Genetic and pharmacologic abrogation of Snail1 inhibits acinar-to-ductal metaplasia in precursor lesions of pancreatic ductal adenocarcinoma and pancreatic injury.

Pancreatic cancer (PDAC) is one of the most dismal of human malignancies. Inhibiting or delaying the progression of precursor lesions of PDAC, pancreatic intraepthial neoplasia (PanINs), to invasive cancer, would be a major step. In the present study, we used a transgenic murine model of pancreatic cancer to evaluate the impact of a conditional knockout of the transcription factor Snail1, a major factor in epithelial-to-mesenchymal transition, on acinar-to-ductal formation and on PanIN progression. By interbreeding conditional LsL-Snail floxf/wt ; LsL-Kras G12D and Pdx1-Cre strains, we obtained LsL-Kras G12D ;Pdx1-Cre(KP) mice, Snail1 heterozygous knockout LsL-Kras G12D ; LsL-Snail flox/- ;Pdx1-Cre(KPShet) mice or Snail1 homozygous knockout LsL-Kras G12D ;LsL-Snail flox/flox ;Pdx1-Cre(KPS) mice. Mice were then followed in a longitudinal study for 2, 4, 6, 8, 10, and 12 months. Furthermore, in mice with a genetic or pharmacological inhibition of Snail1, using the Snail1 inhibitor GN25, a model of pancreatic injury by administration of cerulein was introduced to evaluate ADM formation in this setting. A translational approach with a tissue microarray (TMA) of human PanINs and an in vivo nude mouse platform to test GN25 in human pancreatic adenocarcinoma was then adopted. Quantification of PanINs showed delayed initiation and progression of PanIN lesions at all ages in both homozygous and heterozygous Snaildel1;Pdx-1-Cre;LSL-KrasG12D/+-Mice. PanINs at TMA revealed snail expression in the majority of cases. GN25 showed growth inhibition in 2/2 human pancreatic adenocarcinomas using a nude mice in vivo platform. Genetic and pharmacologic abrogation of Snail1 signaling in exocrine pancreas impairs development of acinar-to-ductal metaplasia following cerulein-mediated pancreatic injury. The present study suggests a fundamental new approach to delay the progression of PDAC.

MicroRNA-196a and -196b as Potential Biomarkers for the Early Detection of Familial Pancreatic Cancer.

Screening programs are recommended for individuals at risk (IAR) from families with familial pancreatic cancer (FPC). However, reliable imaging methods or biomarkers for early diagnosis of pancreatic ductal adenocarcinoma (PC) or its precursor lesions are still lacking. The ability of circulating microRNAs (miRNAs) to discriminate multifocal high-grade precursor lesions or PC from normal was examined. The presence of miRNA-21, -155, -196a, -196b and -210 was analyzed in the serum of transgenic KPC mice to test their ability to distinguish mice with different grades of pancreatic intraepithelial neoplasia (mPanIN1-3) or PC from control mice. Serum levels of miR-196a and -196b were significantly higher in mice with PanIN2/3 lesions (n = 10) or PC (n = 8) as compared to control mice (n = 10) or mice with PanIN1 lesions (n = 10; P = .01). In humans, miR-196a and -196b were also diagnostic. Patients with PC, sporadic (n = 9) or hereditary (n = 10), and IAR with multifocal PanIN2/3 lesions (n = 5) had significantly higher serum levels than patients with neuroendocrine pancreatic tumors (n = 10) or chronic pancreatitis (n = 10), IAR with PanIN1 or no PanIN lesions (n = 5), and healthy controls (n = 10). The combination of both miR-196a and -196b reached a sensitivity of 1 and specificity of 0.9 (area under the curve = 0.99) to diagnose PC or high-grade PanIN lesions. In addition, preoperative elevated serum levels of miR-196a and -196b in patients with PC or multifocal PanIN2/3 lesions dropped to normal after potential curative resection. The combination of miR-196a and -196b may be a promising biomarker test for the screening of IAR for FPC.

Increased rate of clinically relevant pancreatic fistula after deep enucleation of small pancreatic tumors.

PURPOSE: Only small, potentially benign pancreatic tumors located ≥3 mm distant from the main pancreatic duct (MPD) are considered good candidates for enucleation. This study evaluates the outcome of enucleations with regard to their distance to the MPD. METHODS: Clinical characteristics, complications, and outcomes of prospectively documented patients with small (≤30 mm), potentially benign pancreatic tumors, who underwent enucleation, were retrospectively analyzed. Patients were divided in two groups, either deep enucleation (DE, distance ≤3 mm) or standard enucleation (SE, distance >3 mm), as determined by intraoperative ultrasonography (IOUS). RESULTS: Sixty patients underwent DE (n = 30) or SE (n = 30) with IOUS. Both groups did not differ regarding age, tumor size, pathology, and operating time. Complications occurred in 24/30 (80 %) patients of the DE group compared to 15/30 (50 %) patients after SE (P = 0.029). Mortality was nil. The most frequent complication was pancreatic fistula (POPF) occurring in 22/30 (73.3 %) patients after DE and 9/30 (30 %) patients undergoing SE (P = 0.002). Especially, the rate of clinically significant POPF types B and C was higher after DE (21 of 30 patients) compared to SE (7 of 30 patients, P = 0.0006). Univariate and multivariate analyses revealed DE as the only significant factor that negatively influenced the occurrence of POPF. Postoperative hospital stay tended to be longer after DE (15 vs. 11.5 days, P = 0.050). All but two patients with metastatic gastrinoma and two patients, who died of unrelated causes, showed no evidence of disease after a median follow-up of 24 (3-235) months. CONCLUSIONS: Deep enucleation of small, potentially benign pancreatic tumors should be considered with caution given the high rate of clinically relevant POPF.

Reduced complication rate after modified binding purse-string-mattress sutures pancreatogastrostomy versus duct-to-mucosa pancreaticojejunostomy.

BACKGROUND AND PURPOSE: A 2011 metaanalysis demonstrated no difference in postoperative complications between pancreatogastrostomy and pancreaticojejunostomy after pancreaticoduodenectomy with the limitation of heterogeneity among the analysed studies. The present study compares postoperative complications after duct-to-mucosa pancreaticojejunostomy with a modified binding purse-string-mattress sutures pancreatogastrostomy in a teaching hospital. METHODS: One-hundred consecutive pancreaticoduodenectomies were reconstructed either by pancreaticojejunostomy (n = 50, 2004-2008) or modified pancreatogastrostomy (n = 50, 2008-2011). Prospective patients' data was retrospectively analysed for postoperative complications. MAIN FINDINGS: Complications occurred significantly less after modified pancreatogastrostomy compared to pancreaticojejunostomy (p = 0.016). This was mainly due to a significantly lower rate of pancreatic fistula (p = 0.029), especially a lower rate of clinically relevant B and C fistulas (p = 0.011). In particular, the fistula rate was reduced in patients with a soft, non-fibrotic pancreas (p = 0.0231). Postoperative mortality was also lower after modified pancreatogastrostomy (p = 0.042). Uni- and multivariate analyses revealed a soft, non-fibrotic pancreatic texture (odds ratio 5.4, p = 0.028), a non-dilatated pancreatic duct (p = 0.047) and pancreaticojejunostomy (odds ratio 10.7, p = 0.026) as independent, negative factors for pancreatic fistula. CONCLUSION: In a teaching hospital, modified pancreatogastrostomy seems to be superior to pancreaticojejunostomy regarding pancreatic fistula, especially in patients with a soft, non-fibrotic pancreas and/or a small duct. An ongoing prospective randomised multicentre trial (RECOPANC) might confirm these results.