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Aryl hydrocarbon receptor regulates pancreatic IL-22 and protects against acute pancreatitis in mice
Abstracts / Pancreatology 13 (2013) e1–e94
Introduction: Insulin dependence following TP-IAT for chronic pancreatitis (CP) is highly dependent on islet dose infused. Oxygen consumption rate (OCR) is a common measure of viability and in islets, also relates to potency. This study was conducted to assess whether OCR can enhance prediction of metabolic outcomes in recipients. Methods: 66 non-diabetic patients with CP undergoing TP-IAT between 2008 and present had results of islet product assayed for OCR and subsequent follow-up on insulin usage (mean follow-up 20.1 +/- 7.8 month). Results of OCR assays, islet dosing, and insulin use were studied for correlation using JMP 9 software. Results: In the 66 patients studied, mean islet equivalents (IEQ) transplanted intraportally was 336,997+/-119,323 (5307+/-1883 per kg), and mean OCR of the islet prep was 112.5+/-21.9 pmol/min*ug DNA. Independence from insulin use was seen in 37.9%, dependence in 31.8%, and partial use in 30.3% (2 previously independent). The total viable tissue dose (OCR/DNA*IEQ tx per kg) correlates strongly with post-tx insulin status (p ¼ 0.0002; R2 ¼ 0.233; by ANOVA) with a mean of 742,894+/-201582 pmol*IEQ/min*kg in the insulin independent group vs. 453,003+/-220619 in the dependent group (p¼0.0001). A cut-off of 520,080 is predictive of insulin status with 96.0% sensitivity and 66.7% specificity, corresponding to a threshold dose of 4622 IEQ per kg at the average OCR of 112.5 pmol/min*ugDNA. This corresponds nicely to a previously reported threshold of 5000 IEQ per kg leading to insulin independence in 74% of recipients. Discussion: Total viable tissue dose is predictive of insulin status in TPIAT and could be further refined by correcting for purity/composition of islet tissue products. Improvement of both islet yield and viability (OCR/ DNA) should lead to improved metabolic outcomes in these patients.
P260. Solid pseudopapillary tumors of the pancreas: An updated experience in single center J. Wu, Z. Qian, C. Dai, K. Jiang, Q. Li, W. Gao, F. Guo, J. Chen, J. Wei, Z. Lu, Y. Miao. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China Introduction: To evaluate the clinical features and surgical results of solid pseudopapillary tumors of the pancreas at one single institution. Method: Thirty-nine consecutive patients who underwent surgery for pathologically confirmed solid pseudopapillary tumors of the pancreas between Oct. 2005 and Jun. 2012 were retrospectively reviewed. Results: Among the patients included 34 female and 5 male, median age at diagnosis was 28.2 years (6–54 years). Abdominal discomfort or pain were the most common symptoms. The tumors appeared on ultrasonography and/or cross-sectional imaging(CT/MRI) as solid or cystic masses. Median tumor size was 5.7cm (2.0–13.0cm). Tumors located in head/neck (n¼20) and distal part (n¼19) of the pancreas. Serum tumor markers (CA19-9, CA50) level were within the normal range. All the patients underwent surgical resection. Surgical procedures included enucleation(n¼6), distal pancreatectomy (n¼16, 9 with spleen preservation, 6 with splenectomy, and one combined with splenectomy, distal gastrectomy & partial colectomy), middle segment pancreatectomy (n¼7) ,Whipple's procedure (n¼6), PPPD (pylorus preservation pancreaticoduodenectomy, n¼1) and Beger's procedure (n¼3). Pancreatic fistula (n¼8) and new onset diabetes mellitus (n¼4) were recorded postoperatively and none reoperation was needed. One patient was readmitted 16 months postoperatively for acute pancreatitis and recovered with preservative threatment. No other severe complications occurred. Histological results showed solid with cystic areas and papillary protrusions. All patients were alive and disease-free at a median follow-up of 20 months (1–80 months). Conclusion: Solid pseudopapillary tumor of the pancreas was rare neoplasm occurred predominantly in young women with low malignant potential. Aggressive resection should always be attempted and could result in long-term survival.
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P261. Systematic review and meta-analysis of outcomes after intraoperative pancreatic duct stent placement during pancreaticoduodenectomy J.J. Xiong 1, K. Altaf 3, R. Mukherjee 3, W. Huang 2, 3, W.M. Hu 1, A. Li 1, N.W. Ke 1, R. Sutton 3, X.B. Liu 1. 1 Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China 2 Sichuan Provincial Pancreatitis Centre, Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan University, Chengdu, China 3 NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool and Broadgreen University Hospitals Trust and University of Liverpool, Liverpool, UK Background: Postoperative pancreatic leakage after pancreaticoduodenectomy (PD) is often serious. Although some studies have suggested that stenting the anastomosis can reduce the incidence of this complication, the value of stenting in the setting of PD remains unclear. Methods: Studies comparing outcomes of stent versus no stent, and internal versus external stent placement for PD were eligible for inclusion. Pooled odds ratios (ORs) with 95 per cent confidence intervals were calculated using fixed- or random-effects models. Results: Five randomized clinical trials (RCTs) and 11 non-randomized observational clinical studies (OCS) involving 1726 patients were selected between January 1973 and September 2011 for inclusion. Meta-analysis of RCTs revealed that placing a stent in the pancreatic duct did not reduce the incidence of postoperative pancreatic fistula (PF). External stents had no advantage over internal stents in terms of clinical outcome. Subgroup analyses revealed that use of an external stent significantly reduced the incidence of PF (RCTs: OR 0.42, 0.24 to 0.76, P ¼ 0.004; OCS: OR 0.43, 0.27 to 0.68, P < 0.001), delayed gastric emptying (RCTs: OR 0.41, 0.19 to 0.87, P ¼ 0.02) and postoperative morbidity (RCTs: OR 0.55, 0.34 to 0.89, P ¼ 0.02) compared with no stent. Conclusion: Pancreatic duct stenting did not reduce the incidence of PF and other complications in PD compared with no stenting. Although no difference was found between external and internal stents in terms of efficacy, external stents seemed to reduce the incidence of PF compared with control.
P262. Aryl hydrocarbon receptor regulates pancreatic IL-22 and protects against acute pancreatitis in mice J. Xue, D.T.C. Nguyen, A. Habtezion. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA Despite significant morbidity and mortality associated with acute pancreatitis, aside from supportive therapy there is lack of active treatment. Recent work indicates that immune response during acute pancreatitis is important in modulating disease severity. IL-22 mediates epithelial cell immunity due to restricted IL-22 receptor (IL-22R) expression in epithelial cells. Herein, we show that CD4+ T cells are the main source of IL-22 in the normal pancreas. In acute pancreatitis, IL-22+ CD4+ T cells are depleted whereas IL-22R is upregulated. Pancreatic acinar cells respond readily to IL-22 through STAT3 and IL-22 ameliorates established acute pancreatitis. Aryl hydrocarbon receptor (AhR) is a critical liganddependent regulator of IL-22 and we find that AhR activation protects whereas AhR inhibition worsens acute pancreatitis. IL-22 rescues AhR non-responsive mice susceptibility to acute pancreatitis, whereas IL-22 blockade abolishes protective role of AhR activation, confirming that IL-22 mediates protective role of AhR in the pancreas. Taken together our data highlight the importance of AhR as a potential novel therapeutic target in acute pancreatitis and in mediating crosstalk between the pancreas leukocytes and epithelial cells via IL-22.
Introduction: Insulin dependence following TP-IAT for chronic pancreatitis (CP) is highly dependent on islet dose infused. Oxygen consumption rate (OCR) is a common measure of viability and in islets, also relates to potency. This study was conducted to assess whether OCR can enhance prediction of metabolic outcomes in recipients. Methods: 66 non-diabetic patients with CP undergoing TP-IAT between 2008 and present had results of islet product assayed for OCR and subsequent follow-up on insulin usage (mean follow-up 20.1 +/- 7.8 month). Results of OCR assays, islet dosing, and insulin use were studied for correlation using JMP 9 software. Results: In the 66 patients studied, mean islet equivalents (IEQ) transplanted intraportally was 336,997+/-119,323 (5307+/-1883 per kg), and mean OCR of the islet prep was 112.5+/-21.9 pmol/min*ug DNA. Independence from insulin use was seen in 37.9%, dependence in 31.8%, and partial use in 30.3% (2 previously independent). The total viable tissue dose (OCR/DNA*IEQ tx per kg) correlates strongly with post-tx insulin status (p ¼ 0.0002; R2 ¼ 0.233; by ANOVA) with a mean of 742,894+/-201582 pmol*IEQ/min*kg in the insulin independent group vs. 453,003+/-220619 in the dependent group (p¼0.0001). A cut-off of 520,080 is predictive of insulin status with 96.0% sensitivity and 66.7% specificity, corresponding to a threshold dose of 4622 IEQ per kg at the average OCR of 112.5 pmol/min*ugDNA. This corresponds nicely to a previously reported threshold of 5000 IEQ per kg leading to insulin independence in 74% of recipients. Discussion: Total viable tissue dose is predictive of insulin status in TPIAT and could be further refined by correcting for purity/composition of islet tissue products. Improvement of both islet yield and viability (OCR/ DNA) should lead to improved metabolic outcomes in these patients.
P260. Solid pseudopapillary tumors of the pancreas: An updated experience in single center J. Wu, Z. Qian, C. Dai, K. Jiang, Q. Li, W. Gao, F. Guo, J. Chen, J. Wei, Z. Lu, Y. Miao. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China Introduction: To evaluate the clinical features and surgical results of solid pseudopapillary tumors of the pancreas at one single institution. Method: Thirty-nine consecutive patients who underwent surgery for pathologically confirmed solid pseudopapillary tumors of the pancreas between Oct. 2005 and Jun. 2012 were retrospectively reviewed. Results: Among the patients included 34 female and 5 male, median age at diagnosis was 28.2 years (6–54 years). Abdominal discomfort or pain were the most common symptoms. The tumors appeared on ultrasonography and/or cross-sectional imaging(CT/MRI) as solid or cystic masses. Median tumor size was 5.7cm (2.0–13.0cm). Tumors located in head/neck (n¼20) and distal part (n¼19) of the pancreas. Serum tumor markers (CA19-9, CA50) level were within the normal range. All the patients underwent surgical resection. Surgical procedures included enucleation(n¼6), distal pancreatectomy (n¼16, 9 with spleen preservation, 6 with splenectomy, and one combined with splenectomy, distal gastrectomy & partial colectomy), middle segment pancreatectomy (n¼7) ,Whipple's procedure (n¼6), PPPD (pylorus preservation pancreaticoduodenectomy, n¼1) and Beger's procedure (n¼3). Pancreatic fistula (n¼8) and new onset diabetes mellitus (n¼4) were recorded postoperatively and none reoperation was needed. One patient was readmitted 16 months postoperatively for acute pancreatitis and recovered with preservative threatment. No other severe complications occurred. Histological results showed solid with cystic areas and papillary protrusions. All patients were alive and disease-free at a median follow-up of 20 months (1–80 months). Conclusion: Solid pseudopapillary tumor of the pancreas was rare neoplasm occurred predominantly in young women with low malignant potential. Aggressive resection should always be attempted and could result in long-term survival.
e85
P261. Systematic review and meta-analysis of outcomes after intraoperative pancreatic duct stent placement during pancreaticoduodenectomy J.J. Xiong 1, K. Altaf 3, R. Mukherjee 3, W. Huang 2, 3, W.M. Hu 1, A. Li 1, N.W. Ke 1, R. Sutton 3, X.B. Liu 1. 1 Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China 2 Sichuan Provincial Pancreatitis Centre, Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan University, Chengdu, China 3 NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool and Broadgreen University Hospitals Trust and University of Liverpool, Liverpool, UK Background: Postoperative pancreatic leakage after pancreaticoduodenectomy (PD) is often serious. Although some studies have suggested that stenting the anastomosis can reduce the incidence of this complication, the value of stenting in the setting of PD remains unclear. Methods: Studies comparing outcomes of stent versus no stent, and internal versus external stent placement for PD were eligible for inclusion. Pooled odds ratios (ORs) with 95 per cent confidence intervals were calculated using fixed- or random-effects models. Results: Five randomized clinical trials (RCTs) and 11 non-randomized observational clinical studies (OCS) involving 1726 patients were selected between January 1973 and September 2011 for inclusion. Meta-analysis of RCTs revealed that placing a stent in the pancreatic duct did not reduce the incidence of postoperative pancreatic fistula (PF). External stents had no advantage over internal stents in terms of clinical outcome. Subgroup analyses revealed that use of an external stent significantly reduced the incidence of PF (RCTs: OR 0.42, 0.24 to 0.76, P ¼ 0.004; OCS: OR 0.43, 0.27 to 0.68, P < 0.001), delayed gastric emptying (RCTs: OR 0.41, 0.19 to 0.87, P ¼ 0.02) and postoperative morbidity (RCTs: OR 0.55, 0.34 to 0.89, P ¼ 0.02) compared with no stent. Conclusion: Pancreatic duct stenting did not reduce the incidence of PF and other complications in PD compared with no stenting. Although no difference was found between external and internal stents in terms of efficacy, external stents seemed to reduce the incidence of PF compared with control.
P262. Aryl hydrocarbon receptor regulates pancreatic IL-22 and protects against acute pancreatitis in mice J. Xue, D.T.C. Nguyen, A. Habtezion. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA Despite significant morbidity and mortality associated with acute pancreatitis, aside from supportive therapy there is lack of active treatment. Recent work indicates that immune response during acute pancreatitis is important in modulating disease severity. IL-22 mediates epithelial cell immunity due to restricted IL-22 receptor (IL-22R) expression in epithelial cells. Herein, we show that CD4+ T cells are the main source of IL-22 in the normal pancreas. In acute pancreatitis, IL-22+ CD4+ T cells are depleted whereas IL-22R is upregulated. Pancreatic acinar cells respond readily to IL-22 through STAT3 and IL-22 ameliorates established acute pancreatitis. Aryl hydrocarbon receptor (AhR) is a critical liganddependent regulator of IL-22 and we find that AhR activation protects whereas AhR inhibition worsens acute pancreatitis. IL-22 rescues AhR non-responsive mice susceptibility to acute pancreatitis, whereas IL-22 blockade abolishes protective role of AhR activation, confirming that IL-22 mediates protective role of AhR in the pancreas. Taken together our data highlight the importance of AhR as a potential novel therapeutic target in acute pancreatitis and in mediating crosstalk between the pancreas leukocytes and epithelial cells via IL-22.