- Email: [email protected]
1036 MUC13 Interaction With Receptor Tyrosine Kinase HER2 Drives Pancreatic Ductal Adenocarcinoma Progression
hazard of mortality. Other factors contributing towards a worse prognosis included older age (>70 years), undergoing a whipple procedure, having positive margins and higher stage disease, p<0.05, all. Conclusion: The majority of patients treated with NAT do not experience a change in stage, despite therapy. However, those who respond to NAT or remain the same stage experience a survival benefit over those who experience disease progression. Neoadjuvant chemotherapy appears to confer similar survival benefits to neoadjuvant chemoradiation in early stage disease.
1037 Increased Pancreatic Cancer Survival with Greater Lymph Node Retrieval in the National Cancer Data Base Carlo M. Contreras, Chee P. Lin, Robert Oster, Sushanth M. Reddy, Thomas N. Wang, Selwyn M. Vickers, Martin M. Heslin Introduction: Robust lymph node (LN) retrieval during resection has been associated with increased survival in the setting of various gastrointestinal malignancies. The purpose of this study is to evaluate the role of LN retrieval in patients undergoing pancreaticoduodenectomy (PD) for pancreatic cancer. Methods: The National Cancer Data Base was utilized which captures tumor, patient, and facility data from academic and community medical centers. Cox regression models were used to assess bivariate & multivariate predictors of time to death, and logistic regression models were used to assess bivariate & multivariate predictors of mortality. Group mean comparisons were performed using the two-group ttest. Results: 30,180 patients with pancreatic adenocarcinoma underwent PD between the years 1998-2011 from 1,268 institutions; 62% (18,862/30,180) had LN metastasis. The mean number of LN retrieved in LN(-) patients was 10.7 vs 14.4 for LN(+) patients (p<0.0001). Patients with <10 LN retrieved had a mean of 1.1 vs 2.8 positive LN for patients with >10 LN retrieved (p<0.0001). Clinically irrelevant differences in the number of LN retrieved were observed related to PD with/without antrectomy, or receipt of neoadjuvant therapy. There were minor associations between pathologic margin status, postoperative days until hospital discharge, or 30-day readmission rate and the number of LN retrieved. The median survival of LN(-) patients exceeded that of LN(+) patients (24.9 vs 15.2 months, p<0.0001). Increasing LN retrieval is a multivariate predictor of survival in all patients, and in node-negative patients. The mean number of LN retrieved at academic centers is greater than at non-academic centers (14 vs 11.5, p<0.0001). The relationship of increased LN retrieval and enhanced survival is a nearly linear trend (see Figure). Conclusions: Greater LN retrieval is associated with increased survival in patients with pancreatic cancer, even in the node-negative subset. Increased nodal retrieval does not correlate with a significant increase in morbidity. Rather than demonstrating an inflection point that defines the extent of adequate lymphadenectomy, this dataset demonstrates an incremental relationship between LN retrieval and survival.
1035 Learning Curve Effect on ‘Step Up Approach' for Management of Severe Acute Pancreatitis Rajesh Gupta, Rahul Gupta, Sunil Shenvi, Raghavendra B. Yelakanti, Rohit K. Nimje, Abhishek Chandna, Surinder S. Rana, Mandeep Kang, Rajinder Singh, Deepak K. Bhasin Background This study was conducted to see if there is learning curve effect on outcome of ‘Step up approach' in a single surgical Unit in a tertiary care centre. Methods Patients of SAP referred to Division of Surgical Gastroenterology from April 2008 to October 2015 were distributed into 3 time periods: Group 1 - April 2008 to August 2011, Group II September 2011 to September 2014 and Group III -October 2014 to October 2015. The three groups were compared for learning curve effect. Results There were total of 170 patients in this period. There were 60 patients each in Group I and II and 50 in Group III. When compared to group I and II, patients in Group III had higher APACHE II score at first intervention (8.28 vs 9.32 vs 9.82, p = 0.073), significantly higher modified CTSI score (8.7 vs 9.1 vs 9.6, p = 0.003), signifiantly more patients with complete necrosis (9 vs 20 vs 20, p = 0.009) and extrapancreatic necrosis (22 vs 39 vs 44, p = 0.000). Microbial spectrum also changed during this period with Escherichia coli being the most common organism in Group I and II (39 vs 33 vs 17, p = 0.004) while Klebsiella pneumoniae was the most common organism in Group III (8 vs 15 vs 18, p = 0.021). Number of PCD procedures performed per patient were highest in Group I and progressive reduction in number of procedures was observed over time (5.1 vs 3.7 vs 2.2, p = 0.002). Significantly less number of patients required surgery in Group III (29 vs 19 vs 9, p = 0.003). Mean duration of hospital stay (47 vs 47 vs 29, p = 0.000) and duration of PCD/drain (66 vs 45 vs 29, p = 0.000) was significantly less in Group III. There was no significant difference in the mortality rate between the three groups (18 vs 14 vs 18, p = 0.3) despite increasing severity of disease. Conclusion This is first study of its kind to analyze the impact of learnng curve on the outcome of Step up approach in the management of SAP. This study demonstrates that with increasing experience, sicker patients can be managed successfully with fewer PCD procedures, lesser need of surgery, shorter hospital stay and shorter duration of drainage without any significant change in the mortality rate.
1036
Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in the United States and has a very poor survival rate due to late diagnosis. MUC13 is a recently identified high molecular weight glycoprotein that is upregulated in PDAC and its progression is allowed via alterations of multiple signaling pathways. MUC13 is aberrantly expressed in PDAC and generally correlates with increased expression of HER2, however, the underlying mechanism remains poorly understood. MUC13 consists of three EGF-like domains that may serve as a ligand for EGF receptors, such as HER2, and modulate EGFR signaling pathways. We sought to better characterize the interaction of MUC13 with HER2 in PDAC. Methods: MUC13 and HER2 interaction was studied using reciprocal coimmunoprecipitation, immunofluorescence, proximity ligation, Western blotting, co-capping assays in human PDAC cell lines and immunohistofluorescence techniques in human tissues. Tissue microarrays prepared from formalin-fixed, paraffin-embedded specimens of PDAC were assessed for expression of MUC13 and HER2 using our own laboratory generated antiMUC13 mouse monoclonal antibody (MAb) through confocal immunofluorescence. The association of MUC13 and HER2 co-localization with nuclear chromatin organization was analyzed to study the stage or degree of aggressiveness of the pancreatic cancer using Dapi stained confocal images of tissues. Results: MUC13 co-localizes and interacts with HER2 in PDAC cell lines. The results from this study demonstrate that MUC13 functionally interacts and activates HER2 at Tyrp1248 in PDAC cells, leading to stimulation of HER2 signaling cascade including, ERK1/2, FAK, AKT and PAK1 as well as regulation of the growth, cytoskeleton remodeling, motility and invasion of PDAC cells - all collectively contributing to PDAC progression. The interaction between MUC13-HER2 binding resulting in their tumorigenic characteristics likely occurs at the 1st and 2nd but not the 3rd domains of MUC13 as the EGF 1 and 2 deletion mutant constructs of MUC13 failed to promote proliferation and invasion of cells. These phenotypic effects of MUC13-HER2 co-localization could be effectively compromised by depleting MUC13. MUC13-HER2 co-localization also held true in PDAC human tissues with a strong functional correlation that contributed to an increased degree of disorder and cancer aggressiveness. Conclusions: 1) MUC13 can be detected in formalin-fixed paraffin-embedded tissues using our anti-MUC13 MAb. 2) MUC13 co-localizes and activates HER2 and its downstream signaling cascade promoting PDAC progression in both cell lines and human tissue. 3) This process is reversed by depletion of MUC13. 4) This MUC13-HER2 interaction may potentially be manipulated for targeted therapeutics in patients harboring PDAC.
Figure. Hazard ratio of lymph node retrieval on survival for node-negative patients undergoing pancreaticoduodenectomy for adenocarcinoma (n=11,318).
Su1147 TJ-14 (Hangeshashinto) Impedes the Development of Reflux-Induced Esophageal Cancer in a Surgical Rat Model Tomoharu Miyashita, Daisuke Matsui, Ryohei Takei, Ali K. Ahmed, John W. Harmon, Sachio Fushida, Tetsuo Ohta Background: Hangeshashinto (TJ-14), a Japanese Kampo medicine, has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2 (PGE2). TJ-14 has also been shown to affect cyclooxygenase activity. M2 phenotype macrophages contribute to tumor development in the immunosuppressive microenvironment. Therefore, targeting the immunosuppressive network in tumor tissues, by inhibiting PGE2, may provide an effective preventive strategy. We evaluated the effectiveness of TJ-14 as a chemoprevention agent in a surgical rat reflux model of esophageal cancer. Methods: The rat reflux model was created by performing an end-to-side esophagojejunostomy on Sprague Dawley rats. The surgery promoted the reflux of gastro-duodenal contents into the esophagus. The rats were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow, containing TJ-14 (TJ14 group). All surviving animals were sacrificed 40 weeks after surgery and their esophagi were examined. The primary antibody against CD163(M2; AbD Serotec) was used for immunohistochemistry. Results: Twenty two rats survived 40 weeks post-surgery and were included in the study. Of these, 12 were included in the control group (Figure 1a), and the remaining 10 received TJ-14 administration (Figure 1b). 67% (8/12) of the controls developed esophageal cancer (Figure 1c), but animals that received TJ-14 had a cancer incidence of 10% (1/10) (p=0.007, Chi-squared) (Table 1). Barrett's metaplasia (Figure 1d) was found in 83% (10/12) of the rats in the control group. However, only 50% (5/10) of the rats in the TJ-14 group displayed signs of Barrett's metaplasia, indicating a protective
S-1203
X : 10052$CH03 03-28-16 22:41:04 PDFd : 10052B : o
Page 1203
SSAT Abstracts
SSAT Abstracts
MUC13 Interaction With Receptor Tyrosine Kinase HER2 Drives Pancreatic Ductal Adenocarcinoma Progression Sheema Khan, Stephen W. Behrman, Nadeem Zafar, Meena Jaggi, Subhash C. Chauhan
1037 Increased Pancreatic Cancer Survival with Greater Lymph Node Retrieval in the National Cancer Data Base Carlo M. Contreras, Chee P. Lin, Robert Oster, Sushanth M. Reddy, Thomas N. Wang, Selwyn M. Vickers, Martin M. Heslin Introduction: Robust lymph node (LN) retrieval during resection has been associated with increased survival in the setting of various gastrointestinal malignancies. The purpose of this study is to evaluate the role of LN retrieval in patients undergoing pancreaticoduodenectomy (PD) for pancreatic cancer. Methods: The National Cancer Data Base was utilized which captures tumor, patient, and facility data from academic and community medical centers. Cox regression models were used to assess bivariate & multivariate predictors of time to death, and logistic regression models were used to assess bivariate & multivariate predictors of mortality. Group mean comparisons were performed using the two-group ttest. Results: 30,180 patients with pancreatic adenocarcinoma underwent PD between the years 1998-2011 from 1,268 institutions; 62% (18,862/30,180) had LN metastasis. The mean number of LN retrieved in LN(-) patients was 10.7 vs 14.4 for LN(+) patients (p<0.0001). Patients with <10 LN retrieved had a mean of 1.1 vs 2.8 positive LN for patients with >10 LN retrieved (p<0.0001). Clinically irrelevant differences in the number of LN retrieved were observed related to PD with/without antrectomy, or receipt of neoadjuvant therapy. There were minor associations between pathologic margin status, postoperative days until hospital discharge, or 30-day readmission rate and the number of LN retrieved. The median survival of LN(-) patients exceeded that of LN(+) patients (24.9 vs 15.2 months, p<0.0001). Increasing LN retrieval is a multivariate predictor of survival in all patients, and in node-negative patients. The mean number of LN retrieved at academic centers is greater than at non-academic centers (14 vs 11.5, p<0.0001). The relationship of increased LN retrieval and enhanced survival is a nearly linear trend (see Figure). Conclusions: Greater LN retrieval is associated with increased survival in patients with pancreatic cancer, even in the node-negative subset. Increased nodal retrieval does not correlate with a significant increase in morbidity. Rather than demonstrating an inflection point that defines the extent of adequate lymphadenectomy, this dataset demonstrates an incremental relationship between LN retrieval and survival.
1035 Learning Curve Effect on ‘Step Up Approach' for Management of Severe Acute Pancreatitis Rajesh Gupta, Rahul Gupta, Sunil Shenvi, Raghavendra B. Yelakanti, Rohit K. Nimje, Abhishek Chandna, Surinder S. Rana, Mandeep Kang, Rajinder Singh, Deepak K. Bhasin Background This study was conducted to see if there is learning curve effect on outcome of ‘Step up approach' in a single surgical Unit in a tertiary care centre. Methods Patients of SAP referred to Division of Surgical Gastroenterology from April 2008 to October 2015 were distributed into 3 time periods: Group 1 - April 2008 to August 2011, Group II September 2011 to September 2014 and Group III -October 2014 to October 2015. The three groups were compared for learning curve effect. Results There were total of 170 patients in this period. There were 60 patients each in Group I and II and 50 in Group III. When compared to group I and II, patients in Group III had higher APACHE II score at first intervention (8.28 vs 9.32 vs 9.82, p = 0.073), significantly higher modified CTSI score (8.7 vs 9.1 vs 9.6, p = 0.003), signifiantly more patients with complete necrosis (9 vs 20 vs 20, p = 0.009) and extrapancreatic necrosis (22 vs 39 vs 44, p = 0.000). Microbial spectrum also changed during this period with Escherichia coli being the most common organism in Group I and II (39 vs 33 vs 17, p = 0.004) while Klebsiella pneumoniae was the most common organism in Group III (8 vs 15 vs 18, p = 0.021). Number of PCD procedures performed per patient were highest in Group I and progressive reduction in number of procedures was observed over time (5.1 vs 3.7 vs 2.2, p = 0.002). Significantly less number of patients required surgery in Group III (29 vs 19 vs 9, p = 0.003). Mean duration of hospital stay (47 vs 47 vs 29, p = 0.000) and duration of PCD/drain (66 vs 45 vs 29, p = 0.000) was significantly less in Group III. There was no significant difference in the mortality rate between the three groups (18 vs 14 vs 18, p = 0.3) despite increasing severity of disease. Conclusion This is first study of its kind to analyze the impact of learnng curve on the outcome of Step up approach in the management of SAP. This study demonstrates that with increasing experience, sicker patients can be managed successfully with fewer PCD procedures, lesser need of surgery, shorter hospital stay and shorter duration of drainage without any significant change in the mortality rate.
1036
Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in the United States and has a very poor survival rate due to late diagnosis. MUC13 is a recently identified high molecular weight glycoprotein that is upregulated in PDAC and its progression is allowed via alterations of multiple signaling pathways. MUC13 is aberrantly expressed in PDAC and generally correlates with increased expression of HER2, however, the underlying mechanism remains poorly understood. MUC13 consists of three EGF-like domains that may serve as a ligand for EGF receptors, such as HER2, and modulate EGFR signaling pathways. We sought to better characterize the interaction of MUC13 with HER2 in PDAC. Methods: MUC13 and HER2 interaction was studied using reciprocal coimmunoprecipitation, immunofluorescence, proximity ligation, Western blotting, co-capping assays in human PDAC cell lines and immunohistofluorescence techniques in human tissues. Tissue microarrays prepared from formalin-fixed, paraffin-embedded specimens of PDAC were assessed for expression of MUC13 and HER2 using our own laboratory generated antiMUC13 mouse monoclonal antibody (MAb) through confocal immunofluorescence. The association of MUC13 and HER2 co-localization with nuclear chromatin organization was analyzed to study the stage or degree of aggressiveness of the pancreatic cancer using Dapi stained confocal images of tissues. Results: MUC13 co-localizes and interacts with HER2 in PDAC cell lines. The results from this study demonstrate that MUC13 functionally interacts and activates HER2 at Tyrp1248 in PDAC cells, leading to stimulation of HER2 signaling cascade including, ERK1/2, FAK, AKT and PAK1 as well as regulation of the growth, cytoskeleton remodeling, motility and invasion of PDAC cells - all collectively contributing to PDAC progression. The interaction between MUC13-HER2 binding resulting in their tumorigenic characteristics likely occurs at the 1st and 2nd but not the 3rd domains of MUC13 as the EGF 1 and 2 deletion mutant constructs of MUC13 failed to promote proliferation and invasion of cells. These phenotypic effects of MUC13-HER2 co-localization could be effectively compromised by depleting MUC13. MUC13-HER2 co-localization also held true in PDAC human tissues with a strong functional correlation that contributed to an increased degree of disorder and cancer aggressiveness. Conclusions: 1) MUC13 can be detected in formalin-fixed paraffin-embedded tissues using our anti-MUC13 MAb. 2) MUC13 co-localizes and activates HER2 and its downstream signaling cascade promoting PDAC progression in both cell lines and human tissue. 3) This process is reversed by depletion of MUC13. 4) This MUC13-HER2 interaction may potentially be manipulated for targeted therapeutics in patients harboring PDAC.
Figure. Hazard ratio of lymph node retrieval on survival for node-negative patients undergoing pancreaticoduodenectomy for adenocarcinoma (n=11,318).
Su1147 TJ-14 (Hangeshashinto) Impedes the Development of Reflux-Induced Esophageal Cancer in a Surgical Rat Model Tomoharu Miyashita, Daisuke Matsui, Ryohei Takei, Ali K. Ahmed, John W. Harmon, Sachio Fushida, Tetsuo Ohta Background: Hangeshashinto (TJ-14), a Japanese Kampo medicine, has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2 (PGE2). TJ-14 has also been shown to affect cyclooxygenase activity. M2 phenotype macrophages contribute to tumor development in the immunosuppressive microenvironment. Therefore, targeting the immunosuppressive network in tumor tissues, by inhibiting PGE2, may provide an effective preventive strategy. We evaluated the effectiveness of TJ-14 as a chemoprevention agent in a surgical rat reflux model of esophageal cancer. Methods: The rat reflux model was created by performing an end-to-side esophagojejunostomy on Sprague Dawley rats. The surgery promoted the reflux of gastro-duodenal contents into the esophagus. The rats were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow, containing TJ-14 (TJ14 group). All surviving animals were sacrificed 40 weeks after surgery and their esophagi were examined. The primary antibody against CD163(M2; AbD Serotec) was used for immunohistochemistry. Results: Twenty two rats survived 40 weeks post-surgery and were included in the study. Of these, 12 were included in the control group (Figure 1a), and the remaining 10 received TJ-14 administration (Figure 1b). 67% (8/12) of the controls developed esophageal cancer (Figure 1c), but animals that received TJ-14 had a cancer incidence of 10% (1/10) (p=0.007, Chi-squared) (Table 1). Barrett's metaplasia (Figure 1d) was found in 83% (10/12) of the rats in the control group. However, only 50% (5/10) of the rats in the TJ-14 group displayed signs of Barrett's metaplasia, indicating a protective
S-1203
X : 10052$CH03 03-28-16 22:41:04 PDFd : 10052B : o
Page 1203
SSAT Abstracts
SSAT Abstracts
MUC13 Interaction With Receptor Tyrosine Kinase HER2 Drives Pancreatic Ductal Adenocarcinoma Progression Sheema Khan, Stephen W. Behrman, Nadeem Zafar, Meena Jaggi, Subhash C. Chauhan