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Autophagy mediates resistance to chemotherapy through a novel E2F1-P300-VMP1 pathway in pancreatic cancer cells carrying oncogenic Kras
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Abstracts / Pancreatology 17 (2017) S1eS68
0284. Pattern of locoregional recurrence after curative resection in pancreatic ductal adenocarcinoma according to the location of the tumor Jae-Ri Kim, Wooil Kwzn, Hongeun Lee, Jin-young Jang, Sun-Whe Kim Seoul National University Hospital, Seoul, Republic of Korea Introduction: Site of recurrence, especially locoregional one, after curative surgery for pancreatic cancer must go to show the adequate extent and approach for pancreatectomy. There are little studies on the recurrence pattern of pancreatic ductal adenocarcinoma (PDAC). Aim: The aim was to establish guideline for surgical management by analyzing the recurrence pattern after curative resection of PDAC according to the tumor location. Background: Clinical trials of different extent and approaches of surgery have failed to show any different outcome. Customized surgery according to the tumor factors including tumor location might be necessary. Method: This study included 361 patients with PDAC who underwent curative-intent surgery between 2007 and 2014. Recurrence pattern was analyzed to see if there is any association with tumor location. Results: Among 361 patients, 75.1% (n¼271) had recurrence during the follow up period (median 31.9month) and the 5-year overall survival rate was 29.4%. The first recurrence patterns were divided as local (n¼48, 13.3%), systemic (n¼168, 46.5%) and combined (n¼55, 15.2%) type. According to the preoperative tumor location, patients with head and uncinate process mass had more local recurrence than those with body and tail mass (47.8% vs.18.2%, p<0.001). Regarding the head and uncinate mass, uncinate process mass showed higher recurrence rate around the superior mesenteric vessels compared to head mass (76.7% vs. 35.6%, p¼0.001). On the other hand, head mass showed more frequent recurrence around the hepatoduodenal ligament including hepatic artery (42.2% vs. 18.6%, p¼0.021). Discussion: Most of the patients with PDAC succumb to the recurrence after curative resection. While systemic recurrence is beyond the hands of surgery, local recur may be prevented by meticulous surgery. With this in mind, different patterns of locoregional recurrence according to the tumor location should be of an important consideration. Conclusion: Customization of the extent of surgery according to the location of tumor is necessary for better local control.
2011 was entered in a prospectively collected database. Patient demographics, local compromise by imaging, serum amylase at admission and before surgery, incidence of associated choledocholithiasis, laparoscopic resolution of biliary disease, postoperative complications, length of hospital stay before surgery, total length of hospital stay and long-term follow-up were recorded. LC was performed the first available operative day after the first 48 hours of admission. Results: In the study period we admitted 148 patient with AP. Only 63 patients met the inclusion criteria. Mean age was 58 yo (r24-84), 33 Women (52%), Balthazar A, B and C was 19, 22 and 22 cases respectively without difference. Exclusion criteria: (a). Severe pancreatitis; (b). Concomitant acute cholangitis (total bilirubin 4 mg/dL þ fever or leukocytosis); (c). Severe medical comorbidities contraindicating surgery; (d). Patient refusal to participate; (e). Presence of large fluid collections or extensive pancreatic necrosis on computed tomography or magnetic resonance imaging. The resolution of Choledocholithiasis was carried out by: laparoscopic transcystic stone extraction in 81%, laparoscopic choledochotomy in 13% and ERCP in 6% of the patients. Morbidity was 4% (Grade I and II according Dindo-Clavien classification) without mortality. Median follow-up was 19 month (r8-37) without AP. Discussion: The local inflammatory response (seen in CT as Balthazar A, B or C) and the systemic inflamatory response of AP raises doubts about when a patient should be intervened to definitively resolve their biliary disease. Many times the value of serum amylase is erroneously considered as an indicator of pancreatic inflammation, so it should not be used in decision making. Staging of systemic inflamatory response syndrome should be performed considering clinical parameters and organ dysfunction. In such case, clinical improvement should be the goal before surgery. Conclusion: The laparoscopic treatment of biliary disease in patients with non-severe AP, after the first 48 hours, is a safe strategy independently the normalization of amylase. In the absence of dysfunction or organ failure, the Balthazar score A, B or C does not conditioned differences in the postoperative evolution.
0296. Autophagy mediates resistance to chemotherapy through a novel E2F1-P300-VMP1 pathway in pancreatic cancer cells carrying oncogenic Kras
0287. Laparoscopic cholecystectomy for non-severe gallstone-associated acute pancreatitis: How early is safe? ~ es 1, Agustin Cristiano 2, Juan Oscar María Mazza 1, Martín de Santiban ~ es 1, Glinka 1, Fernando Alvarez 1, Victoria Ardiles 1, Eduardo de Santiban Juan Pekolj 1 1
Hospital Italiano, Argentina 2 Hospital el Cruce, Argentina Introduction: There is still controversy about the proper timing to perform the laparoscopic cholecystectomy for non-severe gallstone-associated AP. Aim: We aim to present our experience with early treatment of biliary disease in patients with non-severe AP and to evaluate the results according to local compromise in the absence of fluid collections or extensive necrosis using the Balthazar score. Background: Currently there is consensus that in cases of mild acute pancreatitis (AP), biliary surgery should be performed during the initial hospitalization in order to avoid recurrence. Recent evidence supports laparoscopic cholecystectomy (LC) with routine intraoperative cholangiography (IOC) and eventual laparoscopic treatment of common bile duct stones as a feasible and safe approach in experienced centers. However, there is still controversy about the proper timing to perform the LC for non-severe gallstone-associated AP. Method: This is a single-cohort, prospective, observational study. Data for all patients with diagnosis AP between January 2010 and December
Cintia Betiana Catrinacio, Alejandro Ropolo, Tamara Orquera, Maria Ines Vaccaro Universidad de Buenos Aires. Conicet. Instituto de bioquímica y Medicina Molecular (IBIMOL), Argentina Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. Gemcitabine, a deoxycytidine analog, has become the standard chemotherapy for the treatment of advanced pancreatic cancer, despite its poor efficacy because the relatively refractory of human pancreatic tumor cells. Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in both tumor suppression and tumor progression. Aim: To evaluate the regulatory pathways that control VMP1 gene expression and autophagy in pancreatic tumor cells under gemcitabine treatment. Results: We demonstrated that gemcitabine requires VMP1 expression to induce autophagy in highly resistant pancreatic cancer cells PANC-1 carrying activated K-Ras, but not in BxPC-3 cells that do not carry K-Ras mutation. Analysis of the mechanisms identified E2F1, a transcription factor that is regulated by the retinoblastoma pathway, as an effector of gemcitabine-induced autophagy. E2F1 regulates the expression and promoter activity of VMP1. Chromatin immunoprecipitation assays demonstrated that E2F1 binds to the VMP1 promoter in PANC-1 cells. We also identified the histone acetyltransferase p300 as a modulator of this promoter activity. Our data show that the E2F1-p300 activator/co-activator
Abstracts / Pancreatology 17 (2017) S1eS68
complex is part of the regulatory pathway controlling the expression and promoter activity of VMP1 triggered by gemcitabine in PANC 1 cells. Finally, downregulation of VMP1 expression and pharmacological modulation of autophagy sensitize PANC-1 cells to apoptosis and diminish clonogenicity under gemcitabine treatment. Discussion: Therefore, we characterize a new molecular pathway, mediated by VMP1, an autophagy-related protein inducible by activated KRas, by which gemcitabine is able to trigger autophagy in human pancreatic tumor cells. Conclusion: Together, these data provide evidence of a transcriptional regulation mechanism of autophagy that integrates this cellular process into the complex network of events involved in PDAC chemoresistance.
0297. Acute pancreatitis after laparoscopic trans-cystic common bile duct exploration (LTCBDE): An analysis in 447 consecutive patients Matias Czerwonko, Juan Pekolj, Pedro Uad, Oscar Mazza, Rodrigo , Martin de Santiban ~ es, Eduardo de Santiban ~ es, Martin Sanchez-Claria Palavecino Hospital Italiano, Argentina Introduction: In LTCBDE, the risk of acute pancreatitis (AP) is wellrecognized. The aim of the present study is to assess the incidence, risk factors, and clinical impact of AP in patients with choledocholithiasis treated with LTCBDE. Method: A retrospective database was completed including patients who underwent LTCBDE between 2007 and 2017. Univariate and multivariate analysis were performed by logistic regression. Results: After exclusion criteria, 447 patients were identified (136 male and 311 female; mean age þ/- SD, 62.1 ± 18.1). There were 70 patients (22.4%) who showed post-procedure hyperamylasemia, including 20 patients (4.5%: 9 male and 11 female; mean age þ/- SD, 60.5 ± 18.3) who developed post-LTCBDE AP. Of these, 19 were edematous and 1 was a necrotizing pancreatitis. Patients with post-LTCBDE AP were statistically more likely to have leukocytosis (p<0.004) and jaundice (p¼0.019) before surgery and longer operative times (OT) (p<0.001); they were less likely to have incidental intraoperative diagnosis (p¼0.031) or to have biliary colic as the reason for surgery (p¼0.033). In the final multivariate model, leukocytosis (p¼0.008) and operative time (p<0.001) remained significant predictors for AP. Mean postoperative hospital stay (HS) was significantly longer in AP group (1.8 ± 1.3 days vs 6.4 ± 4.3 days, p<0.001). Conclusion: This series shows a low risk of AP following LTCBDE. The risk of AP should be considered in patients with preoperative leukocytosis and jaundice. LTCBDE prolonged the OT and HS. All cases were mild AP.
0299. Isolation, characterization and anti diabetic effect 1,2,3,8,9&;tetramethoxy&;6, 6a, 7, 12&;tetrahydro;5h;12a;aza&; benzo[a] anthracene monohydrate alkaloid from the tubers of stephania glabra and its crystal structure C.K. Ashok Kumar Sree Vidyanikethan College Of Pharmacy, India Introduction: Stephania glabra is a slender, glabrous, twinning, perennial climber with large bulbous root found in lower, middle and upper hill forest upto 700 ft. It is belonging to the family Menispermaceae. The large tubers of this plant have been used in India for variety of disorders including dysentry, tuberculosis, asthma and fever (Chopra et al., 1958). The work described in this paper is the yield of reinvestigation on S.
S59
glabra, which afforded a potent biologically active alkaloid of isoquino&;quinoline system. To the best of our knowledge this compound is isolated for the first time from the above said plant. Aim: To isolate and characterize a chief constituent of Stephania glabra and exploration of its anti diabetic potential Method: Isolation; Column Chromatography Characterization: IR, NMR, M and x-ray crystallography Prelinical: STZ induced diabetes in rats Results: The alkaloid, () 2,3,8,9Tetramethoxy6, 6a, 7, 12tetrahydro 5H 12aaza benzo[a] anthracene monohydrate (1), C21H25NO4.H2O [ASG], showed 1460.81 cm1 (ArN), 1285 cm1 (CN), 10501350 cm1 (OCH3) and 3610 cm1 (OH of H2O) absorption in the IR spectrum. The presence of twenty five protons and twenty one carbons in (1) was evident from 1H NMR and 13C NMR spectrum respectively and its Mþ was observed at m/z 373. The singlet signals observed at Ca d 4.20, 3.87, 3.85 and 3.54 were responsible for presence of four methoxy group in the compound (1). The specific rotation of the isolated material was found to be . Although a basic structure has been established by spectroscopic studies, there remained some ambiguity with respect to the exact position of tertiary Natom, indication of peak at 3610 cm1, the position of H2O, the nature of interaction of H2O and plane of hydrogen at C15 position. Hence Xray crystallographic analysis was carried out for the single crystal obtained from pure isolated compound for gaining deeper insight of the structural features and determined the exact configuration of the said alkaloid. The X&;ray crystallographic analysis finely supports the structure of the alkaloid which was determined from analytical and spectral data. The X&;ray analysis carried out for the said alkaloid, showed that the N&;atom must be located at N1 position (i.e. between C5 and C7 atoms), hydrogen at C15 is above the plane of the ring. The interatomic distances within the CN&;C units of the quinolinyl part of the said alkaloid viz. C15 &; N1 &; C5 and C7 ; N1 &; C5 span the relatively small range 111.6(3) to 106.7(3)Å. The C;N bond length viz. N1;C7 and N1&;C5 are 1.49(5) and 1.532(6) Å respectively and this shortening of N1&;C5 clearly indicates that N&;atom present in the said alkaloid is in direct conjugation with aryl part of the quinolinyl moiety. The said alkaloid showed a dose dependent mild hypoglycaemic effect. This support the claim for its use as hypoglycemic agent by the tribal people of Nepal. The results were significant and comparable with the effect of commercial oral hypoglycaemic drug, glibenclamide that showed 46.9% reduction under similar conditions. Still many enzymatic estimation and free radical scavenging activities supporting the hypoglycaemic effect are to be thoroughly screened to know the exact mechanism of action for the hypoglycaemic effect of the said alkaloid, so that it can be developed into a potent hypoglycaemic agent.
0301. Preoperative risk score for pancreatic fistula after distal pancreatectomy: Derivation and multicenter external validation Matteo de Pastena 1, Timothy H. Mungroop 2, Giovanni Marchegiani 1, Ignace de Hingh 3, Salvatore Paiella 1, Casper van Eijck 4, Marc Besselink 2, Claudio Bassi 1 1
Verona University Hospital, Italy Academical Medical Center, Netherlands 3 Catharina Hospital, Netherlands 4 Erasmus MC, Netherlands 2
Introduction: Postoperative pancreatic fistula (POPF) remains the most common complication after distal pancreatectomy (DP). Despite several known risk factors, a risk model has not been developed yet. Aim: Aim of this study was to develop and externally validate a preoperative distal pancreatectomy risk score for DP Method: Data of patients undergoing DP from 2014 to 2016 were retrieved from the University Hospital of Verona database. The last preoperative imaging was reviewed to measure the pancreatic thickness and duct size, both measured ventral to the portal vein. A prediction model was
Abstracts / Pancreatology 17 (2017) S1eS68
0284. Pattern of locoregional recurrence after curative resection in pancreatic ductal adenocarcinoma according to the location of the tumor Jae-Ri Kim, Wooil Kwzn, Hongeun Lee, Jin-young Jang, Sun-Whe Kim Seoul National University Hospital, Seoul, Republic of Korea Introduction: Site of recurrence, especially locoregional one, after curative surgery for pancreatic cancer must go to show the adequate extent and approach for pancreatectomy. There are little studies on the recurrence pattern of pancreatic ductal adenocarcinoma (PDAC). Aim: The aim was to establish guideline for surgical management by analyzing the recurrence pattern after curative resection of PDAC according to the tumor location. Background: Clinical trials of different extent and approaches of surgery have failed to show any different outcome. Customized surgery according to the tumor factors including tumor location might be necessary. Method: This study included 361 patients with PDAC who underwent curative-intent surgery between 2007 and 2014. Recurrence pattern was analyzed to see if there is any association with tumor location. Results: Among 361 patients, 75.1% (n¼271) had recurrence during the follow up period (median 31.9month) and the 5-year overall survival rate was 29.4%. The first recurrence patterns were divided as local (n¼48, 13.3%), systemic (n¼168, 46.5%) and combined (n¼55, 15.2%) type. According to the preoperative tumor location, patients with head and uncinate process mass had more local recurrence than those with body and tail mass (47.8% vs.18.2%, p<0.001). Regarding the head and uncinate mass, uncinate process mass showed higher recurrence rate around the superior mesenteric vessels compared to head mass (76.7% vs. 35.6%, p¼0.001). On the other hand, head mass showed more frequent recurrence around the hepatoduodenal ligament including hepatic artery (42.2% vs. 18.6%, p¼0.021). Discussion: Most of the patients with PDAC succumb to the recurrence after curative resection. While systemic recurrence is beyond the hands of surgery, local recur may be prevented by meticulous surgery. With this in mind, different patterns of locoregional recurrence according to the tumor location should be of an important consideration. Conclusion: Customization of the extent of surgery according to the location of tumor is necessary for better local control.
2011 was entered in a prospectively collected database. Patient demographics, local compromise by imaging, serum amylase at admission and before surgery, incidence of associated choledocholithiasis, laparoscopic resolution of biliary disease, postoperative complications, length of hospital stay before surgery, total length of hospital stay and long-term follow-up were recorded. LC was performed the first available operative day after the first 48 hours of admission. Results: In the study period we admitted 148 patient with AP. Only 63 patients met the inclusion criteria. Mean age was 58 yo (r24-84), 33 Women (52%), Balthazar A, B and C was 19, 22 and 22 cases respectively without difference. Exclusion criteria: (a). Severe pancreatitis; (b). Concomitant acute cholangitis (total bilirubin 4 mg/dL þ fever or leukocytosis); (c). Severe medical comorbidities contraindicating surgery; (d). Patient refusal to participate; (e). Presence of large fluid collections or extensive pancreatic necrosis on computed tomography or magnetic resonance imaging. The resolution of Choledocholithiasis was carried out by: laparoscopic transcystic stone extraction in 81%, laparoscopic choledochotomy in 13% and ERCP in 6% of the patients. Morbidity was 4% (Grade I and II according Dindo-Clavien classification) without mortality. Median follow-up was 19 month (r8-37) without AP. Discussion: The local inflammatory response (seen in CT as Balthazar A, B or C) and the systemic inflamatory response of AP raises doubts about when a patient should be intervened to definitively resolve their biliary disease. Many times the value of serum amylase is erroneously considered as an indicator of pancreatic inflammation, so it should not be used in decision making. Staging of systemic inflamatory response syndrome should be performed considering clinical parameters and organ dysfunction. In such case, clinical improvement should be the goal before surgery. Conclusion: The laparoscopic treatment of biliary disease in patients with non-severe AP, after the first 48 hours, is a safe strategy independently the normalization of amylase. In the absence of dysfunction or organ failure, the Balthazar score A, B or C does not conditioned differences in the postoperative evolution.
0296. Autophagy mediates resistance to chemotherapy through a novel E2F1-P300-VMP1 pathway in pancreatic cancer cells carrying oncogenic Kras
0287. Laparoscopic cholecystectomy for non-severe gallstone-associated acute pancreatitis: How early is safe? ~ es 1, Agustin Cristiano 2, Juan Oscar María Mazza 1, Martín de Santiban ~ es 1, Glinka 1, Fernando Alvarez 1, Victoria Ardiles 1, Eduardo de Santiban Juan Pekolj 1 1
Hospital Italiano, Argentina 2 Hospital el Cruce, Argentina Introduction: There is still controversy about the proper timing to perform the laparoscopic cholecystectomy for non-severe gallstone-associated AP. Aim: We aim to present our experience with early treatment of biliary disease in patients with non-severe AP and to evaluate the results according to local compromise in the absence of fluid collections or extensive necrosis using the Balthazar score. Background: Currently there is consensus that in cases of mild acute pancreatitis (AP), biliary surgery should be performed during the initial hospitalization in order to avoid recurrence. Recent evidence supports laparoscopic cholecystectomy (LC) with routine intraoperative cholangiography (IOC) and eventual laparoscopic treatment of common bile duct stones as a feasible and safe approach in experienced centers. However, there is still controversy about the proper timing to perform the LC for non-severe gallstone-associated AP. Method: This is a single-cohort, prospective, observational study. Data for all patients with diagnosis AP between January 2010 and December
Cintia Betiana Catrinacio, Alejandro Ropolo, Tamara Orquera, Maria Ines Vaccaro Universidad de Buenos Aires. Conicet. Instituto de bioquímica y Medicina Molecular (IBIMOL), Argentina Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. Gemcitabine, a deoxycytidine analog, has become the standard chemotherapy for the treatment of advanced pancreatic cancer, despite its poor efficacy because the relatively refractory of human pancreatic tumor cells. Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in both tumor suppression and tumor progression. Aim: To evaluate the regulatory pathways that control VMP1 gene expression and autophagy in pancreatic tumor cells under gemcitabine treatment. Results: We demonstrated that gemcitabine requires VMP1 expression to induce autophagy in highly resistant pancreatic cancer cells PANC-1 carrying activated K-Ras, but not in BxPC-3 cells that do not carry K-Ras mutation. Analysis of the mechanisms identified E2F1, a transcription factor that is regulated by the retinoblastoma pathway, as an effector of gemcitabine-induced autophagy. E2F1 regulates the expression and promoter activity of VMP1. Chromatin immunoprecipitation assays demonstrated that E2F1 binds to the VMP1 promoter in PANC-1 cells. We also identified the histone acetyltransferase p300 as a modulator of this promoter activity. Our data show that the E2F1-p300 activator/co-activator
Abstracts / Pancreatology 17 (2017) S1eS68
complex is part of the regulatory pathway controlling the expression and promoter activity of VMP1 triggered by gemcitabine in PANC 1 cells. Finally, downregulation of VMP1 expression and pharmacological modulation of autophagy sensitize PANC-1 cells to apoptosis and diminish clonogenicity under gemcitabine treatment. Discussion: Therefore, we characterize a new molecular pathway, mediated by VMP1, an autophagy-related protein inducible by activated KRas, by which gemcitabine is able to trigger autophagy in human pancreatic tumor cells. Conclusion: Together, these data provide evidence of a transcriptional regulation mechanism of autophagy that integrates this cellular process into the complex network of events involved in PDAC chemoresistance.
0297. Acute pancreatitis after laparoscopic trans-cystic common bile duct exploration (LTCBDE): An analysis in 447 consecutive patients Matias Czerwonko, Juan Pekolj, Pedro Uad, Oscar Mazza, Rodrigo , Martin de Santiban ~ es, Eduardo de Santiban ~ es, Martin Sanchez-Claria Palavecino Hospital Italiano, Argentina Introduction: In LTCBDE, the risk of acute pancreatitis (AP) is wellrecognized. The aim of the present study is to assess the incidence, risk factors, and clinical impact of AP in patients with choledocholithiasis treated with LTCBDE. Method: A retrospective database was completed including patients who underwent LTCBDE between 2007 and 2017. Univariate and multivariate analysis were performed by logistic regression. Results: After exclusion criteria, 447 patients were identified (136 male and 311 female; mean age þ/- SD, 62.1 ± 18.1). There were 70 patients (22.4%) who showed post-procedure hyperamylasemia, including 20 patients (4.5%: 9 male and 11 female; mean age þ/- SD, 60.5 ± 18.3) who developed post-LTCBDE AP. Of these, 19 were edematous and 1 was a necrotizing pancreatitis. Patients with post-LTCBDE AP were statistically more likely to have leukocytosis (p<0.004) and jaundice (p¼0.019) before surgery and longer operative times (OT) (p<0.001); they were less likely to have incidental intraoperative diagnosis (p¼0.031) or to have biliary colic as the reason for surgery (p¼0.033). In the final multivariate model, leukocytosis (p¼0.008) and operative time (p<0.001) remained significant predictors for AP. Mean postoperative hospital stay (HS) was significantly longer in AP group (1.8 ± 1.3 days vs 6.4 ± 4.3 days, p<0.001). Conclusion: This series shows a low risk of AP following LTCBDE. The risk of AP should be considered in patients with preoperative leukocytosis and jaundice. LTCBDE prolonged the OT and HS. All cases were mild AP.
0299. Isolation, characterization and anti diabetic effect 1,2,3,8,9&;tetramethoxy&;6, 6a, 7, 12&;tetrahydro;5h;12a;aza&; benzo[a] anthracene monohydrate alkaloid from the tubers of stephania glabra and its crystal structure C.K. Ashok Kumar Sree Vidyanikethan College Of Pharmacy, India Introduction: Stephania glabra is a slender, glabrous, twinning, perennial climber with large bulbous root found in lower, middle and upper hill forest upto 700 ft. It is belonging to the family Menispermaceae. The large tubers of this plant have been used in India for variety of disorders including dysentry, tuberculosis, asthma and fever (Chopra et al., 1958). The work described in this paper is the yield of reinvestigation on S.
S59
glabra, which afforded a potent biologically active alkaloid of isoquino&;quinoline system. To the best of our knowledge this compound is isolated for the first time from the above said plant. Aim: To isolate and characterize a chief constituent of Stephania glabra and exploration of its anti diabetic potential Method: Isolation; Column Chromatography Characterization: IR, NMR, M and x-ray crystallography Prelinical: STZ induced diabetes in rats Results: The alkaloid, () 2,3,8,9Tetramethoxy6, 6a, 7, 12tetrahydro 5H 12aaza benzo[a] anthracene monohydrate (1), C21H25NO4.H2O [ASG], showed 1460.81 cm1 (ArN), 1285 cm1 (CN), 10501350 cm1 (OCH3) and 3610 cm1 (OH of H2O) absorption in the IR spectrum. The presence of twenty five protons and twenty one carbons in (1) was evident from 1H NMR and 13C NMR spectrum respectively and its Mþ was observed at m/z 373. The singlet signals observed at Ca d 4.20, 3.87, 3.85 and 3.54 were responsible for presence of four methoxy group in the compound (1). The specific rotation of the isolated material was found to be . Although a basic structure has been established by spectroscopic studies, there remained some ambiguity with respect to the exact position of tertiary Natom, indication of peak at 3610 cm1, the position of H2O, the nature of interaction of H2O and plane of hydrogen at C15 position. Hence Xray crystallographic analysis was carried out for the single crystal obtained from pure isolated compound for gaining deeper insight of the structural features and determined the exact configuration of the said alkaloid. The X&;ray crystallographic analysis finely supports the structure of the alkaloid which was determined from analytical and spectral data. The X&;ray analysis carried out for the said alkaloid, showed that the N&;atom must be located at N1 position (i.e. between C5 and C7 atoms), hydrogen at C15 is above the plane of the ring. The interatomic distances within the CN&;C units of the quinolinyl part of the said alkaloid viz. C15 &; N1 &; C5 and C7 ; N1 &; C5 span the relatively small range 111.6(3) to 106.7(3)Å. The C;N bond length viz. N1;C7 and N1&;C5 are 1.49(5) and 1.532(6) Å respectively and this shortening of N1&;C5 clearly indicates that N&;atom present in the said alkaloid is in direct conjugation with aryl part of the quinolinyl moiety. The said alkaloid showed a dose dependent mild hypoglycaemic effect. This support the claim for its use as hypoglycemic agent by the tribal people of Nepal. The results were significant and comparable with the effect of commercial oral hypoglycaemic drug, glibenclamide that showed 46.9% reduction under similar conditions. Still many enzymatic estimation and free radical scavenging activities supporting the hypoglycaemic effect are to be thoroughly screened to know the exact mechanism of action for the hypoglycaemic effect of the said alkaloid, so that it can be developed into a potent hypoglycaemic agent.
0301. Preoperative risk score for pancreatic fistula after distal pancreatectomy: Derivation and multicenter external validation Matteo de Pastena 1, Timothy H. Mungroop 2, Giovanni Marchegiani 1, Ignace de Hingh 3, Salvatore Paiella 1, Casper van Eijck 4, Marc Besselink 2, Claudio Bassi 1 1
Verona University Hospital, Italy Academical Medical Center, Netherlands 3 Catharina Hospital, Netherlands 4 Erasmus MC, Netherlands 2
Introduction: Postoperative pancreatic fistula (POPF) remains the most common complication after distal pancreatectomy (DP). Despite several known risk factors, a risk model has not been developed yet. Aim: Aim of this study was to develop and externally validate a preoperative distal pancreatectomy risk score for DP Method: Data of patients undergoing DP from 2014 to 2016 were retrieved from the University Hospital of Verona database. The last preoperative imaging was reviewed to measure the pancreatic thickness and duct size, both measured ventral to the portal vein. A prediction model was