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Enhancing Immunotherapy by Epigenetic Silencing of Histone and DNA Methylation in Pancreatic Cancer
697 SUCCESSFUL MANAGEMENT OF COMPLETE ESOPHAGOGASTRIC ANASTOMOTIC DISRUPTION USING COMBINED ENDOLUMINAL VACUUM THERAPY Jeffrey R. Watkins, Alexander S. Farivar, Eric Vallieres, Ralph W. Aye, Brian E. Louie Esophagogastric anastomotic leak is one of the most feared complications of esopaphagectomy. Treatment ranges from non-operative conservative management for small leaks to emergent surgical intervention with diverting esophagostomy for near-total disruptions. Endoluminal vacuum assisted closure (EVAC) has been described in the management of esophageal leaks, though very little exists concerning its use in complete anastomotic discontinuity. We present a patient who underwent esophagectomy and cervical esophagogastric anastamosis. The patient experienced total disruption of the cervical anastamosis and mediastinal abscess cavity with successful non-operative EVAC therapy.
698 TRANSGASTRIC LAPAROSCOPIC RESECTION OF A STOMACH MASS AT THE GASTRO-ESOPHAGEAL JUNCTION Spyridon Pagkratis, Bradley Hall, Priscila R. Armijo, Dmitry Oleynikov We present the case of a 61 yo female diagnosed with a mass at the posterior GastroEsophageal Junction treated with transgastric laparoscopic resection. Pre-operative work up suggested a mass of mesenchymal origin so negative margin resection without lymph node dissection was deemed adequate. Three 5 mm trocars were placed through the abdominal wall in the stomach and the mass was resected with the underlying stomach wall in a full thickness fashion. The defect was closed with intra-gastric suturing. The mass was removed through a small incision at the anterior stomach wall that was subsequently stapled. The patient tolerated the procedure well and was discharged on POD 2 on soft diet.
699 LAPAROSCOPIC TRANSGASTRIC POLYPECTOMY Sarah Meade, Desmond H. Birkett, Thomas Schnelldorfer In this video, we present a novel approach to the management of a large gastric polyp at the GE junction. This 66 year old, morbidly obese, female had been followed for nearly ten years at an outside institution with serial endoscopies for a polypoid mass at the GE junction. A recent biopsy was concerning for dysplastic changes and the gastroenterologist deemed the lesion unresectable by endoscopic means due to the size and proximity to the GE junction. We elected to pursue a laparoscopic transgastric polypectomy. This video shows the techniques used in this procedure and highlights the use of a ultrasonic scalpel to facilitate dissection and manage large feeding vessels to the mass.
LYMPH NODE STAGING IN PATIENTS UNDERGOING HEPATECTOMY FOR INTRAHEPATIC CHOLANGIOCARCINOMA: AN INTERNATIONAL MULTICENTRIC ANALYSIS Fabio Bagante, Gaya Spolverato, Matthew J. Weiss, Sorin Alexandrescu, Luca Aldrighetti, Shishir Maithel, Carlo Pulitano, Todd W. Bauer, Feng Shen, George A. Poultsides, Oliver Soubrane, Guillaume Martel, B. Groot Koerkamp, Alfredo Guglielmi, Endu Itaru, Timothy M. Pawlik
810 ENHANCING IMMUNOTHERAPY BY EPIGENETIC SILENCING OF HISTONE AND DNA METHYLATION IN PANCREATIC CANCER Young K. Hong, Harshul Pandit, Neil Bhutiani, Suping Li, Yan Li, Robert C. Martin Background:Polycomb Repressor Complex 2(PRC2), a mediator of stem cell pluripotency, contributes to initiation and progression of pancreatic cancer by epigenetic silencing of tumor suppressor genes and inhibits immunomodulation of T cell migration into tumor. Enhancer of Zeste Homolog 2 (EZH2), the catalytic component of the PRC2, in addition to DNA methyltransferase (DNMT) can be targeted to reverse the transcriptionally repressive hypermethylation at the chromatin and DNA promoter level. Therefore, we aim to demonstrate that clinically available epigenetic therapy can be used on pancreatic cancer to inhibit cell growth, upregulate tumor suppressors, and induce helper T cell (Th1) chemokine expression as a feasible and therapeutic adjunct to augment immunotherapy. Methods: Multiple Panc1 and S2-013 pancreatic adenocarcinoma cell lines were treated with 3Deazaneplanocin A (DZNep) 5uM (EZH2 inhibitor), and 5-Azacytidine (5-AZA) 5uM (DNA methyltransferase inhibitor) in various time trials (24-48HR) followed by IFN-y 10ng/ml exposure. Cell count assay, quantitative RT-PCR (qRT-PCR), immunohistochemistry, and immunoblot were performed to evaluate the drug effect on cell growth, tumor suppressor, and chemokine gene expression after treatment with DZNep, 5-AZA, IFN-y, and combination drug therapy. Results: Pancreatic cancer cell lines demonstrated effective inhibition of cell growth with DZNep and 5-AZA in a dose- and time dependent manner compared to untreated control (68% and 79%, respectively; p = 0.009). The qRT-PCR assay revealed a significant upregulation of immunomodulating T helper (Th1) chemokines, CXCL9 (1.65 x 103 +/231 rel. fold change; p = 0.002) and CXCL10 (4.69 x 106 +/- 1.3x106 rel. fold change; p = 0.025) after dual epigenetic drug treatment and stimulation with IFN-y (Figure 1&2). Furthermore, there was an upregulation of expression of previously transcriptionally silent tumor suppressor genes p21(29.9 +/- 0.42; p = 2.0 x 10-7), p53 (3.8 +/- 0.47; p = 0.004), and p57 (4.1 +/- 1.42; p = 0.09). Conclusion: Epigenetic therapy can be utilized in pancreatic cancer by reversing the gene inhibitory methylation marks and upregulating repressed tumor suppressor. There is a potential role of augmenting immunotherapy at the time of diagnosis in pancreatic cancer by upregulation of immunomodulating chemokines CXCL9 and CXCL10, which would enhance local and systemic response rates through migration of T lymphocyte into the tumor.
Introduction: The role of routine lymphadenectomy for intrahepatic cholangiocarcinoma (ICC) is still controversial and there is no standard approach to assessing regional nodal status. The newly released AJCC 8th edition staging system recommends a minimum number of 6 harvested lymph nodes (HLN) for adequate nodal staging. We sought to define outcome and risk of death among patients who were staged with ≥ 6 HLN vs. < 6 HLN. Materials and Methods: Patients undergoing liver surgery for ICC between 1990 and 2015 at one of 14 major hepatobiliary centers were identified. Data on clinicopathological characteristics, operative details, HLN and pathological LN status were collected and analyzed. Results: Among 1,154 patients undergoing hepatectomy for ICC, 515 (44.6%) had a lymphadenectomy. The median number of HLN was 4 (IQR, 2-8) and 217 (42.1%) patients had ≥6 HLN. On final pathology, among the 1,154 patients, 200 (17.3%) patients had metastatic lymph node (MLN) disease while 315 (27.3%) had no evidence of nodal (NLN) disease. Among the 200 patients with MLN, 110 (55.0%) patients had 1 MLN, 65 (32.5%) 2-5 MLN and 25 (12.5%) >5 MNL. The 5-year OS of patients with NLN was 44.4% (IQR, 36.9-51.6) vs. 15.2% (IQR, 8.7-23.4) for patients with MLN (HR 2.42, 95% CI 1.88-3.13; p<0.001). Among the 315 patients with NLN, HLN was associated with 5-year OS (≥6 HLN, 54.9% (IQR, 41.6-66.3) vs. <6 HLN: 39.4% (IQR, 30.6-48.1); p=0.098). In contrast, HLN did not impact 5-year OS among patients with MLN (≥6 HLN: 17.9% (IQR, 8.6-29.9) vs. <6 HLN: 12.5% (IQR, 4.7-24.2); p=0.71). Rather, the number of MLN was associate with 5-year OS (1 MLN, 22.9% (IQR, 13.2-34.1) vs. 2-5 MLN 10.5% (IQR, 5.1-3.2) vs. >5 MNL 0%; p= 0.02). Of note, among the 217 patients with ≥ 6 HLN survival of N0 patients (54.9%, IQR, 41.6-66.3) was almost 3-fold better than N1 patients (17.9%, IQR, 8.6-29.9)(HR 2.91, 95% CI 1.92-4.42; p<0.001). Conclusion: Only one-fifth of patients undergoing liver resection for ICC had adequate nodal staging according to the AJCC 8th edition staging system. While the 6 HLN cut-off value impacted prognosis of patients staged as N0, the number of MLN rather than the total HLN was associated with long-term survival among patients with N1 disease.
S-1223
SSAT Abstracts
SSAT Abstracts
812
698 TRANSGASTRIC LAPAROSCOPIC RESECTION OF A STOMACH MASS AT THE GASTRO-ESOPHAGEAL JUNCTION Spyridon Pagkratis, Bradley Hall, Priscila R. Armijo, Dmitry Oleynikov We present the case of a 61 yo female diagnosed with a mass at the posterior GastroEsophageal Junction treated with transgastric laparoscopic resection. Pre-operative work up suggested a mass of mesenchymal origin so negative margin resection without lymph node dissection was deemed adequate. Three 5 mm trocars were placed through the abdominal wall in the stomach and the mass was resected with the underlying stomach wall in a full thickness fashion. The defect was closed with intra-gastric suturing. The mass was removed through a small incision at the anterior stomach wall that was subsequently stapled. The patient tolerated the procedure well and was discharged on POD 2 on soft diet.
699 LAPAROSCOPIC TRANSGASTRIC POLYPECTOMY Sarah Meade, Desmond H. Birkett, Thomas Schnelldorfer In this video, we present a novel approach to the management of a large gastric polyp at the GE junction. This 66 year old, morbidly obese, female had been followed for nearly ten years at an outside institution with serial endoscopies for a polypoid mass at the GE junction. A recent biopsy was concerning for dysplastic changes and the gastroenterologist deemed the lesion unresectable by endoscopic means due to the size and proximity to the GE junction. We elected to pursue a laparoscopic transgastric polypectomy. This video shows the techniques used in this procedure and highlights the use of a ultrasonic scalpel to facilitate dissection and manage large feeding vessels to the mass.
LYMPH NODE STAGING IN PATIENTS UNDERGOING HEPATECTOMY FOR INTRAHEPATIC CHOLANGIOCARCINOMA: AN INTERNATIONAL MULTICENTRIC ANALYSIS Fabio Bagante, Gaya Spolverato, Matthew J. Weiss, Sorin Alexandrescu, Luca Aldrighetti, Shishir Maithel, Carlo Pulitano, Todd W. Bauer, Feng Shen, George A. Poultsides, Oliver Soubrane, Guillaume Martel, B. Groot Koerkamp, Alfredo Guglielmi, Endu Itaru, Timothy M. Pawlik
810 ENHANCING IMMUNOTHERAPY BY EPIGENETIC SILENCING OF HISTONE AND DNA METHYLATION IN PANCREATIC CANCER Young K. Hong, Harshul Pandit, Neil Bhutiani, Suping Li, Yan Li, Robert C. Martin Background:Polycomb Repressor Complex 2(PRC2), a mediator of stem cell pluripotency, contributes to initiation and progression of pancreatic cancer by epigenetic silencing of tumor suppressor genes and inhibits immunomodulation of T cell migration into tumor. Enhancer of Zeste Homolog 2 (EZH2), the catalytic component of the PRC2, in addition to DNA methyltransferase (DNMT) can be targeted to reverse the transcriptionally repressive hypermethylation at the chromatin and DNA promoter level. Therefore, we aim to demonstrate that clinically available epigenetic therapy can be used on pancreatic cancer to inhibit cell growth, upregulate tumor suppressors, and induce helper T cell (Th1) chemokine expression as a feasible and therapeutic adjunct to augment immunotherapy. Methods: Multiple Panc1 and S2-013 pancreatic adenocarcinoma cell lines were treated with 3Deazaneplanocin A (DZNep) 5uM (EZH2 inhibitor), and 5-Azacytidine (5-AZA) 5uM (DNA methyltransferase inhibitor) in various time trials (24-48HR) followed by IFN-y 10ng/ml exposure. Cell count assay, quantitative RT-PCR (qRT-PCR), immunohistochemistry, and immunoblot were performed to evaluate the drug effect on cell growth, tumor suppressor, and chemokine gene expression after treatment with DZNep, 5-AZA, IFN-y, and combination drug therapy. Results: Pancreatic cancer cell lines demonstrated effective inhibition of cell growth with DZNep and 5-AZA in a dose- and time dependent manner compared to untreated control (68% and 79%, respectively; p = 0.009). The qRT-PCR assay revealed a significant upregulation of immunomodulating T helper (Th1) chemokines, CXCL9 (1.65 x 103 +/231 rel. fold change; p = 0.002) and CXCL10 (4.69 x 106 +/- 1.3x106 rel. fold change; p = 0.025) after dual epigenetic drug treatment and stimulation with IFN-y (Figure 1&2). Furthermore, there was an upregulation of expression of previously transcriptionally silent tumor suppressor genes p21(29.9 +/- 0.42; p = 2.0 x 10-7), p53 (3.8 +/- 0.47; p = 0.004), and p57 (4.1 +/- 1.42; p = 0.09). Conclusion: Epigenetic therapy can be utilized in pancreatic cancer by reversing the gene inhibitory methylation marks and upregulating repressed tumor suppressor. There is a potential role of augmenting immunotherapy at the time of diagnosis in pancreatic cancer by upregulation of immunomodulating chemokines CXCL9 and CXCL10, which would enhance local and systemic response rates through migration of T lymphocyte into the tumor.
Introduction: The role of routine lymphadenectomy for intrahepatic cholangiocarcinoma (ICC) is still controversial and there is no standard approach to assessing regional nodal status. The newly released AJCC 8th edition staging system recommends a minimum number of 6 harvested lymph nodes (HLN) for adequate nodal staging. We sought to define outcome and risk of death among patients who were staged with ≥ 6 HLN vs. < 6 HLN. Materials and Methods: Patients undergoing liver surgery for ICC between 1990 and 2015 at one of 14 major hepatobiliary centers were identified. Data on clinicopathological characteristics, operative details, HLN and pathological LN status were collected and analyzed. Results: Among 1,154 patients undergoing hepatectomy for ICC, 515 (44.6%) had a lymphadenectomy. The median number of HLN was 4 (IQR, 2-8) and 217 (42.1%) patients had ≥6 HLN. On final pathology, among the 1,154 patients, 200 (17.3%) patients had metastatic lymph node (MLN) disease while 315 (27.3%) had no evidence of nodal (NLN) disease. Among the 200 patients with MLN, 110 (55.0%) patients had 1 MLN, 65 (32.5%) 2-5 MLN and 25 (12.5%) >5 MNL. The 5-year OS of patients with NLN was 44.4% (IQR, 36.9-51.6) vs. 15.2% (IQR, 8.7-23.4) for patients with MLN (HR 2.42, 95% CI 1.88-3.13; p<0.001). Among the 315 patients with NLN, HLN was associated with 5-year OS (≥6 HLN, 54.9% (IQR, 41.6-66.3) vs. <6 HLN: 39.4% (IQR, 30.6-48.1); p=0.098). In contrast, HLN did not impact 5-year OS among patients with MLN (≥6 HLN: 17.9% (IQR, 8.6-29.9) vs. <6 HLN: 12.5% (IQR, 4.7-24.2); p=0.71). Rather, the number of MLN was associate with 5-year OS (1 MLN, 22.9% (IQR, 13.2-34.1) vs. 2-5 MLN 10.5% (IQR, 5.1-3.2) vs. >5 MNL 0%; p= 0.02). Of note, among the 217 patients with ≥ 6 HLN survival of N0 patients (54.9%, IQR, 41.6-66.3) was almost 3-fold better than N1 patients (17.9%, IQR, 8.6-29.9)(HR 2.91, 95% CI 1.92-4.42; p<0.001). Conclusion: Only one-fifth of patients undergoing liver resection for ICC had adequate nodal staging according to the AJCC 8th edition staging system. While the 6 HLN cut-off value impacted prognosis of patients staged as N0, the number of MLN rather than the total HLN was associated with long-term survival among patients with N1 disease.
S-1223
SSAT Abstracts
SSAT Abstracts
812