Hiroyuki Ozasa

Modulation of inflammatory response in sepsis by proteasome inhibition

The Ubiquitin‐proteasome system has recently been shown to be involved in the regulation of cytokine expression. We tested the hypothesis of whether the in vivo administration of proteasome inhibitor MG‐132 can modulate cytokine response and mortality in sepsis. Sepsis was induced in mice by caecal ligation and puncture (CLP). Animals were divided into four groups: control, CLP, CLP and 1 μg MG‐132/g of b.w. intraperitoneally, and CLP and 10 μg MG‐132/g of b.w. Plasma levels of interleukin (IL)‐1, tumour necrosis factor‐α (TNF‐α, IL‐6 and IL‐10 were determined by ELISA 6 h after the induction of sepsis. CLP induced significant increase in plasma levels of all measured cytokines. MG‐132 treatment resulted in lower increase in IL‐1, TNF‐α and IL‐10 levels. IL‐6 was not significantly affected. A mortality study revealed prolonged survival in MG‐132 treated mice. We conclude that MG‐132 treatment decreases inflammatory response and prolongs survival in the CLP model of sepsis.

The MMP-9 expression determined the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer

Background: The aim of this study was to determine any correlation between the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines and the matrix metalloproteinase 9 (MMP-9) expression in primary colorectal cancer tissues. Patients and Methods: The data on 307 patients with colorectal cancer at stage II or III, who underwent potentially curative resection with lymphadenectomy, were reviewed. Of these, 188 received postoperative administration of oral fluoropyrimidines such as UFT and 5′-DFUR (chemotherapy group), while the other 119 patients underwent surgery alone (surgery-alone group). Immunostaining for MMP-9 was performed using surgical specimens of all 307 primary tumors and 18 recurrent tumors. Results: Overall, MMP-9 was positively expressed in the primary tumor in 44% of patients. Multivariate analysis revealed that the MMP-9 expression was a worse prognostic factor with a second highest hazard ratio for recurrence. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery-alone group. However, no significant difference in disease-free survival rate between the two groups was found in patients with a tumor positive for MMP-9. There was a strong positive correlation of MMP-9 expression between the primary tumors and the recurrent liver or lung tumors. Conclusions: The efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5′-DFUR may not be as great for patients with a tumor positive for MMP-9 having a greater risk to postoperative recurrence.

Leukocytapheresis for the treatment of active pouchitis: a pilot study

BackgroundPouchitis is a major long-term complication of ileal pouch-anal anastomosis for ulcerative colitis. The aim of this study is to investigate the efficacy of leukocytapheresis for the treatment of active pouchitis.MethodsEight patients with active pouchitis received leukocytapheresis weekly for 5 weeks in an open-label treatment protocol together with baseline therapy.ResultsPatients showed significant improvement in their pouchitis disease activity index scores, from 9.5 (range, 8–10) to 4.0 (range, 2–8) (P < 0.05). Six (75%) of the 8 treated patients achieved remission. No adverse events were observed.ConclusionsLeukocytapheresis therapy could be a new therapeutic strategy for patients with pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. These encouraging results lead us to propose a randomized controlled trial.