Up-regulation of integrin β3 in radioresistant pancreatic cancer impairs adenovirus-mediated gene therapy

Adenovirus-mediated gene therapy is a promising approach for the treatment of pancreatic cancer. We previously reported that radiation enhanced adenovirus-mediated gene expression in pancreatic cancer, suggesting that adenoviral gene therapy might be more effective in radioresistant pancreatic cancer cells. In the present study, we compared the transduction efficiency of adenovirus-delivered genes in radiosensitive and radioresistant cells, and investigated the underlying mechanisms. We used an adenovirus expressing the hepatocyte growth factor antagonist, NK4 (Ad-NK4), as a representative gene therapy. We established two radioresistant human pancreatic cancer cell lines using fractionated irradiation. Radiosensitive and radioresistant pancreatic cancer cells were infected with Ad-NK4, and NK4 levels in the cells were measured. In order to investigate the mechanisms responsible for the differences in the transduction efficiency between these cells, we measured expression of the genes mediating adenovirus infection and endocytosis. The results revealed that NK4 levels in radioresistant cells were significantly lower ( P  < 0.01) than those in radiosensitive cells, although there were no significant differences in adenovirus uptake between radiosensitive cells and radioresistant cells. Integrin β3 was up-regulated and the Coxsackie virus and adenovirus receptor was down-regulated in radioresistant cells, and inhibition of integrin β3 promoted adenovirus gene transfer. These results suggest that inhibition of integrin β3 in radioresistant pancreatic cancer cells could enhance adenovirus-mediated gene therapy. ( Cancer Sci  2009; 100: 1902–1907)     

Surgical bypass versus metallic stent for unresectable pancreatic cancer

With the development of interventional radiology and endoscopy, the practice of inserting expandable metallic stents for malignant jaundice has become widespread. Many studies have compared surgical bypass with polyethylene stents, or metallic stents with polyethylene stents. However, few data are available on the comparison of surgical bypass and metallic stents. The aim of this study was to compare the patient's postprocedure course and the cost performance of surgical bypass and metallic stents in patients with unresectable pancreatic cancer. The parameters analyzed were the rates of procedural and therapeutic success, duration of hospital stay, prevalence of early and late complications, cost performance, and prognosis. The rates of procedural and therapeutic success were excellent with both palliative treatments. With surgical bypass, there was a low prevalence of late complications, but duodenal obstruction sometimes occurred in patients without gastric bypass. With metallic stents, there was shorter hospitalization and lower cost, but a higher prevalence of late complications. Stent occlusion tended to occur in patients with uncovered metallic stents. There was no difference in the prognosis between the two palliative treatments. Thus, in consideration of the poor prognosis of pancreatic cancer, in patients with unresectable pancreatic cancer, insertion of covered metallic stents would be preferable to surgical bypass, because of the subsequent short hospitalization and the low cost. On the other hand, in patients with a relatively long expected prognosis, or in those with existing duodenal obstruction, biliary bypass with gastrojejunostomy may provide an advantage.     

MicroRNA-203 Expression as a New Prognostic Marker of Pancreatic Adenocarcinoma

Background  

Detection of aberrant microRNA (miR) expression may contribute to diagnosis and prognosis of various cancers. The aim of this study is to evaluate the correlation between miR-203 expression and prognosis of patients with pancreatic adenocarcinoma after curative resection.     

Augmented reality navigation system for laparoscopic splenectomy in children based on preoperative CT image using optical tracking device

Purpose

In endoscopic surgery, limited views and lack of tactile sensation restrict the surgeon’s abilities and cause stress to the surgeon. Therefore, an intra-operative navigation system is strongly recommended. We developed an augmented reality (AR) navigation system based on preoperative CT imaging. The purpose of this study is to evaluate the usefulness, feasibility, and accuracy of this system using laparoscopic splenectomy in children.

Methods

Volume images were reconstructed by three-dimensional (3D) viewer application. We used an optical tracking system for registration between volume image and body surface markers. The AR visualization was superimposed preoperative 3D CT images onto captured laparoscopic live images. This system was applied to six cases of laparoscopic splenectomy in children. To evaluate registration accuracy, distances from the marker position to the volume data were calculated.

Results

The operator recognized the hidden vascular variation of the splenic artery and vein, accessory spleen, and pancreatic tail by overlaying an image onto a laparoscopic live image. The registration accuracy of six cases was 5.30?±?0.08, 5.71?±?1.70, 10.1?±?0.60, 18.8?±?3.56, 4.06?±?1.71, and 7.05?±?4.71.

Conclusion

This navigation system provides real-time anatomical information, which cannot be otherwise visualized without navigation. The registration accuracy was acceptable in clinical operation.     

Significance of combination therapy of zoledronic acid and gemcitabine on pancreatic cancer

In the present study, we examined the cytotoxic effects of combination therapy with zoledronic acid (ZOL) and gemcitabine (GEM) on pancreatic cancer cells in vitro and in vivo. Four human pancreatic cancer cell lines were treated with ZOL, GEM or a combination of both, and the effects of the respective drug regimens on cell proliferation, invasion and matrix metalloproteinase (MMP) expression were examined. A pancreatic cancer cell line was also intrasplenically or orthotopically implanted into athymic mice and the effects of these drugs on tumor metastasis and growth in vivo were evaluated by histological and immunohistochemical analyses. Combination treatment with low doses of ZOL and GEM efficiently inhibited the proliferation (P < 0.001) and invasion (P < 0.001) of pancreatic cancer cells in vitro. Western blotting assay revealed that MMP-2 and MMP-9 expression levels were decreased after ZOL treatment. In vivo, combined treatment significantly inhibited tumor growth (P < 0.05) and the development of liver metastasis (P < 0.05). These data revealed that ZOL and GEM, when used in combination, have significant antitumor, anti-metastatic and anti-angiogenic effects on pancreatic cancer cells. The present study is the first to report the significance of the combination treatment of ZOL and GEM in pancreatic cancer using an in vivo model. These data are promising for the future application of this drug regimen in patients with pancreatic cancer.     

Association of plasminogen activator inhibitor-1 with insulin resistance in Japan where obesity is rare

The association between plasminogen activator inhibitor-1 (PAI-1) and insulin resistance is established in western countries. The major component of this association is obesity. Accordingly, we examined this association in Japan where the prevalence of obesity is low. Data for fasting PAI-1 levels of 404 subjects were obtained from a general population in a farming area. We measured body mass index (BMI), systolic and diastolic blood pressure, high-density lipoprotein (HDL)-cholesterol, triglycerides, fasting plasma glucose (FPG), insulin, creatinine, and uric acid. The use of alcohol was ascertained by a questionnaire. The formula for the homeostasis model assessment (HOMA) score was used as an index of insulin resistance. Uni- and multivariate analyses were applied for the determinants of plasma PAI-1. Age and sex did not affect plasma PAI-1. The average BMI was 23.0 +/- 3.2 kg/m(2). Thus, most of the subjects were not obese. Because, even in this population, BMI (P <.001) was the strongest determinant for PAI-1 after univariate analysis, we performed multiple linear regression analyses after adjustment for BMI. The significance of triglycerides, FPG, insulin, and the HOMA score still remained. PAI-1 levels were linearly related to the HOMA score. From the subanalysis of the non-obese subjects (BMI < 25; n = 298), waist-hip ratio, triglycerides, FPG, and HOMA scores were significant determinants of PAI-1. This is the first demonstration that increased PAI-1 levels were significantly related to insulin resistance in a Japanese general population. PAI-1 levels are associated with insulin resistance, irrespective of obesity.