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Glycolytic regulation of the plasma membrane Ca2+ atpase in pancreatic ductal adenocarcinoma
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Abstracts / Pancreatology 13 (2013) e1–e94
P87. Giant solid pseudopapillary neoplasm of the pancreas in a middleaged man: A case report M. Iseki 1, M. Mizuma 1, H. Yoshida 1, T. Okada 1, K. Nakagawa 1,2, H. Hayashi 1, T. Morikawa 1, S. Ottomo 1, N. Sakata 1, H. Ohtsuka 1, K. Fukase 1, T. Aoki 1, F. Motoi 1, T. Naitoh 1, Y. Katayose 1,2, S. Egawa 1, M. Unno 1. 1 Division of Hepato-Biliary-Pancretic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Japan 2 Division of Integrated Surgery and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, Japan Introduction: A solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm of low malignant potential. It typically afflicts in young women, but uncommon in men. We report giant solid pseudopapillary neoplasm of the pancreas in a middle-aged man. Case report: A 47-year-old man was admitted to the previous hospital for continuous epigastric pain and body weight loss. A giant mass was palpated in the upper abdominal area. The abdominal CT scan revealed 21 cm mass with central necrosis and peripheral calcification in the pancreas. This tumor showed enhanced solid component in the marginal area. The patient underwent total pancreatectomy with portal vein resection and reconstruction. In the resected specimen, 26 cm tumor of the pancreas, surrounded by a fibrous pseudocapsule, gave rise to central necrosis and intratumoral hemorrhage. Histological examination revealed that the tumor cells with enlarged nucleus and granular eosinophillic cytoplasm were arranged in sheets and nests, forming pseudopapilla formation. They were immunohistologically positive for CD10 and vimentin. Since nuclear accumulation of beta-catenin protein was shown, this tumor was pathologically diagnosed with SPN. This had malignant potential, indicated by venous invasion. Discussion: This case show atypical clinical feature (age, gender) and typical radiographical feature, including the enhancement of solid component and peripheral calcification. Giant SPN with central necrosis and intratumoral hemorrhage is similar to other giant pancreatic tumors, such as neuroendcrine tumor. Giant SPN is difficult to diagnose by imaging modalities preoperatively, especially in men.
P88.
infection due to stent dysfunction (n¼5), emphysema of mediastinum (n¼1), and stent migration (n¼1), which was rescued by using basket clamp. These complications were improved with conservative therapy. Conclusions: Endoscopic transmural drainage is a minimally invasive, effective and safe approach in the management of pancreatic pseudocysts.
P89. Glycolytic regulation of the plasma membrane Ca2+ atpase in pancreatic ductal adenocarcinoma A. James 1, A. Chan 2, O. Erice 1, A. Siriwardena 2, J. Bruce 1. 1
Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, United Kingdom 2 Hepatobiliary Surgery Unit, Manchester Royal Infirmary, Manchester, United Kingdom Pancreatic ductal adenocarcimona (PDAC) is an aggressive form of cancer with both extremely poor prognosis and severely limited treatment options. Cancer cells rely primarily on glycolysis rather than oxidative phosphorylation to generate ATP, a phenomenon known as the ‘Warburg Effect’. Moreover, cells require ATP to fuel Ca2+ signalling mechanisms, in particular the ATP-dependent plasma membrane Ca2+ ATPase (PMCA). Using fura-2 fluorescence microscopy, we show that Na+-Ca2+ exchange (NCX) plays no role in the clearance of cytosolic Ca2+ ([Ca2+]i) in PaNC1 and MIAPaCa-2 cells, and is instead achieved by the PMCA. Furthermore, the glycolytic inhibitors iodoacetate and 3-bromopyruvate reduced PMCA activity, irreversibly increased resting [Ca2+]i and caused ATP depletion after 15 minutes as measured using firefly luciferase luminescence. In contrast, the mitochondrial inhibitors CCCP and oligomycin had no effect. Treatment with 3-bromopyruvate also induced cell death in PaNC1 cells, while treatment with CCCP had no effect. As a result of the Warburg Effect, lactic acid production increases and is extruded from the cell via monocarboxylate transporters (MCTs). Inhibition of MCTs using a-cyano-4-hydroxycinnamate (CHC) resulted in reduced PMCA activity. However, despite PMCA activity being coupled to H+ influx, acidic extracellular pH did not increase PMCA activity, suggesting that blockade of MCTs slows PMCA activity via a mechanism other than by attenuating lactic acid induced extracellular acidification. Inhibition of glycolysis or MCTs may therefore present novel therapeutic avenues to induce [Ca2+]i overload-mediated cell death in PDAC via inhibition of the PMCA due to ATP depletion, whilst sparing healthy cells.
Efficacy of endoscopic-ultrasound-guided transmural drainage in patients with pancreatic pseudocysts T. Ishihara, M. Tada, K. Tawada, J. Kurosawa, M. Saito, R. Mikata, S. Itho, K. Ishii, H. Ohyama, T. Nishikawa, H. Sugiyama, Y. Sakai, T. Tsuyuguchi, O. Yokosuka. Department Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan Aim: To determine the results of the endoscopic-ultrasound (EUS) guided drainage of Pancreatic pseudocysts (PPCs). Methods: Between September 1999 and November 2011, EUS-guided drainage of PPCs was carried out in 73 (Male; 54, Female; 19, mean age; 49.5 yrs) patients. The criteria of EUS-guided drainage in our institute are as follows; 1) PPC (diameter) > 60 mm, which did not shrink in 6 weeks, 2) PPC with any symptom, or 3) PPC with infection. We used 7 Fr double pigtail endoprosthesis for internal drainage, and 7.2 Fr endoscopic nasopancreatic cyst drainage (ENCD) tube for external drainage. Results: The cause of the PPCs was chronic pancreatitis (n¼32, alcoholic; 25, idiopathic; 7), acute pancreatitis (n¼35), trauma (n¼4), and pancreatic cancer (n¼2). The mean size of PPCs is 91.8 mm. PPCs are located in the pancreatic head (17%), body (21%), tail (36%), body+tail (23%), and whole pancreas (3%). The success rate of the puncture of the PPCs was 100 % (73/73). The success rate of continuous drainage was 94.1% (65/69). Continuous drainage was performed with pigtail endoprosthesis (n¼24), ENCD tube (n¼9), or both (n¼32), whereas 8 patients were treated with temporary aspiration only. EUS-guided drainage led to size reduction of PPCs in 61/65 cases (93.8%) in all; 30/32(93.8%) in internal+external drainage, 22/24(91.7%) in internal drainage alone, 9/9(100%) in external drainage alone and 5/ 8(57.1%) in temporary aspiration. The procedure-related complications were
P90. Sphingosine kinase expression is associated with poor prognosis in resectable pancreatic ductal adenocarcinoma N.B. Jamieson 1, C.R. Carter 1, E.J. Dickson 1, J. Edwards 2, C.J. McKay 1. 1
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, UK Institute of Cancer Sciences, University of Glasgow, UK Background and aim: As patient outcome in pancreatic ductal adenocarcinoma (PDAC) is not reliably predicted using pathological factors alone, markers of tumor behavior are required. Sphingosine 1-phosphate (S1P) is a bioactive lipid with pathophysiological roles. There is evidence that sphingosine kinase (SK1), the enzyme activating S1P, plays a key role in cancer progression, and that SK1 over-expression might provide a growth advantage. Our aim was to investigate sphingosine pathway expression in PDAC patients. Methods: Immunohistochemical staining for SK1 and S1P receptors were assessed in a tissue microarray cohort of 115 patients undergoing pancreaticoduodenectomy for PDAC with full clinicopathological and follow-up data. Kaplan-Meier analysis and Cox proportional hazards models were used to assess mortality risk. Results: 10% of tumors had minimal SK1 expression. In univariate analysis, high SK1 expression (> median expression) associated with significantly reduced median overall survival (15.4months [95%CI:9.7–21.0]) compared to patients with low expression (23.1months [95%CI:18.1– 28.1,P¼0.001]). Furthermore, patients with very high SK1 expression had a significantly worse outcome (11.3 months [95%CI:8.1–14.0]). Most 2
Abstracts / Pancreatology 13 (2013) e1–e94
P87. Giant solid pseudopapillary neoplasm of the pancreas in a middleaged man: A case report M. Iseki 1, M. Mizuma 1, H. Yoshida 1, T. Okada 1, K. Nakagawa 1,2, H. Hayashi 1, T. Morikawa 1, S. Ottomo 1, N. Sakata 1, H. Ohtsuka 1, K. Fukase 1, T. Aoki 1, F. Motoi 1, T. Naitoh 1, Y. Katayose 1,2, S. Egawa 1, M. Unno 1. 1 Division of Hepato-Biliary-Pancretic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Japan 2 Division of Integrated Surgery and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, Japan Introduction: A solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm of low malignant potential. It typically afflicts in young women, but uncommon in men. We report giant solid pseudopapillary neoplasm of the pancreas in a middle-aged man. Case report: A 47-year-old man was admitted to the previous hospital for continuous epigastric pain and body weight loss. A giant mass was palpated in the upper abdominal area. The abdominal CT scan revealed 21 cm mass with central necrosis and peripheral calcification in the pancreas. This tumor showed enhanced solid component in the marginal area. The patient underwent total pancreatectomy with portal vein resection and reconstruction. In the resected specimen, 26 cm tumor of the pancreas, surrounded by a fibrous pseudocapsule, gave rise to central necrosis and intratumoral hemorrhage. Histological examination revealed that the tumor cells with enlarged nucleus and granular eosinophillic cytoplasm were arranged in sheets and nests, forming pseudopapilla formation. They were immunohistologically positive for CD10 and vimentin. Since nuclear accumulation of beta-catenin protein was shown, this tumor was pathologically diagnosed with SPN. This had malignant potential, indicated by venous invasion. Discussion: This case show atypical clinical feature (age, gender) and typical radiographical feature, including the enhancement of solid component and peripheral calcification. Giant SPN with central necrosis and intratumoral hemorrhage is similar to other giant pancreatic tumors, such as neuroendcrine tumor. Giant SPN is difficult to diagnose by imaging modalities preoperatively, especially in men.
P88.
infection due to stent dysfunction (n¼5), emphysema of mediastinum (n¼1), and stent migration (n¼1), which was rescued by using basket clamp. These complications were improved with conservative therapy. Conclusions: Endoscopic transmural drainage is a minimally invasive, effective and safe approach in the management of pancreatic pseudocysts.
P89. Glycolytic regulation of the plasma membrane Ca2+ atpase in pancreatic ductal adenocarcinoma A. James 1, A. Chan 2, O. Erice 1, A. Siriwardena 2, J. Bruce 1. 1
Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, United Kingdom 2 Hepatobiliary Surgery Unit, Manchester Royal Infirmary, Manchester, United Kingdom Pancreatic ductal adenocarcimona (PDAC) is an aggressive form of cancer with both extremely poor prognosis and severely limited treatment options. Cancer cells rely primarily on glycolysis rather than oxidative phosphorylation to generate ATP, a phenomenon known as the ‘Warburg Effect’. Moreover, cells require ATP to fuel Ca2+ signalling mechanisms, in particular the ATP-dependent plasma membrane Ca2+ ATPase (PMCA). Using fura-2 fluorescence microscopy, we show that Na+-Ca2+ exchange (NCX) plays no role in the clearance of cytosolic Ca2+ ([Ca2+]i) in PaNC1 and MIAPaCa-2 cells, and is instead achieved by the PMCA. Furthermore, the glycolytic inhibitors iodoacetate and 3-bromopyruvate reduced PMCA activity, irreversibly increased resting [Ca2+]i and caused ATP depletion after 15 minutes as measured using firefly luciferase luminescence. In contrast, the mitochondrial inhibitors CCCP and oligomycin had no effect. Treatment with 3-bromopyruvate also induced cell death in PaNC1 cells, while treatment with CCCP had no effect. As a result of the Warburg Effect, lactic acid production increases and is extruded from the cell via monocarboxylate transporters (MCTs). Inhibition of MCTs using a-cyano-4-hydroxycinnamate (CHC) resulted in reduced PMCA activity. However, despite PMCA activity being coupled to H+ influx, acidic extracellular pH did not increase PMCA activity, suggesting that blockade of MCTs slows PMCA activity via a mechanism other than by attenuating lactic acid induced extracellular acidification. Inhibition of glycolysis or MCTs may therefore present novel therapeutic avenues to induce [Ca2+]i overload-mediated cell death in PDAC via inhibition of the PMCA due to ATP depletion, whilst sparing healthy cells.
Efficacy of endoscopic-ultrasound-guided transmural drainage in patients with pancreatic pseudocysts T. Ishihara, M. Tada, K. Tawada, J. Kurosawa, M. Saito, R. Mikata, S. Itho, K. Ishii, H. Ohyama, T. Nishikawa, H. Sugiyama, Y. Sakai, T. Tsuyuguchi, O. Yokosuka. Department Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan Aim: To determine the results of the endoscopic-ultrasound (EUS) guided drainage of Pancreatic pseudocysts (PPCs). Methods: Between September 1999 and November 2011, EUS-guided drainage of PPCs was carried out in 73 (Male; 54, Female; 19, mean age; 49.5 yrs) patients. The criteria of EUS-guided drainage in our institute are as follows; 1) PPC (diameter) > 60 mm, which did not shrink in 6 weeks, 2) PPC with any symptom, or 3) PPC with infection. We used 7 Fr double pigtail endoprosthesis for internal drainage, and 7.2 Fr endoscopic nasopancreatic cyst drainage (ENCD) tube for external drainage. Results: The cause of the PPCs was chronic pancreatitis (n¼32, alcoholic; 25, idiopathic; 7), acute pancreatitis (n¼35), trauma (n¼4), and pancreatic cancer (n¼2). The mean size of PPCs is 91.8 mm. PPCs are located in the pancreatic head (17%), body (21%), tail (36%), body+tail (23%), and whole pancreas (3%). The success rate of the puncture of the PPCs was 100 % (73/73). The success rate of continuous drainage was 94.1% (65/69). Continuous drainage was performed with pigtail endoprosthesis (n¼24), ENCD tube (n¼9), or both (n¼32), whereas 8 patients were treated with temporary aspiration only. EUS-guided drainage led to size reduction of PPCs in 61/65 cases (93.8%) in all; 30/32(93.8%) in internal+external drainage, 22/24(91.7%) in internal drainage alone, 9/9(100%) in external drainage alone and 5/ 8(57.1%) in temporary aspiration. The procedure-related complications were
P90. Sphingosine kinase expression is associated with poor prognosis in resectable pancreatic ductal adenocarcinoma N.B. Jamieson 1, C.R. Carter 1, E.J. Dickson 1, J. Edwards 2, C.J. McKay 1. 1
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, UK Institute of Cancer Sciences, University of Glasgow, UK Background and aim: As patient outcome in pancreatic ductal adenocarcinoma (PDAC) is not reliably predicted using pathological factors alone, markers of tumor behavior are required. Sphingosine 1-phosphate (S1P) is a bioactive lipid with pathophysiological roles. There is evidence that sphingosine kinase (SK1), the enzyme activating S1P, plays a key role in cancer progression, and that SK1 over-expression might provide a growth advantage. Our aim was to investigate sphingosine pathway expression in PDAC patients. Methods: Immunohistochemical staining for SK1 and S1P receptors were assessed in a tissue microarray cohort of 115 patients undergoing pancreaticoduodenectomy for PDAC with full clinicopathological and follow-up data. Kaplan-Meier analysis and Cox proportional hazards models were used to assess mortality risk. Results: 10% of tumors had minimal SK1 expression. In univariate analysis, high SK1 expression (> median expression) associated with significantly reduced median overall survival (15.4months [95%CI:9.7–21.0]) compared to patients with low expression (23.1months [95%CI:18.1– 28.1,P¼0.001]). Furthermore, patients with very high SK1 expression had a significantly worse outcome (11.3 months [95%CI:8.1–14.0]). Most 2