and HIF-1 alpha protein expression correlate with a significant increase in VEGF production by RCC. In turn it is associated with a more aggressive tumor phenotype.
Crawling waves, which are interfering shear wave patterns, can be generated in liver tissue over a range of frequencies. Some important biomechanical properties of the liver can be determined by imaging the crawling waves using Doppler techniques and analyzing the patterns. We report that the dispersion of shear wave velocity and attenuation, that is, the frequency dependence of these parameters, are strongly correlated with the degree of steatosis in a mouse liver model, ex vivo. The results demonstrate the possibility of assessing liver steatosis using noninvasive imaging methods that are compatible with color Doppler scanners and, furthermore, suggest that liver steatosis can be separated from fibrosis by assessing the dispersion or frequency dependence of shear wave propagations.
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