The vacuolar-ATPase (v-ATPase) is a proton transporter found on many intra-cellular organelles and the plasma membrane (PM). The v-ATPase on PMs of cancer cells may contribute to their invasive properties in vitro. Its relevance to human cancer tissues remains unclear. We investigated whether the expression and cellular localization of v-ATPase corresponded to the stage of human pancreatic cancer, and its effect on matrix metalloproteinase (MMP) activation in vitro. The intensity of v-ATPase staining increased significantly across the range of pancreatic histology from normal ducts to pancreatic intra-epithelial neoplasms (PanIN) and finally pancreatic ductal adenocarcinoma (PDAC). Low-grade PanIN lesions displayed polarized staining confined to the basal aspect of the cell in the majority (86%) of fields examined. High-grade PanIN lesions and PDAC demonstrated intense and diffuse v-ATPase localization. In pancreatic cancer cells, PM-associated v-ATPase co-localized with cortactin, a component of the leading edge that helps direct MMP release. Blockade of the v-ATPase with concanamycin or shRNA targeting the V1E subunit reduced MMP-9 activity; this effect was greatest in cells with prominent PM-associated v-ATPase. In cells with detectable MMP-2 activities, however, treatment with concanamycin markedly increased MMP-2’s most activated forms. V-ATPase blockade inhibited functional migration and invasion in those cells with predominantly MMP-9 activity. These results indicate that human PDAC specimens demonstrate loss of v-ATPase polarity and increased expression that correlates with increasing invasive potential. Thus, v-ATPase selectively modulates specific MMPs that may be linked to an invasive cancer phenotype.

Background and Aims-Protease activation within the pancreatic acinar cell is a key early event in acute pancreatitis and may require low pH intracellular compartments. Clinical studies suggest that acidosis may affect the risk for developing pancreatitis. We hypothesized that exposure to an acid load might sensitize the acinar cell to secretagogue-induced pancreatitis.

Introduction Transanal total mesorectal excision (TaTME) has rapidly emerged as a novel approach for rectal cancer surgery. Safety profiles are still emerging and more comparative data is urgently needed. This study aimed to compare indications and short‐term outcomes of TaTME, open, laparoscopic, and robotic TME internationally. Methods A pre‐planned analysis of the European Society of Coloproctology (ESCP) 2017 audit was performed. Patients undergoing elective total mesorectal excision (TME) for malignancy between 1 January 2017 and 15 March 2017 by any operative approach were included. The primary outcome measure was anastomotic leak. Results Of 2579 included patients, 76.2% (1966/2579) underwent TME with restorative anastomosis of which 19.9% (312/1966) had a minimally invasive approach (laparoscopic or robotic) which included a transanal component (TaTME). Overall, 9.0% (175/1951, 15 missing outcome data) of patients suffered an anastomotic leak. On univariate analysis both laparoscopic TaTME (OR 1.61, 1.02–2.48, P = 0.04) and robotic TaTME (OR 3.05, 1.10–7.34, P = 0.02) were associated with a higher risk of anastomotic leak than non‐transanal laparoscopic TME. However this association was lost in the mixed‐effects model controlling for patient and disease factors (OR 1.23, 0.77–1.97, P = 0.39 and OR 2.11, 0.79–5.62, P = 0.14 respectively), whilst low rectal anastomosis (OR 2.72, 1.55–4.77, P < 0.001) and male gender (OR 2.29, 1.52–3.44, P < 0.001) remained strongly associated. The overall positive circumferential margin resection rate was 4.0%, which varied between operative approaches: laparoscopic 3.2%, transanal 3.8%, open 4.7%, robotic 1%. Conclusion This contemporaneous international snapshot shows that uptake of the TaTME approach is widespread and is associated with surgically and pathologically acceptable results.

Introduction The mainstay of management for locally advanced rectal cancer is chemoradiotherapy followed by surgical resection. Following chemoradiotherapy, a complete response may be detected clinically and radiologically (cCR) prior to surgery or pathologically after surgery (pCR). We aim to report the overall complete pathological response (pCR) rate and the reliability of detecting a cCR by conventional pre‐operative imaging. Methods A pre‐planned analysis of the European Society of Coloproctology (ESCP) 2017 audit was performed. Patients treated by elective rectal resection were included. A pCR was defined as a ypT0 N0 EMVI negative primary tumour; a partial response represented any regression from baseline staging following chemoradiotherapy. The primary endpoint was the pCR rate. The secondary endpoint was agreement between post‐treatment MRI restaging (yMRI) and final pathological staging. Results Of 2572 patients undergoing rectal cancer surgery in 277 participating centres across 44 countries, 673 (26.2%) underwent chemoradiotherapy and surgery. The pCR rate was 10.3% (67/649), with a partial response in 35.9% (233/649) patients. Comparison of AJCC stage determined by post‐treatment yMRI with final pathology showed understaging in 13% (55/429) and overstaging in 34% (148/429). Agreement between yMRI and final pathology for T‐stage, N‐stage, or AJCC status were each graded as ‘fair’ only (n = 429, Kappa 0.25, 0.26 and 0.35 respectively). Conclusion The reported pCR rate of 10% highlights the potential for non‐operative management in selected cases. The limited strength of agreement between basic conventional post‐chemoradiotherapy imaging assessment techniques and pathology suggest alternative markers of response should be considered, in the context of controlled clinical trials.

Background Laparoscopy has now been implemented as a standard of care for elective colonic resection around the world. During the adoption period, studies showed that conversion may be detrimental to patients, with poorer outcomes than both laparoscopic completed or planned open surgery. The primary aim of this study was to determine whether laparoscopic conversion was associated with a higher major complication rate than planned open surgery in contemporary, international practice. Methods Combined analysis of the European Society of Coloproctology 2017 and 2015 audits. Patients were included if they underwent elective resection of a colonic segment from the caecum to the rectosigmoid junction with primary anastomosis. The primary outcome measure was the 30‐day major complication rate, defined as Clavien‐Dindo grade III‐V. Results Of 3980 patients, 64% (2561/3980) underwent laparoscopic surgery and a laparoscopic conversion rate of 14% (359/2561). The major complication rate was highest after open surgery (laparoscopic 7.4%, converted 9.7%, open 11.6%, P < 0.001). After case mix adjustment in a multilevel model, only planned open (and not laparoscopic converted) surgery was associated with increased major complications in comparison to laparoscopic surgery (OR 1.64, 1.27–2.11, P < 0.001). Conclusions Appropriate laparoscopic conversion should not be considered a treatment failure in modern practice. Conversion does not appear to place patients at increased risk of complications vs planned open surgery, supporting broadening of selection criteria for attempted laparoscopy in elective colonic resection.