| 1. |
Tanaka H, Tamura K, Abe T, Yoshida T, Macgregor-Das A, Dbouk M, Blackford AL, Borges M, Lennon AM, He J, Burkhart R, Canto MI, Goggins M, Serum Carboxypeptidase Activity and Genotype-Stratified CA19-9 to Detect Early-Stage Pancreatic Cancer, Clin Gastroenterol Hepatol., 10.1016/j.cgh.2021.10.008., 2021.10. |
| 2. |
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.. |
| 3. |
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.. |
| 4. |
Tamura K, Ohtsuka T, Date K, Fujimoto T, Matsunaga T, Kimura H, Watanabe Y, Miyazaki T, Ohuchida K, Takahata S, Ishigami K, Oda Y, Mizumoto K, Nakamura M, Tanaka M, Distinction of Invasive Carcinoma Derived From Intraductal Papillary Mucinous Neoplasms From Concomitant Ductal Adenocarcinoma of the Pancreas Using Molecular Biomarkers, Pancreas, 10.1097/MPA.0000000000000563, 45, 6, 826-835, 2016.04, 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 d
istinct 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.. |
| 5. |
Tamura K, Yu J, Hata T, Suenaga M, Shindo K, Abe T, MacGregor-Das A, Borges M, Wolfgang CL, Weiss MJ, He J, Canto MI, Petersen GM, Gallinger S, Syngal S, Brand RE, Rustgi A, Olson SH, Stoffel E, Cote ML, Zogopoulos G, Potash JB, Goes FS, McCombie RW, Zandi PP, Pirooznia M, Kramer M, Parla J, Eshleman JR, Roberts NJ, Hruban RH, Klein AP, Goggins M, Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer, Proc Natl Acad Sci U S A, 10.1073/pnas.1720588115, 115, 18, 4767-4772, 2018.04, To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (PRSS1, CPA1, CTRC, and SPINK1) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1, CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls (P = 0.020), with a combined prev
alence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls (P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P = 0.025; odds ratio, 9.36 (95% CI, 1.15-76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls (P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.. |
