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Metabolic state may define and predict resistance to mTOR-targeting therapies in pancreatic neuroendocrine tumors
S90
Abstracts / Pancreatology 16 (2016) S1eS130
Abstract ID: 1580, Oral-33. Metabolic state may define and predict resistance to mTOR-targeting therapies in pancreatic neuroendocrine tumors Jerome Cros 1, Bucaut Margot 2, Jerome Raffenne 2, M'barka Soukeur 2, Florent Dumont 3, Leanne De Koning 4, Olivia Hentic 5, Vincianne Rebours 5, Sauvanet Alain 6, Philippe Levy 5, Pierre Bedossa 1, Valerie Paradis 1, Philippe Ruszniewski 5, Anne Couvelard 1 1
Department of Pathology, Bichat-Beaujon University Hospital, France INSERM UMR1149, France 3 Genomic plateform, Institut Cochin, France 4 RPPA platform, Institut Curie, France 5 Department of Gastroenterology, Bichat-Beaujon University Hospital, France 6 Department of Biliary and Pancreatic Surgery, Beaujon University Hospital, France 2
Introduction: The mTOR inhibitor Everolimus is approved for the treatment of well-differentiated PNET. The heterogeneity of the response rate and the potential toxicity warrant predictive biomarkers. Aims: Define through a dual high throughput proteomic and transcriptomic approach predictive biomarkers of Everolimus sensitivity. Patients & methods: Fifteen well-differentiated PNET obtained postoperatively were minced in 300mM slices and cultured for 48h with Everolimus. Resistance was defined by Caspase-3 levels below the median, assessed by immunohistochemistry at 48h. Proteins and RNA from the frozen corresponding tumors were extracted. Transcriptomic profiles were determined and key proteins involved in oncogenic pathways quantified by reverse phase protein array (RPPA) and immunohistochemistry. A validation cohort of 17 patients with a PNET treated by everolimus was used. Results: Nine tumors were defined as resistant to mTOR inhibitors. RPPA showed that resistant tumors had higher level of the activated phosphorylated forms of several mTOR pathway components (mTOR/ p70S6K/S6) together with p38 and b-catenin. Transcriptomic signatures of hypoxia and glycolysis were enriched in resistant tumors. This pseudohypoxic phenotype was confirmed by immunohistochemistry with an increased expression of GLUT-1/HIF1a and CAIX in resistant tumors while pVHL level and microvascular density remained unchanged. Patients with a short time-to-progression when treated by Everolimus also displayed an activation of mTOR pathway and higher expression of pseudo-hypoxic markers such as CAIX. Conclusion: Resistant tumors to everolimus harbor non-canonical activation of the mTOR pathway together with a pseudo-hypoxic phenotype suggesting a metabolic switch toward Warburg aerobic glycolysis. The predictive value of these markers is confirmed in vivo.
Abstract ID: 1584. Laparoscopic Whipple procedure. Initial experience
gastroenterostomy. ERAS program was used in postoperative period. There were 7 men and 8 women with median age 63 (58-68). 11 patients were operated due to pancreatic head cancer and 4 for ampullary cancer. Results: The median operation time was 430 min. (405-470) with blood loss 200 ml. (100-400). The median length of hospital stay was 12 days (9-16). Complications were observed in 8 patients. However severe postoperative complications according to Dindo-Clavien (more than grade 3) were observed in 4 patients. There were 2 clinically significant postoperative pancreatic fistulas. One patient died due to severe postoperative necrotising pancreatitis. Readmission was required in 1 case. Conclusion: LapPD is a safe procedure and a good surgical option for localized pancreatic head and ampullary tumors. Laparoscopy together with use of the ERAS protocol provides early postoperative rehabilitation and earlier beginning of adjuvant therapy.
Abstract ID: 1587. Serum levels of insulin-like growth factor 1 (IGF-1) and insulin like growth factor binding protein 2 (IGFBP-2) in patients with pancreatic adenocarcinoma (PDAC) Barbara Wlodarczyk, Anna Borkowska, Ewa Malecka-Panas, Anita Gasiorowska Department of Digestive Tract Diseases, Poland Introduction: IGF-1 and IGFBP-2 are the part of IGF-axis which is involved in glucose and lipid metabolism and may also promote a cancer growth. A few studies support the fact that IGF-1 is enrolled in early carcinogenesis in animals and human. IGF-1 and IGFBP-2 serum estimation in PDAC may be a value in the early diagnosis of this disease. Aims: The aim of this study was to evaluate the serum concentrations of IGF-1 and IGFBP-2 in patients with newly diagnosed PDAC. Their values in diabetes (DM) in PDAC were also assessed. Materials & methods: The study included 69 patients with PDAC diagnosed within last 6 months and 20 patients as a control group. The concentrations of IGF-1 and IGFBP-2 were estimated with ELISA (Corgenix UK Ltd R&D Systems). Results: PDAC patients compared to controls have significantly lower serum IGF-1 level (45,83±30,03ng/ml vs 70,66±60,57ng/ml;p<0,0001). In contrast, in PDAC patients, IGFBP-2 level was significantly higher compared to the controls (225,06±86,37ng/ml vs 51,92±29,40ng/ ml;p<0,0001). The sensitivity (a) and specificity (b) of the IGF-1/IGFBP-2 ratio as a diagnostic indicator of PDAC was tested. The results show that at the 0,01 sensitivity level (99% of PDAC-positive patients are correctly diagnosed),IGF-1/IGFBP-2 ratio lower than 0,85 points indicates PDAC. At this level of sensitivity the test has the specificity of 0,097, which translates into 9,7% of healthy controls misdiagnosed with cancer (a¼0,01; b¼0,097;IGF-1/IGFBP-20,85). Conclusion: Our results show that IGF-1 to IGFBP-2 ratio0,85 may be the powerful PDAC indicator. Further studies in this area in larger patients group are necessary in order to confirm this findings.
Zahar Kovalenko, Vladimir Lyadov, Konstantin Lyadov, Ivan Kozyrin, Alexey Bogdanov, Olga Ilina, Alexandr Kachur, Vladimir Milovanov Federal Medical and Rehabilitaion center, Russia Introduction: Laparoscopic pancreatoduodenectomy (lapPD) is one of the recent trends in surgical treatment of pancreatic head and periampullary tumors. The main advantages of lapPD are: minimization of a surgical trauma and early postoperative recovery. We present here the first single institution experience of lapPD. Aims: The aims of this study were to estimate safety and feasibility of laparoscopic approach in PD. Materials & methods: There were 15 lapPD during the period from august 2014 till December 2015. In additional 3 cases procedure was begun laparoscopically, however the conversion was required due to confirmation of portal vein invasion. We routinely use a 4 troacar technique with intracorporal pancreatico- and hepaticojejunostomy and extracorporal
Abstract ID: 1588. Implication of fast track protocol in pancreatoduodenectomy Zahar Kovalenko, Vladimir Lyadov, Konstantin Lyadov, Ivan Kozyrin, Alla Kamalova, Natalia Saltynskaya Federal Medical and Rehabilitation center, Russia Introduction: Modern ERAS protocols are the «gold standart» of care in abdominal surgery. The aims of ERAS are: acceleration of postoperative rehabilitation, optimization of treatment strategy after major adominal surgery in specialize high-volume centers. Aims: The aims of this study were safety and efficiency assessment of Fast Track program in pancreatoduodenectomy (PD).
Abstracts / Pancreatology 16 (2016) S1eS130
Abstract ID: 1580, Oral-33. Metabolic state may define and predict resistance to mTOR-targeting therapies in pancreatic neuroendocrine tumors Jerome Cros 1, Bucaut Margot 2, Jerome Raffenne 2, M'barka Soukeur 2, Florent Dumont 3, Leanne De Koning 4, Olivia Hentic 5, Vincianne Rebours 5, Sauvanet Alain 6, Philippe Levy 5, Pierre Bedossa 1, Valerie Paradis 1, Philippe Ruszniewski 5, Anne Couvelard 1 1
Department of Pathology, Bichat-Beaujon University Hospital, France INSERM UMR1149, France 3 Genomic plateform, Institut Cochin, France 4 RPPA platform, Institut Curie, France 5 Department of Gastroenterology, Bichat-Beaujon University Hospital, France 6 Department of Biliary and Pancreatic Surgery, Beaujon University Hospital, France 2
Introduction: The mTOR inhibitor Everolimus is approved for the treatment of well-differentiated PNET. The heterogeneity of the response rate and the potential toxicity warrant predictive biomarkers. Aims: Define through a dual high throughput proteomic and transcriptomic approach predictive biomarkers of Everolimus sensitivity. Patients & methods: Fifteen well-differentiated PNET obtained postoperatively were minced in 300mM slices and cultured for 48h with Everolimus. Resistance was defined by Caspase-3 levels below the median, assessed by immunohistochemistry at 48h. Proteins and RNA from the frozen corresponding tumors were extracted. Transcriptomic profiles were determined and key proteins involved in oncogenic pathways quantified by reverse phase protein array (RPPA) and immunohistochemistry. A validation cohort of 17 patients with a PNET treated by everolimus was used. Results: Nine tumors were defined as resistant to mTOR inhibitors. RPPA showed that resistant tumors had higher level of the activated phosphorylated forms of several mTOR pathway components (mTOR/ p70S6K/S6) together with p38 and b-catenin. Transcriptomic signatures of hypoxia and glycolysis were enriched in resistant tumors. This pseudohypoxic phenotype was confirmed by immunohistochemistry with an increased expression of GLUT-1/HIF1a and CAIX in resistant tumors while pVHL level and microvascular density remained unchanged. Patients with a short time-to-progression when treated by Everolimus also displayed an activation of mTOR pathway and higher expression of pseudo-hypoxic markers such as CAIX. Conclusion: Resistant tumors to everolimus harbor non-canonical activation of the mTOR pathway together with a pseudo-hypoxic phenotype suggesting a metabolic switch toward Warburg aerobic glycolysis. The predictive value of these markers is confirmed in vivo.
Abstract ID: 1584. Laparoscopic Whipple procedure. Initial experience
gastroenterostomy. ERAS program was used in postoperative period. There were 7 men and 8 women with median age 63 (58-68). 11 patients were operated due to pancreatic head cancer and 4 for ampullary cancer. Results: The median operation time was 430 min. (405-470) with blood loss 200 ml. (100-400). The median length of hospital stay was 12 days (9-16). Complications were observed in 8 patients. However severe postoperative complications according to Dindo-Clavien (more than grade 3) were observed in 4 patients. There were 2 clinically significant postoperative pancreatic fistulas. One patient died due to severe postoperative necrotising pancreatitis. Readmission was required in 1 case. Conclusion: LapPD is a safe procedure and a good surgical option for localized pancreatic head and ampullary tumors. Laparoscopy together with use of the ERAS protocol provides early postoperative rehabilitation and earlier beginning of adjuvant therapy.
Abstract ID: 1587. Serum levels of insulin-like growth factor 1 (IGF-1) and insulin like growth factor binding protein 2 (IGFBP-2) in patients with pancreatic adenocarcinoma (PDAC) Barbara Wlodarczyk, Anna Borkowska, Ewa Malecka-Panas, Anita Gasiorowska Department of Digestive Tract Diseases, Poland Introduction: IGF-1 and IGFBP-2 are the part of IGF-axis which is involved in glucose and lipid metabolism and may also promote a cancer growth. A few studies support the fact that IGF-1 is enrolled in early carcinogenesis in animals and human. IGF-1 and IGFBP-2 serum estimation in PDAC may be a value in the early diagnosis of this disease. Aims: The aim of this study was to evaluate the serum concentrations of IGF-1 and IGFBP-2 in patients with newly diagnosed PDAC. Their values in diabetes (DM) in PDAC were also assessed. Materials & methods: The study included 69 patients with PDAC diagnosed within last 6 months and 20 patients as a control group. The concentrations of IGF-1 and IGFBP-2 were estimated with ELISA (Corgenix UK Ltd R&D Systems). Results: PDAC patients compared to controls have significantly lower serum IGF-1 level (45,83±30,03ng/ml vs 70,66±60,57ng/ml;p<0,0001). In contrast, in PDAC patients, IGFBP-2 level was significantly higher compared to the controls (225,06±86,37ng/ml vs 51,92±29,40ng/ ml;p<0,0001). The sensitivity (a) and specificity (b) of the IGF-1/IGFBP-2 ratio as a diagnostic indicator of PDAC was tested. The results show that at the 0,01 sensitivity level (99% of PDAC-positive patients are correctly diagnosed),IGF-1/IGFBP-2 ratio lower than 0,85 points indicates PDAC. At this level of sensitivity the test has the specificity of 0,097, which translates into 9,7% of healthy controls misdiagnosed with cancer (a¼0,01; b¼0,097;IGF-1/IGFBP-20,85). Conclusion: Our results show that IGF-1 to IGFBP-2 ratio0,85 may be the powerful PDAC indicator. Further studies in this area in larger patients group are necessary in order to confirm this findings.
Zahar Kovalenko, Vladimir Lyadov, Konstantin Lyadov, Ivan Kozyrin, Alexey Bogdanov, Olga Ilina, Alexandr Kachur, Vladimir Milovanov Federal Medical and Rehabilitaion center, Russia Introduction: Laparoscopic pancreatoduodenectomy (lapPD) is one of the recent trends in surgical treatment of pancreatic head and periampullary tumors. The main advantages of lapPD are: minimization of a surgical trauma and early postoperative recovery. We present here the first single institution experience of lapPD. Aims: The aims of this study were to estimate safety and feasibility of laparoscopic approach in PD. Materials & methods: There were 15 lapPD during the period from august 2014 till December 2015. In additional 3 cases procedure was begun laparoscopically, however the conversion was required due to confirmation of portal vein invasion. We routinely use a 4 troacar technique with intracorporal pancreatico- and hepaticojejunostomy and extracorporal
Abstract ID: 1588. Implication of fast track protocol in pancreatoduodenectomy Zahar Kovalenko, Vladimir Lyadov, Konstantin Lyadov, Ivan Kozyrin, Alla Kamalova, Natalia Saltynskaya Federal Medical and Rehabilitation center, Russia Introduction: Modern ERAS protocols are the «gold standart» of care in abdominal surgery. The aims of ERAS are: acceleration of postoperative rehabilitation, optimization of treatment strategy after major adominal surgery in specialize high-volume centers. Aims: The aims of this study were safety and efficiency assessment of Fast Track program in pancreatoduodenectomy (PD).