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Objectives: To clarify the usefulness of molecular biomarkers for distinguishing invasive carcinoma derived from intraductal papillary mucinous neoplasms (IPMNs [Inv-IPMN]) from concomitant pancreatic ductal adenocarcinoma (PDAC)., Methods: Data from 19 patients with resected concomitant PDAC were retrospectively reviewed. KRAS/GNAS mutations and immunohistochemical (IHC) expression of p53 and p16/CDKN2A were assessed in both IPMN and distinct PDAC. As controls, KRAS/GNAS mutations and IHC labeling were assessed between invasive and noninvasive components in 1 lesion of 22 independent patients., Results: KRAS/GNAS mutation status of invasive and noninvasive components in Inv-IPMN was consistent in 18 (86%) of 21 patients. Conversely, mutational patterns in IPMN and distinct PDAC in the same pancreas differed from each other in 17 (89%) of 19. There were 10 (53%) and 8 (42%) of 19 patients who showed the same p53 and p16/CDKN2A staining between concomitant PDAC and distinct IPMN. In the Inv-IPMN cohort, 19 (86%) of 22 patients showed the same IHC expression pattern between the noninvasive and invasive components., Conclusions: It may be possible to distinguish Inv-IPMN from concomitant PDAC by assessing these molecular biomarkers. More precise distinction of Inv-IPMN and concomitant PDAC will lead to adequate recognition of the natural history of IPMNs and hence optimal management.

Objectives: As a strategy to diagnose early-stage pancreatic ductal adenocarcinoma (PDAC) is urgently needed, we aimed to clarify characteristics of early-stage PDAC., Methods: We retrospectively reviewed medical records of 299 consecutive patients who underwent R0 or R1 surgical resection for PDAC between 1994 and 2013 and compared clinical characteristics between patients with early-stage (stages 0-I by Japanese General Rules for Pancreatic Cancer) and advanced-stage (stages II-IV) disease. Diagnostic processes were also analyzed., Results: Twenty-four patients (8%) had early-stage PDAC (stage 0: 11; stage I: 13). Univariate and multivariate analyses showed that presence or history of intraductal papillary mucinous neoplasm (P < 0.01), history of pancreatitis (P < 0.01), and presence or history of extrapancreatic malignancies (P = 0.01) independently predicted detection of early-stage PDAC. Cytological examination during endoscopic retrograde pancreatography cytology was ∼65% sensitive in preoperative diagnosis of early-stage PDAC, whereas other imaging modalities were only 29% to 38% sensitive; 9 of 24 early-stage PDACs were diagnosed by endoscopic retrograde pancreatography cytology alone., Conclusions: Endoscopic retrograde pancreatography cytology for patients with intraductal papillary mucinous neoplasm or pancreatitis may help diagnose early-stage PDAC. Surveillance of extrapancreatic malignancies might also provide opportunities to detect early-stage PDAC as a second malignancy.

The cell surface protein Transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors, and its expression on tumor cells is implicated in cancer cell metastasis and patient prognosis. The role of TM4SF1 in malignant tumors remains poorly understood, particularly in pancreatic cancer. We performed immunohistochemical staining to analyze the expression of TM4SF1 in resected pancreatic tissues and investigated the correlation between TM4SF1 expression and prognosis. The function of TM4SF1 in the invasion and migration of pancreatic cancer cells was analyzed in vitro using an RNA interference technique. In pancreatic cancer tissues, TM4SF1 expression was detected in cancer cells, and patients with high tumor levels of TM4SF1 showed longer survival times than those with low TM4SF1 levels (P=0.0332). In vitro, reduced TM4SF1 expression enhanced the migration (P<0.05) and invasion (P<0.05) of pancreatic cancer cells partially via decreased E-cadherin expression. TM4SF1 protein levels were also reduced after TGF-β1-induced epithelial-mesenchymal transition (EMT).TM4SF1 expression is associated with better prognosis in pancreatic cancer. Loss of TM4SF1 contributes to the invasion and migration of pancreatic cancer cells.

Objective: The aims of this study were to investigate the GNAS mutational status in pancreatic intraductal papillary mucinous neoplasm (IPMN) with and without distinct pancreatic ductal adenocarcinoma (PDAC) and to evaluate the significance of GNAS analysis using duodenal fluid (DF) in patients with IPMN., Methods: The clinicopathologic features of 110 patients with IPMN including 16 with distinct PDAC were reviewed. The GNAS status in the IPMN tissue and 23 DF specimens was assessed by sensitive mutation scanning methods., Results: The GNAS mutation rate in IPMN with distinct PDAC was significantly lower than that in IPMN without PDAC (4/16, 25%, vs 61/94, 65%; P = 0.0047). By multivariate analysis, GNAS wild-type and gastric type IPMNs were significantly associated with distinct PDAC. Of 45 GNAS wild-type IPMNs, 10 (43%) of 23 gastric type IPMNs had distinct PDAC, whereas only 2 (9%) of 22 non-gastric type IPMNs had distinct PDAC (P = 0.017). The GNAS status in DF was consistent with that in tissue in 21 (91%) of 23 patients., Conclusions: Distinct PDACs frequently develop in the pancreas with gastric type IPMN without GNAS mutations. Duodenal fluid DNA test would predict the GNAS status of IPMN, whereas the detection of the gastric subtype using noninvasive test remains to be determined.

Background: Main duct intraductal papillary mucinous neoplasms (MD-IPMNs) may occur in 1 or multiple segments of the pancreatic duct. Unlike multifocal branch duct (BD)-IPMNs, the clonality of multisegmental MD-IPMNs remains unclear. GNAS mutations are common and specific for IPMNs, and mutational assessment might be useful to determine the clonality of IPMNs as well as to detect high-risk IPMN with distinct ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]). Our aim was to clarify clonality using GNAS status in multisegmental MD-IPMNs., Methods: We retrospectively reviewed the medical records of 70 patients with MD-IPMN. Histologic subtypes and KRAS/GNAS mutations were investigated, and the clonal relationships among multisegmental MD-IPMNs were assessed. Mutational analysis was performed using high-resolution melting analysis and subsequent Sanger/pyrosequencing., Results: Thirteen patients had multiple synchronous and/or metachronous lesions. Seven of these 13 patients had multiple MD-IPMNs; 3 had multiple MD-IPMNs and distinct BD-IPMNs; 1 had multiple MD-IPMNs and a distinct PDAC; 1 had a solitary MD-IPMN, BD-IPMN, and PDAC; and 1 had a solitary MD-IPMN and PDAC. KRAS/GNAS mutations were consistent in 10 of 11 multisegmental MD-IPMNs, whereas MD-IPMNs, BD-IPMNs, and PDACs tended to show different mutational patterns. The frequency of malignant IPMNs was significantly higher in the multisegment cohort; malignant IPMNs constituted 90% (9/10) of the multiple cohort and 56% (32/57) of the solitary cohort (P = .04). Mutant GNAS was more frequently observed in the intestinal subtype (94%) than the others., Conclusion: MD-IPMNs can be characterized by monoclonal skip progression. Close attention should be paid to the possible presence of skip areas during or after partial pancreatectomy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Routine endoscopic retrograde pancreatography (ERP) for pancreatic juice cytology (PJC) during management of intraductal papillary mucinous neoplasm (IPMN) is not recommended in the international consensus guidelines 2012. The aim of the present study was to investigate the roles of PJC in relation to the new stratification of clinical findings in the consensus guidelines 2012., Methods: Medical records of 70 consecutive patients who underwent preoperative PJC, subsequent pancreatectomy, and a pathological diagnosis of IPMN were reviewed. Diagnostic ability of PJC to detect malignant lesions was calculated by the stratification of clinical findings., Results: Forty patients had malignant lesions, including 29 with malignant IPMN, 10 with concomitant pancreatic adenocarcinoma, and one with both. Accuracies of PJC in all 70 patients and in 59 patients with IPMN alone were 77 and 80 %, respectively. The sensitivity and accuracy of PJC in patients with "worrisome features" were 100 and 94 %, respectively. Eight of 11 patients with concomitant pancreatic adenocarcinoma had non-malignant IPMN without risk factors, and 3 significant lesions could be diagnosed only by ERP/PJC. In addition, the management plan based on imaging study changed from observation to resection in two patients who had the single "worrisome feature" of branch duct IPMN and positive PJC results. As a result, PJC altered the management plan in 5 patients., Conclusions: Pancreatic juice cytology potentially has important roles to determine the adequate treatment choice in patients with IPMNs with "worrisome features," and to detect significant lesions that could not be detected by other imaging modalities.

Objectives: The 2012 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas stratified patients into 2 clinical categories, "high-risk stigmata" and "worrisome features," and recommended different therapeutic strategies for these groups. The aim of this study was to elucidate the significance of these categories in terms of predicting malignant IPMNs., Methods: The medical records of 100 consecutive patients who underwent pancreatectomy for IPMNs were retrospectively reviewed. Seventy patients with branch duct IPMNs (BD-IPMNs) were stratified into 3 groups. The relationships between the number of predictive factors and histopathologic grade were investigated., Results: The prevalence rates of malignant IPMN, invasive carcinoma, and lymph node metastasis in the high-risk group were 80%, 55%, and 20%, respectively, with these percentages significantly increasing in a stepwise manner according to the number of predictive factors. In contrast, there was no significant correlation between the number of worrisome features and grade of malignancy in patients stratified as having worrisome BD-IPMNs., Conclusions: The number of high-risk stigmata correlated significantly with the grade of malignancy of BD-IPMNs. The presence of at least 1 high-risk stigma in patients with BD-IPMNs indicates a need for pancreatectomy with lymphadenectomy.

Purpose: In patients with pancreatic ductal carcinoma (PDAC), EUS-FNA carries a risk of cancer seeding. To avoid this risk, we attempted to obtain preoperative cytological confirmation of adenocarcinoma by ERCP. The aim of this study was to assess the validity of our diagnostic strategy., Methods: The medical records of 124 consecutive patients who were investigated for potentially resectable PDAC were retrospectively reviewed, and the ability to detect adenocarcinoma by ERCP was evaluated., Results: ERCP was performed in 115 patients, 69 of whom had positive cytology results. Thirty-four patients underwent EUS-FNA, 29 of whom had positive cytology results. A total of 98 patients (79 %), therefore, had preoperative cytological confirmation of adenocarcinoma, which was more frequent in patients with lesions of the head of the pancreas than in those with lesions of the body or tail of the pancreas. The postoperative pathological diagnosis demonstrated malignant pancreatic neoplasms in 122 patients (98 %), including 111 with PDAC. EUS-FNA did not affect the rate of postoperative peritoneal dissemination., Conclusions: Our strategy using ERCP as the initial diagnostic modality for obtaining cytological confirmation of potentially resectable PDAC seems to be adequate, yielding a high rate of positive cytology, especially in cases with tumors of the head of the pancreas.

Background: CD166, also known as activated leukocyte cell adhesion molecule (ALCAM), is expressed by various cells in several tissues including cancer. However, the role of CD166 in malignant tumors is controversial, especially in pancreatic cancer. This study aimed to clarify the role and significance of CD166 expression in pancreatic cancer., Methods: We performed immunohistochemistry and flow cytometry to analyze the expression of CD166 in surgical pancreatic tissues and pancreatic cancer cell lines. The differences between isolated CD166+ and CD166- pancreatic cancer cells were analyzed by invasion and migration assays, and in mouse xenograft models. We also performed quantitative RT-PCR and microarray analyses to evaluate the expression levels of CD166 and related genes in cultured cells., Results: Immunohistochemistry revealed high expression of CD166 in pancreatic cancer tissues (12.2%; 12/98) compared with that in normal pancreas controls (0%; 0/17) (p = 0.0435). Flow cytometry indicated that CD166 was expressed in 33.8-70.2% of cells in surgical pancreatic tissues and 0-99.5% of pancreatic cancer cell lines. Invasion and migration assays demonstrated that CD166- pancreatic cancer cells showed stronger invasive and migratory activities than those of CD166+ cancer cells (p<0.05). On the other hand, CD166+ Panc-1 cells showed a significantly stronger colony formation activity than that of CD166- Panc-1 cells (p<0.05). In vivo analysis revealed that CD166+ cells elicited significantly greater tumor growth than that of CD166- cells (p<0.05) in both subcutaneous and orthotopic mouse tumor models. mRNA expression of the epithelial-mesenchymal transition activator Zeb1 was over-expressed in CD166- cells (p<0.001). Microarray analysis showed that TSPAN8 and BST2 were over-expressed in CD166+ cells, while BMP7 and Col6A1 were over-expressed in CD166- cells., Conclusions: CD166+ pancreatic cancer cells are strongly tumorigenic, while CD166- pancreatic cancer cells exhibit comparatively stronger invasive and migratory activities. These findings suggest that CD166 expression is related to different functions in pancreatic cancer cells.

Background: Peroral pancreatoscopy (POPS) using a mother-baby endoscope system is often useful for assessment of intraductal papillary mucinous neoplasm (IPMN) of the pancreas with main pancreatic duct (MPD) involvement, but is not widely used for several reasons. The aim of this study was to evaluate the usefulness of the SpyGlass Direct Visualization System for assessment of IPMN., Methods: Seventeen patients diagnosed with possible IPMN with MPD dilation underwent peroral pancreatoscopy using the SpyGlass system at our institution. The quality of visualization and the sensitivities of cytological and pathological investigations for diagnosing malignant lesions were evaluated., Results: Peroral pancreatoscopy was performed using the SpyScope in 12 patients and an endoscopic retrograde cholangiopancreatography (ERCP) catheter in five patients. Sufficient visualization was achieved in 92% of cases using the SpyScope and 40% of cases using the ERCP catheter. Biopsy under direct visualization was successful in seven patients. Biopsy specimens showed adenocarcinoma in one patient, benign neoplastic epithelium in five patients, and regenerative changes in one patient; and had 25% sensitivity and 100% specificity for detecting malignancy. SpyGlass pancreatoscopy with irrigation cytology had 100% sensitivity and 100% specificity for detecting malignancy. SpyGlass pancreatoscopy was useful for determining the operative excision line in three patients. There were no severe procedure-related adverse events., Conclusions: Peroral pancreatoscopy using the SpyGlass system seems to be feasible and useful for assessment of IPMN with a dilated MPD., (© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: It is difficult to predict the malignant potential of pancreatic neuroendocrine tumors (PNETs) precisely. This study investigated the validity of a new grading system adopted by the World Health Organization 2010 classification to determine risk factors for recurrence of PNETs., Methods: Data of 70 patients with PNETs who underwent curative resection were retrospectively examined by uni- and multivariate analyses. Histopathological findings were re-reviewed by experienced pathologists. NET G1 was defined as mitotic count <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index, and NET G2 as 2-20 mitosis per 10 HPF and/or 3-20% Ki67 index., Results: There were 58 patients with NET G1 and 12 with NET G2. Incidence of recurrence was 11.4%. Univariate analysis demonstrated significant risk factors for recurrence including NET G2 of histological grade (P = 0.0089), male gender (P = 0.0333), tumor size ≥ 20 mm (P = 0.0117), lymph node metastasis (P = 0.0004), liver metastasis (P < 0.0001), lymphatic invasion (P = 0.046), and neural invasion (P = 0.0002). By multivariate analysis, histological grade (hazard ratio; 59.76, P = 0.0022) and neural invasion (hazard ratio; 147.49, P = 0.0016) were significantly associated with recurrence of PNETs., Conclusions: This study confirmed the prognostic relevance of the new grading classification and that evaluation of perineural invasion and histological grade should be considered as prognostic predictors in well-differentiated PNETs (NET G1 and G2)., (© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Although autoantibodies to cancer antigens are candidates for biomarkers, no comprehensive studies to detect cancer-specific antibodies have been performed. This study identified autoantibodies in the sera of pancreatic cancer (PC) patients using proteomics based on a wheat germ cell-free protein production system., Methods: We constructed a biotinylated protein library of 2,183 genes. Interactions between biotinylated proteins and serum antibodies were detected by AlphaScreen® assay. Relative luminescence signals of each protein in 37 PC patients and 20 healthy controls were measured, and their sensitivity and specificity for PC were calculated., Results: Luminescence signals of nine proteins were significantly higher than those of healthy controls, with calcium and integrin binding 1 (CIB1) protein showing the greatest significance (p = 0.002). Sensitivity, specificity, positive predictive value and negative predictive value of CIB1 autoantibody alone for PC were 76, 70, 82, and 61 %, respectively, and 97, 35, 74, and 88 %, respectively, when the four most significant proteins were combined. Presence of these autoantibodies did not vary significantly with other clinicopathological characteristics., Conclusion: Several autoantibodies, including CIB1, are potential biomarkers for PC.

Background/aims: This retrospective study was conducted to find preoperatively assessable risk factors for postoperative pancreatic fistula (POPF) in patients undergoing laparoscopic distal pancreatectomy (LDP) using a slow compression method with a stapler, which we call pen-firing compression (PFC)., Methodology: Fifty-two patients underwent LDP, of whom 42 underwent PFC for pancreatic division using a stapler. The relationship between preoperatively assessable factors and the incidence of clinical POPF was statistically analyzed., Results: Overall rate of POPF was 7.1% in 42 patients. Univariate analysis showed that greater BMI (p = 0.004) and thicker pancreatic stump (0.0022) were significant risk factors for POPF. BMI and stump thickness remained significant (P < 0.0001, P < 0.0001) by multivariate analysis. Cutoff points estimated by ROC curve were 27 kg/m2 for BMI and 27 mm for stump thickness., Conclusions: High BMI value and thick pancreatic stump are significant risk factors for POPF after LDP. Alternative treatment of the pancreatic stump may prevent POPF in high-risk patients.

Background: Mucinous cystic neoplasms (MCN) of the pancreas frequently develop in the distal pancreases of young women. Laparoscopic surgery can enhance cosmetic benefits and ease of surgery. This study assessed the feasibility of laparoscopic surgery for MCN., Methods: The medical records of 21 patients pathologically diagnosed with benign MCN after laparoscopic resection were reviewed. Clinical data were compared in the 11 patients with tumors ≥ 45 mm (large tumor group) and the 10 patients with tumors < 45 mm (small tumor group)., Results: Laparoscopic resection was completed in all patients, including distal pancreatectomy with (n = 9) and without (n = 11) spleen preservation and enucleation for pancreatic head lesion (n = 1). Operation time, blood loss, postoperative morbidity, and hospital stay were similar in the two groups. Spleen-preserving pancreatectomy could be more frequently completed in the small MCN group (P = 0.02). No recurrence was observed during a median follow-up period of 12 months., Conclusions: Laparoscopic surgery can be completed in all patients with benign MCN, even those with large tumors, and patients with small MCN can get the additional benefit of spleen preservation., (© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objectives: Aberrant expression of several microRNAs (miRs) has been reported in various neoplasms including intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. MicroRNA-196a (miR-196a) is up-regulated in Barrett esophagus (characterized by intestinal metaplasia) and in colorectal cancer; this relationship between intestinal characteristics and miR-196a might also be applicable to intestinal-type IPMNs. The aim of this study was to evaluate whether intestinal-type IPMNs can be discriminated from non-intestinal-type IPMNs by the expression level of miR-196a in tissue and pancreatic juice samples., Methods: Thirty-seven formalin-fixed paraffin-embedded tissue samples (including 3 of normal pancreatic ducts) and 36 pancreatic juice samples were obtained. The expression level of miR-196a measured by quantitative reverse transcription-polymerase chain reaction assays was compared between intestinal-type and non-intestinal-type IPMNs., Results: MicroRNA-196a expression in intestinal-type IPMN tissue samples (n = 18) was significantly higher than that of non-intestinal-type IPMNs (n = 16) (P < 0.001). Similarly, miR-196a expression in pancreatic juice samples of intestinal-type IPMNs (n = 6) was significantly higher than that of non-intestinal-type IPMNs (n = 30) (P = 0.008), and the sensitivity and specificity for prediction of intestinal-type IPMNs using pancreatic juice samples were both 83%., Conclusions: Elevated expression of miR-196a in pancreatic juice samples is predictive of intestinal-type IPMNs.

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.

We herein present a 71-year-old man who underwent pancreatoduodenectomy with the diagnosis of follicular pancreatitis. We could not completely deny malignancy by a preoperative imaging study. Endoscopic ultrasonography-guided fine needle aspiration biopsy demonstrated clusters of benign acinar cells and no proliferation of atypical lymphoid cells or rich plasma cells. Histologically, the prominent lymphoid follicle formation was seen in an ill-defined mass, 15 mm in size, in the pancreatic parenchyma. Duct-centered fibrotic rims were seen in the pancreatic ducts accompanied by mild fibrotic change between the follicles and obliterative phlebitis. No neoplastic epithelial cells were observed in the resected specimen, and infiltrating lymphocytes did not show any morphological atypia and monoclonal proliferation by immunohistochemical staining with B and T cell markers. In addition, we could exclude IgG4-related disease, because plasmacytic cells were rarely positive for IgG4. Although follicular pancreatitis is rare, this mass-forming inflammatory disease (pancreatitis) should be included in the preoperative differential diagnosis of pancreatic cancer., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Background: Patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas may have concomitant distinct pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and usefulness of intraoperative irrigation cytology of the remnant pancreas (IICP) during pancreatectomy to detect remnant distinct PDAC in patients with IPMN., Methods: The records of all 48 patients with IPMN who underwent IICP during partial pancreatectomy at our institution from April 2007 to March 2012 were reviewed retrospectively. After division of the pancreas, a 4-French tube was inserted into the main pancreatic duct of the remnant pancreas from the cut edge, and fluid for cytologic examination was obtained by saline irrigation through the tube. If the third IICP was positive, patients underwent additional pancreatic resection. Clinical and pathologic outcomes were evaluated., Results: The third IICP was positive in 5 patients. Postoperative pathologic examination showed that these patients all had remnant distinct PDAC in the additionally resected specimen, which was not detectable on preoperative imaging examination or on intraoperative macroscopic examination, ultrasonography, or palpation. This PDAC was stage 0 in 4 patients and stage III in 1 patient. No procedure-related complications were observed. One patient developed peritoneal metastasis after 10 months, 1 developed liver metastasis after 20 months, and 1 developed PDAC in the remnant pancreas after 24 months., Conclusion: IICP seems to be a safe and useful method for detection of early stage PDAC concomitant with IPMN that cannot be detected by preoperative imaging or intraoperative examination., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background/aims: The majority of patients with pancreatic cancer present with far advanced disease and jaundice. With the advancement of endoscopic interventional techniques, the role of surgical bypass has declined. However, surgical bypass is still considered to be appropriate in patients who are able to tolerate surgery. We performed hepaticocholecystojejunostomy consecutively as a palliative surgical biliary bypass for the purpose of long-term palliation. The aim of this study was to analyze the results of our palliative surgical biliary bypass, hepaticocholecystojejunostomy., Methodology: Between January 2001 through December 2009, 69 patients received palliative surgical biliary bypass (bypass group) and 33 patients received endoscopic biliary stenting (stent group) for unresectable pancreatic cancers. Mortality, morbidity and survival between the two groups were compared., Results: There was no in-hospital death in the bypass group, but 2 patients (6%) in the stent group died in the hospital (p = 0.04). The surgical morbidity rate was 15% in the bypass group, while 20 patients (61%) in the stent group developed complications, mainly due to stent blockage. There was no significant difference in overall survival between the two groups. Among patients who underwent systemic chemotherapy but did not present with jaundice at the time of diagnosis, those who underwent prophylactic surgical biliary bypass before chemotherapy showed better survival than those who underwent systemic chemotherapy preceding biliary bypass or biliary stenting after occurrence of jaundice (p = 0.01)., Conclusions: Hepaticocholecystojejunostomy resulted in negligible mortality, low morbidity and effective long-term palliation. Prophylactic surgical biliary bypass with gastrointestinal bypass might be a good treatment option for non-jaundiced patients undergoing chemotherapy for unresectable pancreatic cancer.

Objectives: CD105 expression correlates with prognosis for several cancers. However, its significance in pancreatic cancer is unclear., Methods: We analyzed CD105 expression in resected pancreatic cancer tissue and pancreatic cancer cell lines, compared the properties of CD105(+) and CD105(-) cells using quantitative RT-PCR and migration assays, and evaluated the relationship between CD105(+) cells and pancreatic stellate cells (PSCs)., Results: Immunohistochemistry showed that the frequency of CD105 expression was higher in pancreatic cancer than that in normal tissue(8% vs 0%, respectively). In flow cytometry, CD105 was expressed in pancreatic cancer cells, whereas weak CD105 expression was detected in normal pancreatic ductal epithelial cells. Quantitative RT-PCR showed that E-cadherin mRNA expression was suppressed and vimentin mRNA was overexpressed in CD105(+) cells (P < 0.05). Migration of CD105(+) cancer cells was strongly enhanced (more than that of CD105(+) cells) in coculture with PSCs (P < 0.05). CD105 expression did not correlate to clinicopathologic characteristics or the Kaplan-Meier survival analysis., Conclusions: Suppression of an epithelial marker and over expression of a mesenchymal marker suggest that epithelial-mesenchymal transition is induced in CD105(+) pancreatic cancer cells. CD105(+) pancreatic cancer cell migration is strongly enhanced by PSCs, suggesting that these cells play a role in the pancreatic cancer microenvironment.

Background: Pancreatic cancer is associated with a devastating prognosis, partially because of its aggressive metastatic ability. Identification of prognostic markers of metastasis would be useful in the clinical management of postoperative patients with pancreatic cancer. Mal, T-cell differentiation protein 2 (MAL2) has been identified as a molecule predictive of metastases; the clinical relevance of MAL2 in pancreatic cancer is unknown., Methods: Orthotopic human pancreatic cancer xenografts from the pancreatic cancer cell line SUIT-2 were established in nude mice. Only liver metastasis was harvested and cultured. These metastatic cycles were repeated 5 times to establish a highly metastatic cell line, termed metastatic SUIT-2 (MS). We investigated proliferation and motility of MS cells compared with those of the parent SUIT-2. Microarray analysis was performed to investigate differences in gene expression. We also performed immunohistochemical analysis of 89 formalin-fixed, paraffin-embedded human pancreatic cancer tissue samples to investigate the clinical significance of MAL2 expression., Results: MS cells showed a greater metastatic rate after orthotopic implantation than parental SUIT-2. MS cells had increased motility but decreased proliferation compared with parental SUIT-2. Microarray analyses showed that 26 genes were significantly upregulated (>10-fold) in MS cells compared with parental SUIT-2, particularly MAL2 expression. Immunohistochemical analysis showed that high expression of MAL2 was associated with a lesser survival of postoperative patients (P = .03) and a high rate of distant metastasis (P = .008)., Conclusion: We characterized a newly established pancreatic cancer cell line with highly metastatic potential. MAL2 is a promising predictive marker for distant metastasis and short survival in patients with resected pancreatic cancer., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Context: There are few studies regarding the surveillance period and interval of resected or observed branch duct intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in terms of early detection of concomitant pancreatic ductal adenocarcinoma. Despite a strict surveillance protocol, some patients are diagnosed with metastatic distinct ductal adenocarcinoma after resection of IPMN., Case Report: We herein report a patient with unresectable pancreatic ductal adenocarcinoma that developed in the remnant pancreas 18 months after resection of branch duct IPMN. Although the patient was surveyed every 6 months after the operation and imaging studies at 6 and 12 months postoperatively demonstrated no evidence of recurrence, invasive ductal adenocarcinoma with liver metastasis appeared 18 months after the operation. The patient subsequently underwent chemotherapy; however, he died 9 months after the diagnosis of metachronous pancreatic ductal adenocarcinoma., Conclusions: In some patients with branch duct IPMNs, 6-month surveillance seems to be insufficient to detect resectable concomitant pancreatic ductal adenocarcinoma. Therefore, identification of high-risk patients who require surveillance at shorter intervals is urgently needed.

Intraductal papillary mucinous neoplasms (IPMN) are drawing more attention and being detected more frequently. This review focuses on current understanding of the management of IPMN, regarding morphological classification, subclassification by cell lineage features, molecular abnormalities, radiological and imaging evaluation, progression to cancer, incidence and risk factors for malignancy, risk of distinct pancreatic adenocarcinoma and extrapancreatic malignancies, treatment strategy, and types of surgical resection. In particular, missing links in solving the IPMN puzzles are described with regard to differential diagnosis, role of cyst fluid analysis, multifocal IPMN, histological evaluation of the surgical specimen, observation without resection, follow up of patients after resection, role of adjuvant therapy for invasive carcinoma, screening for other neoplasms in patients with IPMN on follow up, prognostic factors influencing long-term outcomes, and role of endoscopic therapy.

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.

The treatment of choice for gastroentero-pancreatic neuroendocrine tumor(NET)is resection. Because it is difficult to determine the histological grade of NET before operation, the treatment strategy is usually made based on an imaging study including the tumor's size. Some selected gastrointestinal NETs are indicated for endoscopic resection, while others are resected surgically with lymph node dissection. The types of resections for pancreatic NETs vary from enucleation to pancreatectomy with or without regional lymph node dissection, based on the type of excessive hormone, tumor size, distance from the main pancreatic duct, and the presence of type 1 multiple endocrine neoplasia. Hepatic metastases are also resected, if indicated, and even in patients having unresectable metastatic lesions, multidisciplinary therapy including reduction surgery of over 90% of tumor volume might lead to a favorable prognosis. Postoperative adjuvant therapy is recommended for neuroendocrine carcinoma, while there is no evidence to support adjuvant therapy for curatively resected well-differentiated NET.

Objectives: The aim of this study was to establish a minimally invasive and simple screening test for detection of pancreatic ductal adenocarcinoma (PDAC) using duodenal juice (DJ)., Methods: Duodenal juice was collected prospectively before endoscopic retrograde cholangiopancreatography in 46 patients. A protease inhibitor was not added to the samples collected during the initial 2.5 minutes but was added in the latter 2.5 minutes. Thereafter, secretin was administered intravenously, and DJ was subsequently collected for additional 10 minutes. The sensitivities of carcinoembryonic antigen (CEA), S100 calcium-binding protein P (S100P), and interleukin 8 in DJ and pancreatic juice were assessed., Results: There were 30 patients with PDAC and 16 with benign lesions. It was possible to collect an adequate amount of DJ without secretin administration. In the PDAC group, CEA concentrations in DJ were significantly higher than those in the benign group, even without the use of a protease inhibitor. S100P levels in DJ in the PDAC group were significantly higher than those in the benign group in the presence of the protease inhibitor., Conclusions: Duodenal juice collection during routine upper endoscopy and assessments of CEA and S100P in DJ might become a useful screening test for detection of PDAC.

Background: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is often found with distinct pancreatic ductal adenocarcinoma (PDAC) in the same pancreas. The aim of this study was to clarify whether endoscopic retrograde pancreatography (ERP) would be useful for the early detection of concomitant PDACs in patients with IPMNs., Methods: Medical records of 179 patients who were histologically confirmed to have IPMNs after resection between 1987 and 2011 were reviewed. The patients having concomitant PDACs were selected, and the diagnostic abilities to detect concomitant PDACs of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS), and ERP were compared between early (stages 0-I according to Japanese General Rules for Pancreatic Cancer) and advanced (stages II-IV) PDACs., Results: A total of 23 PDACs developed synchronously or metachronously in 20 patients, and the prevalence of PDACs concomitant with IPMNs was 11.2 % (20/179). Sensitivities of CT (16 vs. 87 %), MRI (29 vs. 93 %), and EUS (29 vs. 92 %) in the early group were significantly lower than those in the advanced group (p < 0.01). On the other hand, the sensitivity of ERP in the early group was as high as that in the advanced group (86 vs. 82 %, respectively, p > 0.99). Among 7 early PDACs, 3 were diagnosed only by ERP., Conclusions: ERP has an important role in the early diagnosis of distinct PDACs in patients with IPMNs. Further investigation is necessary to clarify the indication and the timing of ERP during management of IPMNs in term of early detection of concomitant PDACs.

Background/aims: Although adjuvant chemotherapy (AC) using gemcitabine improves the prognosis of patients with resectable pancreatic cancer, the effect of gemcitabine AC on the prognosis of patients with borderline resectable pancreatic cancer is not clear., Methodology: We analyzed the prognosis of patients with pancreatic cancer who underwent curative pancreatoduodenectomy or total pancreatectomy in combination with portal/superior mesenteric vein resection (PVR) [PVR (+) group] or without PVR [PVR(-) group]., Results: MST of the PVR (+) group was significantly shorter than that of the PVR(-) group (p=0.017). In contrast, when we focused on the patients with gemcitabine AC, there was no significant difference in MST between the PVR (+) and the PVR (-) groups (p=0.247). Furthermore, we compared MST of two subgroups in the PVR (+) group depending on gemcitabine AC status. In the PVR (+) group, MST of the patients with gemcitabine AC was significantly longer than that without gemcitabine AC (p=0.003). This was also true for the patients with pancreatic cancer which had histologically proven invasion to portal/superior mesenteric vein (PV/SMV) (p=0.001)., Conclusions: The prognosis of patients with pancreatic cancer invading PV/SMV can be improved by combination therapy with PVR and gemcitabine adjuvant chemotherapy.

Aim: The purpose of this study was to evaluate the feasibility and advantages of extensive distal pancreatectomy (ExDP)., Patients and Methods: We retrospectively analyzed our experience in 24 patients, who underwent ExDP or total pancreatectomy (TP) for the treatment of pancreatic cancer (22 patients) or benign tumor (two patients)., Results: ExDP was associated with less blood loss (p=0.0189), shorter operative times (p=0.024), lower rates of worsening of diabetes mellitus (p<0.0001), and shorter hospital stays (p=0.0009) than TP. ExDP also had a lower complication rate than TP (1/11 cases versus 4/13 cases), but this was not a significant difference. There was no difference in the curative resection rate for pancreatic cancer between the two procedures (p=0.685)., Conclusion: ExDP is a feasible and function-preserving operation for the treatment of pancreatic tumors in the body of the pancreas near the portal vein.

Objectives: Branch duct intraductal papillary mucinous neoplasms of the pancreas (BD-IPMNs) often are composed of multifocal lesions. We aimed to clarify the clinicopathologic features of multifocal BD-IPMNs., Methods: Medical records of 211 patients with BD-IPMNs (169 solitary and 42 multifocal) were retrospectively analyzed. We compared the pathological grade of resected IPMNs and the resulting clinical course between solitary and multifocal BD-IPMNs., Results: Sixty-nine patients (54 with solitary and 15 with multifocal BD-IPMNs) underwent pancreatectomy, and of these patients, 62 exhibited at least 1 malignant predictor. There was no significant difference in the prevalence of malignancy in the resected BD-IPMNs between the 2 groups. In the remaining 142 patients who exhibited no malignant predictors, both groups demonstrated no differences in morphologic changes of BD-IPMNs. Seventeen distinct ductal carcinomas were identified in both groups, and there was no difference in the prevalence of ductal carcinoma between the 2 groups. Moreover, there was no significant difference in the disease-specific survival rate between the 2 groups., Conclusions: In patients with multifocal BD-IPMNs, resection is only warranted for lesions that exhibit malignancy predictors; moreover, closer attention to the potential presence or development of distinct ductal carcinoma in patients with multifocal and solitary BD-IPMNs is warranted.

Background: A dilated orifice of the duodenal papilla found during screening endoscopy or ERCP is well-known as one of the specific findings of intraductal papillary mucinous neoplasm (IPMN). However, its clinical significance is still unclear., Objective: To assess the diagnostic significance of a dilated orifice of the duodenal papilla and evaluate whether this could be a factor predictive of malignancy or a subtype of IPMN., Design: Retrospective study., Setting: University hospital., Patients: This study involved 149 patients who underwent pancreatectomy for IPMN between January 1987 and June 2011., Intervention: ERCP., Main Outcome Measurements: The rate of malignant and intestinal type IPMNs in patients with and without papillary dilation., Results: A dilated orifice of the duodenal papilla was significantly associated with intestinal type IPMN (P < .001), but this finding could not predict the malignant grade of IPMN (P = .13). Multivariate analysis revealed that a dilated orifice was a significant factor for predicting intestinal type in both main duct (P = .01) and branch duct IPMNs (P < .001)., Limitations: The validity of the definition of papillary dilation, selection bias, and a retrospective study., Conclusion: A dilated orifice of the duodenal papilla could be a significant factor for predicting intestinal type IPMN. This may lead to better clinical management of patients with IPMN., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background: Identification of prognostic markers would be useful in the clinical management of patients with pancreatic ductal adenocarcinoma (PDAC). The clinical relevance of claudin-4 (CLDN4), recently identified as overexpressed in PDAC, is unknown., Methods: Using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), we analyzed CLDN4 mRNA expression in a panel of 9 pancreatic cancer cell lines and formalin-fixed paraffin-embedded (FFPE) tissues from 100 patients with PDAC. The CLDN4 expression levels were then correlated with clinicopathological variables and patient outcome. We also performed immunohistochemical analysis in 20 FFPE samples of PDAC to investigate the expression of CLDN4 protein., Results: Increased expression of CLDN4 was confirmed in all the pancreatic cancer cell lines tested compared with normal ductal epithelial cells and fibroblasts. We found that low expression of CLDN4 was significantly associated with shorter survival in patients with PDAC (hazard ratio; 1.362, 95% confidence interval; 1.011-1.873, P = 0.0419). Patients with high CLDN4 expression survived longer for a median of 63.0 months, compared with 14.7 months in patients with low CLDN4 expression (P = 0.0067). In immunohistochemical analysis, the level of CLDN4 mRNA expression was significantly correlated with the expression of CLDN4 protein (P = 0.0168)., Conclusion: Increased expression of CLDN4 mRNA predicts better prognosis in PDAC.

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production., Methods: Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated., Results: There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%; P = 0.08). The size of PNETs with lymph node metastasis was significantly larger than that of the PNETs without metastasis (P = 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis (P < 0.0001). Only 2 (8%) of 26 PNETs with a tumor size of <15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of <15 mm., Conclusions: Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.

Background: The hedgehog (Hh) signaling pathway is aberrantly activated in many cancers. Overproduction of sonic hedgehog (Shh), a ligand in the Hh pathway, increases Hh signaling activity by inhibiting Patched-1 (Ptch1), a suppressive receptor in the Hh pathway. The purpose of this study was to establish a novel strategy for treating pancreatic cancer and other Hh-dependent cancers through control of the tumor-suppressive function of Ptch1., Methods: We synthesized seven interacting peptides to the amino-acid sequence of the Ptch1 docking site for Shh. Human pancreatic cancer cell lines (AsPC-1, SUIT2) were cultured in the presence or absence of the peptides. Cell proliferation was assessed by cell counting and by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The activity of the Hh pathway was estimated by real-time polymerase chain reaction of the target gene product Gli1. To confirm their anti-tumor activity in vivo, the effect of the peptides in a mouse model of pancreatic cancer was determined. Finally, the Hh signaling activity of the xenograft was examined., Results: Three of the interacting peptides to Ptch1 suppressed the proliferation of the two pancreatic cancer cell lines and decreased the expression of Gli1, both in vitro and in vivo., Conclusions: This study suggests that interacting peptides to Ptch1 may be a new tool for controlling the Hh-dependent growth of pancreatic cancer.

Pancreatic stellate cells (PSCs) play a crucial role in the aggressive behavior of pancreatic cancer. Although heterogeneity of PSCs has been identified, the functional differences remain unclear. We characterized CD271⁺ PSCs in human pancreatic cancer. Immunohistochemistry for CD271 was performed for 31 normal pancreatic tissues and 105 pancreatic ductal adenocarcinomas (PDACs). We performed flow cytometry and quantitative RT-PCR, and assessed CD271 expression in PSCs isolated from pancreatic tissues and the changes in CD271 expression in PSCs cocultured with cancer cells. We also investigated the pattern of CD271 expression in a SCID mouse xenograft model. In the immunohistochemical analyses, the CD271-high staining rates in pancreatic stroma in normal pancreatic tissues and PDACs were 2/31 (6.5%) and 29/105 (27.6%), respectively (p = 0.0069). In PDACs, CD271⁺ stromal cells were frequently observed on the edge rather than the center of the tumors. Stromal CD271 high expression was associated with a good prognosis (p = 0.0040). Flow cytometric analyses demonstrated CD271-positive rates in PSCs were 0-2.1%. Quantitative RT-PCR analyses revealed that CD271 mRNA expression was increased in PSCs after coculture with pancreatic cancer cells. However, the level of CD271 mRNA expression subsequently decreased after the transient increase. Furthermore, CD271 mRNA expression was decreased in PSCs migrating toward pancreatic cancer cells through Matrigel. In the xenograft model, CD271⁺ PSCs were present at tumor margins/periphery and were absent in the tumor core. In conclusion, CD271 was expressed in PSCs around pancreatic tumors, but not in the center of the tumors, and expression decreased after long coculture with pancreatic cancer cells or after movement toward pancreatic cancer cells. These findings suggest that CD271⁺ PSCs appear at the early stage of pancreatic carcinogenesis and that CD271 expression is significantly correlated with a better prognosis in patients with PDAC.

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 factor's 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., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Claudin-4, encoding a protein for tight junction formation and function, is highly overexpressed in pancreatic ductal adenocarcinoma and is also associated with invasive adenocarcinomas arising in intraductal papillary mucinous neoplasms of the pancreas. However, the expression pattern of claudin-4 during neoplastic progression of intraductal papillary mucinous neoplasms remains unknown. Using quantitative real-time reverse transcription-PCR, we analyzed claudin-4 mRNA in a panel of 14 pancreatic cancer cell lines and in formalin-fixed paraffin-embedded tissues from 80 patients with intraductal papillary mucinous neoplasms of different histological grades and papillary subtypes. Increased expression of claudin-4 was confirmed in all the pancreatic cancer cell lines tested as compared with normal ductal epithelial cells and fibroblast cultures. The claudin-4 expression was significantly higher in high-grade intraductal papillary mucinous neoplasms (borderline neoplasm and carcinoma) than in low-grade intraductal papillary mucinous neoplasms (adenoma) (P<0.0001). In addition, claudin-4 mRNA levels were significantly higher in intestinal-type intraductal papillary mucinous neoplasms than in non-intestinal-type intraductal papillary mucinous neoplasms based on papillary subclassification (P<0.0001). Our findings suggest that claudin-4 expression is associated with neoplastic progression of intraductal papillary mucinous neoplasms and, especially, with a distinct pathway to intestinal differentiation.

Context: Cytological assessment of pancreatic juice is commonly used to diagnose pancreatic ductal adenocarcinoma; however, the sensitivity of cytological assessment has been reported to be low. MicroRNAs are small RNAs regulating various cellular processes and have recently been identified as possible markers of malignant diseases including pancreatic ductal adenocarcinoma., Objective: The purposes of this study were to prove the existence of microRNAs in pancreatic juice and to determine whether specific microRNAs in pancreatic juice could be used for detecting pancreatic ductal adenocarcinoma., Methods: Relative expression levels of microRNA-21 and microRNA-155 in formalin-fixed paraffin-embedded tissues of resected specimens (no. 13) and pancreatic juice samples collected using preoperative endoscopic retrograde cholangiopancreatography (no. 21) were quantified and their expression levels were then compared to pancreatic ductal adenocarcinoma and chronic pancreatitis., Results: Relative expression levels of microRNA-21 in tissue and pancreatic juice samples were significantly higher in pancreatic ductal adenocarcinoma than those in chronic pancreatitis (P=0.009 and P=0.021, respectively). The same results were obtained in the expression levels of microRNA-155 in tissue and pancreatic juice between pancreatic ductal adenocarcinoma and chronic pancreatitis (P=0.014 and P=0.021, respectively). Expression levels of microRNA-21 and microRNA-155 did not correlate with the preoperative cytological results of pancreatic juice., Conclusion: MicroRNA-21 and microRNA-155 in pancreatic juice have the potential of becoming biomarkers for diagnosing pancreatic ductal adenocarcinoma.

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.

Purpose: To clarify if the portal venous phase is helpful for the differential diagnosis of groove pancreatic carcinomas and groove pancreatitis., Materials and Methods: MDCT and MRI of groove pancreatic carcinomas (n=7) and groove pancreatitis (n=15) were retrospectively reviewed by two radiologists independently. The signal intensity on T2-weighted images was subjectively assessed. The presence or absence of common bile duct (CBD) and main pancreatic duct (MPD) strictures, calcifications, and cystic lesions was evaluated. Additionally, the appearance of groove pancreatic carcinoma and that of groove pancreatitis in the portal venous phase on dynamic MDCT and MRI were compared., Results: There were no significant differences in the signal intensity on T2-weighted images and in the presence or absence of CBD and MPD strictures, calcifications, and cystic lesions between groove pancreatic carcinomas and groove pancreatitis. However, patchy focal enhancement in the portal venous phase was more commonly observed in groove pancreatitis than groove pancreatic carcinoma (Reviewers 1 and 2: 14/15 [93.3%] vs. 1/7 [14.3%], P<0.0001). In addition, peripheral enhancement was only seen in groove pancreatic carcinomas (Reviewer 1: 4/7 [57.1%] vs. 0/15 [0%], P<0.005, and Reviewer 2: 3/7 [42.9%] vs. 0/15 [0%], P<0.05)., Conclusion: The portal venous phase may be helpful for the differential diagnosis of groove pancreatic carcinomas and groove pancreatitis., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright 2010 Mosby, Inc. All rights reserved.)

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 (> or =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.

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.

A 77-year-old man was referred to our hospital for further investigation of pancreatic masses. Imaging studies revealed hypovascular masses in the pancreatic head and body. Total pancreatectomy was performed under the diagnosis of double primary pancreatic carcinomas. Macroscopic examination revealed 3 nodules: one each in the pancreatic head, body, and tail. Microscopically, all 3 lesions showed similar carcinoma cells, which communicated with each other via the intraductal component, indicating a single large tumor. Incidentally, we also identified an adenocarcinoma of the common bile duct (CBD). The final diagnosis was synchronous double cancer involving the whole pancreas and the CBD.