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My life in pancreatic research ― Unexpected results may open the door
Abstracts / Pancreatology 16 (2016) S1eS192
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ML. My life in pancreatic research d Unexpected results may open the door Makoto Otsuki University of Occupational and Environmental Health, Japan The George E. Palade Medal is the highest honor awarded by the International Association of Pancreatology to an individual who has made outstanding contributions to our understanding of the pancreas and pancreatic diseases. As the 2016 recipient of this award, I accept it with gratitude, but also with embarrassment. I made a fresh start to work in pancreatic research without teachers after completing the postgraduate course of endocrinology at Kobe University. I visited several institutions to learn various techniques necessary to conduct pancreatic research and to discuss unsolved problems. I learned how to prepare isolated perfused rat pancreas from Professor Kanno at Hokkaido University, and isolated pancreatic acini from Professor Williams at the University of California. With the support of collaborators, I have accomplished many projects such as amylase isoenzymes, relationship between exocrine and endocrine pancreatic functions, acute and chronic pancreatitis, and the mechanism of activation of isolated rat pancreatic satellite cells. In addition, I conducted a nationwide survey of acute and chronic pancreatitis in Japan, proposing diagnostic criteria for early chronic pancreatitis and autoimmune pancreatitis, and guidelines for improvement of case fatality of severe acute pancreatitis as the chief investigator of the Research Committee of Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare in Japan. Questions and hypotheses that arise during the research and clinical studies must be solved one by one. Research must not be ended as research or self-satisfaction. The clinical or experimental results must be published, and the patients or research results that are different from those expected must be kept in mind. Research involving these unexpected results may open the door and lead to great discoveries.
PL. Discipline with refining in my career in pancreatology Shuji Isaji Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Japan My first interest in pancreatology began in 1981 when Professor R. Mizumoto provided me with research theme concerning the role of pancreatic phospholipase A2 (PLA2) in cell membrane damage in the pathophysiology of acute pancreatitis. Thereafter, my research interests have expanded into chronic pancreatitis, pancreatic regeneration after major pancreatectomy, organ-preserving pancreatectomy and treatment strategy for locally advanced pancreatic cancer as well. The role of pancreatic and nonpancreatic PLA2 in the pathogenesis and aggravation of acute pancreatitis has been emphasized. Two major families are identified: secretory PLA2 (sPLA2) and cytosolic PLA2 (cPLA2). Using animal models, we had studied extensively the role of pancreatic PLA2 (type I sPLA2) in the pathophysiology of acute pancreatitis, and the results suggested a strong association with the development of pancreatic necrosis, pulmonary damage through the destruction of alveolar surfactant, and renal tubular damage. Since the discovery of nonpancreatic sPLAs (type II), type II sPLA2 has also been found to be associated with aggravation of pancreatitis. Using a inhibitor of cPLAs, we demonstrated that cPLAs inhibitor exerted a potentially therapeutic effect on experimental acute pancreatitis by mitigating the degree of damage to the pancreas, lung, and kidney. Our experimental study, which was supervised by Professor CF Frey, revealed that acute pancreatitis promoted bacterial translocation (BT), which in turn led to infection of the pancreas and septic complications. We had thereafter demonstrated that continuous regional arterial infusion (CRAI) of an antibiotic was more effective than intravenous administration
in preventing pancreatic infection and improving survival, in a canine model of acute necrotizing pancreatitis. Our another experimental study revealed that CRAI of an antibiotic via the superior mesenteric artery (SMA) was effective in mitigating intestinal mucosal damage and preventing BT in acute pancreatitis, thereby improving survival. Zinc is a functional component of many metalloenzymes, which are highly involved in cell proliferation and protein synthesis. The pancreas is a major site of zinc metabolism. We studied the effect of oral zinc administration on functional and morphological regeneration of the remnant pancreas after 80% pancreatectomy in a canine model. A high-zinc diet with pancreatic enzyme after major pancreatectomy was effective in maintaining the zinc concentration in pancreatic tissue, which not only enhanced early cell proliferation in the remnant pancreas but also improved pancreatic functions in the late period, promoting pancreatic regeneration. We have clinically demonstrated that pancreaticoduodenectomy (PD) is associated with development of non-alcoholic fatty liver disease (NAFLD), suggesting the contribution of malnutrition due to pancreatic exocrine deficiency. Furthermore, we revealed that remnant pancreatic volume and status of postoperative infection paradoxically influenced the development of NAFLD after PD. Organ-preserving pancreatectomies have been used for the treatment of benign and sometime, malignant diseases of the pancreatic head region. We developed a new procedure, pancreatic head resection with secondportion duodenectomy, which was supervised by Professor Y. Kawarada, Our new procedure facilitates complete resection of the pancreatic head and a reliable option as an organ-preserving procedure for surgical treatment of benign lesions, low-grade malignancies, and early stage carcinomas involving the pancreatic head. Borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) tumors are those associated with a significant likelihood of an incomplete resection when surgery is used as primary therapy. BR-PDAC includes two distinct categories of tumors: BR-PV (those with PV/SMV invasion alone) and BR-A (those with major arterial invasion). In an attempt to increase R0 resection rate in patients with locally advanced PDAC, our institution has been performing preoperative chemoradio-therapy (CRT) since February 2005. Our CRT protocols for BR-PDAC appears to improve survival, especially in the patients with BR-A tumors, by enhancing R0 resection rate. Adjuvant surgery for initially unresectable PDAC patients with a long-term favorable response to nonsurgical anticancer treatments is safe and effective. Our treatment protocol of CRT followed by surgery for locally unresectable PDAC may also allow for the identification of candidates for aggressive resection at the time of reassessment and to improve prognosis of patients who undergo R0 resection. During the period of these 35 years, I have annually presented our research outcomes at this meeting, and I have been every time trained (disciplined) by having their weakness pointed out. After thorough reconsideration I have presented our outcomes refined. This is what I call “Tan Ren” (discipline with refining) in my career in pancreatology.
SA-1. Minnelide, a novel therapy against pancreatic cancer: Bench to bedside and back to bench Ashok K. Saluja Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, USA Pancreatic cancer is one of the most lethal human malignancies, with an all-stage 5-year survival of <5%, a number that highlights the urgent need for more effective therapeutic strategies. Our studies have shown that triptolide, a diterpenoid, is effective against pancreatic cancer cells in vitro as well as in vivo. However, triptolide is poorly soluble in water, limiting its clinical utility. We have recently synthesized a water-soluble pro-drug of triptolide, Minnelide that has shown tremendous promise in preclinical studies. Since its synthesis, Minnelide has been extensively evaluated in preclinical studies. In orthotopic mouse models with very aggressive cell lines, the Minnelide treated mice showed a definite regression and
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ML. My life in pancreatic research d Unexpected results may open the door Makoto Otsuki University of Occupational and Environmental Health, Japan The George E. Palade Medal is the highest honor awarded by the International Association of Pancreatology to an individual who has made outstanding contributions to our understanding of the pancreas and pancreatic diseases. As the 2016 recipient of this award, I accept it with gratitude, but also with embarrassment. I made a fresh start to work in pancreatic research without teachers after completing the postgraduate course of endocrinology at Kobe University. I visited several institutions to learn various techniques necessary to conduct pancreatic research and to discuss unsolved problems. I learned how to prepare isolated perfused rat pancreas from Professor Kanno at Hokkaido University, and isolated pancreatic acini from Professor Williams at the University of California. With the support of collaborators, I have accomplished many projects such as amylase isoenzymes, relationship between exocrine and endocrine pancreatic functions, acute and chronic pancreatitis, and the mechanism of activation of isolated rat pancreatic satellite cells. In addition, I conducted a nationwide survey of acute and chronic pancreatitis in Japan, proposing diagnostic criteria for early chronic pancreatitis and autoimmune pancreatitis, and guidelines for improvement of case fatality of severe acute pancreatitis as the chief investigator of the Research Committee of Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare in Japan. Questions and hypotheses that arise during the research and clinical studies must be solved one by one. Research must not be ended as research or self-satisfaction. The clinical or experimental results must be published, and the patients or research results that are different from those expected must be kept in mind. Research involving these unexpected results may open the door and lead to great discoveries.
PL. Discipline with refining in my career in pancreatology Shuji Isaji Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Japan My first interest in pancreatology began in 1981 when Professor R. Mizumoto provided me with research theme concerning the role of pancreatic phospholipase A2 (PLA2) in cell membrane damage in the pathophysiology of acute pancreatitis. Thereafter, my research interests have expanded into chronic pancreatitis, pancreatic regeneration after major pancreatectomy, organ-preserving pancreatectomy and treatment strategy for locally advanced pancreatic cancer as well. The role of pancreatic and nonpancreatic PLA2 in the pathogenesis and aggravation of acute pancreatitis has been emphasized. Two major families are identified: secretory PLA2 (sPLA2) and cytosolic PLA2 (cPLA2). Using animal models, we had studied extensively the role of pancreatic PLA2 (type I sPLA2) in the pathophysiology of acute pancreatitis, and the results suggested a strong association with the development of pancreatic necrosis, pulmonary damage through the destruction of alveolar surfactant, and renal tubular damage. Since the discovery of nonpancreatic sPLAs (type II), type II sPLA2 has also been found to be associated with aggravation of pancreatitis. Using a inhibitor of cPLAs, we demonstrated that cPLAs inhibitor exerted a potentially therapeutic effect on experimental acute pancreatitis by mitigating the degree of damage to the pancreas, lung, and kidney. Our experimental study, which was supervised by Professor CF Frey, revealed that acute pancreatitis promoted bacterial translocation (BT), which in turn led to infection of the pancreas and septic complications. We had thereafter demonstrated that continuous regional arterial infusion (CRAI) of an antibiotic was more effective than intravenous administration
in preventing pancreatic infection and improving survival, in a canine model of acute necrotizing pancreatitis. Our another experimental study revealed that CRAI of an antibiotic via the superior mesenteric artery (SMA) was effective in mitigating intestinal mucosal damage and preventing BT in acute pancreatitis, thereby improving survival. Zinc is a functional component of many metalloenzymes, which are highly involved in cell proliferation and protein synthesis. The pancreas is a major site of zinc metabolism. We studied the effect of oral zinc administration on functional and morphological regeneration of the remnant pancreas after 80% pancreatectomy in a canine model. A high-zinc diet with pancreatic enzyme after major pancreatectomy was effective in maintaining the zinc concentration in pancreatic tissue, which not only enhanced early cell proliferation in the remnant pancreas but also improved pancreatic functions in the late period, promoting pancreatic regeneration. We have clinically demonstrated that pancreaticoduodenectomy (PD) is associated with development of non-alcoholic fatty liver disease (NAFLD), suggesting the contribution of malnutrition due to pancreatic exocrine deficiency. Furthermore, we revealed that remnant pancreatic volume and status of postoperative infection paradoxically influenced the development of NAFLD after PD. Organ-preserving pancreatectomies have been used for the treatment of benign and sometime, malignant diseases of the pancreatic head region. We developed a new procedure, pancreatic head resection with secondportion duodenectomy, which was supervised by Professor Y. Kawarada, Our new procedure facilitates complete resection of the pancreatic head and a reliable option as an organ-preserving procedure for surgical treatment of benign lesions, low-grade malignancies, and early stage carcinomas involving the pancreatic head. Borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) tumors are those associated with a significant likelihood of an incomplete resection when surgery is used as primary therapy. BR-PDAC includes two distinct categories of tumors: BR-PV (those with PV/SMV invasion alone) and BR-A (those with major arterial invasion). In an attempt to increase R0 resection rate in patients with locally advanced PDAC, our institution has been performing preoperative chemoradio-therapy (CRT) since February 2005. Our CRT protocols for BR-PDAC appears to improve survival, especially in the patients with BR-A tumors, by enhancing R0 resection rate. Adjuvant surgery for initially unresectable PDAC patients with a long-term favorable response to nonsurgical anticancer treatments is safe and effective. Our treatment protocol of CRT followed by surgery for locally unresectable PDAC may also allow for the identification of candidates for aggressive resection at the time of reassessment and to improve prognosis of patients who undergo R0 resection. During the period of these 35 years, I have annually presented our research outcomes at this meeting, and I have been every time trained (disciplined) by having their weakness pointed out. After thorough reconsideration I have presented our outcomes refined. This is what I call “Tan Ren” (discipline with refining) in my career in pancreatology.
SA-1. Minnelide, a novel therapy against pancreatic cancer: Bench to bedside and back to bench Ashok K. Saluja Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, USA Pancreatic cancer is one of the most lethal human malignancies, with an all-stage 5-year survival of <5%, a number that highlights the urgent need for more effective therapeutic strategies. Our studies have shown that triptolide, a diterpenoid, is effective against pancreatic cancer cells in vitro as well as in vivo. However, triptolide is poorly soluble in water, limiting its clinical utility. We have recently synthesized a water-soluble pro-drug of triptolide, Minnelide that has shown tremendous promise in preclinical studies. Since its synthesis, Minnelide has been extensively evaluated in preclinical studies. In orthotopic mouse models with very aggressive cell lines, the Minnelide treated mice showed a definite regression and