Masashi Kishiwada

The Cytoprotective Effects of Addition of Activated Protein C into Preservation Solution on Small-for-Size Grafts in Rats

Small‐for‐size liver grafts are a serious obstacle for partial orthotopic liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, is known to have cell‐protective properties due to its anti‐inflammatory and antiapoptotic activities. This study was designed to examine the cytoprotective effects of a preservation solution containing APC on small‐for‐size liver grafts, with special attention paid to ischemia‐reperfusion injury and shear stress in rats. APC exerted cytoprotective effects, as evidenced by (1) increased 7‐day graft survival; (2) decreased initial portal pressure and improved hepatic microcirculation; (3) decreased levels of aminotransferase and improved histological features of hepatic ischemia‐reperfusion injury; (4) suppressed infiltration of neutrophils and monocytes/macrophages; (5) reduced hepatic expression of tumor necrosis factor α and interleukin 6; (6) decreased serum levels of hyaluronic acid, which indicated attenuation of sinusoidal endothelial cell injury; (7) increased hepatic levels of nitric oxide via up‐regulated hepatic endothelial nitric oxide synthesis expression together with down‐regulated hepatic inducible nitric oxide synthase expression; (8) decreased hepatic levels of endothelin 1; and (9) reduced hepatocellular apoptosis by down‐regulated caspase‐8 and caspase‐3 activities. These results suggest that a preservation solution containing APC is a potential novel and safe product for small‐for‐size liver transplantation, alleviating graft injury via anti‐inflammatory and antiapoptotic effects and vasorelaxing conditions. Liver Transpl 16:1–11, 2010.

Influence of preoperative anti-cancer therapy on resectability and perioperative outcomes in patients with pancreatic cancer: Project study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery

Little is known about the effects of neoadjuvant therapy on outcomes in patients with pancreatic cancer. This study evaluated the effects of neoadjuvant therapy on resectability and perioperative outcomes.

Paradoxical impact of the remnant pancreatic volume and infectious complications on the development of nonalcoholic fatty liver disease after pancreaticoduodenectomy

The aim of the present study was to evaluate perioperative risk factors for development of nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), paying special attention to remnant pancreatic volume (RPV) and postoperative infection.

Lipopolysaccharide‐induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFκB activation: involvement of membrane‐bound CD14 and toll‐like receptor‐4

Summary.  Background: The vitamin K‐dependent protein S (PS), mainly synthesized in hepatocytes and endothelial cells, plays a critical role in the anticoagulant activity of plasma. The decreased plasma level of PS in sepsis is associated with thrombotic tendency, but the mechanism is unclear. Objectives: In the present study, we examined the effect of lipopolysaccharide (LPS) on PS expression in vivo in rat liver, and in vitro in isolated hepatocytes and sinusoidal endothelial cells (SECs) from normal rats. Results: LPS induced a progressive decrease of plasma PS antigen level up to 12 h with a slight recovery at 24 h, and a transient decrease of liver PS mRNA level at 4–8 h with a complete recovery at 24 h. In the in vitro studies, LPS decreased PS antigen and mRNA levels in both hepatocytes and SECs. After LPS treatment, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6) and interferon‐γ (IFN‐γ) transiently increased in plasma. IL‐6 increased the protein expression of PS from hepatocytes, while TNF‐α decreased it from SECs. LPS increased CD14 in hepatocytes and decreased it in SECs, but did not affect toll‐like receptor‐4 (TLR‐4) expression in both cells. Antirat CD14 and antirat TLR‐4 antibodies inhibited LPS‐induced NFκB activation, and a NFκB inhibitor suppressed LPS‐induced decreased PS expression in both cells. Furthermore, MEK inhibitor blocked LPS‐induced decreased PS expression in both cells. Conclusions: These findings suggest that LPS‐induced decreased PS expression in hepatocytes and SECs is mediated by MEK/ERK signaling and NFκB activation and that membrane‐bound CD14 and TLR‐4 are involved in this mechanism. These findings may explain in part the decreased level of plasma PS and thrombotic tendency in sepsis.

Gemcitabine-based chemoradiotherapy followed by surgery for borderline resectable and locally unresectable pancreatic ductal adenocarcinoma: significance of the CA19-9 reduction rate and intratumoral human equilibrative nucleoside transporter 1 expression.

Objectives This study aimed to evaluate the efficacy of gemcitabine-based chemoradiotherapy followed by surgery (gem-CRTS) for pancreatic ductal adenocarcinoma (PDAC) for borderline resectable (BR) and locally unresectable (UR) tumors. Methods One hundred patients with PDAC who underwent the gem-CRTS protocol were classified into 3 groups, namely, resectable (R; 14), BR (44), and UR (42). After chemoradiotherapy, the patients were reassessed for curative-intent resection. Results At reassessment, distant metastases became apparent in 27% of R patients, in 12% of BR patients, and in 18% of UR patients. The multivariate analysis of preoperative factors indicated that the CA19-9 reduction rate was an independent prognostic factor in the BR group. Among reassessed patients, the resection rate was 63.6% in R, 83.7% in BR, and 50.0% in UR patients. In 63 patients that underwent curative-intent resection, the 3-year survival rate was 83.3% in R, 33.0% in BR, and 7.8% in UR patients. Using multivariate analysis, the independent prognostic factor was found to be the surgical margin in BR patients and human equilibrative nucleoside transporter 1 expression in UR patients. Conclusions We consider that our gem-CRTS protocol, even for locally UR PDAC, allows for the identification of candidates for aggressive resection at the time of reassessment and improved prognosis in the patients with positive human equilibrative nucleoside transporter 1 expression.

Impact of histological response after neoadjuvant chemoradiotherapy on recurrence-free survival in UICC-T3 pancreatic adenocarcinoma but not in UICC-T4.

Objectives Although the prognostic benefit of neoadjuvant chemoradiotherapy (NCRT) against pancreatic cancer has been indicated by several reports, it is controversial whether histological response is associated with prognosis. The objective was to explore the relationship between histological response and prognosis in T3 and T4 pancreatic adenocarcinoma. Methods We histologically examined the resected specimens obtained from 58 patients (T3, n = 40; and T4, n = 18) for whom we performed curative-intent resection after NCRT. Histological response was evaluated according to Evans’s criteria to determine whether it influenced survival. Results In T3 tumors, 13 (32.5%) belonged to high responders (tumor destruction of >50%) (R0, n = 13) and 27 (67.5%) belonged to low responders (tumor destruction of ⩽50%) (R0, n = 22, R1, n = 3, R2, n = 2). Recurrence-free survival rate was significantly higher in high responders than in low responders (3-year recurrence-free survival rates: 71.3% vs 13.1%, P = 0.0095). In T4 tumors, however, only 1 (5.6%) was a high responder, and R0 resection was obtained only in 5 patients (27.8%). Conclusions In T3 tumors, histological response is considered a significant prognostic indicator, securing the surgical margin, whereas in T4 tumors, NCRT did not provide beneficial histological response, not securing the surgical margin.

Dual cytoprotective effects of splenectomy for small-for-size liver transplantation in rats.

The problems associated with small‐for‐size liver grafts (ie, high mortality rates, postoperative complications, and acute rejection) remain critical issues in partial orthotopic liver transplantation (OLT). In association with partial OLT, splenectomy (SP) is a procedure used to reduce the portal pressure. However, the precise effects of SP on partial OLT have been unclear. In this study, using small‐for‐size liver grafts in rats, we examined the cytoprotective effects of SP on OLT. Liver grafts were assigned to 2 groups: a control group (OLT alone) and an SP group (OLT after SP). SP significantly increased animal survival and decreased liver damage. SP exerted the following cytoprotective effects: (1) it improved hepatic microcirculation and prevented increases in the portal pressure after OLT, (2) it suppressed the hepatic infiltration of neutrophils and macrophages through the direct elimination of splenic inflammatory cells before OLT, (3) it decreased the hepatic expression of tumor necrosis factor α and interleukin‐6, (4) it attenuated sinusoidal endothelial injury, (5) it decreased plasma endothelin 1 levels and increased hepatic heme oxygenase 1 expression, (6) it suppressed hepatocellular apoptosis through the down‐regulation of hepatic caspase‐3 and caspase‐8 activity, and (7) it increased hepatic regeneration. In conclusion, SP for small‐for‐size grafts exerts dual cytoprotective effects by preventing excessive portal vein hepatic inflow and eliminating splenic inflammatory cell recruitment into the liver; this in turn inhibits hepatocellular apoptosis and improves liver regeneration. Liver Transpl, 2012.

International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017

This statement was developed to promote international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) which was adopted by the National Comprehensive Cancer Network (NCCN) in 2006, but which has changed yearly and become more complicated. Based on a symposium held during the 20th meeting of the International Association of Pancreatology (IAP) in Sendai, Japan, in 2016, the presenters sought consensus on issues related to BR-PDAC. We defined patients with BR-PDAC according to the three distinct dimensions: anatomical (A), biological (B), and conditional (C). Anatomic factors include tumor contact with the superior mesenteric artery and/or celiac artery of less than 180° without showing stenosis or deformity, tumor contact with the common hepatic artery without showing tumor contact with the proper hepatic artery and/or celiac artery, and tumor contact with the superior mesenteric vein and/or portal vein including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum. Biological factors include potentially resectable disease based on anatomic criteria but with clinical findings suspicious for (but unproven) distant metastases or regional lymph nodes metastases diagnosed by biopsy or positron emission tomography-computed tomography. This also includes a serum carbohydrate antigen (CA) 19-9 level more than 500 units/ml. Conditional factors include the patients with potentially resectable disease based on anatomic and biologic criteria and with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. The definition of BR-PDAC requires one or more positive dimensions (e.g. A, B, C, AB, AC, BC or ABC). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumor and vessels, but that biological and conditional dimensions are also important. The aim in presenting this consensus definition is also to highlight issues which remain controversial and require further research.

Activated protein C prevents hepatic ischaemia–reperfusion injury in rats

Background: Hepatic ischaemia–reperfusion injury (IRI) is a serious complication of liver surgery, especially extended hepatectomy and liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, has been shown to have cell‐protective properties by virtue of its anti‐inflammatory and anti‐apoptotic activities.

Human Equilibrative Nucleoside Transporter 1 Expression in Endoscopic Ultrasonography-Guided Fine-Needle Aspiration Biopsy Samples Is a Strong Predictor of Clinical Response and Survival in the Patients With Pancreatic Ductal Adenocarcinoma Undergoing Gemcitabine-Based Chemoradiotherapy.

ObjectivesThis study aimed to clarify whether pretreatment human equilibrative nucleoside transporter (hENT1) expressions in endoscopic ultrasonography-guided fine-needle aspiration biopsy (EUS-FNAB) specimens obtained from resectable, borderline resectable, and locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC) are concordant with those in the resected specimen after gemcitabine-based chemoradiotherapy (Gem-CRT) and to validate the utility of hENT1 expression using EUS-FNAB samples as a prognostic marker. MethodsWe evaluated the relationship between hENT1 expressions assessed by immunohistochemical staining and clinical outcomes in 51 of 76 patients with PDAC who were diagnosed by EUS-FNAB and received preoperative Gem-CRT. ResultsThe concordance rate of hENT1 expressions was 89.2% (K = 0.681). Median survival time (month) in the 51 whole patients and 37 patients with resection was significantly longer in hENT1 positive than in hENT1 negative: 25.0 and 30.0 versus 9.0 and 9.0, respectively. A multivariate analysis confirmed that hENT1 expression was an independent prognostic factor in both whole patients and those with resection. Regardless of T3 and T4, hENT1-positive patients with resection had significantly better prognosis than hENT1-negative patients, whose prognosis was similar to those without resection. ConclusionsThe assessment of hENT1 expression using EUS-FNAB samples before Gem-CRT provides important information on patients with PDAC who can benefit from curative-intent resection.