identified with the following clinical stages at diagnosis: 1B (n=9), IIA (n=32), IIB (n=31),stage III (n=5). Uncomplicated ERCP SEMS placement was successful in 100%. 6/77 patients(7.8%) did not complete NeoRx due to disease progression, poor tolerance, or were lost tofollow-up. Of these 77 SEMS, 8 (10.4%) developed signs of stent dysfunction; recurrentjaundice (n=2), cholangitis (n=1), or stent occlusion (n=5), and all were managed successfullywith repeat ERCP. 66 patients (85.7 %) completed NeoRx, of which 27 (40.9%) progressed.Among the remaining 39 patients, 7 (17.9 %) were unresectable due to occult metastases(n=3), vascular encasement (n=2), or medical comorbidities (n=2). No intraoperative com-plications were attributed to SEMS. 29 patients achieved R0 status, and 3 were R1. 4minor and 3 major complications were observed within the first 60 days postoperatively.Conclusions: Early SEMS placement permits neoadjuvant therapy with a low complicationand occlusion rate and no interference with surgery. Use of biliary SEMS eliminates theneed for repeat ERCP to change from plastic stents. A multicenter trial of SEMS prior toneoadjuvant therapy is required.

Mo1934

Restoration of Death Receptor-Induced Apoptosis in Chemo-ResistantPancreatic Cancer Stem Cells Inhibits Peritoneal CarcinomatosisYi Shen, Ryan Herde, Courtney L. Scaife, Jill E. Shea, Scott K. Kuwada

Cancer stem cells have been shown to be sufficient for new tumor formation and metastasisin mouse models. We recently found that pancreatic cancer stem cells express TNFalphafamily death receptors, but are resistant to FASL- and TRAIL- induced apoptosis. AIMS: Todetermine how death receptor resistance can be overcome in pancreatic cancer stem cells(PCSC) In Vitro and In Vivo. METHODS: SU.86 and PL-45 human pancreatic cancer celllines that express endogenous FAS, DR4, and DR5 death receptors were stably transfectedwith firefly luciferase to allow detection by bioluminescence. PCSC were enriched fromSU.86 and PL-45 by FACS using CD133 antibodies. PCSC were co-cultured on primaryhuman mesothelial cell monolayers, that express endogenous FASL and TRAIL. PCSC wereinjected intraperitoneally (IP) into athymic mice and peritoneal carcinomatosis observedand quantified by bioluminescent tumor detection (IVIS system) after IP administration ofD-luciferin. RESULTS: PCSC were 1-1.5 log orders more efficient in generating peritonealtumors at one week. Athymic mice received 2.5mg/kg BAY 11-7085 IP or equimolar concen-trations of bortezomib or gemcitabine IP 4 hours prior to and every 3 days following IPinjection of 40,000 PCSC for 3 weeks. BAY 11-7085 treatment resulted in 1000-, 86-, and1,100-fold reductions in peritoneal tumor burden (photons/cm2) compared with vehicle,gemcitabine, and bortezomib, respectively (p<0.05 for all comparisons). In a large screenof cell survival proteins, 10μM BAY 11-7085, but not bortezomib or gemcitabine, inhibitedFLIP expression in PCSC. PCSC were found to express FLIP protein while CD133- pancreaticcancer cells did not, which could explain why BAY 11-7085, but neither bortezomib orgemcitabine, inhibited peritoneal carcinomatosis. In the co-culture system, FAS or TRAILreceptor blocking antibodies rescued PCSC from apoptosis during adhesion to mesothelialcells. BAY 11-7085 induced JNK activation, which in turn caused FLIP degradation in PCSC.Inhibition of atypical but not classical or novel PKC isoforms inhibited BAY 11-7085-induced JNK activation, FLIP degradation and PCSC death. CONCLUSIONS: The ability topharmacologically inhibit FLIP represents a novel method of decreasing peritoneal seedingby allowing normal mesothelial cells lining the peritoneum to activate death receptor signalingin PCSC. This may represent a novel treatment to prevent peritoneal seeding during pancreaticcancer resection.

Mo1935

The Effects of Metformin on Survival After Diagnosis of Colorectal Cancer inDiabetic PatientsJin Ha Lee, Tae Il Kim, Soung Min Jeon, Sung Pil Hong, Jae Hee Cheon, Won Ho Kim

Background & Aims: Metformin use has been associated with decreased cancer risk andmortality. However, the effects of metformin on clinical outcomes after colorectal cancer(CRC) diagnosis are not defined. This study aimed to evaluate the relationship betweenprediagnosis metformin use and mortality after CRC diagnosis in diabetic patients. Methods:We identified 676 consecutive patients who were diagnosed both CRC and diabetes mellitusbetween 2000 and 2008. Pateints were compared by two groups; 258 diabetic patientstaking metformin and 337 diabetic patients not taking metformin. Patients demographics,clinical characteristics, relapse free survival, overall mortality, and CRC-specific mortalitywere analyzed. Results: After a median follow-up of 41 months, there were 71 total deaths(27.5%) and 55 CRC-specific deaths (21.3%) among 258 patients who used metformin,compared with 136 total deaths (40.4%) and 104 CRC-specific deaths (30.9%) among 337patients who did not use metformin. Metformin use was associated with decreased overallmortality (P=0.018) and CRC-specific mortality (P=0.042) by univariate analysis. Afteradjustment for clinically relevant factors, including age at diagnosis, sex, stage of cancer,BMI, family history of CRC, smoking status, use of aspirin prediagnosis, use of insulin anduse of thiazolidinedione, metformin use showed lower risk of overall mortality (HR, 1.448;95% CI, 1.084-1.934; P=0.016) and CRC-specific mortality (HR, 1.436; 95% CI, 1.026-2.0609; P=0.035) in CRC patients with diabetes. In subgroup analysis, these effects wereshown in stage 3 CRC patients, not in other stages of CRC. Conclusions: CRC patients withdiabetes receiving metfornin have lower mortality than do diabetics not receiving metformin.This is the first study to demonstrate an antitumor effect of metformin against CRC indiabetic patients. Further studies to evaluate the potential of metformin as an antitumoragent are warranted.Univariate and multivariate adjusted overall survival and CRC-specific survival analysis

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HR hazard ratio, CI confidence interval, CRC colorectal cancer

Mo1936

A Combination of Intratumoral Interferon-Alpha Gene Transfer and SyngeneicHematopoietic Stem Cell Transplantation Induces an Effective AntitumorImmunity for Solid CancersKenta Narumi, Toshihide Okada, Masakazu Yamagishi, Takahiro Ochiya, Kazunori Aoki

In an autologous hematopoietic stem cell transplantation, the transfused T cells recognizelow-affinity self antigens including tumor-associated antigens under the condition of lymph-openia-induced homeostatic proliferation (HP) and lead to a break in tolerance againsttumors. HP-driven antitumor responses, however, decay gradually since they are vulnerableto a development of tolerance. Type I interferon (IFN) has important roles in regulating theinnate and adaptive immune system. In this study, we examined whether HP-inducedantitumor activity can be enhanced by IFN-alpha gene transfer during a physiologic immunereconstitution and investigated mechanisms of the enhancement. First, to examine whetherHP of T cells induces antitumor immunity in lymphopenic hosts, lethally irradiated BALB/c mice were injected subcutaneously with CT26 colon cancer cells shortly after irradiation,and syngeneic bone marrow and T cells were transfused (syngeneic hematopoietic stem celltransplantation; SynHSCT). The growth of CT26 subcutaneous tumors was significantlysuppressed in the SynHSCT recipients. Then, to examine whether a combination of intratu-moral IFN-alpha gene transfer enhances antitumor immunity after SynHSCT, the IFN-alpha-expressing plasmid complexed with cationic liposome was injected into the tumors 7 daysafter HSCT. The combination of IFN-alpha gene transfer and SynHSCT resulted in a syner-gistic tumor suppression. The suppression was evident even in distant tumors that were notinjected with the IFN-alpha plasmid in the liver metastasis models. In the treated mice, theproliferation and activation of tumor-specific T lymphocytes were confirmed by ELISpotassay. There was no significant toxicity in the treated animals. To analyze antitumor immunemechanisms of the combination therapy, we isolated CD11c+ cells from the tumors treatedby IFN-alpha gene transfer in SynHSCT mice. An ELISpot assay showed that a culture oflymphocytes with the CD11c+ cells resulted in a higher number of IFN-gamma spots thancultures with control CD11c+ cells isolated from tumors treated with SynHSCT alone,demonstrating that IFN-alpha gene transfer effectively augmented antitumor immunity medi-ated by CD11c+ cells. An analysis of cytokine profile showed that the CD11c+ cells secreteda significant amount of IL-6. It is known that IL-6 suppresses the proliferation and differenti-ation of regulatory T cells. In fact, the inhibitory activity of regulatory T cells was significantlysuppressed by co-culture with the CD11c+ cells treated by a combination therapy, suggestingthat the CD11c+ cells suppress the regulatory T cells. A combination of the intratumoralIFN-alpha gene transfer with SynHSCT is a promising immunotherapy for solid cancers,based on the activation of tumor-specific immunity, suppression of the immunotolerantenvironment and an excellent safety features.

Mo1937

DARPP-32 Mediates Activation of PI3K Signaling and Resistance to Gefitinibin Gastric CancerShoum Zhu, Abbes Belkhiri, Alexander Zaika, Wael El-Rifai

Background: Gastric cancer is an aggressive tumor that is often resistant to chemotherapeutics.The 17q amplicon genes, including dopamine and cAMP regulated phosphoprotein MW32 kDa (DARPP-32), are overexpressed in two-thirds of gastric adenocarcinomas and mayinduce chemotherapy resistance via abrogation of apoptosis. EGFR plays an important rolein tumor growth and activation of the PI3K pathway. Gefitinib (Iressa) is a specific andeffective EGFR inhibitor that has shown antitumor activity in clinical trials against severalgastrointestinal cancers, including gastric cancers. However, molecular mechanisms thatmediate resistance to gefitinib remain poorly understood. Methods and Results: The expres-sion of DARPP-32 in the multi-step carcinogenesis cascade was examined using IHC analysison 533 samples. The composite expression score, calculated from immunostaining patterns,progressively increased significantly from normal or gastritis to metaplasia, dysplasia, andadenocarcinoma (p<0.001). Using clonogenic survival assays, and ATP-GLO cell viabilityassays, we found that overexpression of DARPP-32 leads to a 3-fold increase in gefitinib

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