Kenei Furukawa

Negative impact of blood transfusion on recurrence and prognosis of hepatocellular carcinoma after hepatic resection.

BackgroundIn perioperative management of hepatic resection for hepatocellular carcinoma, excessive blood loss and blood transfusion greatly influence postoperative complications and prognosis of the patients. We evaluated the influence of blood products use on postoperative recurrence and prognosis of patients with hepatocellular carcinoma.MethodsThe subjects were 66 patients who underwent elective hepatic resection for hepatocellular carcinoma without concomitant microwave or radiofrequency ablation therapy nor other malignancies between January 2001 and June 2006. We retrospectively investigated the influence of the use of blood products including red cell concentration and fresh frozen plasma on recurrence of hepatocellular carcinoma and overall survival.ResultsIn multivariate analysis, the dose of blood products transfusion was a significant predictor of disease-free and overall survival. Both disease-free and overall survival rates of those who were given blood products were significantly worse than those who did not receive. On the other hand, in univariate analysis of disease-free and overall survival after hepatic resection and clinical variables, the amount of blood loss was not a significant predictor of recurrence or death.ConclusionTransfusion of blood products is associated with increased recurrence rate and worse survival after elective hepatic resection for patients with hepatocellular carcinoma.

Combination chemotherapy of serine protease inhibitor nafamostat mesilate with oxaliplatin targeting NF-κB activation for pancreatic cancer

In this study, we assessed if nafamostat mesilate may enhance anti-tumor effects of oxaliplatin on Panc-1 cells and pancreatic cancer mouse model. In combination treatment with nafamostat mesilate and oxaliplatin, NF-κB activation was inhibited by suppressing IκBα phosphorylation, and caspase-8-mediated apoptosis was more prominent than that treated with oxaliplatin alone, both in vitro and in vivo. Nafamostat mesilate reduced proliferation rate of Panc-1 cells as compared with oxaliplatin alone in vitro and enhanced oxaliplatin-induced tumor growth inhibition in vivo. Combination chemotherapy using nafamostat mesilate and oxaliplatin induces synergistic cytotoxicity in pancreatic cancer and could be a novel strategy for treatment.

Perioperative change in peripheral blood monocyte count may predict prognosis in patients with colorectal liver metastasis after hepatic resection

Prognostic value of perioperative change in peripheral blood leukocyte subset count of cancer patients have not been fully investigated. Therefore, we retrospectively investigated the relation between perioperative change in peripheral blood monocyte count and disease‐free as well as overall survival after hepatic resection for colorectal liver metastasis (CRLM).

Tetrahydrouridine inhibits cell proliferation through cell cycle regulation regardless of cytidine deaminase expression levels.

Tetrahydrouridine (THU) is a well characterized and potent inhibitor of cytidine deaminase (CDA). Highly expressed CDA catalyzes and inactivates cytidine analogues, ultimately contributing to increased gemcitabine resistance. Therefore, a combination therapy of THU and gemcitabine is considered to be a potential and promising treatment for tumors with highly expressed CDA. In this study, we found that THU has an alternative mechanism for inhibiting cell growth which is independent of CDA expression. Three different carcinoma cell lines (MIAPaCa-2, H441, and H1299) exhibited decreased cell proliferation after sole administration of THU, while being unaffected by knocking down CDA. To investigate the mechanism of THU-induced cell growth inhibition, cell cycle analysis using flow cytometry was performed. This analysis revealed that THU caused an increased rate of G1-phase occurrence while S-phase occurrence was diminished. Similarly, Ki-67 staining further supported that THU reduces cell proliferation. We also found that THU regulates cell cycle progression at the G1/S checkpoint by suppressing E2F1. As a result, a combination regimen of THU and gemcitabine might be a more effective therapy than previously believed for pancreatic carcinoma since THU works as a CDA inhibitor, as well as an inhibitor of cell growth in some types of pancreatic carcinoma cells.

Inhibition of Nuclear Factor Kappa-B Enhances the Antitumor Effect of Combination Treatment with Tumor Necrosis Factor-Alpha Gene Therapy and Gemcitabine for Pancreatic Cancer in Mice

BACKGROUND Combination therapy with tumor necrosis factor-alpha (TNF-α) gene delivery and gemcitabine is a new therapeutic approach for pancreatic cancer. However, the efficacy of both TNF-α and gemcitabine is suppressed due to activation of nuclear factor-kappa B (NF-κB). We hypothesized that nafamostat mesilate (FUT175), an NF-κB inhibitor, enhances the antitumor effect of combination treatment with an adenoviral vector-expressing TNF-α (AxCAhTNF-α) and gemcitabine for pancreatic cancer in mice. STUDY DESIGN In vitro, we assessed that FUT175 inhibited both TNF-α- and gemcitabine-induced NF-κB activation and enhanced apoptosis in human pancreatic cancer cell lines (MIAPaCa-2 and AsPC-1). In vivo, we established a xenograft pancreatic cancer model in mice by subcutaneous injection of MIAPaCa-2 and AsPC-1. The animals were treated with AxCAhTNF-α intratumorally and gemcitabine intraperitoneally once a week (combination group) or AxCAhTNF-α intratumorally and gemcitabine intraperitoneally once a week as well as FUT175 intraperitoneally 3 times a week (triple combination group). RESULTS In vitro, FUT175 inhibited both TNF-α- and gemcitabine-induced NF-κB activation and enhanced induction of apoptosis. In the triple combination group, tumor growth in vivo was significantly slower and there were more apoptotic cells than in the combination group (p < 0.05). CONCLUSIONS Inhibition of NF-κB by FUT175 enhances the antitumor effect of combined TNF-α gene therapy and gemcitabine for pancreatic cancer.

Combination treatment using adenovirus vector-mediated tumor necrosis factor-alpha gene transfer and a NF-κB inhibitor for pancreatic cancer in mice

Gene therapy using an adenoviral vector expressing tumor necrosis factor-alpha (TNF-α) is a new therapeutic approach for pancreatic cancer. However, the efficacy of TNF-α is limited, because it activates nuclear factor-κB (NF-κB). We investigated the combined use of AxCAhTNF-α, adenoviral vector-expressing human TNF-α, and nafamostat mesilate, a serine-protease inhibitor, a NF-κB inhibitor, using pancreatic cancer in mice. In vitro, nafamostat mesilate inhibited TNF-α-induced NF-κB activation and enhanced TNF-α-induced apoptosis in human cancer cell line (MIAPaCa-2). In vivo, we assessed combination treatment of AxCAhTNF-α and nafamostat mesilate using xenograft models in nude mice by subcutaneous injection of MIAPaCa-2. When the implanted tumor size reached 8.0mm, TNF-α group (n=12), was injected AxCAhTNF-α intra-tumorally once a week, while combination group (n=12), was injected AxCAhTNF-α intra-tumorally once a week and nafamostat mesilate intraperitoneally thrice a week. In combination group, tumor growth was significantly slower, and the number of apoptosis cells was significantly greater than those in AxCAhTNF-α group (p<0.05). In conclusion, adenovirus vector-mediated TNF-α gene therapy combined with nafamostat mesilate was effective for pancreatic cancer in mice.

Combination paclitaxel and inhibitor of nuclear factor κB activation improves therapeutic outcome for model mice with peritoneal dissemination of pancreatic cancer.

Objectives: Paclitaxel (PTX) is a useful treatment for peritoneal dissemination of malignant tumors. However, chemoresistance due to PTX-induced nuclear factor &kgr;B (NF-&kgr;B) activation is an important cause of suboptimal therapeutic effect. We previously reported nafamostat mesilate (FUT175) inhibits NF-&kgr;B activation and promotes apoptosis in pancreatic cancer. We hypothesized that addition of FUT175 to PTX may enhance the antitumor effect in peritoneal dissemination of pancreatic cancer. Methods: In vitro, we assessed NF-&kgr;B activity and apoptosis by the combination of FUT175 and PTX using human pancreatic cancer cell line (AsPc-1). In vivo, we established peritoneal dissemination in nude mice by intraperitoneal injection of AsPc-1 cells. The animals were treated with intraperitoneal injection thrice a week of FUT175, once a week of PTX, or a combination of thrice a week of FUT175 and once a week of PTX (combination group). Results: In the combination groups, PTX-induced NF-&kgr;B activation was inhibited, and apoptosis was enhanced in comparison with other groups both in vitro and in vivo. In the combination group, tumor growth, serum tumor marker, and survival rate were significantly better than those in other groups (P < 0.05). Conclusions: Combination chemotherapy using PTX with FUT175 exerts an antitumor effect for peritoneal dissemination of pancreatic cancer.

Dual inhibition of nuclear factor kappa-B and Mdm2 enhance the antitumor effect of radiation therapy for pancreatic cancer

INTRODUCTION Radiation therapy, alone or in combination with chemotherapy, is effective for patients with locally advanced and recurrent pancreatic cancer. Ionizing radiation induces cell cycle arrest and cell apoptosis through enhancement several signals such as p53, p21(Waf1/Cip1), and caspase. However, the therapeutic efficacy is attenuated by radiation-induced activation of NF-κB. Nafamostat mesilate, a synthetic serine protease inhibitor, inhibits NF-κB activation in pancreatic cancer. Therefore, we hypothesized that nafamostat mesilate inhibited radiation-induced activation of NF-κB and improves therapeutic outcome. RESULTS In combination group, NF-κB activation was significantly inhibited in comparison with that of radiation group. Nafamostat mesilate obviously down-regulated the expression levels of Mdm2 compared with control cells or irradiated cells. Consequently, p53 expression was stabilized inversely in correlation with Mdm2 protein expression level. The expression levels of p53, p21(Waf1/Cip1), cleaved caspase-3 and -8 were the highest in the combination group. Nafamostat mesilate enhanced ionizing radiation-induced cell apoptosis and G2/M cell cycle arrest. In combination group, cell proliferation and tumor growth were significantly slower than those in other groups. CONCLUSION Combination therapy of radiation with nafamostat mesilate exerts enhanced anti-tumor effect against human pancreatic cancer.

Switching from tacrolimus to cyclosporine A to prevent primary biliary cirrhosis recurrence after living-donor liver transplantation.

Recurrence of primary biliary cirrhosis (PBC) after liver transplantation has been shown to negatively affect graft and patient survival. Recently, protective effects of cyclosporine A against PBC recurrence after liver transplantation have been reported. Participants were 4 patients who underwent living-donor liver transplantation (LDLT) for end-stage liver disease due to PBC. Tacrolimus was used for initial immunosuppression, and this was switched to cyclosporine A at least 3 months after liver transplantation. Targeted trough level of cyclosporine A was 20 times that of tacrolimus. We assessed liver and renal function, as well as antimitochondrial M2 antibody for recipients prior to LDLT, as well as before and after switching immunosuppressive agents. Patients were 1 man and 3 women, and they were ages 45 to 47 years at LDLT. Timing of switching from tacrolimus to cyclosporine A was 13, 3, 7, and 4 months respectively after liver transplantation, and all 4 patients have been on cyclosporine A without adverse effects at 20 to 46 months after transplantation. In 2 of 4 patients who had high titers of antimitochondrial M2 antibody before transplantation, antibody titer did not elevate after LDLT. In the other 2 patients without elevation of antimitochondrial M2 antibody, the titer did not turn positive. Switching from tacrolimus to cyclosporine A was possible without medical problems, and all patients exhibit no recurrence of PBC. Cyclosporine A may be useful for prevention of PBC recurrence after LDLT.

Usage of eltrombopag for chronic immune thrombocytopenia as a pretreatment for splenectomy.

consensus exists on the ideal platelet count for surgical procedures. There are some problems related to IVIG or platelet transfusion, such as headache, fever, aseptic meningitis, alloimmune hemolysis, unknown infection and the extremely high medical costs. Thrombopoietin receptor agonists are also recommended for adult patients with ITP at risk of bleeding, who relapse after splenectomy or who cannot undergo splenectomy as a second-line treatment [1] (grade 1B). On the other hand, the safety of long-term administration of thrombopoietin receptor agonists has not been confirmed [4] . To know the benefits of the novel preoperative treatment for splenectomy for ITP in adult patients, we conducted a study using a thrombopoietin receptor agonist as a preoperative preparation. Eltrombopag, a synthetic nonpeptide thrombopoietin receptor agonist, is a once-daily oral drug [5] , so a dose adjustment could be performed easily and this is why we chose it for this trial. This preoperative treatment could have many advantages. The avoidance of adverse events induced by blood products and reductions in cost may be beneficial in health and medical economics. Unknown risk caused by long-term administration of eltrombopag could also be avoided, if splenectomy is effective in increasing platelet According to the evidence-based practice guideline for immune thrombocytopenia (ITP) presented by the American Society of Hematology, splenectomy is recommended for adult patients with ITP who have failed corticosteroid therapy [1] (grade 1B). The Japanese Ministry of Health, Labour and Welfare also recommends splenectomy for such patients with resistance to Helicobacter pylori eradication and corticosteroid therapy. On the other hand, surgical procedures for such patients sometimes cause perioperative bleeding. The guideline for the proper use of blood products issued by the Japanese Ministry of Health, Labour and Welfare proposes that a preoperative platelet count of 6 50 ! 10 9 /l is enough for surgical procedures. Therefore, when a rapid increase in platelet count is required for operation, high-dose intravenous immunoglobulin (IVIG) with or without platelet transfusion, is regarded as an effective preoperative preparation [2] . The patients with a platelet count of ! 50 ! 10 9 /l or hemorrhagic diathesis require a rapid increase in platelet count. On the other hand, Keidar et al. [3] reported that a platelet count of 20 ! 10 9 /l is enough to perform a laparoscopic splenectomy safely on patients with chronic ITP. However, most of those patients received IVIG or pulsed oral high-dose dexamethasone, suggesting that no Published online: October 31, 2012