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Bridging the gap between bench and bedside: Systematic review of treatment in experimental acute pancreatitis
Abstracts / Pancreatology 13 (2013) e1–e94
importantly, in multivariate analysis, high SK1 expression remained a predictor of poor overall survival (Hazard ratio¼2.38, P<0.0001) independent of stage, resection margin, lymph node involvement and chemotherapy. Discussion: We have shown novel evidence that high tumor SK1 expression is an independent predictor of poor prognosis for patients with resectable PDAC. There is evidence that SK1 inhibitors may target vascularization, fibrosis, cell proliferation and apoptosis. These data suggest that SK1 expression may provide useful prognostic information and suggest that sphingosine kinase axis inhibition may provide a novel therapeutic strategy for PDAC.
P91. Clinical characteristics of intraductal papillary mucinous neoplasm of the pancreas (IPMN) manifesting as acute pancreatitis or acute recurrent pancreatitis (AP/ARP) J.W. Jang 1, M.H. Kim 2, S.U. Jeong 2, D.H. Park 2, S.S. Lee 2, D.W. Seo 2, S.K. Lee 2, J.H. Kim 3. 1 Department of Gastroenterology, Eulji University College of Medicine, Eulji University Hospital, Daejeon, South Korea 2 Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 3 Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea Objectives: Comparatively little is known about AP/ARP with IPMN as the causative lesion although there have been many reports about the malignant potential of IPMN as a premalignant lesion. Methods: From 2000 to 2008, 489 patients fulfilled our diagnostic criteria of IPMN among 784 patients coded by ICD-10 with IPMN. After careful exclusion of all known causes of AP, 34 patients with IPMN as the cause of AP/ARP were enrolled. Branch-duct type IPMN (BD-IPMN) patients were matched with control BD-IPMN patients who had never suffered from pancreatitis after a 5 year follow-up. Results: AP/ARP caused by IPMN occurred in 34 of 488 (7%) patients with IPMN, and the prevalence rate of AP/ARP was higher in the mainduct/combined type than the branch-duct type (14% [16/111] vs. 5% [18/ 378], P¼0.002). The severity of pancreatitis was mild, based on the CTSI score (median 2, range 0–4). Histologic review of 24 patients with surgical resection revealed 4 adenomas, 17 borderline malignancies, two carcinomas in situ, and one invasive carcinoma. AP/ARP did not recur in any of 24 surgically resected patients during the follow-up period (median 52 months, range 38-115 months). Multivariate analysis showed that factors associated with AP/ARP in patients with BD-IPMN included younger age (odds ratio [OR]¼0.879, p¼0.045), male gender (OR¼7.16, p¼0.048) and more dilated main pancreatic duct (OR¼2.17, p¼0.024). Conclusions: AP/ARP caused by IPMN occurred more frequently in the main-duct/combined type than in the branch-duct type. Most cases were mild in severity and benign in pathology. Younger age, male gender and a more dilated main pancreatic duct were predictive of AP/ARP in patients with BD-IPMN. Acute pancreatitis can be, though uncommon, an initial manifestation of IPMN which leads to diagnosis. IPMN should be considered in the list of potential causes of AP/ARP if the etiology is unclear.
P92.
e37
Objective: To evaluate current evidence for the treatment of experimental AP and assess the translation of these preclinical studies into randomised clinical trials (RCTs) in patients with AP. Methods: A comprehensive online search of Medline, Embase, Pubmed and the Cochrane Library was conducted by two independent reviewers of all published preclinical studies and corresponding RCTs of AP treatment undertaken from the first reported studies to January 2012. Results: 142 compounds have been tested in 257 experimental studies. Of these, only 21 compounds have been tested in 116 RCTs. Modes of action included microcirculatory modification [Trials (T) 38, Compounds (C) 19; RCTs 4, Multiple compounds in individual RCTs (CRCT) 2], anti-inflammatory agents (T 31, C 21, RCTs 0), eicosanoid modulators (T 32, C 16; RCTs 3, CRCT 1), immune-modulators (T 35, C 23; RCTs 13, CRCT 5), protease inhibitors (T 31, C 12; RCTs 34, CRCT 5), secretion inhibitors (T 28, C 13; RCTs 40, CRCT 2), antioxidants (T 18, C 8; RCTs 14, CRCT 4) and multiple actions (T 24, C 16; RCTs 6, CRCT 2). Conclusion: While attrition is expected in drug development, our findings identify a significant translational gap between animal studies and RCTs in AP. We propose standardised reporting of preclinical studies to improve the quality, comparability and translation of experimental AP treatment.
P93. Involvement of the MPTP in minocycline-induced mitochondrial dysfunction in murine pancreatic acinar cells M.A. Javed 1, 2, W. Li 1, D. Collier 2, T. Jin 1, W. Huang 1, M. Awais 1, A. Tepikin 2, D.N. Criddle 1, 2, R. Sutton 1. 1 Liverpool NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK 2 Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK Introduction: Mitochondrial dysfunction is a key feature of pancreatic injury leading to acute pancreatitis (AP), which may be mediated via formation of the mitochondrial permeability transition pore (MPTP). Minocycline and other tetracycline antibiotics have been implicated in causing AP in patients, although the underlying mechanism has not been investigated. Objective: To determine the effects of minocycline on murine pancreatic acinar cell (PAC) mitochondrial function and its mode of action. Methods: Confocal and TIRF microscopy were used to evaluate mitochondrial membrane potential (Δjm: TMRM), cytosolic and mitochondrial Ca2+ levels ([Ca2+]c, Fura-2; [Ca2+]m, X-Rhod-1, respectively) in live perfused PACs isolated from wild type (CD1) and Ppif -/- (cyclophilin D knockout) mice. Activation of necrotic cell death pathway was detected using propidium iodide. Results: Application of minocycline (10 - 100 mM) for 10 mins induced rapid and sustained falls of Δjm (44% at 10 mM) associated with increases of [Ca2+]m in wild type (WT) PACs. The protonophore CCCP (10 mM) was applied after minocycline to show maximal depolarisation. Comparison of the effects of 10 mM minocycline indicated that mitochondrial depolarisation was significantly less pronounced (p<0.05) in the Ppif -/- mice although some loss of Δjm (23.4%) was still apparent. Perfusion of WT PACs with minocycline (10 - 100 mM) did not alter [Ca2+]c, whereas cholecystokinin (20 pM), applied after minocycline, induced typical oscillatory elevations. Treatment of WT PACs with 10 mM minocycline increased necrotic cell death pathway activation (10 % cont. vs 30 % min. gp, p<0.05). Conclusion: Minocycline causes mitochondrial inhibition in murine PACs, an effect that appears, at least in part, to be mediated via opening of the MPTP.
Bridging the gap between bench and bedside: Systematic review of treatment in experimental acute pancreatitis M.A. Javed 1, 2, K. Altaf 1, W. Huang 1, D.N. Criddle 1, 2, R. Sutton 1. 1
Liverpool NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK 2 Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK Introduction: Experimental animal models of acute pancreatitis (AP) are well characterised, have been used to investigate disease mechanisms and test potential therapies before human trials.
P94. Trends in laparoscopic pancreaticoduodenectomy S. Jegatheeswaran, A.K. Siriwardena. Hepato-Pancreato-Biliary Surgery Unit, Manchester Royal Infirmary, Manchester, UK Introduction: Pancreaticoduodenectomy (PD) is the standard of care for cancer localised to the head of the pancreas. The resectional component
importantly, in multivariate analysis, high SK1 expression remained a predictor of poor overall survival (Hazard ratio¼2.38, P<0.0001) independent of stage, resection margin, lymph node involvement and chemotherapy. Discussion: We have shown novel evidence that high tumor SK1 expression is an independent predictor of poor prognosis for patients with resectable PDAC. There is evidence that SK1 inhibitors may target vascularization, fibrosis, cell proliferation and apoptosis. These data suggest that SK1 expression may provide useful prognostic information and suggest that sphingosine kinase axis inhibition may provide a novel therapeutic strategy for PDAC.
P91. Clinical characteristics of intraductal papillary mucinous neoplasm of the pancreas (IPMN) manifesting as acute pancreatitis or acute recurrent pancreatitis (AP/ARP) J.W. Jang 1, M.H. Kim 2, S.U. Jeong 2, D.H. Park 2, S.S. Lee 2, D.W. Seo 2, S.K. Lee 2, J.H. Kim 3. 1 Department of Gastroenterology, Eulji University College of Medicine, Eulji University Hospital, Daejeon, South Korea 2 Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 3 Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea Objectives: Comparatively little is known about AP/ARP with IPMN as the causative lesion although there have been many reports about the malignant potential of IPMN as a premalignant lesion. Methods: From 2000 to 2008, 489 patients fulfilled our diagnostic criteria of IPMN among 784 patients coded by ICD-10 with IPMN. After careful exclusion of all known causes of AP, 34 patients with IPMN as the cause of AP/ARP were enrolled. Branch-duct type IPMN (BD-IPMN) patients were matched with control BD-IPMN patients who had never suffered from pancreatitis after a 5 year follow-up. Results: AP/ARP caused by IPMN occurred in 34 of 488 (7%) patients with IPMN, and the prevalence rate of AP/ARP was higher in the mainduct/combined type than the branch-duct type (14% [16/111] vs. 5% [18/ 378], P¼0.002). The severity of pancreatitis was mild, based on the CTSI score (median 2, range 0–4). Histologic review of 24 patients with surgical resection revealed 4 adenomas, 17 borderline malignancies, two carcinomas in situ, and one invasive carcinoma. AP/ARP did not recur in any of 24 surgically resected patients during the follow-up period (median 52 months, range 38-115 months). Multivariate analysis showed that factors associated with AP/ARP in patients with BD-IPMN included younger age (odds ratio [OR]¼0.879, p¼0.045), male gender (OR¼7.16, p¼0.048) and more dilated main pancreatic duct (OR¼2.17, p¼0.024). Conclusions: AP/ARP caused by IPMN occurred more frequently in the main-duct/combined type than in the branch-duct type. Most cases were mild in severity and benign in pathology. Younger age, male gender and a more dilated main pancreatic duct were predictive of AP/ARP in patients with BD-IPMN. Acute pancreatitis can be, though uncommon, an initial manifestation of IPMN which leads to diagnosis. IPMN should be considered in the list of potential causes of AP/ARP if the etiology is unclear.
P92.
e37
Objective: To evaluate current evidence for the treatment of experimental AP and assess the translation of these preclinical studies into randomised clinical trials (RCTs) in patients with AP. Methods: A comprehensive online search of Medline, Embase, Pubmed and the Cochrane Library was conducted by two independent reviewers of all published preclinical studies and corresponding RCTs of AP treatment undertaken from the first reported studies to January 2012. Results: 142 compounds have been tested in 257 experimental studies. Of these, only 21 compounds have been tested in 116 RCTs. Modes of action included microcirculatory modification [Trials (T) 38, Compounds (C) 19; RCTs 4, Multiple compounds in individual RCTs (CRCT) 2], anti-inflammatory agents (T 31, C 21, RCTs 0), eicosanoid modulators (T 32, C 16; RCTs 3, CRCT 1), immune-modulators (T 35, C 23; RCTs 13, CRCT 5), protease inhibitors (T 31, C 12; RCTs 34, CRCT 5), secretion inhibitors (T 28, C 13; RCTs 40, CRCT 2), antioxidants (T 18, C 8; RCTs 14, CRCT 4) and multiple actions (T 24, C 16; RCTs 6, CRCT 2). Conclusion: While attrition is expected in drug development, our findings identify a significant translational gap between animal studies and RCTs in AP. We propose standardised reporting of preclinical studies to improve the quality, comparability and translation of experimental AP treatment.
P93. Involvement of the MPTP in minocycline-induced mitochondrial dysfunction in murine pancreatic acinar cells M.A. Javed 1, 2, W. Li 1, D. Collier 2, T. Jin 1, W. Huang 1, M. Awais 1, A. Tepikin 2, D.N. Criddle 1, 2, R. Sutton 1. 1 Liverpool NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK 2 Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK Introduction: Mitochondrial dysfunction is a key feature of pancreatic injury leading to acute pancreatitis (AP), which may be mediated via formation of the mitochondrial permeability transition pore (MPTP). Minocycline and other tetracycline antibiotics have been implicated in causing AP in patients, although the underlying mechanism has not been investigated. Objective: To determine the effects of minocycline on murine pancreatic acinar cell (PAC) mitochondrial function and its mode of action. Methods: Confocal and TIRF microscopy were used to evaluate mitochondrial membrane potential (Δjm: TMRM), cytosolic and mitochondrial Ca2+ levels ([Ca2+]c, Fura-2; [Ca2+]m, X-Rhod-1, respectively) in live perfused PACs isolated from wild type (CD1) and Ppif -/- (cyclophilin D knockout) mice. Activation of necrotic cell death pathway was detected using propidium iodide. Results: Application of minocycline (10 - 100 mM) for 10 mins induced rapid and sustained falls of Δjm (44% at 10 mM) associated with increases of [Ca2+]m in wild type (WT) PACs. The protonophore CCCP (10 mM) was applied after minocycline to show maximal depolarisation. Comparison of the effects of 10 mM minocycline indicated that mitochondrial depolarisation was significantly less pronounced (p<0.05) in the Ppif -/- mice although some loss of Δjm (23.4%) was still apparent. Perfusion of WT PACs with minocycline (10 - 100 mM) did not alter [Ca2+]c, whereas cholecystokinin (20 pM), applied after minocycline, induced typical oscillatory elevations. Treatment of WT PACs with 10 mM minocycline increased necrotic cell death pathway activation (10 % cont. vs 30 % min. gp, p<0.05). Conclusion: Minocycline causes mitochondrial inhibition in murine PACs, an effect that appears, at least in part, to be mediated via opening of the MPTP.
Bridging the gap between bench and bedside: Systematic review of treatment in experimental acute pancreatitis M.A. Javed 1, 2, K. Altaf 1, W. Huang 1, D.N. Criddle 1, 2, R. Sutton 1. 1
Liverpool NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK 2 Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK Introduction: Experimental animal models of acute pancreatitis (AP) are well characterised, have been used to investigate disease mechanisms and test potential therapies before human trials.
P94. Trends in laparoscopic pancreaticoduodenectomy S. Jegatheeswaran, A.K. Siriwardena. Hepato-Pancreato-Biliary Surgery Unit, Manchester Royal Infirmary, Manchester, UK Introduction: Pancreaticoduodenectomy (PD) is the standard of care for cancer localised to the head of the pancreas. The resectional component