Double Percutaneous Transesophageal Gastrotubing for Gastric Cancer: A Pilot Study.

BACKGROUND: The management of gastric cancer causing gastric outlet obstruction and dilatation must include decompression of the stomach and intravenous nutrition. Percutaneous transesophageal gastrotubing (PTEG) is an effective technique for either gastric decompression or enteral nutrition. Here, we investigated the efficacy and safety of double PTEG (dPTEG), that is, using PTEG for both purposes simultaneously, in patients with gastric cancer. MATERIALS AND METHODS: Eleven patients with gastric outlet obstruction due to gastric cancer were admitted to our hospital between January 2015 and March 2017 and enrolled in this study. Each patient underwent dPTEG as soon as possible. After dPTEG tubes were placed, gastric decompression was started immediately and enteral nutrition was started within 1 d. Feeding and decompression through the double tubes were continued until the day before operation. Using data from these patients, we investigated the efficacy and safety of dPTEG. RESULTS: dPTEG was performed successfully in all patients and no critical adverse effects were observed. Eight of the 11 patients underwent radical or palliative resection. Decompression of the stomach was achieved and nutritional status was significantly improved after dPTEG in all patients. CONCLUSIONS: We conclude that dPTEG is a safe and effective management technique for patients with gastric outlet obstruction and gastric dilatation due to gastric cancer.

New treatment strategy with nuclear factor-κB inhibitor for pancreatic cancer.

BACKGROUND: Because of difficulties with early diagnosis, most patients with pancreatic cancer receive chemotherapy. The National Comprehensive Cancer Network guidelines (version 2.2015) suggest therapy with gemcitabine (GEM) plus nab-paclitaxel (nPTX) as a category 1 recommendation for metastatic pancreatic ductal adenocarcinoma. According to the results of many studies, the activation of chemotherapeutic agents-induced nuclear factor-κB (NF-κB) causes chemoresistance. Hence, we hypothesized that the addition of nafamostat mesilate (NM), a potent NF-κB inhibitor, to GEM/nPTX therapy could enhance the antitumor effect in the treatment of pancreatic ductal adenocarcinoma. MATERIALS AND METHODS: In vitro, we assessed NF-κB activity and apoptosis under treatment with NM alone (80 µg/mL), with GEM/nPTX, or with a combination of NM and GEM/nPTX in human pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and AsPC-1). In vivo, orthotopic pancreatic cancer mice (BALBc nu/nu) were divided into four groups: control (n = 13), NM (n = 13), GEM/nPTX (n = 13), and triple combination (n = 13). NM (30 mg/kg) was delivered intraperitoneally three times a week, and GEM/nPTX was injected intravenously once a week to orthotopic pancreatic cancer model mice. In the triple combination group, mice received NM followed by GEM/nPTX on the first day to avoid GEM/nPTX-induced NF-κB activation. RESULTS: In vitro and in vivo, NM inhibited GEM/nPTX-induced NF-κB activation, and a synergistic effect of apoptosis was observed in the triple combination group. Furthermore, tumor growth was significantly suppressed in the triple combination group compared with the other groups. CONCLUSIONS: NM enhances the antitumor effect of GEM/nPTX chemotherapy for orthotopic pancreatic cancer by inhibition of NF-κB activation.

The C-reactive Protein to Albumin Ratio Predicts Long-Term Outcomes in Patients with Pancreatic Cancer After Pancreatic Resection.

BACKGROUND: The C-reactive protein to albumin (CRP/Alb) ratio, a novel inflammation-based prognostic score, is associated with outcomes in septic patients. The prognostic value of CRP/Alb ratio has not been established in cancer patients. The aim of this study is to evaluate the significance of CRP/Alb ratio in therapeutic outcome after pancreatic resection for pancreatic cancer. METHODS: The study comprised 113 patients who had undergone pancreatic resection for pancreatic cancer between April 2001 and December 2011. We retrospectively investigated the relation between CRP/Alb ratio and disease-free as well as overall survival. RESULTS: The optimal cut-off level of the CRP/Alb ratio was 0.03. For disease-free survival, preoperative biliary drainage (p = 0.011), advanced tumor-node-metastasis (TNM) classification (p = 0.002), and higher CRP/Alb ratio (p = 0.049) by univariate analysis, and advanced TNM classification (p = 0.003) by multivariate analysis, were independent and significant predictors of cancer recurrence. For overall survival, preoperative biliary drainage (p = 0.012), advanced TNM classification (p = 0.001), and higher CRP/Alb ratio (p = 0.023) by univariate analysis, and advanced TNM classification (p = 0.003) and higher CRP/Alb ratio (p = 0.035) by multivariate analysis, were independent and significant predictors of poor patient outcome. CONCLUSIONS: The CRP/Alb ratio may be an independent and significant indicator of poor long-term outcomes in patients with pancreatic cancer after pancreatic resection.

Glasgow prognostic score predicts outcome after surgical resection of gallbladder cancer.

BACKGROUND: Systemic inflammation as evidenced by the Glasgow prognostic score (GPS) predicts cancer-specific survival in various types of cancer. The aim of this study was to evaluate the significance of GPS in therapeutic outcome after surgical resection of gallbladder cancer. METHODS: The subjects were 51 patients who underwent surgical resection for gallbladder cancer. For the assessment of systemic inflammatory response using the GPS, patients were classified into three groups: patients with normal albumin (≥3.5 g/dl) and normal C-reactive protein (CRP) (≤1.0 mg/dl) as GPS 0 (n = 38), those with low albumin (<3.5 g/dl) or elevated CRP (>1.0 mg/dl) as GPS 1 (n = 8), and those with low albumin (<3.5 g/dl) and elevated CRP (>1.0 mg/dl) as GPS 2 (n = 5). We retrospectively investigated the relation between patient characteristics including GPS, and disease-free as well as overall survival. RESULTS: In disease-free survival, advanced tumor stage based on pathology (p = 0.006), positive lymph node metastasis (p = 0.001), and GPS 1 or 2 (p = 0.006) were independent predictors of cancer recurrence in multivariate analysis. In overall survival, positive lymph node metastasis (p = 0.002) and GPS 1 or 2 (p = 0.032) were independent predictors of poor patient outcome in multivariate analyses. CONCLUSION: The GPS in patients with gallbladder cancer is an independent prognostic predictor after surgical resection.

Combination chemotherapy of nafamostat mesylate with gemcitabine for gallbladder cancer targeting nuclear factor-κB activation.

BACKGROUND: Gemcitabine is an effective chemotherapeutic agent for advanced gallbladder cancer. However, chemoresistance attributable to gemcitabine-induced nuclear factor-κB (NF-κB) activation has been reported. We previously reported that nafamostat mesylate inhibited NF-κB activation and induced apoptosis in pancreatic cancer. Therefore, we hypothesized that nafamostat mesylate inhibits gemcitabine-induced NF-κB activation and enhances apoptosis induced by gemcitabine in gallbladder cancer. MATERIALS AND METHODS: In vitro, we assessed NF-κB activation of a gallbladder cancer cell line (NOZ) treated with nafamostat mesylate, gemcitabine, or a combination of both. In vivo, we established a xenograft gallbladder cancer model in mice by subcutaneous injection of NOZ cells. Five weeks after implantation, the animals were treated with nafamostat mesylate three times a week in the nafamostat mesylate group, with gemcitabine once a week in the gemcitabine group, or with a combination of nafamostat mesylate three times a week and gemcitabine once a week in the combination group, respectively. In the control group, only the vehicle of gemcitabine and nafamostat mesylate was injected at the same time course. RESULTS: In the combination group, NF-κB activation was inhibited and apoptosis was enhanced compared with gemcitabine alone in vitro and vivo. Tumor growth in the combination group was significantly slower than that in the gemcitabine group (P < 0.001). At the end of the study, the tumor weight and volume in the combination group were significantly lower than those in the gemcitabine group (P = 0.039 and 0.028, respectively). CONCLUSIONS: Combination chemotherapy of gemcitabine with nafamostat mesylate enhances the anti-tumor effect against xenograft gallbladder cancer model in mice.

Inhibition of nuclear factor-κB enhances the antitumor effect of paclitaxel against gastric cancer with peritoneal dissemination in mice.

BACKGROUND: Intraperitoneal (i.p.) administration of paclitaxel is useful for treating malignant tumors with peritoneal dissemination, but the therapeutic efficacy is limited. Chemoresistance due to paclitaxel-induced nuclear factor-kappa B (NF-κB) activation is an important cause of suboptimal therapeutic efficacy. AIMS: The purpose of this study was to prove that addition of nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor and an NF-κB inhibitor, to i.p. paclitaxel enhances antitumor effects of paclitaxel against gastric cancer with peritoneal dissemination. METHODS: In vitro, we assessed NF-κB activity and apoptosis in response to treatment with FUT-175 alone, paclitaxel alone, or a combination of FUT-175 and paclitaxel in a human gastric cancer cell line (MKN-45). In vivo, we established peritoneal dissemination in nude mice by i.p. injection of MKN-45 cells. The animals received i.p. injections of FUT-175 alone three times a week (FUT-175 group), of paclitaxel alone once a week (paclitaxel group), or a combination of FUT-175 and paclitaxel (combination group) three times and once a week, respectively. RESULTS: In the combination group, paclitaxel-induced NF-κB activation was inhibited and apoptosis was enhanced in comparison with those in the other groups both in vitro and in vivo. In the combination group, number and weight of peritoneal nodules were significantly lower than those in the paclitaxel group (p = 0.0009 and p = 0.0417, respectively). In the survival analysis, the combination group had a significantly better survival than the paclitaxel group (p = 0.0048). CONCLUSION: FUT-175 enhances the antitumor effect of i.p. paclitaxel against gastric cancer with peritoneal dissemination by inhibiting NF-κB activation in mice.

Successful resection of port site recurrence of pancreatic ductal adenocarcinoma after laparoscopic distal pancreatectomy.

BACKGROUND: There are many reports of port site recurrence after laparoscopic surgery for various types of cancer. However, only two cases of port site recurrence after laparoscopic pancreatectomy have been reported to date. We herein report a case of port site recurrence after laparoscopic distal pancreatectomy. CASE PRESENTATION: A 73-year-old woman was diagnosed with pancreatic tail cancer and underwent laparoscopic distal pancreatectomy with splenectomy. Histopathological examination revealed pancreatic ductal carcinoma (pT1N0M0 pStage I). The patient was discharged on postoperative day 14 with no complications. However, 5 months after surgery, computed tomography showed a small tumor at the right abdominal wall. No distant metastasis had appeared after 7 months of follow-up. Under the diagnosis of port site recurrence without any other metastases, we resected this abdominal tumor. Histopathological examination showed port site recurrence of pancreatic ductal carcinoma. No recurrence was observed 15 months postoperatively. CONCLUSIONS: This is the report of successful resection of port site recurrence of pancreatic cancer.

Dynamics of the prognostic nutritional index in preoperative chemotherapy in patients with colorectal liver metastases.

BACKGROUND: Identifying the prognostic indicators that reflect the efficacy of preoperative chemotherapy is necessary. In this study, we investigated the prognostic indicators targeting the systemic inflammatory response for the administration of preoperative chemotherapy in patients with colorectal liver metastases. METHODS: Data for 192 patients were retrospectively analyzed. The relationship between overall survival and clinicopathological variables, including biomarkers such as the prognostic nutritional index, was investigated in patients who underwent upfront surgery or preoperative chemotherapy. RESULTS: In the upfront surgery group, extrahepatic lesion (p=0.01) and low prognostic nutritional index (p < 0.01) were significant prognostic indicators, whereas a decrease in the prognostic nutritional index (p=0.01) during preoperative chemotherapy were independent poor prognostic factors in the preoperative chemotherapy group. In particular, a decrease in the prognostic nutritional index was a significant prognostic marker in patients aged <75 years (p=0.04). In patients with a low prognostic nutritional index aged <75 years, preoperative chemotherapy significantly prolonged overall survival (p=0.02). CONCLUSION: A decrease in the prognostic nutritional index during preoperative chemotherapy predicted overall survival of patients with colorectal liver metastases after hepatic resection, and preoperative chemotherapy may be effective for patients aged <75 years with a low prognostic nutritional index.

D1 Distal Pancreatectomy for Left-sided Pancreatic Ductal Adenocarcinoma Is Justifiable: A Propensity-score Matched Multicenter Study.

BACKGROUND/AIM: Evidence on the optimal extent of lymph node dissection for left-sided pancreatic ductal adenocarcinoma (PDAC) is scarce. The aim of the current study was to compare the long-term outcomes of patients who underwent D1 distal pancreatectomy (DP) with D2 DP for left-sided PDAC. PATIENTS AND METHODS: Patients undergoing DP for left-sided PDAC at the four institutions affiliated to The Jikei University were enrolled in this study. Patients were divided into D1 and D2 groups. Patients' clinical characteristics, overall survival (OS), and relapse-free survival (RFS) were compared between the two groups before and after propensity-score matched (PSM) analysis. RESULTS: Of 145 patients with left-sided PDAC, 55 patients underwent D1 DP and 90 underwent D2 DP, of whom 38 matched pairs were included in the PSM analytic cohort. In the unmatched cohort, no significant difference was found between the D1 and D2 groups for both OS (median 2.51 vs. 3.07 years; p=0.709) and RFS (median 1.47 vs. 1.27 years; p=0.565). After PSM, OS (median 2.37 vs. 3.56 years; p=0.407) and RFS (median 1.35 vs. 1.11 years; p=0.542) were not significantly different between the two groups. In a comparison of regional and systemic recurrence sites, no significant difference was observed between the two groups (p=0.500). CONCLUSION: The long-term survival of D1 DP for left-sided PDAC was not inferior to D2 DP. In an era in which the importance of multidisciplinary treatment for PDAC has been documented, unnecessary extended surgery should be avoided.

Ischemic small bowel perforation caused by cholesterol crystal embolism following transcatheter arterial chemoembolization for recurrent hepatocellular carcinoma: a case report.

BACKGROUND: Cholesterol crystal embolism (CCE) following transcatheter arterial chemoembolization (TACE) is rare. CASE PRESENTATION: A 71-year-old man underwent TACE for recurrence of hepatocellular carcinoma (HCC). On postoperative day (POD) 5, he developed abdominal pain and fever. Computed tomography revealed intraperitoneal free air. The patient was diagnosed with gastrointestinal perforation with peritonitis, for which partial intestinal resection and covering ileostomy were performed. Histological examination revealed perforation of the small intestine caused by CCE. The patient made a satisfactory recovery and was discharged on POD 30. The patient showed no recurrence of cholesterol crystal embolism or HCC for 2 years after surgery. CONCLUSION: We reported a successfully treated case of ischemic small bowel perforation due to cholesterol crystal embolism following transcatheter arterial chemoembolization for recurrent HCC.

Assessment of Outcome of Hepatic Resection for Extremely Elderly Patients With a Hepatic Malignancy.

BACKGROUND/AIM: We aimed to assess surgical outcome and long-term survival after elective hepatic resection for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in patients aged 80 years or older. PATIENTS AND METHODS: This study included 100 patients aged 70 years or older, who underwent hepatic resection for HCC or CRLM between January 2000 and December 2012. Outcomes and clinicopathological data were compared between the elderly (aged 70-79 years; n=84) and extremely elderly groups (aged 80 years or older; n=16). RESULTS: Incidence of postoperative complications, in-hospital mortality, and postoperative OS in the extremely elderly group were comparable with those of the elderly group. In patients with HCC, the extremely elderly group was associated with shorter DFS (p=0.030) in univariate analysis, while multivariate analysis showed significant and independent factors of cancer recurrence. CONCLUSION: Hepatic resection for HCC and CRLM in patients aged 80 years and older may be safe and acceptable with appropriate selection. For HCC in patients aged 80 years and older, hepatic resection may be effective when negative surgical margins can be achieved.

Risk Factors for Deterioration of Remnant Liver Function After Hepatic Resection for Hepatocellular Carcinoma.

BACKGROUND/AIM: After primary resection of hepatocellular carcinoma (HCC), the impact of patient's characteristics at the initial hepatectomy, on long-term remnant liver function has not been reported. The aim of this study was to identify factors associated with the deterioration of remnant liver function among patients who developed recurrent HCC. PATIENTS AND METHODS: A total of 51 patients with intrahepatic recurrence after initial hepatic resection for HCC were included. We retrospectively investigated the relation between patient characteristics and the degree of deterioration of remnant liver function upon recurrence. RESULTS: In univariate analysis, significant predictors of deterioration of remnant liver function consisted of preoperative gastro-esophageal varices (p=0.0101), preoperative transcatheter arterial chemoembolization (p=0.0230) and hepatectomy beyond Makuuchi's criteria (p=0.0101). In multivariate analysis, the only significant independent predictor of deterioration of remnant liver function was hepatectomy beyond Makuuchi's criteria (p=0.0498). CONCLUSION: Hepatectomy beyond Makuuchi's criteria at the initial hepatectomy may predict deterioration of remnant liver function upon recurrence of HCC.

Assessment of Outcome of Hepatic Resection for Extremely Elderly Patients With a Hepatic Malignancy.

BACKGROUND/AIM: We aimed to assess surgical outcome and long-term survival after elective hepatic resection for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in patients aged 80 years or older. PATIENTS AND METHODS: This study included 100 patients aged 70 years or older, who underwent hepatic resection for HCC or CRLM between January 2000 and December 2012. Outcomes and clinicopathological data were compared between the elderly (aged 70-79 years; n=84) and extremely elderly groups (aged 80 years or over; n=16). RESULTS: Incidence of postoperative complications, in-hospital mortality, and postoperative OS in the extremely elderly group were comparable with those of the elderly group. In patients with HCC, the extremely elderly group was associated with shorter DFS (p=0.030) in univariate analysis, while multivariate analysis showed significant and independent factors of cancer recurrence. CONCLUSION: Hepatic resection for HCC and CRLM in patients aged 80 years and over may be safe and acceptable with appropriate selection. For HCC in patients aged 80 years and over, hepatic resection may be effective when negative surgical margins can be achieved.

Glycogen synthase kinase-3ß activity plays a key role in the antitumor effect of nafamostat mesilate in pancreatic cancer cells.

Pancreatic cancer is often resistant to chemotherapy. We previously showed the efficacy of combination treatment using gemcitabine and nafamostat mesilate (FUT-175) for patients with unresectable pancreatic cancer. However, the mechanisms that affect the sensitivity of FUT-175 are not fully understood. The purpose of the present study was to clarify the mechanism of the sensitivity to FUT-175, with a focus on the activity of glycogen synthase kinase-3ß (GSK-3ß). In vitro, we assessed sensitivity to FUT-175 in human pancreatic cancer cell lines (PANC-1 and MIAPaCa-2) and difference of signaling in these cells by cell proliferation assay, Western blot analysis and microarray. Next, we assessed cell viability, apoptotic signal and nuclear factor-kappa B (NF-κB) activity in response to treatment with FUT-175 alone and in combination with GSK-3 inhibitor or protein phosphatase 2A (PP2A) by cell proliferation assay, Western blot analysis and enzyme-linked immunosorbent assay. Phosphorylated GSK-3ß level was significantly higher in MIAPaCa-2 (high sensitivity cell) than in PANC-1 (low sensitivity cell). Cell viability and NF-κB activity were significantly decreased by addition of GSK-3 inhibitor to FUT-175, and levels of cleaved caspase-8 were increased by inhibition of GSK-3. PP2A inhibitor increased the levels of phosphorylated GSK-3ß and sensitized both cell lines to FUT-175 as measured by cell viability and apoptotic signal. The results indicate that GSK-3ß activity plays a key role in the antitumor effect of FUT-175 in pancreatic cancer cells, and regulation of GSK-3ß by PP2A inhibition could be a novel therapeutic approach for pancreatic cancer.

Pomalidomide promotes chemosensitization of pancreatic cancer by inhibition of NF-κB.

INTRODUCTION: Nuclear factor κB (NF-κB) plays an important role in cancer progression and causes therapeutic resistance to chemotherapy. Pomalidomide, a third-generation immunomodulating drug derived from thalidomide, has been approved for uncontrolled multiple myeloma. We hypothesized that pomalidomide may inhibit the anticancer agent-induced NF-κB activity and enhance chemosensitization of combination chemotherapy with gemcitabine and S1 (Gem/S1) in pancreatic cancer. METHODS: In vitro, we assessed NF-κB activity, induction of caspase cascade, cell apoptosis and cell proliferation using human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). In vivo, we established an orthotopic xenograft mouse model for human pancreatic cancer by injection of PANC-1 cells. At 5 weeks after injection, the animals were randomly divided into four groups and treated with Gem (100 mg/kg) /S1 (10 mg/kg), with oral administration of pomalidomide (0.5 mg/kg), with combination of gemcitabine, S1, and pomalidomide or vehicle only. RESULTS: Although chemotherapeutic agents induced NF-κB activation in pancreatic cancer cells, pomalidomide inhibited anticancer agent-induced NF-κB activation (p < 0.01). Of the four groups tested for the apoptosis-related caspase signals and apoptosis under both in vitro and in vivo conditions, Gem/S1/Pomalidomide group demonstrated the strongest activation of the caspase signals and proapoptotic effect. In Gem/S1/Pomalidomide group, cell proliferation and tumor growth were slower than those in other groups both in vitro and in vivo (p < 0.01). There were no obvious adverse effects except for thrombocytosis by using pomalidomide. CONCLUSIONS: Pomalidomide promotes chemosensitization of pancreatic cancer by inhibiting chemotherapeutic agents-induced NF-κB activation.

Optimal timing of preoperative indocyanine green administration for fluorescent cholangiography during laparoscopic cholecystectomy using the PINPOINT® Endoscopic Fluorescence Imaging System.

INTRODUCTION: The PINPOINT® Endoscopic Fluorescence Imaging System (Novadaq, Mississauga, Canada) allows surgeons to visualize the bile ducts during laparoscopic cholecystectomy. Surgeons can continue operation while confirming the bile ducts' fluorescence with a bright-field/color image. However, strong fluorescence of the liver can interfere with the surgery. Here, we investigated the optimal timing of indocyanine green administration to allow fluorescent cholangiography to be performed without interference from the liver fluorescence. METHODS: A total of 72 patients who underwent laparoscopic cholecystectomy were included in this study. The timing of indocyanine green administration was set immediately before surgery and at 3, 6, 9, 12, 15, 18, and 24 h before surgery. The luminance intensity ratios of gallbladder/liver, cystic duct/liver, and common bile duct/liver were measured using the ImageJ software (National Institutes of Health, Bethesda, USA). Visibility of the gallbladder and bile ducts was classified into three categories (grades A, B, and C) based on the degree of visibility in contrast to the liver. RESULTS: The luminance intensity ratio for the gallbladder/liver, cystic duct/liver, and common bile duct/liver was ≥1 in the 15-, 18-, and 24-h groups. The proportion of cases in which evaluators classified the visibility of the gallbladder and bile ducts as grade A (best visibility) reached a peak in the 15-h group and decreased thereafter. CONCLUSIONS: In the present study, the optimal timing of indocyanine green administration for fluorescent cholangiography during laparoscopic cholecystectomy using the PINPOINT Endoscopic Fluorescence Imaging System was 15 h before surgery.

Inhibitory Effect of Anti-rheumatic Drug Iguratimod for Hepatocellular Carcinogenesis by Inhibition of Serum Interleukin-8 Production.

BACKGROUND/AIM: Angiogenesis is a known factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess the property of iguratimod, that is an anti-inflammatory drug for rheumatoid arthritis, on anti-angiogenesis and anti-carcinogensis for HCC. MATERIALS AND METHODS: In vitro, human umbilical vein endothelial cells were cultured under interleukin-8 (IL-8) with or without iguratimod. In vivo, a rat model with HCC received iguratimod or distilled water for 6 weeks. Diameter of the largest tumor, number of tumors and serum interleukin-8 concentration were compared between iguratimod and control groups. RESULTS: By an in vitro angiogenesis assay, it was found angiogenesis in iguratimod group was significantly lower than that in control group (p=0.013). In vivo, largest tumor diameter (p=0.036), number of the tumor (p=0.011) and serum interleukin-8 concentration (p=0.036) in the iguratimod group were significantly smaller and lower than those in the control group. CONCLUSION: Iguratimod may inhibit hepatocellular carcinogensis by inhibition of interleukin-8 production in a rat model.

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.

Neutrophil to Lymphocyte Ratio Predicts Therapeutic Outcome After Pancreaticoduodenectomy for Carcinoma of the Ampulla of Vater.

BACKGROUND: Preoperative systemic inflammatory response is associated with a poor long-term prognosis after resection of malignant tumors. Several indicators of systemic inflammation have been reported to be predictive of outcomes, but have not been fully investigated. The aim of the present study was to evaluate the significance of the preoperative neutrophil to lymphocyte ratio (NLR) in therapeutic outcomes after pancreaticoduodenectomy for carcinoma of the ampulla of Vater. PATIENTS AND METHODS: The study comprised of 37 patients who had undergone pancreaticoduodenectomy for carcinoma of the ampulla of Vater between January 2000 and December 2011. We retrospectively investigated the relation between preoperative NLR and disease-free as well as overall survival. RESULTS: In multivariate analysis, preoperative biliary drainage (p=0.044) and pN2 or pN3 (p=0.027) status were independent and significant predictors of cancer recurrence, while significant predictors of overall survival consisted of pN2 or pN3 (p=0.025) and NLR ≥3 (p=0.026). CONCLUSION: Preoperative NLR is an independent and significant indicator of long-term outcome in patients with carcinoma of the ampulla of Vater after pancreaticoduodenectomy. Measurement of NLR may help decision making in the postoperative management of patients with carcinoma of the ampulla of Vater.

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.