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Intraoperative islet isolation for pancreas autotransplantation: A novel technique
Abstracts / Pancreatology 13 (2013) e1–e94
P34. Pancreatic cancer care quality measures in rural Americans C.J. Chow 1, E.B. Habermann 2, Y. Zhu 1, A. Abraham 1, V. Dudeja 1, S.M. Vickers 1, W.B. Al-Refaie 3. 1
Department of Surgery, University of Minnesota, Minneapolis, MN, USA Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 3 Department of Surgery, University of Minnesota and Minneapolis VA, Minneapolis, MN, USA Introduction: Despite the fifty million people living in rural America, investigation into the impact of rural residence on the quality of complex pancreatic cancer care is noticeably absent. We hypothesize that patient rurality is associated with pancreatic cancer care quality measures. Methods: Using the 1996-2008 California Cancer Registry, we identified 8821 patients with stages I-IV pancreatic cancer. Rural residence was reported by the registry. Baseline characteristics were compared by rurality status. Controlling for covariates, multivariate regression explored the impact of rurality on stage at diagnosis, undergoing pancreatectomy for operable disease and receipt of adjuvant chemotherapy for operable pancreatic cancer. Cox proportional hazards regression examined the impact of rurality on survival in the entire cohort. Sensitivity analysis and interaction testing were also performed. Results: Of all patients diagnosed with pancreatic cancer, 15.2% resided in rural areas. Non-Hispanic white race, American Indian race, un/underinsurance and younger age were predictors of rurality. Our multivariate models demonstrated that rural residence did not impact stage of diagnosis (OR 1.11, 95% CI 0.95-1.29), the likelihood of undergoing pancreatectomy (OR 0.92, 95% CI 0.71-1.18) nor the receipt of adjuvant chemotherapy for operable pancreatic cancer (OR 0.89, 95% CI 0.72-1.10). In addition, rurality was not associated with worse cancer specific mortality (HR 1.02, 95% CI 0.95-1.10). Conclusions: Our study found no association between rural residence and poor performance on selected quality measures. While we could not determine the hospital location where rural patients sought care, these results do suggest that rural patients benefited from the increased regionalization of pancreatic cancer care. 2
P35. Impact of extended resection and older age on outcome of pancreatoduodenectomy in two Dutch tertiary centers K.P. Cieslak 1, M.G. Besselink 1, A.P. Rijkers 2, M.S. van Leeuwen 3, F.P. Vleggaar 4, M. Bruno 5, K. Biermann 6, I.H. Borel Rinkes 1, C.H. van Eijck 2, I.Q. Molenaar 1. 1
Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands 2 Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands 3 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands 4 Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands 5 Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands 6 Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands Objectives: To evaluate the impact of extended resection and older age on complications and survival after pancreatoduodenectomy (PD). Methods: 275 consecutive patients who underwent PD for suspected resectable pancreatic or periampulary tumor between 2007 and 2010 in two Dutch tertiary centres were included. Results: In 218/275 patients (79%) the tumor could be resected by PD with or without an extended resection, 30-day mortality was 4,1%. Malignancy was confirmed in 190/218 patients (80% no tumor in resection margin). 15% of the patients developed intra-abdominal complications requiring an intervention. 86 patients were diagnosed with adenocarcinoma with 1- and 2-year survival rates of 63% and 34%.
e21
In the 27 patients (12% of resected patients) who underwent an extended resection because of oncological reasons (e.g. portal vein resection, n¼19), mortality was 0% and the 1-year and 2-year survival rates were comparable to patients with a standard resection. In the 81 patients aged 70 or older (37% of resected patients), the postoperative mortality and survival were similar as in younger patients. Conclusion: Both limited tumor extension and high age are no absolute contraindications for resection as comparable postoperative outcome and survival benefit can be obtained.
P36. The role of preoperative EUS in addition to CT in patients suspected of pancreatic or periampullary cancer K.P. Cieslak 2, H.C. van Santvoort 1, F.P. Vleggaar 2, M.S. van Leeuwen 3, F.J. ten Kate 4, M.G. Besselink 1, I.Q. Molenaar 1. 1 Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands 2 Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands 3 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands 4 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands Introduction: In patients suspected of pancreatic and periampullary cancer, abdominal computed tomography (CT) is the standard diagnostic modality to decide on laparotomy with curative intent. A supplementary endoscopic ultrasound (EUS) is often performed, without supportive evidence of added diagnostic value. Aim: To evaluate the additional diagnostic value of EUS in deciding on exploratory laparotomy in patients suspected of pancreatic or periampullary cancer. Methods: We retrospectively analyzed 86 consecutive patients who routinely underwent CT and EUS before exploratory laparotomy with or without resection for suspected pancreatic or periampullary carcinoma between 2007 and 2010. Primary outcomes were visibility of a mass and resectability (i.e. no locally advanced tumor or distant metastases) on CT/ EUS, and resection with curative intent. Results: A mass was visible on CT in 72/86 (84%) patients. In these 72 patients, EUS demonstrated a mass in 64 (89%) patients. Resectability was accurately predicted by CT in 65/72 (90%) and by EUS in 58/72 (81%) patients. In 14/86 (16%) patients no mass was seen on CT. EUS showed a mass in 12/14 (86%) of these patients. Overall, resectability was accurately predicted by CT and EUS in 90% (77/86) and 84% (72/86), respectively. Conclusion: In patients with a visible mass on CT, suspected for pancreatic or periampullary cancer, EUS has no obvious additional diagnostic value and does not influence the decision to perform surgical exploration. However, in patients without a mass on CT, EUS is useful to confirm the presence of a tumor.
P37. Intraoperative islet isolation for pancreas autotransplantation: A novel technique M. Cooper, N. Desai, K. Hirose, Z. Sun, D. Warren, V. Singh, R. Kalyani, E. Hall, K. Knott, L. Asad, D. Anderson, M. Shamblott, M. Makary. Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA Background: Pancreas islet autotransplantation has been associated with prolonged intraoperative wait times due to the islet separation technique being performed in a remote laboratory, or sometimes even at a different institution. Depending on the courier times to and from the laboratory, strategies have been developed to use a two-stage operation approach or create novel methods for islet infusion after the operation.
e22
Abstracts / Pancreatology 13 (2013) e1–e94
Methods: We assembled an islet isolation laboratory within a large operating room where the pancreatectomies were performed. This consisted of a hooded workstation (Labconco Class II Type A2), a centrifuge (Beckman Coulter Allegra 25R), and an islet isolation system (Biorep Ricordi Islet Isolator) comparable to those used in the standard laboratory setting. A pancreatectomy was performed with immediate isolation of the islets within the operating room. As soon as the islets were suspended in the final preparation solution, they were infused into the portal venous system. The gastrojejunostomy and hepaticojejunostomy were performed during the intraoperative islet isolation. Results: We report 8 patients who underwent successful intraoperative islet isolation with reinfusion over an 8-month period (8/2011 – 4/2012). Mean total operative time was 8.8 hrs (range 7.3 - 13 hrs). Mean islet equivalent (IEQ) yield was 707,235 islets (range 250,000-1,400,000 islets). Of these, 88% (7/8) are producing C peptide. Conclusion: We describe the first report of a totally intraoperative islet isolation series, which eliminates the time, cost and risk of processing the gland in a separate remote laboratory. Intraoperative islet isolation resulted in comparable islet yield to that described with utilization of a remote laboratory. The transplanted islets using this novel technique had a good functional outcome.
P38. Oncolytic adenovirus for imaging and treatment of pancreatic cancer
3
Department of Medicine, Columbia University, New York, NY, USA Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease due to lack of early detection, making the study of initiating events invaluable. An aberrant epithelial structure consistently associated with PDA development is the metaplastic ductal lesion (MDL), hypothesized to be pre-neoplastic. Through lineage tracing and immunohistochemistry we have determined that MDLs derive from acinar cells that have transdifferentiated to structures resembling the developmentally related biliary duct gland. Consistent with this process, MDLs co-express the transcription factors PDX1+/SOX17+ a molecular signature reserved for pancreatobiliary progenitor cells during organ development. Additionally, we have found that tuft cells (TCs) are consistently associated; a characteristic of the normal bile duct. Assumption of a biliary phenotype provides an explanation for multiple characteristics associated with tumorigenesis. For instance, TCs express stem cell markers, suggesting a source of cancer stem cells. In addition, TCs are an abundant source of prostaglandins and endorphins, giving them the potential to greatly influence the disease state, such as inflammation and diseaserelated pain. To probe the importance of pancreas-to-biliary metaplasia, we utilized a transgenic SOX17 overexpressing murine model. We found that modest SOX17 levels are sufficient to drive a metaplastic, pro-inflammatory disease state, complete with TC transdifferentiation, whereas high levels will lead to biliary-like replacement of pancreatic epithelium. Overexpression in the context of injury impairs recovery and perpetuates the disease state, indicating SOX17 as a potential driver of PDA progression. 4
J. Davydova 1, M. Trujillo 2, M. Oneal 2, S. McDonough 2, J. Han 1, S. Vickers 1, J. Morris 2, M. Yamamoto 1. 1 Department of Surgery, University of Minnesota, Minneapolis, MN, USA 2 Division of Endocrinology, Mayo Clinic, Rochester, MN, USA The natural expression of sodium-iodide symporter (NIS) in the thyroid has been successfully exploited as a way to achieve non-invasive imaging and radiotherapy of thyroid cancer for more than 50 years. In this research, we hypothesized that diagnosis and treatment of pancreatic cancer would benefit greatly from the development of oncolytic adenovirus expressing NIS selectively in pancreatic cancer cells. NIS will induce uptake of radionuclide and facilitate: i) high-sensitivity detection of pancreatic cancer, and ii) radiotherapy with 131I. Clinical application of this approach may bring the following advances: i) Simultaneous delivery of diagnostic and therapeutic agents may greatly improve management of pancreatic cancer; ii) SPECT/CT imaging of selective NIS expression may give more sensitivity and specificity than other imaging modalities; iii) The combination of enhanced oncolytic virus efficacy with the bystander effect of 131I therapy may offer a new approach for treatment of inoperable pancreatic cancer patients. We cloned and generated a novel Conditionally-Replicative Adenovirus (CRAd) overexpressing NIS. This vector exhibited selective and greatly improved oncolytic potency in S2O13, S2VP10, AsPC1 and MiaPaca2 pancreatic cancer cells. Radioiodine uptake was shown to be time- and dosedependent and was significantly greater than that with a replication-deficient control counterpart. The therapeutic and imaging abilities of novel CRAd were further evaluated in a subcutaneous prostate cancer model in mice. A single intravenous injection of CRAd efficiently suppressed tumor growth and resulted in sufficient noninvasive SPECT/CT tumor imaging. Importantly, survival rate was greatly improved when it was combined with 131 I. This indicates the feasibility of our system to treat and visualize cancer upon systemic CRAd delivery and efficacy of combination therapy with 131I.
P39. Tumor-associated pancreatic metaplasia assumes a biliary duct gland phenotype K.E. DelGiorno 1, 2, K. Takeuchi 2, J. Hall 1, 2, K.P. Olive 3, J. Wells 4, H.C. Crawford 1, 2. 1 Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA 2 Department of Cancer Biology, The Mayo Clinic, Jacksonville, FL, USA
P40. MicroRNAs with prognostic significance in neuroendocrine pancreatic tumours F.F. di Mola 1, F. Tavano 1, F.P. Burbaci 1, L. Lombardi 2, M. Copetti 3, E. Maiello 2, P. di Sebastiano 1. 1
Department of Surgery, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 2 Unit of Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 3 Unit of Biostatistics, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy Background: MicroRNAs (miRNAs) deregulation has been well documented in human malignancies including pancreatic cancer, however it is still poorly investigated in neuroendocrine pancreatic tumours (PETs). Aim: Tissue expression levels of 13 miRNAs were analysed to evaluate their possible associations with clinical-pathological features in patients with PETs. Methods: MiRNAs were isolated from matched-pairs of tumour and non-cancerous tissue samples collected from 10 patients underwent surgical resection for PETs. Relative expression levels of miR-145, miR-23a, miR-455-3p miR-708, miR-151-5p, miR-30c, miR-let-7i, miR-199a-5p, miR-30a, miR-143, miR-21, miR-155* and miR-31 were analysed by means of TaqMan MicroRNA Assay. Association analysis was performed by using Spearman correlation coefficient and Mann-Whitney U-test. Results: The first 4 miRNAs showed no significant association with cancer patients phenotype. Conversely, miR-151-5p expression was inversely correlated with age at diagnosis (r¼-0.77, p¼0.009), while both miR-30a and miR-let-7i levels were positively associated with tumour size (r¼0.69, p¼0.027 and r¼0.67, p¼0.034). In addition, both miR-199a-5p and miR-30c were over-expressed in males while in females they were down-regulated (p¼0.046 and p¼0.003). Further original finding was association between miR-143, miR-21 and miR-155* levels and tumour mitotic index (p¼0.04, p¼0.0002 and p<0.0001), while expression of both miR-31 and miR-30c was associated with tumour proliferation index (p¼0.003 and p¼0.01). Furthermore, miRNAs expression levels were also found to be correlated with each others in PETs tissue samples. Conclusions: These data suggest a prognostic significance for specific miRNAs in PETs. Understanding the associations between miRNA expression levels could help identify novel regulatory network involved biology of PETs.
P34. Pancreatic cancer care quality measures in rural Americans C.J. Chow 1, E.B. Habermann 2, Y. Zhu 1, A. Abraham 1, V. Dudeja 1, S.M. Vickers 1, W.B. Al-Refaie 3. 1
Department of Surgery, University of Minnesota, Minneapolis, MN, USA Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 3 Department of Surgery, University of Minnesota and Minneapolis VA, Minneapolis, MN, USA Introduction: Despite the fifty million people living in rural America, investigation into the impact of rural residence on the quality of complex pancreatic cancer care is noticeably absent. We hypothesize that patient rurality is associated with pancreatic cancer care quality measures. Methods: Using the 1996-2008 California Cancer Registry, we identified 8821 patients with stages I-IV pancreatic cancer. Rural residence was reported by the registry. Baseline characteristics were compared by rurality status. Controlling for covariates, multivariate regression explored the impact of rurality on stage at diagnosis, undergoing pancreatectomy for operable disease and receipt of adjuvant chemotherapy for operable pancreatic cancer. Cox proportional hazards regression examined the impact of rurality on survival in the entire cohort. Sensitivity analysis and interaction testing were also performed. Results: Of all patients diagnosed with pancreatic cancer, 15.2% resided in rural areas. Non-Hispanic white race, American Indian race, un/underinsurance and younger age were predictors of rurality. Our multivariate models demonstrated that rural residence did not impact stage of diagnosis (OR 1.11, 95% CI 0.95-1.29), the likelihood of undergoing pancreatectomy (OR 0.92, 95% CI 0.71-1.18) nor the receipt of adjuvant chemotherapy for operable pancreatic cancer (OR 0.89, 95% CI 0.72-1.10). In addition, rurality was not associated with worse cancer specific mortality (HR 1.02, 95% CI 0.95-1.10). Conclusions: Our study found no association between rural residence and poor performance on selected quality measures. While we could not determine the hospital location where rural patients sought care, these results do suggest that rural patients benefited from the increased regionalization of pancreatic cancer care. 2
P35. Impact of extended resection and older age on outcome of pancreatoduodenectomy in two Dutch tertiary centers K.P. Cieslak 1, M.G. Besselink 1, A.P. Rijkers 2, M.S. van Leeuwen 3, F.P. Vleggaar 4, M. Bruno 5, K. Biermann 6, I.H. Borel Rinkes 1, C.H. van Eijck 2, I.Q. Molenaar 1. 1
Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands 2 Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands 3 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands 4 Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands 5 Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands 6 Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands Objectives: To evaluate the impact of extended resection and older age on complications and survival after pancreatoduodenectomy (PD). Methods: 275 consecutive patients who underwent PD for suspected resectable pancreatic or periampulary tumor between 2007 and 2010 in two Dutch tertiary centres were included. Results: In 218/275 patients (79%) the tumor could be resected by PD with or without an extended resection, 30-day mortality was 4,1%. Malignancy was confirmed in 190/218 patients (80% no tumor in resection margin). 15% of the patients developed intra-abdominal complications requiring an intervention. 86 patients were diagnosed with adenocarcinoma with 1- and 2-year survival rates of 63% and 34%.
e21
In the 27 patients (12% of resected patients) who underwent an extended resection because of oncological reasons (e.g. portal vein resection, n¼19), mortality was 0% and the 1-year and 2-year survival rates were comparable to patients with a standard resection. In the 81 patients aged 70 or older (37% of resected patients), the postoperative mortality and survival were similar as in younger patients. Conclusion: Both limited tumor extension and high age are no absolute contraindications for resection as comparable postoperative outcome and survival benefit can be obtained.
P36. The role of preoperative EUS in addition to CT in patients suspected of pancreatic or periampullary cancer K.P. Cieslak 2, H.C. van Santvoort 1, F.P. Vleggaar 2, M.S. van Leeuwen 3, F.J. ten Kate 4, M.G. Besselink 1, I.Q. Molenaar 1. 1 Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands 2 Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands 3 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands 4 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands Introduction: In patients suspected of pancreatic and periampullary cancer, abdominal computed tomography (CT) is the standard diagnostic modality to decide on laparotomy with curative intent. A supplementary endoscopic ultrasound (EUS) is often performed, without supportive evidence of added diagnostic value. Aim: To evaluate the additional diagnostic value of EUS in deciding on exploratory laparotomy in patients suspected of pancreatic or periampullary cancer. Methods: We retrospectively analyzed 86 consecutive patients who routinely underwent CT and EUS before exploratory laparotomy with or without resection for suspected pancreatic or periampullary carcinoma between 2007 and 2010. Primary outcomes were visibility of a mass and resectability (i.e. no locally advanced tumor or distant metastases) on CT/ EUS, and resection with curative intent. Results: A mass was visible on CT in 72/86 (84%) patients. In these 72 patients, EUS demonstrated a mass in 64 (89%) patients. Resectability was accurately predicted by CT in 65/72 (90%) and by EUS in 58/72 (81%) patients. In 14/86 (16%) patients no mass was seen on CT. EUS showed a mass in 12/14 (86%) of these patients. Overall, resectability was accurately predicted by CT and EUS in 90% (77/86) and 84% (72/86), respectively. Conclusion: In patients with a visible mass on CT, suspected for pancreatic or periampullary cancer, EUS has no obvious additional diagnostic value and does not influence the decision to perform surgical exploration. However, in patients without a mass on CT, EUS is useful to confirm the presence of a tumor.
P37. Intraoperative islet isolation for pancreas autotransplantation: A novel technique M. Cooper, N. Desai, K. Hirose, Z. Sun, D. Warren, V. Singh, R. Kalyani, E. Hall, K. Knott, L. Asad, D. Anderson, M. Shamblott, M. Makary. Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA Background: Pancreas islet autotransplantation has been associated with prolonged intraoperative wait times due to the islet separation technique being performed in a remote laboratory, or sometimes even at a different institution. Depending on the courier times to and from the laboratory, strategies have been developed to use a two-stage operation approach or create novel methods for islet infusion after the operation.
e22
Abstracts / Pancreatology 13 (2013) e1–e94
Methods: We assembled an islet isolation laboratory within a large operating room where the pancreatectomies were performed. This consisted of a hooded workstation (Labconco Class II Type A2), a centrifuge (Beckman Coulter Allegra 25R), and an islet isolation system (Biorep Ricordi Islet Isolator) comparable to those used in the standard laboratory setting. A pancreatectomy was performed with immediate isolation of the islets within the operating room. As soon as the islets were suspended in the final preparation solution, they were infused into the portal venous system. The gastrojejunostomy and hepaticojejunostomy were performed during the intraoperative islet isolation. Results: We report 8 patients who underwent successful intraoperative islet isolation with reinfusion over an 8-month period (8/2011 – 4/2012). Mean total operative time was 8.8 hrs (range 7.3 - 13 hrs). Mean islet equivalent (IEQ) yield was 707,235 islets (range 250,000-1,400,000 islets). Of these, 88% (7/8) are producing C peptide. Conclusion: We describe the first report of a totally intraoperative islet isolation series, which eliminates the time, cost and risk of processing the gland in a separate remote laboratory. Intraoperative islet isolation resulted in comparable islet yield to that described with utilization of a remote laboratory. The transplanted islets using this novel technique had a good functional outcome.
P38. Oncolytic adenovirus for imaging and treatment of pancreatic cancer
3
Department of Medicine, Columbia University, New York, NY, USA Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease due to lack of early detection, making the study of initiating events invaluable. An aberrant epithelial structure consistently associated with PDA development is the metaplastic ductal lesion (MDL), hypothesized to be pre-neoplastic. Through lineage tracing and immunohistochemistry we have determined that MDLs derive from acinar cells that have transdifferentiated to structures resembling the developmentally related biliary duct gland. Consistent with this process, MDLs co-express the transcription factors PDX1+/SOX17+ a molecular signature reserved for pancreatobiliary progenitor cells during organ development. Additionally, we have found that tuft cells (TCs) are consistently associated; a characteristic of the normal bile duct. Assumption of a biliary phenotype provides an explanation for multiple characteristics associated with tumorigenesis. For instance, TCs express stem cell markers, suggesting a source of cancer stem cells. In addition, TCs are an abundant source of prostaglandins and endorphins, giving them the potential to greatly influence the disease state, such as inflammation and diseaserelated pain. To probe the importance of pancreas-to-biliary metaplasia, we utilized a transgenic SOX17 overexpressing murine model. We found that modest SOX17 levels are sufficient to drive a metaplastic, pro-inflammatory disease state, complete with TC transdifferentiation, whereas high levels will lead to biliary-like replacement of pancreatic epithelium. Overexpression in the context of injury impairs recovery and perpetuates the disease state, indicating SOX17 as a potential driver of PDA progression. 4
J. Davydova 1, M. Trujillo 2, M. Oneal 2, S. McDonough 2, J. Han 1, S. Vickers 1, J. Morris 2, M. Yamamoto 1. 1 Department of Surgery, University of Minnesota, Minneapolis, MN, USA 2 Division of Endocrinology, Mayo Clinic, Rochester, MN, USA The natural expression of sodium-iodide symporter (NIS) in the thyroid has been successfully exploited as a way to achieve non-invasive imaging and radiotherapy of thyroid cancer for more than 50 years. In this research, we hypothesized that diagnosis and treatment of pancreatic cancer would benefit greatly from the development of oncolytic adenovirus expressing NIS selectively in pancreatic cancer cells. NIS will induce uptake of radionuclide and facilitate: i) high-sensitivity detection of pancreatic cancer, and ii) radiotherapy with 131I. Clinical application of this approach may bring the following advances: i) Simultaneous delivery of diagnostic and therapeutic agents may greatly improve management of pancreatic cancer; ii) SPECT/CT imaging of selective NIS expression may give more sensitivity and specificity than other imaging modalities; iii) The combination of enhanced oncolytic virus efficacy with the bystander effect of 131I therapy may offer a new approach for treatment of inoperable pancreatic cancer patients. We cloned and generated a novel Conditionally-Replicative Adenovirus (CRAd) overexpressing NIS. This vector exhibited selective and greatly improved oncolytic potency in S2O13, S2VP10, AsPC1 and MiaPaca2 pancreatic cancer cells. Radioiodine uptake was shown to be time- and dosedependent and was significantly greater than that with a replication-deficient control counterpart. The therapeutic and imaging abilities of novel CRAd were further evaluated in a subcutaneous prostate cancer model in mice. A single intravenous injection of CRAd efficiently suppressed tumor growth and resulted in sufficient noninvasive SPECT/CT tumor imaging. Importantly, survival rate was greatly improved when it was combined with 131 I. This indicates the feasibility of our system to treat and visualize cancer upon systemic CRAd delivery and efficacy of combination therapy with 131I.
P39. Tumor-associated pancreatic metaplasia assumes a biliary duct gland phenotype K.E. DelGiorno 1, 2, K. Takeuchi 2, J. Hall 1, 2, K.P. Olive 3, J. Wells 4, H.C. Crawford 1, 2. 1 Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA 2 Department of Cancer Biology, The Mayo Clinic, Jacksonville, FL, USA
P40. MicroRNAs with prognostic significance in neuroendocrine pancreatic tumours F.F. di Mola 1, F. Tavano 1, F.P. Burbaci 1, L. Lombardi 2, M. Copetti 3, E. Maiello 2, P. di Sebastiano 1. 1
Department of Surgery, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 2 Unit of Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 3 Unit of Biostatistics, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy Background: MicroRNAs (miRNAs) deregulation has been well documented in human malignancies including pancreatic cancer, however it is still poorly investigated in neuroendocrine pancreatic tumours (PETs). Aim: Tissue expression levels of 13 miRNAs were analysed to evaluate their possible associations with clinical-pathological features in patients with PETs. Methods: MiRNAs were isolated from matched-pairs of tumour and non-cancerous tissue samples collected from 10 patients underwent surgical resection for PETs. Relative expression levels of miR-145, miR-23a, miR-455-3p miR-708, miR-151-5p, miR-30c, miR-let-7i, miR-199a-5p, miR-30a, miR-143, miR-21, miR-155* and miR-31 were analysed by means of TaqMan MicroRNA Assay. Association analysis was performed by using Spearman correlation coefficient and Mann-Whitney U-test. Results: The first 4 miRNAs showed no significant association with cancer patients phenotype. Conversely, miR-151-5p expression was inversely correlated with age at diagnosis (r¼-0.77, p¼0.009), while both miR-30a and miR-let-7i levels were positively associated with tumour size (r¼0.69, p¼0.027 and r¼0.67, p¼0.034). In addition, both miR-199a-5p and miR-30c were over-expressed in males while in females they were down-regulated (p¼0.046 and p¼0.003). Further original finding was association between miR-143, miR-21 and miR-155* levels and tumour mitotic index (p¼0.04, p¼0.0002 and p<0.0001), while expression of both miR-31 and miR-30c was associated with tumour proliferation index (p¼0.003 and p¼0.01). Furthermore, miRNAs expression levels were also found to be correlated with each others in PETs tissue samples. Conclusions: These data suggest a prognostic significance for specific miRNAs in PETs. Understanding the associations between miRNA expression levels could help identify novel regulatory network involved biology of PETs.