Background: Resection margin (RM) status in pancreatic head adenocarcinoma is assessed histologically, but pathological examination is not standardized. The aim of this study was to assess the influence of standardized pathological examination on the reporting of RM status. Methods: A standardized protocol (SP) for pancreaticoduodenectomy specimen examination, involving multicolour margin staining, axial slicing and extensive tissue sampling, was developed. R1 resection was defined as tumour within 1 mm of the RM. A prospective series reported according to this protocol (SP series, n = 54) was compared with a historical matched series in which a non-standardized protocol was used (NSP series, n = 48). Results: Implementation of the SP resulted in a higher R1 rate overall, and for pancreatic (22 of 26 85 per cent) compared with ampullary (four of 15) and bile duct (six of 13) cancer. Sampling of the circumferential RM was more extensive in the SP series and correlated with RM status. RM involvement was often multifocal (14 of 32), affecting the posterior RM most frequently (21 of 32). Survival correlated with RM status for the entire SP series (P < 0·001), but not for the NSP series. There was a trend towards better median and actuarial 5-year survival after R0 resection in the SP pancreatic cancer subgroup. Conclusion: Standardized examination influences the reporting of RM status.

Objective: Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery.Design: Gemcitabine metabolites were analysed in LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation.Results: Gemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2′,2′-difluorodeoxycytidine-5′-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2′,2′-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5′-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%.Conclusions: Our findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.