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Blockade of REG Proteins’ Receptor EXTL3 Sensitizes Human Pancreatic Cancer Cells to Gemcitabine in a Mouse Orthotopic Model
S130
Scientific Forum Abstracts
J Am Coll Surg
coverage for patients undergoing pancreatoduodenectomy. The additional impact of neoadjuvant therapy on biliary bacteriology has not been investigated. METHODS: A retrospective review from 2010 to 2015 was performed using an institutional registry to identify patients who underwent pancreatoduodenectomy alone (PD) or after neoadjuvant therapy (NT). Demographics, intraoperative biliary cultures, infectious complications, and pancreatic fistulas were analyzed. Chi-square and Student’s t-tests were performed. RESULTS: Twenty-five patients had PD alone and 34 patients had NT. Sixty-eight percent (17) of PD patients had positive intraoperative bile cultures compared to 85% (29) of NT patients (p ¼ 0.11). NT patients had more Klebsiella (62 vs 32%, p<0.05) and Enterococcus (65 vs 40%, p ¼ 0.06) compared to the PD patients. Six PD patients and 4 NT patients had multidrug resistant bacteria. Of patients with bactobilia, 88% and 93% were resistant to cephalosporins in PD and NT patients, respectively. Eight PD patients and 10 NT patients had a postoperative surgical site infection. Clinically relevant pancreatic fistulas (Grades B and C) were more common in PD patients (12% vs 3%, p ¼ 0.17). CONCLUSIONS: The biliary microbiome is altered in patients undergoing pancreatoduodenectomy (PD) who receive neoadjuvant therapy. The majority of PD patients with biliary stents have microorganisms that are resistant to cephalosporins. Broader antibiotic prophylaxis is warranted in these patients.
Association Between the (GT)n Polymorphism of the Heat Shock Proteins (HSP)-32 (HO-1), HSP-70, and HSP-90 Promoter Region Polymorphism and Acute Pancreatitis Aiste Gulla, MD, Tieqiang Hu, MD, Antanas Gulbinas, MD, PhD, Zilvinas Dambrauskas, MD, PhD Thomas Jefferson University Hospital, Philadelphia, PA; Lithuanian University of Health Sciences, Kaunas, Lithuania; Vilnius University Hospital, Santariskiu Clinics, Vilnius, Lithuania WITHDRAWN
Blockade of REG Proteins’ Receptor EXTL3 Sensitizes Human Pancreatic Cancer Cells to Gemcitabine in a Mouse Orthotopic Model Kaylene Barrera, MD, Albert Stanek, MD, Zuzia Niewiadomska, Peiqi Ou, Cathy M Mueller, Michael Weber, Devon G John, MD, Antonio E Alfonso, MD, FACS, Chongmin Huan, MD, PhD State University of New York, Downstate, Brooklyn, NY INTRODUCTION: Pancreatic cancer remains a leading cause of cancer mortality. Gemcitabine, a major component of therapy, has limited benefits due to chemoresistance. We previously reported the role of REG/EXTL3-mediated pro-survival signaling in gemcitabine resistance based on our observations of gemcitabine-induced EXTL3 expression and REG1-promoted survival via enhanced AKT activation in cultured pancreatic cancer cells. Others have also reported upregulated REG levels in pancreatic cancer patients. Here, we investigate whether blocking EXTL3 can reduce gemcitabine resistance in a mouse orthotopic model of human pancreatic cancer. METHODS: Nine immunodeficient Rag1-/- mice were implanted with 1 million GFP-expressing Mia-Paca-2 cells in their pancreatic tails 2 weeks prior to receiving gemcitabine (50 mg/kg intraperitoneal, twice weekly) with either an EXTL3 blocking antibody or a control IgG (4 mg/kg IV, weekly) for 2 weeks. One week after treatment, tissues were collected for histologic and biochemical analysis of tumor growth and cellular apoptosis. RESULTS: The average growth of the implanted cancers, calculated by comparing the sizes of GFP-expressing areas measured 1 week before and after the treatment, was reduced up to 10fold by EXTL3 blockade, although the difference was not statistically significant (p ¼ 0.083) due to the small sample size. Furthermore, hematoxylin and eosin and immunohistochemical staining and Western blot analysis of the cancer tissues showed more apoptotic bodies and cleaved caspase 3 in the EXTL3 blocked samples. CONCLUSIONS: Blockade of EXTL3 appears to reduce gemcitabine resistance in implanted pancreatic cancers in this pilot study. Ongoing extensive animal studies in the lab could more accurately predict the effectiveness of this potential therapeutic strategy.
Scientific Forum Abstracts
J Am Coll Surg
coverage for patients undergoing pancreatoduodenectomy. The additional impact of neoadjuvant therapy on biliary bacteriology has not been investigated. METHODS: A retrospective review from 2010 to 2015 was performed using an institutional registry to identify patients who underwent pancreatoduodenectomy alone (PD) or after neoadjuvant therapy (NT). Demographics, intraoperative biliary cultures, infectious complications, and pancreatic fistulas were analyzed. Chi-square and Student’s t-tests were performed. RESULTS: Twenty-five patients had PD alone and 34 patients had NT. Sixty-eight percent (17) of PD patients had positive intraoperative bile cultures compared to 85% (29) of NT patients (p ¼ 0.11). NT patients had more Klebsiella (62 vs 32%, p<0.05) and Enterococcus (65 vs 40%, p ¼ 0.06) compared to the PD patients. Six PD patients and 4 NT patients had multidrug resistant bacteria. Of patients with bactobilia, 88% and 93% were resistant to cephalosporins in PD and NT patients, respectively. Eight PD patients and 10 NT patients had a postoperative surgical site infection. Clinically relevant pancreatic fistulas (Grades B and C) were more common in PD patients (12% vs 3%, p ¼ 0.17). CONCLUSIONS: The biliary microbiome is altered in patients undergoing pancreatoduodenectomy (PD) who receive neoadjuvant therapy. The majority of PD patients with biliary stents have microorganisms that are resistant to cephalosporins. Broader antibiotic prophylaxis is warranted in these patients.
Association Between the (GT)n Polymorphism of the Heat Shock Proteins (HSP)-32 (HO-1), HSP-70, and HSP-90 Promoter Region Polymorphism and Acute Pancreatitis Aiste Gulla, MD, Tieqiang Hu, MD, Antanas Gulbinas, MD, PhD, Zilvinas Dambrauskas, MD, PhD Thomas Jefferson University Hospital, Philadelphia, PA; Lithuanian University of Health Sciences, Kaunas, Lithuania; Vilnius University Hospital, Santariskiu Clinics, Vilnius, Lithuania WITHDRAWN
Blockade of REG Proteins’ Receptor EXTL3 Sensitizes Human Pancreatic Cancer Cells to Gemcitabine in a Mouse Orthotopic Model Kaylene Barrera, MD, Albert Stanek, MD, Zuzia Niewiadomska, Peiqi Ou, Cathy M Mueller, Michael Weber, Devon G John, MD, Antonio E Alfonso, MD, FACS, Chongmin Huan, MD, PhD State University of New York, Downstate, Brooklyn, NY INTRODUCTION: Pancreatic cancer remains a leading cause of cancer mortality. Gemcitabine, a major component of therapy, has limited benefits due to chemoresistance. We previously reported the role of REG/EXTL3-mediated pro-survival signaling in gemcitabine resistance based on our observations of gemcitabine-induced EXTL3 expression and REG1-promoted survival via enhanced AKT activation in cultured pancreatic cancer cells. Others have also reported upregulated REG levels in pancreatic cancer patients. Here, we investigate whether blocking EXTL3 can reduce gemcitabine resistance in a mouse orthotopic model of human pancreatic cancer. METHODS: Nine immunodeficient Rag1-/- mice were implanted with 1 million GFP-expressing Mia-Paca-2 cells in their pancreatic tails 2 weeks prior to receiving gemcitabine (50 mg/kg intraperitoneal, twice weekly) with either an EXTL3 blocking antibody or a control IgG (4 mg/kg IV, weekly) for 2 weeks. One week after treatment, tissues were collected for histologic and biochemical analysis of tumor growth and cellular apoptosis. RESULTS: The average growth of the implanted cancers, calculated by comparing the sizes of GFP-expressing areas measured 1 week before and after the treatment, was reduced up to 10fold by EXTL3 blockade, although the difference was not statistically significant (p ¼ 0.083) due to the small sample size. Furthermore, hematoxylin and eosin and immunohistochemical staining and Western blot analysis of the cancer tissues showed more apoptotic bodies and cleaved caspase 3 in the EXTL3 blocked samples. CONCLUSIONS: Blockade of EXTL3 appears to reduce gemcitabine resistance in implanted pancreatic cancers in this pilot study. Ongoing extensive animal studies in the lab could more accurately predict the effectiveness of this potential therapeutic strategy.