Beneficial effects of perioperative chemotherapy for pancreatic cancer.

448 Background: We retrospectively assessed the benefits of 5-fluorouracil (5-FU)- and heparin-based portal infusion chemotherapy (PI) combined with systemic administration of mitomycin C (MMC) and cisplatin (CDDP) for 4 weeks following surgery (PI4W). The goal was to determine if this treatment prevented liver metastasis and improved survival for patients with potentially curative resection of pancreatic cancer. Methods: 263 patients who underwent pancreatectomy from January 1985 to December 2013 were treated. Of these cases, 50 patients received portal infusion with 5-FU (250 mg/day) for 2 weeks (PI2W) following surgery (1985 `2001 Group A), while 94 patients received PI4W therapy (250 mg/day of 5-FU with 2,000 IU/day of heparin for 4 weeks, 4 mg MMC on days 6, 13, 20, 27, and 10 mg CDDP on days 7, 14, 21, 28)(2001 `2013 Group B). The remaining 119 patients (Ct) without adjuvant therapy during the perioperative period divided Group A (n=58) and Group B (n=61). Results: The cumulative overall survival rate in the PI2W was significantly higher than those in Ct of Group A. The cumulative overall survival rate in the PI4W also was significantly higher than those in Ct of Group B. Furthermore, in the PI4W group, the rate of liver metastasis is lower than Ct. Conclusions: PI therapy after surgery, especially PI4W, could become a promising adjuvant therapy in patients with potentially curative resection of pancreatic cancer. Clinical trial information: 000002976.

Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic micorcirculatory dysfunction during endotoxemia

Hydrogen sulfide (H2S) affects vascular resistance; however, its effect on the hepatic microcirculation has not been investigated. Hepatic sinusoidal perfusion is dysregulated during sepsis, contributing to liver injury. Therefore, the present study determined the effect of H2S on the hepatic microcirculation and the contribution of endogenous H2S to hepatic microcirculatory dysfunction in an endotoxin model of sepsis. Portal infusion of H2S increased portal pressure in vivo (6.8 ± 0.2 mmHg before H2S vs. 8.6 ± 0.8 mmHg peak during H2S infusion, P < 0.05). Using intravital microscopy, we observed decreased sinusoidal diameter (6.2 ± 0.27 μm before H2S vs. 5.7 ± 0.3 μm after H2S, P < 0.05) and increased sinusoidal heterogeneity during H2S infusion ( P < 0.05) and net constriction. Since hepatic H2S levels are elevated during sepsis, we used the cystathionine γ lyase inhibitor dl-propargylglycine (PAG) to determine the contribution of H2S to the hypersensitization of the sinusoid to the vasoconstrictor effect of endothelin-1 (ET-1). PAG treatment significantly attenuated the sinusoidal sensitization to ET-1 in endotoxin-treated animals. ET-1 infusion increased portal pressure to 175% of baseline in endotoxemic animals, which was reduced to 143% following PAG treatment ( P < 0.05). PAG abrogated the increase in sinusoidal constriction after ET-1 infusion in LPS-treated rats (30.9% reduction in LPS rats vs. 11.6% in PAG/LPS rats, P < 0.05). Moreover, PAG treatment significantly attenuated the increase in NADH fluorescence following ET-1 exposure during endotoxemia (61 grayscale units LPS vs. 21 units in PAG/LPS, P < 0.05), suggesting an improvement in hepatic oxygen availability. This study is the first to demonstrate a vasoconstrictor action of H2S on the hepatic sinusoid and provides a possible mechanism for the protective effect of PAG treatment during sepsis.