Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Noboru Ideno Last modified date:2021.07.09

Assistant Professor / Department of Surgery and Oncology / Department of Clinical Medicine / Faculty of Medical Sciences


Papers
1. Mori Y, Otsuka T, Kono H, Ideno N, Aso T, Nagayoshi Y, Takahata S, Nakamura M, Ishigami K, Aishima S, Oda Y, Tanaka M, Management strategy for multifocal branch duct intraductal papillary mucinous neoplasms of the pancreas., Pancreas, 41, 7, 1008-1012, 2012.04, 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.
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2. Aso T, Ohtsuka T, Ideno N, Kono H, Nagayoshi Y, Mori Y, Ohuchida K, Ueda J, Takahata S, Morimatsu K, Aishima S, Igarashi H, Ito T, Ishigami K, Mizumoto K, Tanaka M, Diagnostic significance of a dilated orifice of the duodenal papilla in intraductal papillary mucinous neoplasm of the pancreas, Gastrointest Endosc, 76, 2, 313-320, 2012.04,
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.


Comment in
Pancreatic cancer: Dilated orifice of the duodenal papilla predicts intestinal type IPMN. [Nat Rev Gastroenterol Hepatol. 2012]
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3. Otsuka T, Ideno N, Aso T, Nagayoshi Y, Kono H, Mori Y, Takahata S, Oda Y, Aishima S, Igarashi H, Ito T, Ishigami K, Nakamura M, Mizumoto K, Tanaka M, Role of endoscopic retrograde pancreatography for early detection of pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm of the pancreas., J Hepatobiliary Pancreat Sci, 20, 3, 356-361, 2013.04, 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.
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4. Ideno N, Ohtsuka T, Kono H, Fujiwara K, Oda Y, Aishima S, Ito T, Tokunaga S, Ohuchida K, Takahata S, Nakamura M, Mizumoto K, Tanaka M, Intraductal Papillary Mucinous Neoplasms of the Pancreas with Distinct Pancreatic Ductal Adenocarcinoma Are Frequently of Gastric Subtype, Ann Surg, 258, 1, 141-151, 2013.04, 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 an
d 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 pa
tterns 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..
5. Mori Y, Otsuka T, Kono H, Nagayoshi Y, Ideno N, Aso T, Kozono S, Ohuchida K, Takahata S, Nakamura M, Mizumoto K, Tanaka M, A minimally invasive and simple screening test for detection of pancreatic ductal adenocarcinoma using biomarkers in duodenal juice., Pancreas, 42, 2, 187-192, 2013.04, 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.
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6. Tamura K, Ohtsuka T, Ideno N, Aso T, Shindo K, Aishima S, Ohuchida K, Takahata S, Ushijima Y, Ito T, Oda Y, Mizumoto K, Tanaka M, Treatment Strategy for Main Duct Intraductal PapillaryMucinous Neoplasms of the Pancreas Based on the Assessmentof Recurrence in the Remnant Pancreas After ResectionA Retrospective Review, Ann Surg, 10.1097/SLA.0b013e3182a690ff, 259, 2, 360-368, 2014.04, 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.
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7. Ohtsuka T, Tamura K, Ideno N, Aso T, Nagayoshi Y, Kono H, Ueda J, Takahata S, Aso A, Igarashi H, Ushijima Y, Ookubo F, Oda Y, Mizumoto K, Tanaka M, The role of ERCP in the era of EUS-FNA for preoperative cytological confirmation of resectable pancreatic ductal adenocarcinoma, Surg Today, 44, 10, 1887-1892, 2014.04, 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.
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8. Ohtsuka T, Matsunaga T, KImura H, Watanabe Y, Tamura K, ideno N, Aso T, Miyasaka Y, Ueda J, Takahata S, Osoegawa T, Igarashi H, Ito T, Ushijima Y, Ookubo F, Oda Y, Mizumoto K, Tanaka M, Role of pancreatic juice cytology in the preoperative management of intraductal papillary mucinous neoplasm of the pancreas in the era of international consensus guidelines 2012, World J Surg, 38, 11, 2994-3001, 2014.04, 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.
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9. Nakamura M, Shindo K, Ideno N, Ueda J, Takahata S, Nakashima H, Ohtsuka T, Shimizu S, Oda Y, Tanaka M, Prediction of Pancreatic Fistula by Preoperatively Assessable Factors; Retrospective Review of Unified Operations by Single Surgeon, Hepatogastroenterology, 2014, 61, 834-837, 2014.04, Abstract
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.
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10. Nagayoshi Y, Aso T, Ohtsuka T, Kono H, Ideno N, Igarashi H, Takahata S, Oda Y, Ito T, Tanaka M, Peroral pancreatoscopy using the SpyGlass system for the assessment of intraductal papillary mucinous neoplasm of the pancreas, J Hepatobiliary Pancreat Sci, 21, 6, 410-417, 2014.04, 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.
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11. Mori Y, Ohtsuka T, Tamura K, Ideno N, Aso T, Kono H, Nagayoshi Y, Ueda J, Takahata S, Aishima S, Ookubo F, Oda Y, Tanaka M, Intraoperative irrigation cytology of the remnant pancreas to detect remnant distinct pancreatic ductal adenocarcinoma in patients with intraductal papillary mucinous neoplasm undergoing partial pancreatectomy, Surgery, 155, 1, 67-73, 2014.04, Abstract
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..
12. Aso T, Ohtsuka T, Matsunaga T, Kimura H, Watanabe Y, Tamura K, Ideno N, Osoegawa T, Takahata S, Shindo K, Ushijima Y, Aishima S, Oda Y, Ito T, Mizumoto K, Tanaka M, High-risk stigmata of the 2012 international consensus guidelines correlate with the malignant grade of branch duct intraductal papillary mucinous neoplasms of the pancreas, Pancreas, 43, 8, 1239-1243, 2014.04, Objectives: The 2012 international consensus guidelines for themanagementof intraductal papillary mucinous neoplasm (IPMN) of the pancreasstratified patients into 2 clinical categories, “high-risk stigmata” and “worrisomefeatures,” and recommended different therapeutic strategies forthese groups. The aim of this study was to elucidate the significance ofthese categories in terms of predicting malignant IPMNs.Methods: The medical records of 100 consecutive patients whounderwent pancreatectomy for IPMNs were retrospectively reviewed. Seventypatients with branch duct IPMNs (BD-IPMNs) were stratified into 3groups. The relationships between the number of predictive factors and histopathologicgrade were investigated.Results: The prevalence rates of malignant IPMN, invasive carcinoma,and lymph node metastasis in the high-risk group were 80%, 55%, and20%, respectively, with these percentages significantly increasing in a stepwisemanner acc
ording to the number of predictive factors. In contrast,there was no significant correlation between the number of worrisome featuresand grade of malignancy in patients stratified as having worrisomeBD-IPMNs.Conclusions: The number of high-risk stigmata correlated significantlywith the grade of malignancy of BD-IPMNs. The presence of at least 1high-risk stigma in patients with BD-IPMNs indicates a need for pancreatectomywith lymphadenectomy..
13. Cases AI, Ohtsuka T, Fujino M, Ideno N, Kozono S, Zhao M, Ohuchida K, Aishima S< Nomura M, Oda Y, Mizumoto K, Tanaka M, Expression of glucagon-like Peptide 1 receptor and its effects on biologic behavior in pancreatic neuroendocrine tumors., Pancreas, 43, 1, 1-6, 2014.04, OBJECTIVES:

Glucagon-like peptide 1 (GLP-1) interacts with its specific high-affinity receptor, glucagon-like peptide 1 receptor (GLP-1R), and induces cellular growth and inhibition of apoptosis in pancreatic β cells. The aim of this study was to investigate the significance of GLP-1R expression in pancreatic neuroendocrine tumors (PNETs).

METHODS:

Glucagon-like peptide 1 receptor expression was semiquantitatively evaluated by immunohistochemical staining in 50 resected PNETs, and the correlation between the GLP-1R expression and clinicopathologic features was investigated.

RESULTS:

There were 23 PNETs with positive expression and 27 PNETs with negative expression of GLP-1R. Positive expression of GLP-1R was more frequently observed in insulinoma than in gastrinoma and nonfunctioning tumor (P < 0.05). Although expression status of GLP-1R did not affect the prognosis of the patients with PNETs (P = 0.82), most of the metastatic sites such as lymph node and liver showed positive staining for GLP-1R (8 of 11 PNETs, 73%).

CONCLUSIONS:

Glucagon-like peptide 1 receptor would be a diagnostic marker of insulinoma and might become a molecular target for treatment of metastatic PNETs and hormonal regulation of insulin.
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14. Aso T, Ohtsuka T, Tamura K, Ideno N, Kono H, Nagayoshi Y, Ohuchida K, Ueda J, Takahata S, Shindo K, Aishima S, Oda Y, Mizumoto K, Tanaka M, Elevated Expression Level of MicroRNA-196a Is Predictive of Intestinal-Type Intraductal Papillary Mucinous Neoplasm of the Pancreas, Pancreas, 43, 3, 361-366, 2014.04, AbstractOBJECTIVES: 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: Mi
croRNA-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..
15. Kimura H, Ohtsuka T, Matsunaga T, Watanabe Y, Tamura K, Ideno N, Aso T, Miyazaki T, Osoegawa T, Aishima S, Miyasaka Y, Ueda J, Ushijima Y, Igarashi H, Ito T, Takahata S, Oda Y, Mizumoto K, Tanaka M, Predictors and Diagnostic Strategies for Early-Stage Pancreatic Ductal Adenocarcinoma: A Retrospective Study, Pancreas, 44, 7, 1148-1154, 2015.04, 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.
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16. Watanabe Y, Ohtsuka T, Matsunaga T, Kimura H, Tamura K, Ideno N, Aso T, Miyasaka Y, Ueda J, Takahata S, Igarashi H, Inoguchi T, Ito T, Tanaka M, Long-term outcomes after total pancreatectomy: special reference to survivors' living conditions and quality of life, World J Surg, 39, 5, 1231-1239, 2015.04, Abstract
BACKGROUND:
Although recent studies have confirmed the safety of total pancreatectomy (TP), appropriate selection of patients for TP has not been well documented. Because patients require lifelong medical treatment and self-management of pancreatic insufficiency after TP, indications for TP should be determined carefully according not only to disease factors but also to the social background of patients. We aimed to clarify long-term outcomes after TP, including the living conditions and quality of life (QoL), of surviving patients.
METHODS:
Medical records of 44 consecutive patients who underwent TP between 1990 and 2013 were reviewed retrospectively; 25 survivors completed cross-sectional clinical surveys and responded to a questionnaire about QoL using Short Form 36v2.
RESULTS:
Prevalence of morbidity and mortality after TP was 32 and 5 %, respectively. Postoperative complications occurred more frequently in elderly patients than in young patients (48 vs. 14 %; P = 0.02); however, there was no significant difference in mortality, postoperative hospital stay, or survival. Twenty-four of 25 survivors (96 %) could manage pancreatogenic diabetes by themselves, and the median level of glycosylated hemoglobin was 7.4 %. Although one-third of patients after TP complained of diarrhea and the QoL scores of patients with diarrhea were lower than those of patients without diarrhea, QoL scores after TP were virtually comparable with those of the national population, even in elderly patients.
CONCLUSIONS:
TP can be performed safely, even in elderly patients. QoL after TP seems to be acceptable if patients are capable of self-management..
17. Ideno N, Ohtsuka T, Matsunaga T, Kimura H, Watanabe Y, Tamura K, Aso T, Aishima S, Miyasaka Y, Ohuchida K, Ueda J, Takahata S, Oda Y, Mizumoto K, Tanaka M, Clinical Significance of GNAS Mutation in Intraductal Papillary Mucinous Neoplasm of the Pancreas With Concomitant Pancreatic Ductal Adenocarcinoma, Pancreas, 44, 2, 311-320, 2015.04, 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.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.
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18. Watanabe Y, Ohtsuka T, Kimura H, Matsunaga T, Tamura K, Ideno N, Aso T, Miyasaka Y, Ueda J, Takahata S, Tanaka M, Braun enteroenterostomy reduces delayed gastric emptying after pylorus-preserving pancreatoduodenectomy: a retrospective review, Am J Surg, 209, 2, 369-377, 2015.04, BACKGROUND: Several recent studies have suggested that Braun enteroenterostomy (BEE) during conventional pancreatoduodenectomy might decrease delayed gastric emptying (DGE). However, the advantages and disadvantages of performing BEE during pylorus-preserving pancreatoduodenectomy (PPPD) remain controversial.METHODS: The medical records of 185 patients who underwent PPPD either with or without BEE between January 2008 and June 2013 were retrospectively reviewed, and the postoperative course of the 2 groups was compared.RESULTS: Ninety-eight patients underwent PPPD with BEE and 87 without BEE. DGE occurred in 4% of patients with BEE and in 21% of those without BEE (P < .01). The addition of BEE did not affect postoperative complications other than DGE. By multivariate analysis, the omission of BEE was the only independent factor associated with DGE (odds ratio 5.04, 95% confidence interval: 1.59 to 19.66; P < .01).CONCLUSIONS: BEE during PPPD reduced the
incidence of DGE..
19. Tamura K, Ohtsuka T, Matsunaga T, Kimura H, Watanabe Y, Ideno N, Aso T, Miyazaki T, Ohuchida K, Takahata S, Ito T, Ushijima Y, Oda Y, Mizumoto K, Tanaka M, Assessment of Clonality of Multisegmental Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas Based on GNAS Mutation Analysis, Surgery, 157, 2, 277-284, 2015.04, Background: Main duct intraductal papillary mucinous neoplasms (MD-IPMNs) may occur in one 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 (PDAC). Our aim was to clarify clonality using GNAS status in multisegmental MD-IPMNs.Methods: Medical records of 70 patients with MD-IPMN were retrospectively reviewed. Histological 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 multip
le MD-IPMNs; three had multiple MD-IPMNs and distinct BD-IPMNs; one had multiple MD-IPMNs and a distinct PDAC; one had a solitary MD-IPMN, BD-IPMN, and PDAC; and one had a solitary MD-IPMN and PDAC. KRAS/GNAS mutations were consistent in 10 of 11 multisegmental MD-IPMNs, while 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=0.04). Mutant GNAS was more frequently observed in the intestinal subtype (94%) than the others.Conclusions: MD-IPMNs can be characterized by monoclonal skip progression. Close attention should be paid to the possible presence of skip areas during/after partial pancreatectomy..
20. Ideno N, Yamaguchi H, Ghosh B, Gupta S, Okumura T, Steffen DJ, Fisher CG, Wood LD, Singhi AD, Nakamura M, Gutkind JS, Maitra A, GNASR201C Induces Pancreatic Cystic Neoplasms in Mice That Express Activated KRAS by Inhibiting YAP1 Signaling, Gastroenterology, 10.1053/j.gastro.2018.08.006 , 155, 5, 1593-1607, 2018.04, Abstract
BACKGROUND & AIMS:
Mutations at hotspots in GNAS, which encodes stimulatory G-protein, α subunits, are detected in approximately 60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We generated mice with KRAS-induced IPMNs that also express a constitutively active form of GNAS in pancreas and studied tumor development.
METHODS:
We generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras;Gnas mice); pancreatic tissues of these mice express activated KRAS and also express a mutant form of GNAS (GNASR201C) upon doxycycline administration. Mice that were not given doxycycline were used as controls, and survival times were compared by Kaplan-Meier analysis. Pancreata were collected at different time points after doxycycline administration and analyzed by histology. Pancreatic ductal adenocarcinomas (PDACs) were isolated from mice and used to generate cell lines, which were analyzed by reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and colony formation and invasion assays. Full-length and mutant forms of yes-associated protein (YAP) were expressed in PDAC cells. IPMN specimens were obtained from 13 patients with IPMN undergoing surgery and analyzed by immunohistochemistry.
RESULTS:
All Kras;Gnas mice developed pancreatic cystic lesions that resemble human IPMNs; the grade of epithelial dysplasia increased with time. None of the control mice developed cystic lesions. Approximately one third of Kras;Gnas mice developed PDACs at a median of 30 weeks after doxycycline administration, whereas 33% of control mice developed PDACs. Expression of GNASR201C did not accelerate the development of PDACs compared with control mice. However, the neoplasms observed in Kras;Gnas mice were more differentiated, and expressed more genes associated with ductal phenotypes, than in control mice. PDACs isolated from Kras;Gnas mice had activation of the Hippo pathway; in cells from these tumors, phosphorylated YAP1 was sequestered in the cytoplasm, and this was also observed in human IPMNs with GNAS mutations. Sequestration of YAP1 was not observed in PDAC cells from control mice.
CONCLUSIONS:
In mice that express activated KRAS in the pancreas, we found expression of GNASR201C to cause development of more differentiated tumors, with gene expression pattern associated with the ductal phenotype. Expression of mutant GNAS caused phosphorylated YAP1 to be sequestered in the cytoplasm, altering tumor progression.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
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21. Matsunaga T, Ohtsuka T, Asano K, Kimura H, Ohuchida K, Kitada H, Ideno N, Mori Y, Tokunaga S, Oda Y, Guha S, Raimondo M, Nakamura M, Tanaka M, S100P in Duodenal Fluid Is a Useful Diagnostic Marker for Pancreatic Ductal Adenocarcinoma, Pancreas, 10.1097/MPA.0000000000000940, 46, 10, 1288-1295, 2017.04, Abstract
OBJECTIVES:
The development of an effective screening method for pancreatic ductal adenocarcinoma (PDAC) is of paramount importance. This study assessed the diagnostic utility in pancreatic diseases of duodenal markers during upper gastrointestinal endoscopy (GIE) or endoscopic ultrasonography.

METHODS:
This study prospectively enrolled 299 consecutive participants, including 94 patients with PDACs, 144 patients with other pancreatic diseases, and 61 normal individuals as control subjects. All subjects underwent upper GIE or endoscopic ultrasonography either at Kyushu University Hospital (Fukuoka, Japan) or the Mayo Clinic (Jacksonville, Fla) from October 2011 to July 2014. Duodenal fluid (DF) was collected without secretin stimulation and of carcinoembryonic antigen and S100 calcium-binding protein P (S100P) concentrations were measured.

RESULTS:
Concentrations of S100P in DF were significantly higher in patients with PDAC and chronic pancreatitis than in control subjects (P < 0.01). A logistic regression model that included age found that the sensitivity and specificity of S100P concentration in diagnosing stages 0/IA/IB/IIA PDAC were 85% and 77%, respectively, with an area under the receiver operating characteristic curve of 0.82. Carcinoembryonic antigen concentrations in DF of patients with pancreatic disease did not differ significantly from control subjects.

CONCLUSIONS:
Analysis of S100P concentration in DF, in combination with routine screening upper GIE, may facilitate the detection of PDAC..
22. Ideno N, Yamaguchi H, Okumura T, Huang J, Brun MJ, Ho ML, Suh J, Gupta S, Maitra A, Ghosh B, A pipeline for rapidly generating genetically engineered mouse models of pancreatic cancer using in vivo CRISPR-Cas9-mediated somatic recombination, Lab Invest, 10.1038/s41374-018-0171-z, 99, 8, 1233-1244, 2019.04.