Shunichi Takahata

MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance.

Due to the poor prognosis of pancreatic cancer, novel diagnostic modalities for early diagnosis and new therapeutic strategy are urgently needed. Recently, microRNA-21 (miR-21) was reported to be strongly overexpressed in pancreatic cancer as well as in other solid cancers. We investigated the functional roles of miR-21, which have not been fully elucidated in pancreatic cancer. miR-21 expression was assessed in pancreatic cancer cell lines (14 cancer cell lines, primary cultures of normal pancreatic epithelial cells and fibroblasts, and a human normal pancreatic ductal epithelial cell line) and pancreatic tissue samples (25 cancer tissues and 25 normal tissues) by quantitative real-time reverse transcription-PCR amplification. Moreover, we investigated the proliferation, invasion, and chemoresistance of pancreatic cancer cells transfected with miR-21 precursor or inhibitor. miR-21 was markedly overexpressed in pancreatic cancer cells compared with nonmalignant cells, and miR-21 in cancer tissues was much higher than in nonmalignant tissues. The cancer cells transfected with the miR-21 precursor showed significantly increased proliferation, Matrigel invasion, and chemoresistance for gemcitabine compared with the control cells. In contrast, inhibition of miR-21 decreased proliferation, Matrigel invasion, and chemoresistance for gemcitabine. Moreover, miR-21 positively correlated with the mRNA expression of invasion-related genes, matrix metalloproteinase-2 and -9, and vascular endothelial growth factor. These data suggest that miR-21 expression is increased in pancreatic cancer cells and that miR-21 contributes to the cell proliferation, invasion, and chemoresistance of pancreatic cancer.[Mol Cancer Ther 2009;8(5):1067–74]

Long-term consequence of endoscopic sphincterotomy for bile duct stones

BACKGROUND There are many reports of early- and intermediate-term results of endoscopic sphincterotomy. However, few data are available on long-term clinical outcome of endoscopic sphincterotomy for removal of common bile duct stones. METHODS Of 419 patients who underwent endoscopic sphincterotomy, follow-up data were obtained in 410 patients (98%). The period ranged from 1 month to 20 years (average 122 months). RESULTS Late complications included recurrence of stones (12.3%), acute cholangitis, acute cholecystitis (22% of 32 patients with gallstones, 0% of 88 patients without gallstones), new gallstone formation (6 patients), liver abscess (5 patients), and biliary carcinoma (8 patients). All of the recurrent stones were bilirubinate irrespective of the type of stone at sphincterotomy. Cholangitis and liver abscess occurred in 31% and 11%, respectively, of patients with residual intrahepatic stones but not in patients with complete intrahepatic stone clearance. CONCLUSIONS Late complications occur in a considerable proportion of patients after endoscopic sphincterotomy for the treatment of common bile duct stones, including stone recurrence, acute cholecystitis (which occurs only in patients with gallstones), liver abscess in patients with residual intrahepatic stones, and biliary carcinoma. The fact that the recurrent stones are invariably of the bilirubinate type, irrespective of the type of stones at initial treatment, suggests that bacterial infestation due to ablation of the sphincter mechanism may have a causative role.

Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas

Objective:Invasive ductal carcinoma (DC) of the pancreas arising as an independent lesion in association with intraductal papillary mucinous neoplasm (IPMN) has occasionally been reported. However, clinicopathological features related to the presence of DC in patients with IPMN remain largely unknown. The purpose of the present study was to determine the factors predicting the presence of concomitant DC in those with IPMN. Materials and Methods:We retrospectively reviewed the clinicopathological data of a consecutive series of 236 patients with IPMN treated by surgical resection or followed up at our institution between January 1987 and June 2008. In an attempt to identify predictors for the presence of DC, clinicopathological variables were compared between IPMN patients with concomitant DC and those without concomitant DC. Results:Of 236 patients with IPMN, concomitant DC was detected synchronously or metachronously in 22 patients (9.3%). All the 22 IPMNs were of branch duct type and histological grades of 12 resected IPMNs were adenoma(n = 8) and borderline (n = 4). Multivariate analysis revealed 2 significant predictive factors for the presence of DC in IPMN, including worsening diabetes mellitus (P < 0.001) and an abnormal serum CA 19–9 level (P = 0.024). Conclusion:In view of the high prevalence of DC careful inspection of the entire pancreatic gland is necessary for early detection of DC in patients with branch duct IPMNs, especially when worsening diabetes mellitus and an abnormal serum CA 19–9 level are manifested.

Cyst size indicates malignant transformation in branch duct intraductal papillary mucinous neoplasm of the pancreas without mural nodules.

Objectives: In branch duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas, the importance of the cyst size to predict malignancy is still controversial. Our aim was to elucidate the malignant potential of branch duct IPMN without mural nodules (flat branch duct IPMN). Methods: Seventy-three patients with flat branch duct IPMNs were studied in our institution. Results: There were 6 malignant IPMNs in this series, all of which were 30 mm or more in size, whereas there was no malignancy in IPMNs of less than 30 mm. Statistically significant predictors of malignancy were atypical cytological condition and main pancreatic duct (MPD) diameter of 5 mm or more. The cyst size of 30 mm or more tended to be associated with malignancy. The frequency of malignancy in flat branch duct IPMNs with the size of 30 mm or more and MPD diameter of less than 5 mm was 3.6%, whereas there were 5 malignant cases (26.3%) in flat branch duct IPMNs with the size of 30 mm or more and MPD diameter of 5 mm or more. Conclusions: We conclude that the size criteria (≥30 mm) to predict malignancy proposed in the international consensus guidelines is appropriate and resection or meticulous follow-up using cytological examination and MPD dilatation is needed in patients with flat branch duct IPMNs.

Invasive carcinoma derived from the nonintestinal type intraductal papillary mucinous neoplasm of the pancreas has a poorer prognosis than that derived from the intestinal type.

BACKGROUND Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is divided into 4 subtypes: an intestinal type, a gastric type, a pancreatobiliary type, and an oncocytic type. The purposes of this study were to clarify the outcomes and the characteristics of invasive carcinoma derived from IPMN (invasive IPMC) by focusing on these subtypes with a comparison to conventional invasive ductal carcinoma (IDC) of the pancreas. METHODS A total of 30 patients with invasive IPMC were reviewed, and the tumors were divided into 2 pathologic subtypes, intestinal and nonintestinal type. The prognosis and characteristics of the 2 subtypes were evaluated. Furthermore, the prognosis of 119 patients with conventional IDC was compared with that of patients with invasive carcinoma derived from the intestinal or nonintestinal type IPMN. RESULTS The 5-year survival rate of patients with the nonintestinal type (0.0%) was as poor as that of patients with conventional IDC (19.9%; P = .67). The patients with the intestinal type (66.7%) had a more favorable prognosis than patients with conventional IDC (P < .001). The nonintestinal type was characterized by positive lymphatic invasion and tubular invasive pattern. CONCLUSION Invasive carcinoma derived from the nonintestinal type IPMN characterized by lymphatic invasion and tubular invasive pattern is associated with a poor prognosis.

Follow-up study after resection of intraductal papillary mucinous neoplasm of the pancreas; special references to the multifocal lesions and development of ductal carcinoma in the remnant pancreas

BACKGROUND Frequency and characteristics of metachronous occurrence of multifocal intraductal papillary mucinous neoplasms (IPMNs) or distinct pancreatic ductal adenocarcinomas (PDACs) in the remnant pancreas during follow-up evaluation after pancreatectomy for IPMNs have not been well known. The aim of this study was to investigate the outcomes after resection of IPMNs, especially focusing on the metachronous occurrence of multifocal IPMNs and distinct PDACs. METHODS Medical records of 172 patients who underwent resection of IPMNs were reviewed retrospectively, and the data regarding the occurrence of metachronous IPMNs or PDACs in the remnant pancreas during a mean postoperative follow-up period of 64 months were collected. RESULTS The incidence including synchronous and metachronous multifocal occurrence of IPMNs was 20% (34 of 172), and that of distinct PDACs was 9.9% (17 of 172). Ten metachronous IPMNs developed in the remnant pancreas after a mean time of 23 postoperative months (range, 12-84 mo), and 2 with main duct IPMNs (both were carcinoma in situ) required remnant pancreatectomy. Six distinct PDACs developed in the remnant pancreas after a mean time of 84 postoperative months (range, 12-150 mo). Four of them were found to have a tumor with a size of less than 2 cm, whereas the remaining 2 PDACs were found to be unresectable more than 10 years after resection of IPMNs. CONCLUSIONS Intense long-term follow-up evaluation is necessary for the early detection of metachronous occurrence of distinct PDACs as well as malignant IPMNs after resection of IPMNs.

Intraductal Papillary Mucinous Neoplasms of the Pancreas With Distinct Pancreatic Ductal Adenocarcinomas Are Frequently of Gastric Subtype

Objective:To identify a high-risk group of patients with pancreatic ductal adenocarcinoma (PDAC), independently arising in the pancreas with intraductal papillary mucinous neoplasm (IPMN), using histopathologic subtypes. Background:Pathologic features of IPMN with distinct PDAC, including histopathologic subtypes of IPMN and PDAC phenotypes, have not been well characterized. Mucin expression patterns and the mutational status of GNAS and KRAS are useful to explore the relationship between these 2 lesion types. Methods:Clinicopathologic data of 179 resected IPMNs and 180 resected PDACs without IPMNs as a control group were reviewed. IPMNs were classified into 4 grades (low-grade, intermediate-grade, high-grade dysplasia, and an associated invasive carcinoma) and 4 subtypes (gastric, intestinal, pancreatobiliary, and oncocytic). The expression of MUC1, MUC2, MUC5AC, MUC6, and CDX2 was investigated by immunohistochemistry in IPMNs and PDACs with and without IPMNs. The mutational status of GNAS and KRAS was evaluated by cycle sequencing in PDACs and pre-/coexisting IPMNs. Results:Twenty-six synchronous or metachronous PDACs were identified in 20 patients (11.2%) with IPMNs. Occurrence of concomitant PDACs was more frequently observed in gastric-type IPMNs (18/110, 16.4%) compared with intestinal (1/49, 2.0%), pancreatobiliary (1/17, 5.9%), or oncocytic-type (0/3, 0%) (P = 0.047). Both PDACs with and without IPMNs were frequently positive for MUC1, MUC5AC, and MUC6 expression, as assessed by immunohistochemistry, but were negative for MUC2 and CDX2. The mucin-staining patterns were similar to those of invasive tubular adenocarcinoma arising from gastric-type IPMNs. Mutation of GNAS within codon 201 was not detected in PDACs and gastric-type IPMNs, whereas most of these exhibited KRAS mutations. However, the R201H GNAS mutation was detected in 1 intestinal-type IPMN with distinct PDAC. Conclusions:Mucin expression patterns demonstrate that PDAC without GNAS mutations of an aggressive phenotype frequently arise in the pancreas with benign gastric-type IPMN in the absence of GNAS mutations.

An increase in the number of predictive factors augments the likelihood of malignancy in branch duct intraductal papillary mucinous neoplasm of the pancreas

BACKGROUND International consensus guidelines for the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas provide several factors that can be used to predict which IPMNs will become malignant.The sensitivity of each factors predictive accuracy, however, is relatively low, making it difficult to determine the appropriate treatment in individual cases. The aim of this study was to investigate whether increasing the number of predictive factors might augment the sensitivity of the established guidelines to detect malignant IPMNs. METHODS The medical records of 138 patients with IPMNs resected at our institution were reviewed. Possible malignant predictors were analyzed by univariate and multivariate analysis, and the effects of the number of factors and the predictive score of the pathologic results were examined. The cutoff points for the number of predictors to discriminate between malignant and nonmalignant IPMNs were established by constructing receiver operating characteristic curves. RESULTS A predictive analysis could not be carried out for the main duct IPMNs because of the high prevalence of malignancy and the small number of significant predictors associated with them. For malignant branch duct IPMNs, however, we identified 4 predictive factors that helped determine the correct diagnosis as follows: (1) the presence of a cyst ≥30 mm in diameter; (2) the presence of mural nodules; (3) a history of acute pancreatitis; and (4) atypical results of pancreatic juice cytology. An increase in the number of these factors significantly affected the sensitivity to predict malignancy. The area under the curve for the number of predictors for malignant branch duct IPMNs was 0.856, and the sensitivity and specificity were 96% and 71%, respectively, when the cutoff point was set at 2. The predictive scoring system also showed the same values of sensitivity and specificity for the number of factors. CONCLUSION Patients with branch duct IPMNs who have 2 or more of the 4 predictive factors described above should undergo standard pancreatectomy with lymph node dissection, whereas patients who present with 0 or 1 predictive factor can be treated by minimal pancreatectomy without nodal dissection or by careful observation without resection. All patients with main duct IPMNs, therefore, should be treated with resection as suspected malignancies.

Treatment strategy for main duct intraductal papillary mucinous neoplasms of the pancreas based on the assessment of recurrence in the remnant pancreas after resection: A retrospective review

Objectives:To clarify the recurrence pattern after resection of main duct intraductal papillary mucinous neoplasms (MD-IPMNs) using molecular analyses and determine the most adequate treatment strategy. Background:The most appropriate resection line for MD-IPMNs remains an unresolved issue. Methods:Medical records of 56 patients with pancreatectomy were retrospectively reviewed. Histological subtypes and Kras/GNAS mutations were assessed in patients with recurrence in the remnant pancreas. Results:Forty-nine patients underwent partial pancreatectomy and 7 underwent total pancreatectomy. Thirty-six patients (64%) had malignant MD-IPMNs. Recurrence was observed in 7 of 49 patients (14%), including 6 with malignant IPMNs and 1 with pancreatic ductal adenocarcinoma, all of whom underwent remnant pancreatectomy. The cumulative disease-specific survival rate of patients with pancreatic recurrence was greater than that of patients with extrapancreatic recurrence (P < 0.001). Although the pancreatic margin status at the initial operation did not affect the pancreatic recurrence rate, all 4 recurrent IPMNs examined had histological subtypes and Kras/GNAS mutations identical to those of the initial lesions. Four patients experienced recurrence in the remnant pancreas or systemic recurrence after resection of high-grade dysplasia of MD-IPMN. Three of the 56 patients had concomitant pancreatic ductal adenocarcinomas and MD-IPMNs. Conclusions:One-step total pancreatectomy can be avoided, and remnant total pancreatectomy would lead to favorable outcomes even in patients with pancreatic recurrence, some cases of which seem to involve residual lesions. Postoperative surveillance of high-grade dysplasia should be performed as if malignant, and close attention should be paid to the occurrence of concomitant pancreatic ductal adenocarcinomas in patients with MD-IPMNs.

Comparative Study of Laparoscopic and Open Distal Pancreatectomy

BACKGROUND Laparoscopic distal pancreatectomy (LDP) has been shown to be an effective surgical option for benign lesions in the body and tail of the pancreas. However, its advantages and disadvantages have not been well characterized. In this study, we compared the outcomes of LDP and open pancreatectomy performed in our clinic. MATERIALS AND METHODS Peri- and postoperative outcomes were retrospectively compared between patients with benign pancreatic disorders who underwent open distal pancreatectomy (ODP) (n = 35) and those who underwent LDP (n = 40). The peri- and postoperative factors analyzed included operative time, blood loss, hospital stay, postoperative recovery, biochemical findings, and complications. RESULTS LDP was associated with significantly less operative blood loss (363 versus 606 mL; P = 0.001) and shorter hospital stay (22 versus 27 day; P = 0.009), but longer operative time (342 versus 250 min; P = 0.000), compared with ODP. There were no significant differences between the two groups in complication rates or postoperative recovery, except for the significantly shorter duration of postoperative pain-killer intake and earlier improvement of the biochemical analysis in LDP than in ODP. CONCLUSIONS LDP appears to be a safe, desirable procedure for the management of benign pancreatic diseases, with outcomes similar to ODP.