LC-1000 flow cytometry system complements intraoperative peritoneal cytology for pancreatic and biliary tract cancer.

BACKGROUND: The exfoliative cell analyzer, LC-1000, is medical device that utilizes the principles of flow cytometry, and might provide digital diagnostic information for cytology using a different approach from conventional cytomorphology. In this study, wae examined the usefulness of the LC-1000 as a diagnostic support system for intraoperative peritoneal lavage cytology and its prognostic impact for pancreatic (PC) and biliary tract cancer (BTC). METHODS: Patients with PC and BTC who underwent surgical treatment were included. First, we identified useful indicators of LC-1000 and established cutoff values to discriminate positive cytology. Next, we verified the validity of these cutoff values. RESULTS: In the test set (n = 48), of the LC-1000 indicators examined, only MR-CPIx was significantly different between the negative and positive cytology groups, yielding a cutoff value of 0.86. In the validation set (n = 52), the sensitivity, specificity, positive and negative predictive value of the LC-1000 for cytology results was 1.0, 0.49, 0.11 and 1.0, respectively. In patients who had undergone radical resection, recurrence-free survival rate was significantly higher in the LC-1000 negative group than in the positive group in PC, but not in BTC. CONCLUSION: The LC-1000 was useful as digital support system for peritoneal cytology, and it might have potential as a prognostic factor for PC.

Determinants for in vivo antitumor effect of angiogenesis inhibitor SU5416 formulated in PEGylated emulsion.

Angiogenesis, the sprouting of capillaries from preexisting ones, is essential for the sustained growth of solid tumors. In this study, we used SU5416, a hydrophobic molecule with potent tyrosine kinase inhibitor of type 2 receptor for vascular endothelial growth factor (VEGF), as PEGylated emulsion (SU5416-PE), and evaluated the antitumor potency of this formulation in Lewis lung cancer (LLC), Colon-26 (C26), and B16BL6 melanoma (B16) tumor-bearing mice. Intravenous injection of SU5416-PE into tumor-bearing mice significantly suppressed the growth of C26 and B16 tumors, but had no effect on the growth of LLC tumors. MTT assay revealed that SU5416 inhibited the proliferation of human umbilical vein endothelial cells in a concentration-dependent manner but did not show such an inhibitory effect on all types of tumor cells examined, demonstrating the specificity of SU5416 for endothelial cells. Considering that VEGF levels within C26 and B16 tumors were found to be about 10-fold and 20-fold higher than that in LLC tumors, respectively, it was suggested that SU5416-PE would inhibit angiogenesis in certain types of tumor tissue such as C26 and B16 where VEGF plays a major role for promoting angiogenesis, leading to the suppression of in vivo tumor growth.

Deeper penetration into tumor tissues and enhanced in vivo antitumor activity of liposomal paclitaxel by pretreatment with angiogenesis inhibitor SU5416.

The recently emerged concept of "vessel normalization" implies that judicious blockade of vascular endothelial growth factor (VEGF) signaling may transiently "normalize" the tumor vasculature, making it more suitable for tumor disposition of subsequently administered drugs. In this study, therefore, the effect of pretreatment with SU5416, a selective VEGF receptor-2 inhibitor, on tumor disposition and in vivo antitumor activity of polyethylene glycol (PEG)-modified liposomal paclitaxel (PL-PTX) was evaluated in Colon-26 solid tumor-bearing mice. To improve the solubility and in vivo disposition characteristics of SU5416, the inhibitor was formulated in PEGylated O/W emulsion (PE-SU5416). Pretreatment with PE-SU5416 significantly enhanced the in vivo antitumor effect of PL-PTX, although PE-SU5416 administration alone did not show any antitumor effect. Immunostaining for endothelial cells and pericytes demonstrated that the pretreatment with PE-SU5416 enhanced the pericyte coverage of the tumor vasculature. In addition, tumors treated with PE-SU5416 contained significantly smaller hypoxic regions compared with the nontreated control group, demonstrating that structural normalization of the tumor vasculature resulted in an improvement in tumor vessel functions, including oxygen supply. Furthermore, the pretreatment with PE-SU5416 increased the distribution of PEG liposomes and included PTX in the core region of the tumor, as well as conversely decreasing the ratio of their peripheral distribution. These results suggest that the structural and functional normalization of the tumor vasculature by the pretreatment with PE-SU5416 enabled liposomes to reach the deeper regions within tumor tissues, leading to more potent antitumor activity of PL-PTX.