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Objectives Pancreatic cystic lesions (PCLs) are a risk factor for pancreatic cancer (PC). Which PCLs should be surveilled and necessity of long-term observation are still controversial. Methods From January 2000 to March 2016, we enrolled 1137 patients with PCLs observed for 1 year. We defined PCLs with cyst size of greater than 30 mm, main pancreatic duct (MPD) of greater than 5 mm or mural nodule as high-risk group, and others as low-risk group (LRG). Kaplan-Meier method and Cox proportional hazard model were applied to assess incidence and risk factors of PC. Results In 107 high-risk group and 1030 LRG patients, mean observation period was 4.3 years and 5.0 years, respectively, and 5-year PC incidence was 12.0% and 2.8%, respectively. In LRG, MPD of greater than 3 mm, diabetes mellitus, and presumed branch-duct intraductal papillary mucinous neoplasia (BD-IPMN), defined as PCLs fulfilling any of multilocular formation, multiplicity, or MPD communication, were independent risk factors for PC. In 450 LRG observed for 5 years, 10-year PC incidence was higher in PCLs with our identified risk factors. There was no PC occurrence in PCLs not presumed BD-IPMN after 5-year observation. Conclusions Continuous surveillance is needed after 5-year observation, especially in LRG with our identified risk factors. For discontinuing surveillance, PCLs not presumed BD-IPMN at fifth year could be candidates.

Diabetes mellitus is a well-known risk factor for pancreatic cancer. We focused on hyperglycemia, a main feature of diabetes mellitus, and uncovered its effect on precancerous pancreatic intraepithelial neoplasia (PanIN) progression. In vivo induction of hyperglycemia with 100 mg/kg streptozotocin in Kras LSL G12D Pdx1Cre (KP) mice promoted the PanIN formation and progression. Preconditioning with a high-or low-glucose medium for 28 days showed that a high-glucose environment increased cell viability and sphere formation in PANC-1, a Kras-mutant human pancreatic ductal adenocarcinoma cell line, and mPKC1, a Krasmutant murine pancreatic cancer cell line. In contrast, no changes were observed in BxPC3, a Kras-wild-type human pancreatic cancer cell line. Orthotopic injection of mPKC1 into the pancreatic tails of BL6/J mice showed that cells maintained in high-glucose medium grew into larger tumors than did those maintained in low-glucose medium. Hyperglycemia strengthened the STAT3 phosphorylation, which was accompanied by elevated MYC expression in Kras-mutant cells. Immunohistochemistry showed stronger phosphorylated STAT3 (pSTAT3) and MYC staining in PanINs from diabetic KP mice than in those from euglycemic counterparts. STAT3 inhibition with 1 μM STAT3 inhibitor STATTIC in Krasmutant pancreatic cell lines blocked the cell viability-and sphere formation-enhancing effects of the hyperglycemic environment and reversed the elevated pSTAT3 and MYC expression. MYC knockdown did not affect cell viability but did reduce sphere formation. No decrease in pSTAT3 expression was observed upon siMYC treatment. In conclusion, hyperglycemia, on a Kras-mutant background, aggravates the PanIN progression, which is accompanied by elevated pSTAT3 and MYC expression.

Because pancreatic cancer has a dismal prognosis, a strategy for early diagnosis is required. This study aimed to identify predictive factors of neoplastic progression in patients at high risk for pancreatic cancer and examined the efficiency of surveillance using transabdominal special ultrasonography focusing on the pancreas (special pancreatic US). Patients with slight main pancreatic duct (MPD) dilatation (≥2.5 mm) and/or pancreatic cysts (≥5 mm) were enrolled in a prospective surveillance study with special pancreatic US in a Japanese cancer referral center. A total of 498 patients undergoing surveillance for ≥3 years were included. During the median follow-up of 5.9 years, neoplastic progression developed in 11 patients (2.2%), including 9 patients who underwent pancreatectomy. Eight patients (72.7%) were diagnosed with stage 0/I disease, with an overall survival duration of 8.8 years. Findings of both MPD dilatation and pancreatic cysts at initial surveillance, MPD growth (≥0.2 mm/year) and cyst growth (≥2 mm/year) during surveillance were identified as independent risk factors for neoplastic progression. In summary, surveillance with special pancreatic US for high-risk individuals contributed to earlier detection of neoplastic progression, leading to a favorable prognosis. During surveillance, attention should be paid to MPD growth as well as to cyst growth.

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