- Email: [email protected]
Natural history of small ≤3 cm cystic tumors of the pancreas
Abstracts / Pancreatology 13 (2013) e1–e94
activity increased to 430% over control in KPC cells and 325 % over control in LM cells. Activation of caspase-9 was 1250 % in KPC and 1150 % over control in LM cells. Complementing the ability of triptolide to induce apoptosis in these cells, annexin V positivity, a marker for apoptosis, was present in 71% KPC cells and 52% LM cells 48h post triptolide treatment. Futhermore, supporting the ability of triptolide to deter migration, treatment with triptolide results in decrease in the ability of both KPC and LM cells to recover from wounding, as early as 2 hours post-insult (evaluated by change in resistance using electric cell-substrate impedance sensing). Levels of HSP70, previously shown to be a target for triptolide, showed a decrease at both protein and RNA levels in both KPC and LM cells. Conclusion: Our results show that the highly aggressive KPC and LM cells are susceptible to death by triptolide treatment. Minnelide, a water soluble variant of triptolide is currently in the process of entering Phase I clinical trials.
P211. Natural history of small £3 cm cystic tumors of the pancreas S. Sanyal, A.K. Siriwardena. Hepato-Pancreato-Biliary Surgery Unit, Manchester Royal Infirmary, Manchester, UK Introduction: The Sendai consensus criteria recommend surgical resection for main duct intraductal papillary mucinous neoplasms (IPMN) and for branch-duct lesions over 3cm in size (or with features of malignancy). Small lesions 3 cm in size could be managed non-operatively. Several reports attest to a high risk of malignancy in these small lesions yet establishment of the diagnosis of IPMN is difficult in 3 cm cysts and their natural history is unclear. This study reports the natural history of small 3 cm cystic tumors of the Pancreas managed in a single tertiary Hepato-Pancreato-Biliary service. Patients: During the 3-year period September 2008 to September 2011, 99 patients with cystic tumors were assessed. Forty-five (45%) had lesions that were 3 cm in size. Presenting symptoms in these small lesions 3 cm were: 25/45 (55%) asymptomatic, abdominal pain 10 (22%) and jaundice in 4 (9%). Investigations included computed tomography (CT) in 45 (100%), magnetic resonance scan in 4 (9%) and endoscopic ultrasound with fine needle aspiration (EUS-FNA) in 33 (74%) of patients. Plasma tumor markers were measured in 18 (40%). Results: A definitive diagnosis of side or branch duct IPMN was established in 24/45 (53%) by a combination of CT and EUS-FNA. Twenty one others were cystic lesion (not otherwise categorised). Resection at time of presentation was undertaken in 1 side branch IPMN (high-grade dysplasia). During a median (range) period of 32 (7-115) months followup, 3 of 23 (13%) underwent resection with cancer detected in 1 (4%) sidebranch IPMN and 4 of 21 (19%) other cystic tumors (with resection histology re-categorising all 4 as main duct IPMN). Conclusions: Accurate categorisation of small cystic tumors of the pancreas is difficult. However, in true side-branch IPMN over nearly 3 years follow-up, the cancer risk is low at 4%. Unanswered questions remain about the longer term behaviour of these tumors.
P212. Immuno isolatory device protects islet allograft functions without immunosuppression in non-human primates M. Sasikala, G.V. Rao, R. Pradeep, P. Pavan Kumar, G. Radhika, V. Vijayalakshmi, P. Suresh, M. Sirisha, R. Talukdar, V. Seshadri, D.N. Reddy. Asian Institute of Gastroenterology, Hyderabad, India Background: Autologous and allogenic islet cell transplantation for treatment of diabetes requires intense immunosuppression. Encapsulation of islets using immune isolatory device is reported to provide immuneprotection to the transplanted islets and improve survival in murine models. In this study we investigated viability and functions of islets transplanted using immune-isolatory device in non-human primates.
e71
Methods: Distal pancreatectomy and islet transplantation using immune isolatory device (Theracyte) were performed on Rhesus monkeys (n¼6) without immuno suppression. Two primates received autologous and four allogenic islet transplantation. Devices were loaded with 50008000 Ieq and implanted in the left thigh and inter-scapula region; and were retrieved at 2, 6 and 12 months of implantation. Islet viability (MTT assay, dithiazone and trypan blue staining), functions (glucose stimulated insulin release, GSIR), insulin gene expression (RT-PCR), calcium imaging (Fura 2 labeling) and insulin granules (transmission electron microscopy) were assessed. In vivo functions of implanted islets were evaluated by estimating insulin in the femoral veins after IVGTT. Results: Implanted devices demonstrated vascularization and engraftment potential in non-human primates. The implanted islet numbers increased by 2-folds and 95% of them were viable in autologous and allogenic islet transplants. In vitro GSIR of the islets increased in parallel to the increase in islet numbers. Insulin mRNA was detectable before and after retrieval concomitant with the presence of insulin granules on electron microscopy. In vivo insulin secretion was 20% greater in the femoral vein of the device implanted thigh. Conclusion: Islets transplanted using immune isolatory device could survive and function under in vivo conditions in non-human primates for at least one year without immuno suppression.
P213. Transdifferentiation of pancreatic acinar cells, and the role of stem cell factor and c-kit receptor tyrosine kinase signal transduction system M. Satake 1, 2, G. Eibl 4, T. Hamada 2, H. Ishikawa 2, V.L. Go 4, Y. Fukuda 2, J. Fujimoto 3, T. Tsujimura 1. 1
Department of Pathology, Hyogo College of Medicine, Japan Saysayama Medical Center, Hyogo College of Medicine, Japan 3 Department of Surgery, Hyogo College of Medicine, Japan 4 David Geffen School of Medicine at UCLA, USA Background & aims: Pancreatic Acinar cells (PACs) have transifferentiation capacity into Pancreatic Hepatocytes (PHCs) during a copperdeficient diet regimen fed in rats. Recently we have demonstrated that Stem Cell Factor and c-kit receptor tyrosine kinase system (SCF/KIT) plays the crucial role in the proliferation of liver. Briefly, the proliferation of liver are significantly suppressed in c-kit activity severely impaired Ws/Ws mutant rats (Ws/Ws) when compared with wild type normal (+/+) rats. In pancreas SCF/KIT take part in islet cell development. During embryology, liver and pancreas arise from a common progenitor cell (the ventral foregut endoderm). Therefore, we hypothesize that liver and pancreas may share the signal transduction system during proliferation. The aim of this study is clarify the role of SCF/KIT system in transdifferentiation of PACs. Materials and methods: Wild type normal +/+ rats and c-kit activating or severely impaired mutant Ws/Ws rats were fed with a copper-deficient chow for 8 weeks. Animals were euthanized after 8 weeks (8wk) or return to normal chow for additional 8 weeks (16wk). The body weight, pancreas weight and numbers of PHC in the each group were compared with 0, 8 and 16 weeks. Immunohistochemical stain (IHC) of Albumin, Thyroid Transcription Factor-1 (TTF-1), Alpha-Fetoprotein (AFP), Hepatocyte Nuclear Factor-4 (HNF-4) were carried out for detecting cell characters. Results: Loss of Body weight, loss of exocrine enzyme sympton and wide depletion of PACs was monitored at 8 weeks. At 16 weeks, body weight recovered only in +/+ rats. At 16 wk, IHC showed that PHC were strongly positive for liver specific anc cis-active element, Alb. TTF-1, AFP and HNF-4. Moreover, at 16 wk, when compared with +/+ rats, the number of PHCs and the pancreas-weight was significantly lower in Ws/Ws rat. These results demonstrate that PHS production and pancreatic transdifferentiation is induced by wide apoptosis of PACs only in +/+ rats but weak in Ws/Ws rats. Conclusion: The SCF/KIT system may play a crucial role in the maintenance of the transdifferentiation capacity of PACs may via multipotent PACs progenitor cells. KIT antagonist may become new therapeutic approach for Acinar cell Cancer. 2
activity increased to 430% over control in KPC cells and 325 % over control in LM cells. Activation of caspase-9 was 1250 % in KPC and 1150 % over control in LM cells. Complementing the ability of triptolide to induce apoptosis in these cells, annexin V positivity, a marker for apoptosis, was present in 71% KPC cells and 52% LM cells 48h post triptolide treatment. Futhermore, supporting the ability of triptolide to deter migration, treatment with triptolide results in decrease in the ability of both KPC and LM cells to recover from wounding, as early as 2 hours post-insult (evaluated by change in resistance using electric cell-substrate impedance sensing). Levels of HSP70, previously shown to be a target for triptolide, showed a decrease at both protein and RNA levels in both KPC and LM cells. Conclusion: Our results show that the highly aggressive KPC and LM cells are susceptible to death by triptolide treatment. Minnelide, a water soluble variant of triptolide is currently in the process of entering Phase I clinical trials.
P211. Natural history of small £3 cm cystic tumors of the pancreas S. Sanyal, A.K. Siriwardena. Hepato-Pancreato-Biliary Surgery Unit, Manchester Royal Infirmary, Manchester, UK Introduction: The Sendai consensus criteria recommend surgical resection for main duct intraductal papillary mucinous neoplasms (IPMN) and for branch-duct lesions over 3cm in size (or with features of malignancy). Small lesions 3 cm in size could be managed non-operatively. Several reports attest to a high risk of malignancy in these small lesions yet establishment of the diagnosis of IPMN is difficult in 3 cm cysts and their natural history is unclear. This study reports the natural history of small 3 cm cystic tumors of the Pancreas managed in a single tertiary Hepato-Pancreato-Biliary service. Patients: During the 3-year period September 2008 to September 2011, 99 patients with cystic tumors were assessed. Forty-five (45%) had lesions that were 3 cm in size. Presenting symptoms in these small lesions 3 cm were: 25/45 (55%) asymptomatic, abdominal pain 10 (22%) and jaundice in 4 (9%). Investigations included computed tomography (CT) in 45 (100%), magnetic resonance scan in 4 (9%) and endoscopic ultrasound with fine needle aspiration (EUS-FNA) in 33 (74%) of patients. Plasma tumor markers were measured in 18 (40%). Results: A definitive diagnosis of side or branch duct IPMN was established in 24/45 (53%) by a combination of CT and EUS-FNA. Twenty one others were cystic lesion (not otherwise categorised). Resection at time of presentation was undertaken in 1 side branch IPMN (high-grade dysplasia). During a median (range) period of 32 (7-115) months followup, 3 of 23 (13%) underwent resection with cancer detected in 1 (4%) sidebranch IPMN and 4 of 21 (19%) other cystic tumors (with resection histology re-categorising all 4 as main duct IPMN). Conclusions: Accurate categorisation of small cystic tumors of the pancreas is difficult. However, in true side-branch IPMN over nearly 3 years follow-up, the cancer risk is low at 4%. Unanswered questions remain about the longer term behaviour of these tumors.
P212. Immuno isolatory device protects islet allograft functions without immunosuppression in non-human primates M. Sasikala, G.V. Rao, R. Pradeep, P. Pavan Kumar, G. Radhika, V. Vijayalakshmi, P. Suresh, M. Sirisha, R. Talukdar, V. Seshadri, D.N. Reddy. Asian Institute of Gastroenterology, Hyderabad, India Background: Autologous and allogenic islet cell transplantation for treatment of diabetes requires intense immunosuppression. Encapsulation of islets using immune isolatory device is reported to provide immuneprotection to the transplanted islets and improve survival in murine models. In this study we investigated viability and functions of islets transplanted using immune-isolatory device in non-human primates.
e71
Methods: Distal pancreatectomy and islet transplantation using immune isolatory device (Theracyte) were performed on Rhesus monkeys (n¼6) without immuno suppression. Two primates received autologous and four allogenic islet transplantation. Devices were loaded with 50008000 Ieq and implanted in the left thigh and inter-scapula region; and were retrieved at 2, 6 and 12 months of implantation. Islet viability (MTT assay, dithiazone and trypan blue staining), functions (glucose stimulated insulin release, GSIR), insulin gene expression (RT-PCR), calcium imaging (Fura 2 labeling) and insulin granules (transmission electron microscopy) were assessed. In vivo functions of implanted islets were evaluated by estimating insulin in the femoral veins after IVGTT. Results: Implanted devices demonstrated vascularization and engraftment potential in non-human primates. The implanted islet numbers increased by 2-folds and 95% of them were viable in autologous and allogenic islet transplants. In vitro GSIR of the islets increased in parallel to the increase in islet numbers. Insulin mRNA was detectable before and after retrieval concomitant with the presence of insulin granules on electron microscopy. In vivo insulin secretion was 20% greater in the femoral vein of the device implanted thigh. Conclusion: Islets transplanted using immune isolatory device could survive and function under in vivo conditions in non-human primates for at least one year without immuno suppression.
P213. Transdifferentiation of pancreatic acinar cells, and the role of stem cell factor and c-kit receptor tyrosine kinase signal transduction system M. Satake 1, 2, G. Eibl 4, T. Hamada 2, H. Ishikawa 2, V.L. Go 4, Y. Fukuda 2, J. Fujimoto 3, T. Tsujimura 1. 1
Department of Pathology, Hyogo College of Medicine, Japan Saysayama Medical Center, Hyogo College of Medicine, Japan 3 Department of Surgery, Hyogo College of Medicine, Japan 4 David Geffen School of Medicine at UCLA, USA Background & aims: Pancreatic Acinar cells (PACs) have transifferentiation capacity into Pancreatic Hepatocytes (PHCs) during a copperdeficient diet regimen fed in rats. Recently we have demonstrated that Stem Cell Factor and c-kit receptor tyrosine kinase system (SCF/KIT) plays the crucial role in the proliferation of liver. Briefly, the proliferation of liver are significantly suppressed in c-kit activity severely impaired Ws/Ws mutant rats (Ws/Ws) when compared with wild type normal (+/+) rats. In pancreas SCF/KIT take part in islet cell development. During embryology, liver and pancreas arise from a common progenitor cell (the ventral foregut endoderm). Therefore, we hypothesize that liver and pancreas may share the signal transduction system during proliferation. The aim of this study is clarify the role of SCF/KIT system in transdifferentiation of PACs. Materials and methods: Wild type normal +/+ rats and c-kit activating or severely impaired mutant Ws/Ws rats were fed with a copper-deficient chow for 8 weeks. Animals were euthanized after 8 weeks (8wk) or return to normal chow for additional 8 weeks (16wk). The body weight, pancreas weight and numbers of PHC in the each group were compared with 0, 8 and 16 weeks. Immunohistochemical stain (IHC) of Albumin, Thyroid Transcription Factor-1 (TTF-1), Alpha-Fetoprotein (AFP), Hepatocyte Nuclear Factor-4 (HNF-4) were carried out for detecting cell characters. Results: Loss of Body weight, loss of exocrine enzyme sympton and wide depletion of PACs was monitored at 8 weeks. At 16 weeks, body weight recovered only in +/+ rats. At 16 wk, IHC showed that PHC were strongly positive for liver specific anc cis-active element, Alb. TTF-1, AFP and HNF-4. Moreover, at 16 wk, when compared with +/+ rats, the number of PHCs and the pancreas-weight was significantly lower in Ws/Ws rat. These results demonstrate that PHS production and pancreatic transdifferentiation is induced by wide apoptosis of PACs only in +/+ rats but weak in Ws/Ws rats. Conclusion: The SCF/KIT system may play a crucial role in the maintenance of the transdifferentiation capacity of PACs may via multipotent PACs progenitor cells. KIT antagonist may become new therapeutic approach for Acinar cell Cancer. 2