There is increasing evidence that chronic inflammation is tightly linked to diseases associated with endothelial dysfunction, including the induction of aberrant angiogenesis. While leukocytes have been described as mediators of inflammation-associated angiogenesis, the effects of direct chronic endothelial activation have not been addressed in this context. Using an uncleavable mutant of the transmembrane form of tumor necrosis factor-α (TNF-α), we have established models of stable TNF-α expression in endothelial cells in vitro and in transgenic mice in vivo. In the in vitro model, continuous endothelial activation leads to increased leukocyte cellular adhesion molecule expression and intracellular reactive oxygen species, hallmarks of a proinflammatory and dysfunctional endothelium. In addition, stable expression of TNF-α in endothelial cells increased angiogenic sprout formation in the presence but also in the absence of angiogenic growth factors. The partial neutralization of this effect by TNF-α antibodies and the inability of conditioned media from stable TNF-α-expressing endothelial cells to induce angiogenic activities in control endothelial cells suggest that this effect does not require expression of additional autocrine factors, but is an autonomous effect of the transmembrane TNF on the endothelial cells. Furthermore, using the Matrigel plug assay in vivo, increased angiogenesis was observed in endothelial TNF-α-expressing transgenic versus control mice. In conclusion, chronic inflammatory changes mediated by TNF-α can induce angiogenesis in vitro and in vivo, suggesting endothelial cell activation as a direct link between inflammation and angiogenesis.

The purpose of this study was to evaluate a whole-organ perfusion protocol of the pancreas in patients with primary pancreas carcinoma and to analyse perfusion differences between normal and diseased pancreatic tissue. Thirty patients with primary pancreatic malignancy were imaged on a 320-slice CT unit. Twenty-nine cancers were histologically proven. CT data acquisition was started manually after contrast-material injection (8 ml/s, 350 mg iodine/ml) and dynamic density measurements in the right ventricle. After image registration, perfusion was determined with the gradient-relationship technique and volume regions-of-interest were defined for perfusion measurements. Contrast time-density curves and perfusion maps were generated. Statistical analysis was performed using the Kolmogorov-Smirnov test for analysis of normal distribution and Kruskal-Wallis test (nonparametric ANOVA) with Bonferroni correction for multiple stacked comparisons. In all 30 patients the entire pancreas was imaged, and registration could be completed in all cases. Perfusion of pancreatic carcinomas was significantly lower than of normal pancreatic tissue (P < 0.001) and could be visualized on colored perfusion maps. The 320-slice CT allows complete dynamic visualization of the pancreas and enables calculation of whole-organ perfusion maps. Perfusion imaging carries the potential to improve detection of pancreatic cancers due to the perfusion differences.

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Background: Advanced pancreatic cancer, in addition to its high mortality, is characterized by one of the highest rates of venous thromboembolic events (VTE) as compared to other types of cancer. Enoxaparin, a low molecular weight heparin (LMWH), has proven to be effective for the prevention and treatment of VTE in surgical and general medical patients. Results of some small studies suggest that this benefit might extend to patients with cancer, however, enoxaparin is not currently indicated for this use. This phase IIb study was designed to analyze the efficacy of enoxaparin in patients with locally advanced or metastatic pancreatic cancer undergoing systemic chemotherapy.