Koichiro Haruki

Preoperative platelet to lymphocyte ratio predicts outcome of patients with pancreatic ductal adenocarcinoma after pancreatic resection

BACKGROUND Inflammation plays a crucial role in tumor growth, metastasis, and survival. The preoperative platelet-to-lymphocyte ratio (PLR) has been reported as a significant prognostic indicators in several digestive malignancies. Our objective was to evaluate whether preoperative PLR is a prognostic index in resected pancreatic ductal adenocarcinoma. METHODS Data from 131 patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma were available from a prospectively maintained database. The patients were divided into groups according to a preoperative PLR of <150 or ≥150. Survival data were analyzed. RESULTS In univariate and multivariate analyses, a preoperative PLR of ≥150 was a significant and independent risk factor for cancer recurrence and poor survival, respectively (disease-free survival [DFS]; P= .0014, P = .047; OS, P ≤ .01each). Similarly, lymph node metastasis, and moderate or poor differentiation were independent risk factors for cancer recurrence, whereas tumor diameter, positive surgical margin, and moderate or poor differentiation were independent risk factors for poor patient survival (P ≤ .05 each). CONCLUSION The preoperative PLR in patients with pancreatic ductal adenocarcinoma was an independent predictor in DFS and overall survival after elective resection. Measurement of the PLR may help decision making in the postoperative management of patients with pancreatic ductal adenocarcinoma.

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).

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.

Comprehensive assessment of the prognosis of pancreatic cancer: peripheral blood neutrophil–lymphocyte ratio and immunohistochemical analyses of the tumour site

Abstract Objective Several studies have suggested that an elevated neutrophil–lymphocyte ratio (NLR) is associated with a poorer prognosis in patients with pancreatic cancer (PC). The correlations between the NLR and immunohistochemical (IHC) analysis with regard to the prognosis of patients with PC remain to be elucidated. By using IHC findings, we determined the value of the NLR as a prognostic factor in patients with PC. Material and methods We collected the clinico-pathological data of 28 consecutive patients who underwent surgical resection for PC between January 2008 and December 2012 at The Jikei University Kashiwa Hospital. We investigated whether the NLR and IHC results were related and ensured the consistency of the prognosis of patients with PC. Results The Kaplan–Meier curves for the disease-free survival (DFS) and the overall survival (OS) revealed that an NLR ≥ 5 is an implicit factor for decreased DFS and OS in patients with PC (p = 0.003, p < 0.001, log-rank test). The density of CD163+ macrophages and CD66b+ neutrophils was significantly higher in the high NLR group; on the contrary, the density of CD20+ lymphocytes was significantly higher in the low NLR group. Moreover, a Mann–Whitney U test showed that the NLR was significantly correlated with a high density of CD20+ lymphocytes (p = 0.031) and CD163+ macrophages (p = 0.023), while the NLR was not significantly correlated with CD66b+ neutrophils (p = 0.397). Conclusions Our results demonstrated the validity of the NLR by IHC analyses and we determined that a higher value of NLR is a trustworthy prognostic factor for patients with PC.

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.

A comparison of laparoscopic energy devices on charges in thermal power after application to porcine mesentery.

Introduction: Advances in energy devices have played a major role in the rapid expansion of laparoscopic surgery. However, complications due to these energy devices are occasionally reported, and if the characteristics of these devices are not well understood, serious complications may occur. This study evaluated various typical energy devices and measured temperature rises in the adjacent tissue and in the devices themselves. Equipment and Methods: We used the following 7 types of energy devices: AutoSonix (AU), SonoSurg (SS), Harmonic Scalpel (HS), LigaSure Atlas (LA), LigaSure Dolphin Tip (LD), monopolar diathermy (Mono), and bipolar scissors (Bi). Laparoscopy was performed under general anesthesia in pigs, and the mesentery was dissected using each energy device. Tissue temperature at a distance of 1 mm from the energy device blade before and after dissection was measured. Temperature of the device blade both before and after dissection, time required for dissection, and interval until the temperature fell to 100°C, 75°C, and 50°C were documented. Results: Temperature of the surrounding tissue using each device rose the most with the Mono (50.5±8.0°C) and the least with the HS in full mode (6.2±0.7°C). Device temperature itself rose the highest with the AU in full mode (318.2±49.6°C), and the least with the Bi (61.9±4.8°C). All ultrasonic coagulation and cutting devices (AU, SS, and HS) had device temperatures increase up to ≥100°C, and even at 8 seconds after completing dissection, temperatures remained at ≥100°C. Conclusions: Because the adjacent tissue temperature peaked with the Mono, cautious use near the intestine and blood vessels is necessary. In addition, the active blades of all ultrasonic coagulation and cutting devices, regardless of model, developed high temperatures exceeding 100°C. Therefore, an adequate cooling period after using these devices is therefore necessary between applications.

Enucleation of solid pseudopapillary tumor with a preoperative nasopancreatic drainage stent in a child

Solid pseudopapillary tumor (SPT) is a rare pancreatic tumor with low‐grade malignancy in children. A complete surgical resection can achieve a favorable prognosis. Although several reports have indicated that enucleation is considered a safe and effective treatment, the most significant complication is injury to the main pancreatic duct. The usefulness and safety of tumor enucleation after preoperative placement of an endoscopic nasopancreatic drainage stent (NPDS) has recently been reported. We present the case of SPT in a 10‐year‐old girl. To avoid and detect injury to the main pancreatic duct during operation, an NPDS was endoscopically placed before laparotomy. The patient underwent a complete enucleation of the tumor with the guidance of an NPDS. Our case is the first report of a successful enucleation of an SPT with a preoperative placement of an NPDS. This procedure may lead to safe enucleation of a pancreatic tumor with low malignancy, such as SPT, in children.

The Decline of Amylase Level of Pancreatic Juice After Pancreaticoduodenectomy Predicts Postoperative Pancreatic Fistula.

Objectives Postoperative pancreatic fistula (POPF) is a life-threatening complication after pancreaticoduodenectomy (PD). The aim of this study is to evaluate the significance of pancreatic amylase level of pancreatic juice for PF after PD. Methods The subjects were 46 patients who underwent PD between January 2012 and August 2015 at Jikei University Hospital. We retrospectively investigated the relation between patient characteristics including pancreatic amylase level of pancreatic juice through the pancreatic drainage tube and the incidence of POPF (grade B or grade C according to the International Study Group on the Pancreatic Fistula) using univariate and multivariate analyses. The decline of pancreatic amylase level of pancreatic juice was evaluated by 1 − postoperative day 3/postoperative day 1 ratio. Results In univariate analysis, nonductal adenocarcinoma (P = 0.0252), soft pancreatic remnant (P = 0.0155), and decline of pancreatic amylase level of pancreatic juice ≥ 80% (P = 0.0010) were significant predictors of POPF. In multivariate analysis, decline of pancreatic amylase level of pancreatic juice of 80% or greater (P = 0.0192) was the only significant independent parameter. Conclusions Decline of pancreatic amylase level of pancreatic juice can predict POPF after PD.