Teruhisa Sonoyama

Elevated serum CRP levels after induction chemoradiotherapy reflect poor treatment response in association with IL-6 in serum and local tumor site in patients with advanced esophageal cancer

Elevated serum CRP levels are associated with tumor progression and poor prognosis of esophageal cancer. The aim of this study was to clarify the clinical significance of CRP in relation to response to chemoradiotherapy in patients with esophageal cancer.

Application of Polyethylene Glycolic Acid Felt with Fibrin Sealant to Prevent Postoperative Pancreatic Fistula in Pancreatic Surgery

ObjectiveThe purpose of this nonrandomized retrospective study was to report our new procedures using polyethylene glycolic acid (PGA) felt with fibrin sealant to prevent severe pancreatic fistula in patients undergoing pancreatic surgery.MethodsFrom 2000 to 2008, 54 and 63 patients underwent pancreaticoduodenectomy (PD) and distal pancreatectomy (DP), respectively. Of those patients, we applied PGA felt with fibrin sealant to 18 PD patients and 26 DP patients. In PD patients, the PGA felt was wrapped around the pancreatic suture site, while in DP patients, the PGA felt was wrapped around the predictive division site. The pancreaticojejunostomy site in PD patients and the cut stump in DP patients were coated with fibrin sealant. We compared the occurrence rates for severe postoperative pancreatic fistula (POPF) that occurred after PD or DP both with and without our new procedures.ResultsBefore introduction of our procedures, severe POPF developed in 14 of 36 PD patients (39%) and 10 of 37 DP patients (27%). In contrast, after introduction of our procedures, the incidence of POPF was only one in both of 18 PD (6%; P = 0.016) and 26 DP (4%; P = 0.017) patients.ConclusionIn summary, our procedure using PGA felt with fibrin sealant may reduce the risk of severe POPF.

Attenuated response to liver injury in moesin-deficient mice: Impaired stellate cell migration and decreased fibrosis

Hepatic stellate cells (HSCs) respond to injury with a coordinated set of events (termed activation), which includes migration and upregulation of matrix protein production. Cell migration requires an intact actin cytoskeleton that is linked to the plasma membrane by ezrin-radixin-moesin (ERM) proteins. We have previously found that the linker protein in HSCs is exclusively moesin. Here, we describe HSC migration and fibrogenesis in moesin-deficient mice. We developed an acute liver injury model that involved focal thermal denaturation and common bile duct ligation. HSC migration and collagen deposition were assessed by immunohistology and quantitative real-time PCR. Activated HSCs were isolated from wild-type or moesin-deficient mice for direct examination of migration. Activated HSCs from wild-type mice were positive for moesin. Migration of moesin-deficient HSCs was significantly reduced. In a culture assay, 22.1% of normal HSCs migrated across a filter in 36 h. In contrast, only 1.3% of activated moesin-deficient HSCs migrated. Collagen deposition around the injury area similarly was reduced in moesin-deficient liver. The linker protein moesin is essential for HSC activation and migration in response to injury. Fibrogenesis is coupled to migration and reduced in moesin-deficient mice. Agents that target moesin may be beneficial for chronic progressive fibrosis.

Risk Factors and Management of Postoperative Bile Leakage after Hepatectomy without Bilioenteric Anastomosis

Background/Aims: Bile leakage frequently causes major complications after hepatic resection. We investigated perioperative risk factors and management of postoperative bile leakage after hepatic resection without extrahepatic biliary resection and reconstruction. Methods: We included 247 consecutive patients who underwent elective hepatic resection without bilioenteric anastomosis at our institution between 2002 and 2009. Perioperative risk factors, including patient and surgical variables, were evaluated using univariate and logistic regression analyses. Results: Postoperative bile leakage occurred in 26 patients (10.5%). The surgical drain was retained in 6 patients (23%); 9 (35%) underwent drain salvage and 11 (42%) underwent percutaneous puncture under computed tomography or ultrasound guidance. Eight patients underwent endoscopic nasobiliary drainage (ENBD) for postoperative bile leakage, and bile leakage healed at a median interval of 19.5 days after ENBD. By univariate analysis, postoperative bile leakage was associated with central bisectionectomy, surgical time and intraoperative blood loss. Logistic regression analysis identified central bisectionectomy as an independent risk factor for postoperative bile leakage (p = 0.0003, odds ratio 16.724). Conclusion: Meticulous procedures are necessary during parenchymal hepatic resection, especially during central bisectionectomy. Drain management should be precise in the case of postoperative bile leakage. We believe ENBD may rapidly cure postoperative major bile leakage.

Primary large gastrointestinal stromal tumor of the liver: Report of a case

A 30-year-old man was diagnosed to have a large intra-abdominal tumor in 1999. A histological examination of a resected liver specimen from an operation in 2002 revealed a gastrointestinal stromal tumor (GIST), diagnosed based on positive immunostaining for CD34 and c-kit. Two years after the operation, new lesions developed in the residual liver and the lesser curvature of the stomach. An immunohistological examination of both specimens showed the features of a GIST, thus matching those of the first histological examination of the liver GIST. While there were no mutations at exon 11 of c-kit in the liver GISTs resected in 2002 and 2004, the gastric lesion had a mutation at P577L (CCT to CTT) at exon 11. Therefore, the liver GIST and the gastric lesion were diagnosed to be independent. The patient already has survived for more than 9 years after receiving surgery three times and with administration of imatinib.

Intraoperative Real-Time Cholangiography and C-tube Drainage in Donor Hepatectomy Reduce Biliary Tract Complications

BackgroundIn living-donor liver transplantation, biliary tract complications are a serious problem for recipients and donors.MethodsWe applied intraoperative real-time cholangiography using a C-arm and/or C-tube drainage to reduce biliary tract complications in donor hepatectomy. From 2003 to 2010, intraoperative real-time cholangiography and C-tube drainage was applied to 39 and 19 donor cases, respectively. Fifteen donor cases had both procedures.ResultsWe confirmed the division line of the hepatic duct by visualizing a stricture on the monitor of the C-arm by pulling a thread and dissecting the proper site of the bile duct. The number of hepatic ducts of the graft to be anastomosed was 1 in 11 cases and 2 or 3 in 8 of the 19 cases without intraoperative real-time cholangiography, and it was 1 in 32 cases and 2 in 7 of the 39 cases with intraoperative real-time cholangiography. Bile leakage from the resection occurred in seven donors without, and in none of those with, C-tube drainage.ConclusionIn living-donor liver transplantation, intraoperative real-time cholangiography enables effective determination of the precise division line of the hepatic duct. Moreover, C-tube drainage is effective for reducing bile leakage from the resected surface of the liver of donors.

Laparotomy versus interventional radiological procedures for the implantation of arterial infusion devices

Although there have been numerous reports on implantable infusion devices for chemotherapy of patients with malignancy, we occasionally face problems with this therapy due to trouble with implanfation. We performed a retrospective review of 81 implantations in 77 patients, who were treated with intraarterial chemotherapy via implanted devices from 1985 to 1993. They were divided into two groups according to the procedures: the operative procedure group (group A,n=41) and the interventional radiological procedure group (group B,n=36). Both groups were then analyzed regarding the respective complications. We experienced 25 complications: (a) 9 obstructions of the catheter, (b) 4 infections, (c) 4 dislocations of the catheter, (d) 3 hematomas, (e) 3 breakdowns of the device, (f) 1 pneumothorax, and (g) 1 hepatic artery occlusion. The results of a comparison of the complication rate between groups A and B were (a) 14.0%:8%, (b) 4%:0%, (c) 0%:10%, (d) 4%:2%, (e) 7%:0%, (f) 0%:2%, and (g) 2%:0%, respectively. A statistically significant difference was observed for (b) and (c) (P<0.05). Infection occurred mainly in the cirrhotic cases of group A, but not in group B. In addition, one case fell into fatal sepsis. Based on the above findings, the interventional radiological procedure is thus considered to be the appropriate method for the prevention of infection in the case of a compromised host.

Risk factors for postoperative pancreatic fistula in distal pancreatectomy.

BACKGROUND/AIMS The purpose of this study was to identify risk factors related to severe pancreatic fistula in patients who underwent distal pancreatectomy (DP). METHODOLOGY From 2000 to 2008, 63 patients underwent DP. We retrospectively identified the risk factors for Grade B or C postoperative pancreatic fistula (POPF) occurring after DP. POPF was classified according to the International Study Group on Pancreatic Fistula definition. RESULTS Postoperative mortality and morbidity rate were 0% and 61%, respectively. POPF developed in 32 patients (51%); 21 of fistulas were classified as Grade A, nine as Grade B and two as Grade C. The incidence of severe POPF (Grade B or C) was significantly associated with two factors by univariate analyses: polyethylene glycolic acid (PGA) felt with fibrin sealant and blood loss during operation. To clarify the useful manner in DP, multivariate analysis was performed using 5 surgery-related factors. The use of polyethylene glycolic acid felt (PGA) with fibrin sealant and blood loss during operation were the significant factors for severe POPF (p=0.026 and 0.012, respectively). CONCLUSIONS Using PGA felt with fibrin sealant for the pancreatic stump could reduce the risk of severe POPF.

NK4, an HGF antagonist, prevents hematogenous pulmonary metastasis by inhibiting adhesion of CT26 cells to endothelial cells

Hepatocyte growth factor (HGF) plays a definitive role in invasive, angiogenic, and metastatic activities of tumor cells by binding to the c-Met receptor. NK4, a competitive antagonist for HGF and the c-Met receptor, prevents tumor cell growth and metastasis via its bifunctional properties to act as an HGF antagonist and angiogenesis inhibitor. In the present study, we investigated the inhibitory effectiveness of NK4 on hematogenous pulmonary metastasis of the CT26 murine colon cancer cell line, focusing on tumor cell adhesion to endothelial cells. In an in vitro adhesion assay, HGF facilitated adhesion of CT26 cells to a murine endothelial cell line (F-2) in a dose-dependent manner. Furthermore, the enhancing effect of HGF on CT26-F-2 cell interaction was blocked by NK4 as well as by anti-HGF antibody. Similarly, HGF-induced phosphorylation of focal adhesion kinase (FAK), downstream of integrin signaling, was reduced by NK4 and by anti-HGF antibody. However, distinct integrin expression on the surface of CT26 cells was not altered by HGF. In an in vivo experimental pulmonary metastasis assay, stable NK4 expression potently decreased the number of pulmonary metastatic foci. The NK4-induced suppression of pulmonary metastasis was partially reversed when HGF was intraperitoneally administered in an adhesive phase. These results suggest that NK4 could act on tumor cells to inhibit CT26 adhesion to endothelial cells by reducing FAK phosphorylation, which is regulated by inside-out HGF/c-Met signaling, and thereby suppress hematogenous pulmonary metastasis.

Gene transfer of NK4, an angiogenesis inhibitor, induces CT26 tumor regression via tumor-specific T lymphocyte activation

Hepatocyte growth factor (HGF) has been shown to be involved in malignant behaviors, such as invasion and metastasis, in different tumors. Hence, HGF could be a target molecule for control of the malignant potential of cancer. NK4 is a competitive antagonist for HGF and exerts an antitumor activity, not only by HGF antagonism but also by antiangiogenesis. Here, we studied the participation of cellular immunity in CT26 tumor regression by NK4 gene transfer. In vivo experiments showed that NK4‐induced inhibition of subcutaneous tumor growth (as demonstrated in immunocompetent BALB/c mice) was weakened in T lymphocyte‐deficient nude mice. In addition, the immunocompetent BALB/c mice that had shown complete regression of CT26‐NK4 tumors generated an immune memory against repeated challenge with the same tumor antigen. Immunohistochemistry of tumor‐infiltrating lymphocytes showed that the ratio of CD8/CD4 in CT26‐NK4 tumors was significantly higher than that in control tumors. Also, the presence of tumor‐specific cytotoxic T lymphocytes (CTL) was demonstrated by cytotoxicity assays. Depletion of CD8+ T lymphocytes markedly abrogated the antitumor activity of NK4. However, NK4 had no direct effect on the in vitro cellular immune system. Taken together, these data indicate that NK4 expression by gene transfer, at the tumor site, triggers tumor‐specific CTL activation, resulting in complete CT26 tumor regression in vivo. This action was considered to be due to apoptosis induced by NK4s potent antiangiogenic and HGF antagonistic effects.