with increased overall survival (64±22 vs. 18±5 months). Early lesions (PanIns) were alsopositive for CTSE while no staining was observed in normal ductal cells. Similar patternswere also observed in the transgenic K-Ras model. In contrast, HPDE, BxPC3, MPanc96,Panc1 and MiaPaca2 cells did not express CTSE protein and MOH and HPAC expressedonly low levels. In order to study the functional relevance of our findings we generatedMiaPaca2 cells, which express relatively high levels of CTSE. In contrast to the parentalcells, CTSE expressing cells grew in clusters and readily formed cell adhesions. Proliferationof those cells was significantly decreased compared to control cells (0.4±0.1 vs. 0.6±0.1after 72hrs). Migration was also significantly inhibited by CTSE expression (6±2 vs. 55±9cells/5fields after 30hrs). CTSE expression was associated with increased expression of E-cadherin and decreased expression of vimentin, suggesting a mesenchymal to epithelialtransition. Conclusions: CTSE is highly expressed in PanIn lesions and pancreatic adenocarci-nomas but is lost in cancer cell lines. Positive staining for CTSE correlates with increasedoverall survival. CTSE expression correlated with decreased growth and migration and leadto changes suggesting mesenchymal to epithelial transition. Loss of CTSE may be importantto support the aggressiveness of pancreatic cancer.

M2024

Surgical Resection for Pancreatic Cancer: An Estimation of the NumberNeeded to TreatSarah A. Rodriguez, Douglas O. Faigel

BACKGROUND: Surgical resection is the only curative option for pancreatic cancer. Althoughmost patients present with surgically unresectable disease, advances in surgical techniquessuch as portal vein reconstruction have made more patients eligible for resection and potentialcure. However, many eligible patients still do not undergo surgery. AIM: To calculate thenumber needed to treat with surgical resection to gain one 5 year survival among allpatients with pancreatic cancer, using incidence and mortality data from the SEER database.METHODS: The SEER 9 database was used. The study was limited to 1986-2000 to offsetthe potential survival benefit of chemotherapy, which became more widely used after 1985.Incidence of cancer, incidence of cancer directed surgery, and mortality data were obtainedfor 1986 and 2000. The change in rates of surgery and change in mortality were calculatedand used to approximate the number needed to treat to gain one survival at 3 and 5 years.Data for 1999 was used for 5 year survival calculation. The assumption was made that allincreases in survival were due to increases in surgery. RESULTS: The incidence of cancerin 1986 was 16.4 per 100,000 population and decreased slightly to 15.9/100,000 in 2000.The incidence of cancer-directed surgery increased steadily over the study period from 1.6/100,000 to 3/100,000. The surgery rate for 1986 is calculated by dividing the incidence ofsurgery in 1986 by the incidence of cancer in 1986, resulting in a surgery rate of 9.8%.The surgery rate for 2000 is 18.9%, a difference of +9.1%. 3 year survival for 1986 for allpatients with pancreatic cancer was 3.9%, vs. 6.5% in 2000, an increase of 4.2%. Thenumber needed to treat (NNT) with surgical resection to gain one 3 year survival is thechange in surgical rate divided by the change in survival rate. This calculates to an NNTof 3.5. In other words, about 4 patients would need to undergo surgical resection to gainone 3 year survival. The same calculation was made for 5 year survival using data from1999. The NNT to gain one 5 year survival is 3.95, or about 4 patients. When data waslimited to patients with only local or regional stage disease, the NNT calculation is similarat 4.1. CONCLUSIONS: We have calculated the number of pancreatic cancer patients whoneed to undergo resection to gain one long term survival at about 4. Although this is theminimal possible NNT because it does not account for changes in survival due to improve-ments in chemotherapy, it suggests that a small increase in surgery rate may finally result ina clinically meaningful increase in survival. This NNT will be used for cost-effective analyses.

M2025

Inhibiting Pancreatic Cancer Growth and Sensitizing the Tumor toRadiotherapy Through Downregulation of SP ProteinsShilpa Oberoi, Rajesambhaji Borade, Neal McCollum, Santhi D. Konduri, Jimmie F.Colon, Cheryl H. Baker, Maen Abdelrahim

Sp1, Sp3 and Sp4 proteins play a critical role in the growth and metastasis of pancreaticcancer cells. Initial studies screened a panel of nonsteroidal anti-inflammatory drugs (NSAIDs)and cyclooxygenase 2 (COX-2) and COX-1 inhibitors for their effects on Sp protein expres-sion. Only tolfenamic acid and its derivatives degraded all three Sp proteins. The most activecompound was tolfenamic acid which also inhibited growth of Panc-1, L3.6pl and Panc-28 pancreatic cancer cells. Tolfenamic acid induced proteasome-dependent degradation ofSp1, Sp3 and Sp4, and this response was blocked by the proteasome inhibitors gliotoxinand lactacystin. Tolfenamic acid also inhibited Vascular Endothelial Growth Factor (VEGF)and the antiapoptotic survivin mRNA/protein expression in Panc-1 and L3.6pl cells, andthis was linked to decreased binding to and activation of proximal GC-rich sites in theVEGF and survivin promoter. Orthotopic model for pancreatic tumor growth has been usedto investigate tolfenamic acid-induced antiangiogenic and proapoptotic responses. Treatmentwith 12.5 and 25 mg/kg tolfenamic acid decreased tumor growth, size and weight comparedto solvent (control) and also decreased liver metastasis. In addition, tolfenamic acid increasedsensitivity of pancreatic cancer cells and tumor to radiation therapy and this was mediatedby blocking radiation-induced survivin protein overexpression. Thus, tolfenamic acid actsas a novel anticancer agent and radiation sensitizer through targeted degradation of Spproteins that are highly overexpressed in tumor.

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M2026

New Model for Testing Safety of Oncolytic Fiber-Modified ConditionallyReplicative Adenovirus Designed for Pancreatic CancerJulia Davydova, Eric J. Brown, Selwyn M. Vickers, Masato Yamamoto

We have reported that fiber-modified conditionally replicative adenoviruses show augmentedoncolytic effect for pancreatic cancer. Among them, switching adenovirus (Ad) fiber-knobregion from type 5 to type 3 (5/3 modification) increased tumor transduction and showedhighest anti-tumor effect after intratumoral as well as systemic vector administration (Ramirezet al, Am J Surg, in press). However, one big obstacle for clinical translation is absence ofconvenient animal model for toxicological study. Cotton rats and Syrian hamsters have beenused for the toxicological study of replicative adenovirus without fiber modification, butrodent models are not usable for 5/3 vectors because 5/3 vectors do not infect rodent cellsefficiently. Recently, there was a report about human adenovirus replication in pigs (Jogleret al, J Virol 2006). In this project, we tested the fiber-modified human adenovirus replicationin pig cells in order to determine the applicability for preclinical toxicological test of fiber-modified CRAds. We first evaluated the infectivity of human adenovirus vectors with unmodi-fied, RGD-modified, and 5/3 modified fibers in human (Hs766T pancreatic cancer), mouse(Hepa1-6 hepatoma, Pan02 pancreatic cancer), hamster (HP1 and HapT1 pancreatic cancer),and pig (PK15 kidney) cells, respectively. 5/3 modification showed significant increase ofinfectivity in human cells and modest increase in PK-15 pig cells compared to fiber unmodi-fied virus, while infectivity was 2 order lower in rodent cells. In binding assay, 5/3 virusshowed increased binding to PK15 as well as human cells, while the rodent cells showedlittle binding, indicating absence of receptor for this virus. In concurrent with this, theflowcytometory with Ad5/3 fiber protein revealed that Ad5/3 fiber binds to human and pigcells but not to rodent cells. In the context of cytocidal effect, 5/3 vector efficiently killedPK15 and human cell (A549) but had no effect on rodent cells. When the virus replicationwas evaluated with the vector equipped with luciferase reporter for replication monitoring(Ono et al, Can Res 2005), both fiber-unmodified and 5/3 modified vector showed replicationin PK15 although only fiber-unmodified replicated in rodent cells. This indicate that pigcell (PK15) is usable for toxicological assay for 5/3 modified oncolytic adenovirus. Suchmodel is useful for preclinical evaluation of fiber modified oncolytic adenoviruses that weare developing for GI cancers.

M2027

Inoperable Pancreatic Cancer Patients Receiving ContemporaryChemotherapeutic Regimens Who Have Prolonged Survival Exhibit AnIncreased Risk of Metal Stent Occlusion and CholangitisJames L. Buxbaum, Karen C. Bagatelos, Elmer Y. Chang, Henry K. Niho, James W.Ostroff

Background: Biliary obstruction occurs in 90% of patients with inoperable pancreatic cancer.In the pre-gemcitabine era, the median survival for these patients was 4-5 months. Endoscop-ically placed metal stents, which are patent for a median of 6-9 months, have been thefavored decompressive strategy. In the past decade chemotherapeutic options for advancedpancreatic cancer have improved with a median survival of greater than 7 months in recenttrials. Thus, it is unknown whether metal stents will continue to be the optimal method ofdecompression or alternatively will become an unremovable nidus of infection and obstruc-tion in those treated with chemotherapy. Methods: We reviewed all ERCP's performed forbiliary obstruction in patients with pancreatic adenocarcinoma between November 1999and December 2005 at UCSF Medical Center. Patients receiving chemotherapy, primarilyas part of clinical trials, were included. Those who underwent potentially curative or palliativebiliary diversion procedures were excluded. Results: Among the 202 patients with pancreaticcancer who underwent endoscopic biliary decompression, 56 received chemotherapy anddid not undergo surgery. The median survival of this population was 12 months (mean11.7). Twenty-six patients had locally advanced cancer and thirty had widespread metastases.Gemcitabine was administered to 88% of patients and 75% were treated with multi-agentchemotherapy. Procedures to relieve biliary obstruction were performed a median of onemonth after the diagnosis of malignancy. Decompression was achieved by endoscopic stentingin 93% of patients. Among the total of 111 endoscopic procedures performed, there were2 complications, one post sphincterotomy bleed and one episode of pancreatitis. Metal stentswere used in most of these cases. Seventeen of the patients (30%) required hospitalizationfor cholangitis or biliary obstruction. Sixteen of these cases occurred in patients whosesurvival was greater than or equal to ten months. Thus 50% of the patients surviving greaterthan 10 months (16/32) compared to 4% (1/24) of those surviving less, were hospitalizedfor complications of stent occlusion. The average length of hospitalization was 7.4 days.Conclusion: This cohort of inoperable pancreatic cancer patients undergoing chemotherapysurvived longer than the expected patent period of metal stents employed for biliary decom-pression. The incidence of cholangitis and obstruction requiring hospitalization does increasemarkedly among long term survivors. Periodic plastic stent exchanges may prove to be asafer alternative to early expandable metal stent placement.

M2028

Low Dose Gemcitabine Improves the Prognosis of Elderly Patients withUnresectable Advanced Pancreatic CancerKazuyuki Matsumoto, Tatsuya Toyokawa, Yasuhiro Miyake, Hisae Yasumara, MasahiroTakahara, Eisuke Kaji, Morihito Nakatsu, Masaharu Ando, Mamoru Hirohata

Background: Pancreatic cancer is increasing in incidence and the fourth leading cause ofcancer death in the United States. Up to 90% of patients present with locally advanced ormetastatic disease. Recently, the effect of gemcitabine on advanced pancreatic cancer hasbeen recognized. On the other hand, the effect of gemcitabine on advanced disease in elderlypatients has been unclear. This study was constructed in order to assess the effect of lowdose gemcitabine on the prognosis of elderly patients with unresectable advanced pancreaticcancer. Methods: Fifty-eight patients aged more than 65 years old (32 males and 26 femaleswith a median age of 76 years old) were prospectively included into this analysis. Patients

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