Takaharu Yasui

Multifocal Pancreatic Ductal Adenocarcinomas Concomitant with Intraductal Papillary Mucinous Neoplasms of the Pancreas Detected by Intraoperative Pancreatic Juice Cytology. A Case Report

CONTEXT Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have been detected with increasing frequency as a result of the progression of diagnostic modalities. Recently, invasive ductal carcinoma of the pancreas concomitant with IPMNs has been the focus of attention. CASE REPORT We report the case of a 57-year-old man with multifocal ductal carcinomas of the pancreas concomitant with IPMNs detected by intraoperative cytology. During a follow-up for branch duct IPMNs, a stenotic lesion of the main duct in the pancreatic body was found by ERCP, and brush cytology of the stenosis revealed an adenocarcinoma. A distal pancreatectomy was proposed; however, intraoperative pancreatic juice cytology from the pancreatic head also revealed adenocarcinoma, and a total pancreatectomy was finally carried out. Pathological examination of the resected specimen showed multifocal ductal carcinomas and IPMNs in the distal pancreas, and invasive ductal carcinoma in the pancreatic head which had not been detected by preoperative imaging studies. CONCLUSIONS Surgeons should be aware of the possibility of multifocal carcinomas in patients with concomitant IPMNs. Intraoperative pancreatic juice cytology should always be performed in order to confirm the absence of carcinoma in the pancreas to be left in place after planned resection.

Different incretin responses after pancreatoduodenectomy and distal pancreatectomy.

Objectives Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are known as incretins to stimulate insulin secretion. The aims of this study were to investigate the postoperative &bgr;-cell function and hormonal responses of GLP-1 and GIP after pancreatoduodenectomy (PD) and distal pancreatectomy (DP). Methods Oral glucose tolerance tests were performed in 34 patients (20 PD and 14 DP) before and 1 month after operation. The changes in the serum glucose and insulin concentrations, homeostasis model assessment of insulin resistance, and pancreatic &bgr;-cell function (BCF) were analyzed. GLP-1 and GIP were also measured. Results There was no patient with postoperative deterioration of glucose tolerance after PD, whereas impairment of glucose metabolism was observed after DP. Homeostasis model assessment of insulin resistance decreased after PD, whereas those after DP showed no change. The postoperative BCF were lower than preoperative values in both groups. GLP-1 increased after DP but not after PD, whereas GIP decreased after PD but not after DP. Conclusions The changes in glucose metabolism and incretin responses were different between PD and DP. The increased level of GLP-1 after DP might reflect the relatively insufficient BCF; and thus, perioperative administration of GLP-1 might improve the diabetic condition after DP.

Tumor–stroma interactions reduce the efficacy of adenoviral therapy through the HGF-MET pathway

Many preclinical studies have shown the potential of adenovirus‐based cancer gene therapy. However, successful translation of these promising results into the clinic has not yet been achieved. Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant desmoplastic stroma, and tumor–stromal cell interactions play a critical role in tumor progression. Therefore, we hypothesized that tumor–stroma interactions reduce the efficacy of adenoviral therapy. We investigated the effect of fibroblasts on adenovirus‐based gene therapy using SUIT‐2 and PANC‐1 pancreatic cancer cells cultured with or without fibroblast‐conditioned culture supernatant then infected with Ad‐LacZ. After 48 h, the cells were stained for β‐galactosidase. The results showed that the number of β‐galactosidase‐positive cells was significantly reduced after culture with fibroblast‐conditioned supernatant (P < 0.05). Because the hepatocyte growth factor (HGF)/MET pathway plays an important role in tumor–stroma interactions we next investigated the involvement of this pathway in tumor–stroma interactions leading to the decreased efficacy of adenoviral therapy. SUIT‐2 cells were cultured with or without SU11274 (a MET inhibitor) and/or fibroblast‐conditioned culture supernatant, then infected with Ad‐GFP. After 48 h, GFP‐positive cells were counted. The number of GFP‐positive cells in cultures containing fibroblast‐conditioned supernatant plus SU11274 was significantly greater than in cultures without SU11274. In conclusion, our results suggest that stromal cells in PDAC reduce the efficacy of adenoviral therapy through a mechanism involving the HGF/MET pathway. Control of such tumor–stroma interactions may lead to improvements in adenoviral gene therapy for PDAC. (Cancer Sci 2011; 102: 484–491)

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)