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Tu1917 Systemic Injection of Fiber-Redesigned Oncolytic Adenovirus Eliminates Pancreatic Cancer Tumor Xenografts
AGA Abstracts
Tu1915
Tu1917
Suppression of the mTOR/PI3K Pathway Promotes ERK Pathway Activation in Human Pancreatic Cancer Cells Heloisa P. Soares, Ming Ming, Michelle Mellon, James Sinnett-Smith, Enrique Rozengurt
Systemic Injection of Fiber-Redesigned Oncolytic Adenovirus Eliminates Pancreatic Cancer Tumor Xenografts Yoshiaki Miura, Mizuho Sato, Julia Davydova, Masato Yamamoto
Background: The phosphatidylinositol 3-kinase (PI3K)/Akt/mTORC1/S6K pathway plays a pivotal role in the proliferation and survival of pancreatic ductal adenocarcinoma (PDAC) cells and is aberrantly activated in pancreatic cancer tissues. In addition to growth-promoting signaling, mTORC1/S6K also mediates negative feedback loops that restrain upstream signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feedback loops by selective mTORC1 inhibitors, e.g. by rapamycin and its analogs, unleashes overactivation of the PI3K/Akt pathway that potentially oppose the anti-proliferative effects of mTOR inhibitors. This prompted the development of active-site mTORC1/2 kinase inhibitors (TOR-KIs) and dual PI3K and mTOR inhibitors (PI3K/TOR-KIs). Recently, we reported that TOR-KIs induce an unexpected increase in the activity of the ERK pathway in PDAC cells through a PI3K-independent pathway. Here, we examined whether PI3K/TOR-KIs also induce ERK pathway over-activation in PDAC cells. Results: To determine the effect of dual PI3K/TOR inhibition on ERK activation, we treated serum-starved cultures of PDAC cells (MiaPaca-2 and PANC-1) with increasing concentrations of the dual PI3K/TOR-KI NPVBEZ235 for 2 h followed by stimulation with insulin and neurotensin, a potent mitogenic combination for these cells. As expected, prior exposure to NPV-BEZ235 potently blocked mTORC1 activation (scored by S6 phosphorylation at Ser-240/244) and mTORC2-mediated Akt phosphorylation at Ser-473, in a concentration-dependent manner. Strikingly, we also demonstrate, for the first time that exposure to NPV-BEZ235 markedly enhanced the increase in the phosphorylation of ERK at Thr-202 and Tyr-204. Maximal ERK over-activation coincided with complete inhibition of Akt phosphorylation at Ser-473 (produced at 100500 ηM NPV-BEZ235). ERK over-activation was also seen when PDAC cells were stimulated with 2% fetal bovine serum instead of insulin and neurotensin and when a different PI3K/ TOR-KI (PKI-587) was used instead of NPV-BEZ235. Treatment with the MEK inhibitors U126 or PD0325901 (1-5 μM) prevented ERK over-activation induced by PI3K/TOR-KIs. In order to examine whether the over-activation of the ERK pathway counterbalances the growth-suppressive effect of PI3K/TOR-KIs, PDAC cells were treated with NPV-BEZ235, PD0325901 or a combination of NPV-BEZ235 and PD0325901. The combination of these drugs caused a more pronounced inhibition of cell growth than that produced by each inhibitor added individually. Conclusion: Collectively, our results highlight the importance of discovering novel signaling crosstalk to anticipate mechanisms of tumor resistance to new drugs. The capability of predicting drug resistance can assist in developing rational and effective strategies for developing combination therapies in PDAC.
Pancreatic cancer is an aggressive malignant disease. Despite extensive efforts, systemic therapies have provided only limited efficacy for patients with this disease to date. Adenovirus (Ad) is one of potent oncolytic therapeutic agents for pancreatic cancer, and it is also known for its efficient in vivo gene delivery. However, the low tumor distribution of intravenously injected agents is one of major obstacle for systemic therapy. The better tumor distribution and transduction could overcome the barriers for systemic delivery and enable efficient treatment of spread and/or metastatic lesions of pancreatic cancer. AdML-VTIN was identified as a mesothelin (MSLN) targeted Ad by high-throughput screening of high-diversity (109level) 7 amino acid random peptide targeting motif library placed in the AB-loop of Ad fiber. This AB-loop re-designed Ad represented a potent and selective infectivity to MSLNpositive pancreatic cancer (Panc-1) in vitro. In the examination of in vivo selectivity and anti-tumor effect, the intra-tumor injection of AdML-VTIN showed significant anti-tumor effect against Panc-1 tumors, and about half of the tumor disappeared. Contrarily, the same virus showed no anti-tumor effect in MiaPaCa-2 (MSLN-negative). Viral DNA quantitation supported the selective viral replication only in Panc-1. We compared organ distribution after intravenous injection to the nude mice with subcutaneous Panc-1 xenograft among AdML-VTIN, AdML-5WT (wild type Ad5 fiber), and AdML-GERS (against PC-3, prostate cancer cell). The liver sequestration of both AB-loop redesigned Ads were more than one order of magnitude lower than that with AdML-5WT at 1 hr and 48 hrs after injection. At day 7, the viral copy number of AdML-VTIN in the tumor was more than 3 orders of magnitude higher that those with AdML-5WT. Next, systemic therapeutic effect was examined with same condition of vector distribution. In only VTIN group, tumor volume was significantly decreased, and about one-third of the tumor was eliminated at 15 days after the injection even though viral amount was pretty low (109vp/mouse). In this study, systemic injection of the AB-loop redesigned oncolytic Ad with VTIN motif that was identified by Ad library screening showed remarkable anti-tumor effect in spite of low viral amount. This new oncolytic Ad enabling systemic therapy may embody efficient treatment for pancreatic cancers which are mostly found with spread or metastatic lesions. Tu1918 Requirement of c-Jun N-Terminal Kinase for Effective Expansion of Pancreatic Cancer in Mice Shin Maeda, Yohko Hikiba, Kosuke Sakitani, Soichiro Sue, Wataru Shibata
Tu1916
(Background) Pancreatic cancer is the fourth leading cause of death, with an overall 5-year survival rate of <5%. Thus, there is an urgent medical need to find more effective therapeutic strategies to treat pancreatic cancer. c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family, and it is reportedly involved in the development of several cancers including pancreatic cancer. We have previously shown that JNK inhibitor decreased growth of murine pancreatic cancer and prolonged survival of the mice via the cell cycle inhibition of cancer cells. However, the inhibitor is not completely specific for JNK and entire pictures of JNK function in the development of pancreatic cancer are still unknown. (Methods) KrasG12DPtf1a-cre mouse, a model of pancreatic cancer, was crossed with Jnk1-/- and examined the histopathology at 6 months. Mouse pancreatic cancer cells with wild type JNK were subcutaneously and orthologusly transplanted in wild type and Jnk1-/- mice and examined histopathology at 2 months. Mouse cancer cells were cultured with wild type and Jnk1-/- embryonic fibroblasts (MEFs) and examined the cell growth. (Results) Pancreas from KrasG12DPtf1a-cre/Jnk1-/- were significantly smaller size and weight than KrasG12DPtf1a-cre/Jnk1+/- mice or KrasG12DPtf1a-cre/Jnk1+/+. However, pathological examination showed that PanIN/acina ratio was not changed among genotypes, suggesting that the acinar-ductal metaplasia, which represents the initial stage of pancreatic cancer development, was not inhibited by JNK1 deletion. This was also confirmed in vitro acinar culture system. Subcutaneous or orthologous tumors were significantly smaller in Jnk1-/mice compared with wild type control mice, suggesting that JNK1 in tumor stroma cells rather than in tumor cells played important roles in tumor growth. αSMA-positive myofibroblasts were massively infiltrated into tumor tissues. Tumor cells grew more rapidly with wild type MEFs than with Jnk1-/- MEFs. (Conclusion) JNK inhibition may be a promising therapeutic target for pancreatic cancer by way of the inhibition not only for growth of cancer cells but also for the function of tumor stromal cells.
Berberine Potently Activates AMPK and Inhibits mTORC1, ERK and Cell Cycle Progression of Human Pancreatic Cancer Cells In Vitro and Reduces the Growth of Human Pancreatic Cancer Xenografts In Vivo Ming Ming, Jia Wang, James Sinnett-Smith, Steven H. Young, Enrique Rozengurt Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, with overall 5-year survival rate of only 3-5%. Novel therapeutic strategies are urgently required to treat this aggressive disease. Natural products represent a rich reservoir of potential small chemical molecules exhibiting anti-proliferative and chemopreventive properties. Based on our recent studies with the biguanide metformin, we hypothesize that structurally unrelated phytochemicals that inhibit mitochondrial-mediated ATP synthesis and thereby induce AMP-activated protein kinase (AMPK) activation, including berberine, block mTORC1, ERK and proliferation in vitro and act as chemopreventive agents in vivo. Results: Treatment of PDAC cells (PANC-1, MiaPaCa-2) incubated in medium containing 5 mM glucose with increasing doses of the isoquinoline alkaloid berberine (0.05-5μg/ml) decreased mitochondrial membrane potential and produced a striking dose-dependent decrease in the intracellular levels of ATP in these cells. AMPK, a conserved sensor of cellular energy, is activated when the AMP/ATP ratio increases. Accordingly, berberine induced potent AMPK activation in PANC-1 and MiaPaCa-2 cells, as shown by immunoblotting using antibodies that detect the phosphorylated state of AMPK α subunit at Thr-172 and acetyl-CoA carboxylase (ACC) at Ser-79, a specific substrate of AMPK activity within intact cells. Berberine dose-dependently inhibited mTORC1 activity (scored by S6K phosphorylation at Thr-389, a site phosphorylated by mTORC1 and S6 phosphorylation at Ser-240, a site phosphorylated by S6K), ERK activation and DNA synthesis in PDAC cells stimulated by defined growth factors (e.g. insulin and neurotensin) or fetal bovine serum. Furthermore, berberine inhibited the proliferation of these cells and blocked the progression of their cell cycle in the G1 phase, as revealed by FACS analysis. In order to test the effect of berberine in vivo, MiaPaCa-2 cells were implanted into the flanks of nu/nu mice. After the tumors reached a diameter of 2 mm, the animals were treated with daily intraperitoneal injections of 5mg/kg berberine or vehicle (n=10 for each group). Berberine treatment strikingly reduced the rate of tumor growth. The final volumes of the tumors were 824±158 and 242±38 mm3, in the control and berberinetreated groups, respectively. Conclusion: The natural alkaloid berberine inhibited human pancreatic cell growth in vitro and in vivo. The mechanism of action of berberine is consistent with the hypothesis that structurally unrelated phytochemicals that inhibit mitochondrialmediated ATP synthesis and thereby induce AMPK activation, block mTORC1, ERK and proliferation od pancreatic cancer cells. As berberine has been safely used in humans, this natural compound could be an interesting and potential new candidate for chemopreventive strategies against pancreatic cancer.
AGA Abstracts
Tu1919 Diagnostic Accuracy of Carcinoembryonic Antigen (CEA) in Cyst Fluid Analysis in Histologically Confirmed Pancreatic Cysts: Results From a Large, Multicenter Cohort Study Srinivas Gaddam, Joseph W. Keach, Phillip S. Ge, Daniel Mullady, Norio Fukami, V. Raman Muthusamy, Steven A. Edmundowicz, Riad R. Azar, Raj J. Shah, Faris Murad, Vladimir M. Kushnir, Rabindra R. Watson, Kourosh F. Ghassemi, Alireza Sedarat, Brian C. Brauer, Roy D. Yen, Stuart K. Amateau, Lindsay Hosford, Timothy Donahue, Richard D. Schulick, Barish H. Edil, Dayna S. Early, Sachin Wani Background: EUS plays an integral role in the differentiation of mucinous (MCN) and nonmucinous cystic neoplasms (NMCN) of the pancreas. This is by virtue of high resolution imaging of the morphologic characteristics and ability to sample cyst fluid for cytology and tumor markers such as CEA. The exact cut off value at which pancreatic cyst fluid CEA level distinguishes MCN from NMCN is controversial. Aims: In a large multicenter cohort of patients (pts) with pancreatic cystic lesions, to evaluate and validate the diagnostic accuracy of cyst fluid CEA levels between MCN and NMCN. Methods: This is a multicenter outcomes project of all pts undergoing EUS for evaluation of pancreatic cysts at 3 tertiary referral centers. Consecutive pts who underwent EUS +/- FNA were identified. Pts with histologic confirmation of cyst type - surgical resection and/or cancer on cytology served as the gold standard for this analysis. Demographics and EUS morphology [size, communication with
S-872
Tu1915
Tu1917
Suppression of the mTOR/PI3K Pathway Promotes ERK Pathway Activation in Human Pancreatic Cancer Cells Heloisa P. Soares, Ming Ming, Michelle Mellon, James Sinnett-Smith, Enrique Rozengurt
Systemic Injection of Fiber-Redesigned Oncolytic Adenovirus Eliminates Pancreatic Cancer Tumor Xenografts Yoshiaki Miura, Mizuho Sato, Julia Davydova, Masato Yamamoto
Background: The phosphatidylinositol 3-kinase (PI3K)/Akt/mTORC1/S6K pathway plays a pivotal role in the proliferation and survival of pancreatic ductal adenocarcinoma (PDAC) cells and is aberrantly activated in pancreatic cancer tissues. In addition to growth-promoting signaling, mTORC1/S6K also mediates negative feedback loops that restrain upstream signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feedback loops by selective mTORC1 inhibitors, e.g. by rapamycin and its analogs, unleashes overactivation of the PI3K/Akt pathway that potentially oppose the anti-proliferative effects of mTOR inhibitors. This prompted the development of active-site mTORC1/2 kinase inhibitors (TOR-KIs) and dual PI3K and mTOR inhibitors (PI3K/TOR-KIs). Recently, we reported that TOR-KIs induce an unexpected increase in the activity of the ERK pathway in PDAC cells through a PI3K-independent pathway. Here, we examined whether PI3K/TOR-KIs also induce ERK pathway over-activation in PDAC cells. Results: To determine the effect of dual PI3K/TOR inhibition on ERK activation, we treated serum-starved cultures of PDAC cells (MiaPaca-2 and PANC-1) with increasing concentrations of the dual PI3K/TOR-KI NPVBEZ235 for 2 h followed by stimulation with insulin and neurotensin, a potent mitogenic combination for these cells. As expected, prior exposure to NPV-BEZ235 potently blocked mTORC1 activation (scored by S6 phosphorylation at Ser-240/244) and mTORC2-mediated Akt phosphorylation at Ser-473, in a concentration-dependent manner. Strikingly, we also demonstrate, for the first time that exposure to NPV-BEZ235 markedly enhanced the increase in the phosphorylation of ERK at Thr-202 and Tyr-204. Maximal ERK over-activation coincided with complete inhibition of Akt phosphorylation at Ser-473 (produced at 100500 ηM NPV-BEZ235). ERK over-activation was also seen when PDAC cells were stimulated with 2% fetal bovine serum instead of insulin and neurotensin and when a different PI3K/ TOR-KI (PKI-587) was used instead of NPV-BEZ235. Treatment with the MEK inhibitors U126 or PD0325901 (1-5 μM) prevented ERK over-activation induced by PI3K/TOR-KIs. In order to examine whether the over-activation of the ERK pathway counterbalances the growth-suppressive effect of PI3K/TOR-KIs, PDAC cells were treated with NPV-BEZ235, PD0325901 or a combination of NPV-BEZ235 and PD0325901. The combination of these drugs caused a more pronounced inhibition of cell growth than that produced by each inhibitor added individually. Conclusion: Collectively, our results highlight the importance of discovering novel signaling crosstalk to anticipate mechanisms of tumor resistance to new drugs. The capability of predicting drug resistance can assist in developing rational and effective strategies for developing combination therapies in PDAC.
Pancreatic cancer is an aggressive malignant disease. Despite extensive efforts, systemic therapies have provided only limited efficacy for patients with this disease to date. Adenovirus (Ad) is one of potent oncolytic therapeutic agents for pancreatic cancer, and it is also known for its efficient in vivo gene delivery. However, the low tumor distribution of intravenously injected agents is one of major obstacle for systemic therapy. The better tumor distribution and transduction could overcome the barriers for systemic delivery and enable efficient treatment of spread and/or metastatic lesions of pancreatic cancer. AdML-VTIN was identified as a mesothelin (MSLN) targeted Ad by high-throughput screening of high-diversity (109level) 7 amino acid random peptide targeting motif library placed in the AB-loop of Ad fiber. This AB-loop re-designed Ad represented a potent and selective infectivity to MSLNpositive pancreatic cancer (Panc-1) in vitro. In the examination of in vivo selectivity and anti-tumor effect, the intra-tumor injection of AdML-VTIN showed significant anti-tumor effect against Panc-1 tumors, and about half of the tumor disappeared. Contrarily, the same virus showed no anti-tumor effect in MiaPaCa-2 (MSLN-negative). Viral DNA quantitation supported the selective viral replication only in Panc-1. We compared organ distribution after intravenous injection to the nude mice with subcutaneous Panc-1 xenograft among AdML-VTIN, AdML-5WT (wild type Ad5 fiber), and AdML-GERS (against PC-3, prostate cancer cell). The liver sequestration of both AB-loop redesigned Ads were more than one order of magnitude lower than that with AdML-5WT at 1 hr and 48 hrs after injection. At day 7, the viral copy number of AdML-VTIN in the tumor was more than 3 orders of magnitude higher that those with AdML-5WT. Next, systemic therapeutic effect was examined with same condition of vector distribution. In only VTIN group, tumor volume was significantly decreased, and about one-third of the tumor was eliminated at 15 days after the injection even though viral amount was pretty low (109vp/mouse). In this study, systemic injection of the AB-loop redesigned oncolytic Ad with VTIN motif that was identified by Ad library screening showed remarkable anti-tumor effect in spite of low viral amount. This new oncolytic Ad enabling systemic therapy may embody efficient treatment for pancreatic cancers which are mostly found with spread or metastatic lesions. Tu1918 Requirement of c-Jun N-Terminal Kinase for Effective Expansion of Pancreatic Cancer in Mice Shin Maeda, Yohko Hikiba, Kosuke Sakitani, Soichiro Sue, Wataru Shibata
Tu1916
(Background) Pancreatic cancer is the fourth leading cause of death, with an overall 5-year survival rate of <5%. Thus, there is an urgent medical need to find more effective therapeutic strategies to treat pancreatic cancer. c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family, and it is reportedly involved in the development of several cancers including pancreatic cancer. We have previously shown that JNK inhibitor decreased growth of murine pancreatic cancer and prolonged survival of the mice via the cell cycle inhibition of cancer cells. However, the inhibitor is not completely specific for JNK and entire pictures of JNK function in the development of pancreatic cancer are still unknown. (Methods) KrasG12DPtf1a-cre mouse, a model of pancreatic cancer, was crossed with Jnk1-/- and examined the histopathology at 6 months. Mouse pancreatic cancer cells with wild type JNK were subcutaneously and orthologusly transplanted in wild type and Jnk1-/- mice and examined histopathology at 2 months. Mouse cancer cells were cultured with wild type and Jnk1-/- embryonic fibroblasts (MEFs) and examined the cell growth. (Results) Pancreas from KrasG12DPtf1a-cre/Jnk1-/- were significantly smaller size and weight than KrasG12DPtf1a-cre/Jnk1+/- mice or KrasG12DPtf1a-cre/Jnk1+/+. However, pathological examination showed that PanIN/acina ratio was not changed among genotypes, suggesting that the acinar-ductal metaplasia, which represents the initial stage of pancreatic cancer development, was not inhibited by JNK1 deletion. This was also confirmed in vitro acinar culture system. Subcutaneous or orthologous tumors were significantly smaller in Jnk1-/mice compared with wild type control mice, suggesting that JNK1 in tumor stroma cells rather than in tumor cells played important roles in tumor growth. αSMA-positive myofibroblasts were massively infiltrated into tumor tissues. Tumor cells grew more rapidly with wild type MEFs than with Jnk1-/- MEFs. (Conclusion) JNK inhibition may be a promising therapeutic target for pancreatic cancer by way of the inhibition not only for growth of cancer cells but also for the function of tumor stromal cells.
Berberine Potently Activates AMPK and Inhibits mTORC1, ERK and Cell Cycle Progression of Human Pancreatic Cancer Cells In Vitro and Reduces the Growth of Human Pancreatic Cancer Xenografts In Vivo Ming Ming, Jia Wang, James Sinnett-Smith, Steven H. Young, Enrique Rozengurt Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, with overall 5-year survival rate of only 3-5%. Novel therapeutic strategies are urgently required to treat this aggressive disease. Natural products represent a rich reservoir of potential small chemical molecules exhibiting anti-proliferative and chemopreventive properties. Based on our recent studies with the biguanide metformin, we hypothesize that structurally unrelated phytochemicals that inhibit mitochondrial-mediated ATP synthesis and thereby induce AMP-activated protein kinase (AMPK) activation, including berberine, block mTORC1, ERK and proliferation in vitro and act as chemopreventive agents in vivo. Results: Treatment of PDAC cells (PANC-1, MiaPaCa-2) incubated in medium containing 5 mM glucose with increasing doses of the isoquinoline alkaloid berberine (0.05-5μg/ml) decreased mitochondrial membrane potential and produced a striking dose-dependent decrease in the intracellular levels of ATP in these cells. AMPK, a conserved sensor of cellular energy, is activated when the AMP/ATP ratio increases. Accordingly, berberine induced potent AMPK activation in PANC-1 and MiaPaCa-2 cells, as shown by immunoblotting using antibodies that detect the phosphorylated state of AMPK α subunit at Thr-172 and acetyl-CoA carboxylase (ACC) at Ser-79, a specific substrate of AMPK activity within intact cells. Berberine dose-dependently inhibited mTORC1 activity (scored by S6K phosphorylation at Thr-389, a site phosphorylated by mTORC1 and S6 phosphorylation at Ser-240, a site phosphorylated by S6K), ERK activation and DNA synthesis in PDAC cells stimulated by defined growth factors (e.g. insulin and neurotensin) or fetal bovine serum. Furthermore, berberine inhibited the proliferation of these cells and blocked the progression of their cell cycle in the G1 phase, as revealed by FACS analysis. In order to test the effect of berberine in vivo, MiaPaCa-2 cells were implanted into the flanks of nu/nu mice. After the tumors reached a diameter of 2 mm, the animals were treated with daily intraperitoneal injections of 5mg/kg berberine or vehicle (n=10 for each group). Berberine treatment strikingly reduced the rate of tumor growth. The final volumes of the tumors were 824±158 and 242±38 mm3, in the control and berberinetreated groups, respectively. Conclusion: The natural alkaloid berberine inhibited human pancreatic cell growth in vitro and in vivo. The mechanism of action of berberine is consistent with the hypothesis that structurally unrelated phytochemicals that inhibit mitochondrialmediated ATP synthesis and thereby induce AMPK activation, block mTORC1, ERK and proliferation od pancreatic cancer cells. As berberine has been safely used in humans, this natural compound could be an interesting and potential new candidate for chemopreventive strategies against pancreatic cancer.
AGA Abstracts
Tu1919 Diagnostic Accuracy of Carcinoembryonic Antigen (CEA) in Cyst Fluid Analysis in Histologically Confirmed Pancreatic Cysts: Results From a Large, Multicenter Cohort Study Srinivas Gaddam, Joseph W. Keach, Phillip S. Ge, Daniel Mullady, Norio Fukami, V. Raman Muthusamy, Steven A. Edmundowicz, Riad R. Azar, Raj J. Shah, Faris Murad, Vladimir M. Kushnir, Rabindra R. Watson, Kourosh F. Ghassemi, Alireza Sedarat, Brian C. Brauer, Roy D. Yen, Stuart K. Amateau, Lindsay Hosford, Timothy Donahue, Richard D. Schulick, Barish H. Edil, Dayna S. Early, Sachin Wani Background: EUS plays an integral role in the differentiation of mucinous (MCN) and nonmucinous cystic neoplasms (NMCN) of the pancreas. This is by virtue of high resolution imaging of the morphologic characteristics and ability to sample cyst fluid for cytology and tumor markers such as CEA. The exact cut off value at which pancreatic cyst fluid CEA level distinguishes MCN from NMCN is controversial. Aims: In a large multicenter cohort of patients (pts) with pancreatic cystic lesions, to evaluate and validate the diagnostic accuracy of cyst fluid CEA levels between MCN and NMCN. Methods: This is a multicenter outcomes project of all pts undergoing EUS for evaluation of pancreatic cysts at 3 tertiary referral centers. Consecutive pts who underwent EUS +/- FNA were identified. Pts with histologic confirmation of cyst type - surgical resection and/or cancer on cytology served as the gold standard for this analysis. Demographics and EUS morphology [size, communication with
S-872