Elevated Serum Carcinoembryonic Antigen 19-9 (CA 19-9) Levels Are Highly Specific for Malignancy in Patients Referred for Endoscopic Ultrasound (EUS) With Suspected Pancreatic Cancer but Without a Tissue Diagnosis

AGA Abstracts

pancreatic cancer, as well as acute and chronic pancreatitis. Methods: Orthotopic pancreatic cancer model was created by surgical injection of 500,000 S2VP10 cells. Once palpable tumors were established, blood samples were collected. Acute pancreatitis models were created by serial injections of supramaximal concentration of cerulein (50μg/kg) at hourly intervals for a total of ten hours. One hour after the last injection, the mice were sacrificed and bled by cardiac puncture. Chronic pancreatitis was induced by biweekly injections of high dose cerulein (50 μg/kg x6) for 10 weeks, followed by animal sacrifice and bleeding by cardiac puncture. All serum samples were analyzed by sandwich ELISA using a capture antibody specific for the inducible form of HSP-70. The ELISA results were then confirmed by serum immunoprecipitation followed by Western blotting to comparatively assess the serum HSP-70 levels. Results Five mice in each category of acute pancreatitis, chronic pancreatitis, and orthotopic cancer models were used to determine serum HSP-70 levels. No inducible HSP-70 was detected in the control group. The serum HSP-70 levels for all models were significantly higher than controls with all P-values of <0.002. The average serum HSP-70 levels were 1.37 ng/ml (90% CI 0.9-1.9), 0.95 ng/ml (90% CI 0.8-1.1) and 1.11 (90% CI 0.7-1.7) ng/ml in chronic pancreatitis, acute pancreatitis, and orthotopic pancreatic cancer model respectively. The observed differences between the three groups were not statistically significant with all P-values of >0.3. Conclusions Serum HSP-70 is elevated in mice with orthotopic pancreatic cancer, acute pancreatitis and chronic pancreatitis, without significant difference between the groups. Further research will focus on its role as a prognostic marker in pancreatitis and pancreatic cancer.

Mo2078 Elevated Serum Carcinoembryonic Antigen 19-9 (CA 19-9) Levels Are Highly Specific for Malignancy in Patients Referred for Endoscopic Ultrasound (EUS) With Suspected Pancreatic Cancer but Without a Tissue Diagnosis Michelle A. Anderson, Neil M. Sheth, James Scheiman, Caitlyn M. Plonka, Bin Zhu, Grace H. Elta, Richard S. Kwon, Cyrus R. Piraka, Erik-Jan Wamsteker, B. Joseph Elmunzer Introduction:CA 19-9 for pancreatic cancer diagnosis lacks specificity in the general population due to the rare incidence of the disease. We hypothesized that CA 19-9 would have improved specificity in patients referred for EUS for suspected pancreatic cancer due to greater pre-test probability. Methods:Patients were recruited for a prospective clinical trial of biomarkers for pancreatic cancer diagnosis. Patients were categorized as having pancreatic cancer (CA), chronic pancreatitis (CP) or “other” (non-CA, non- CP) based on histologic evidence of CA or negative fine needle aspiration (FNA) plus at least 12 months survival with no clinical or radiographic evidence of CA. Retrospectively, serum CA 19-9 levels were recorded and compared in the first 100 patients enrolled in the trial. For graphical representation, values of CA 19-9 were log(ln) transformed. Results:Among the first 100 patients enrolled, serum CA 19-9 levels were available in 73 subjects (Final Dx : CA=47, CP=17, Other=9). Subjects had a mean age (SD) of 66.3 y (10.5y) and there were 37 (51%) females. Levels of Ca 19-9 were significantly higher in subjects with CA than with CP or Other diseases (both, p<0.0001) (Table 1 & Figure 1). Among subjects with final Dx of CA who had a negative or non-diagnostic FNA (N=11), serum CA 19-9 > 37 U/mL had specificity of 94%, sensitivity of 67%, PPV of 86%, NPV of 84% and accuracy of 85% for pancreatic cancer. Conclusion: CA 19-9 is highly specific for the differentiation of pancreatic cancer from benign conditions of the pancreas (mainly chronic pancreatitis) in patients referred for endoscopic ultrasound with a suspicion of pancreatic cancer. Prospective studies of this potential biomarker in this selected population are warranted and currently underway. Summary Statistics for CA 19-9 in patients with pancreatic adenocarcinoma (CA), chronic pancreatitis (CP) and other lesions (O)

Mo2076 Assessment of the Effect of Neoadjuvant Chemoradiotherapy on Local Advanced Pancreatic Cancer Yoshiki Naito, Masamichi Nakayama, Hiroto Ishikawa, Shunji Arikawa, Yoshinobu Okabe, Hisafumi Kinoshita, Hirohisa Yano Locally advanced pancreatic cancer (LAPC) is defined as a tumor that involves vascular structures, and resectability is low, with a median survival time of 6 to 11 months. There are many practical and theoretical advantages to neoadjuvant chemoradiotherapy (NeoCRT) for unresectable pancreatic cancer. In this presentation, we studied the clinicopathologic features to assess the effect of neoadjuvant chemoradiotherapy on locally advanced pancreatic cancer. Ten patients underwent preliminary CT and operative or endoscopic staging, and had histologically confirmed LAPC (Male: 7 patinets, Female: 3 patients, Age: 64.9±8.2 years). All patients were treated with preoperative radiation combined with Gemcitabin or TS-1, and subsequently undergone pancreatectomy. Effective NeoCRT was assessed by comparing tumor size of pre-NeoCRT to that of post-NeoCRT. The maximum size of the pancreatic mass on CT was measured on serial axial slices containing the largest portion of the mass, shrinkage of the primary tumor was defined as a >30% reduction of the largest size. In addition, the main tumor specimens were stained with CD31, and calculated microvessel density (MVD, μm2) using WinROOF (MITANI, corp). Mean pre-NeoCRT tumor size was 27.2±9.1mm whereas post-NeoCRT tumor size was 18.6±5.6mm (P=0.0298). Pancreatic mass in 5 patients underwent NeoCRT showed 30% reduction of the largest size. Histological and pathological findings revealed pancreatic carcinoma with low cellularity and severe fibrosis in 6 cases (6/10, 60%). Nine of 10 cases (9/10, 90%) were R0 resection, among of them 4 cases (4/10, 40%) showed lymph node metastasis. According to WinROOF criteria, mean NeoCRT MVD value (1.5±0.9) in tumor was significantly lower compared with that of the normal pancreatic tissue (3.3±0.9) (P = 0.002). However, no significant difference between NeoCRT and non- NeoCRT group (P= 0.449). Interestingly, 5 patients with >30% reduction of tumor size also showed significantly high MVD value, in contrast, 4 patients with <30% reduction of tumor had low MVD value (P=0.027). Neoadjuvant Chemoradiotherapy works to locally advanced pancreatic cancer's advantage might through inhibiting tumor-angiogenesis to reduce tumor size therefore increasing the resectability of this type of tumor.

SD = standard deviation, Min=minimum value, Max= maximum value, 25%= 25 percentile (1st quartile), 75%= 75 percentile (3rd quartile)

Mo2077 Investigating the Role of FGF Signaling in Pancreatic Cancer Stacey J. Coleman, Athina Myrto-Chioni, Richard P. Grose, Hemant Kocher It is now appreciated that, in pancreatic cancer, transformed cells interact with stromal cells, extracellular matrix proteins, and neighboring normal epithelial cells to exploit feedback mechanisms to facilitate tumour progression. The mechanisms driving these events are under intense investigation. We are focusing on the role of a key family of signaling molecules the Fibroblast Growth Factors (FGFs). Aberrant FGF signaling has been linked with many cancers, including the progression of pancreatic cancer (El-Hariry et al., 2001). FGF-10 acting via FGFR2b induces migration and invasion of pancreatic cancer cells through enhancing MT1-MMP and TGFβ1 secretion (Nomura et al., 2008). However, the exact molecular mechanisms underpinning FGF signaling and its relevance In Vivo are still unknown as many of these studies were carried out in physiologically irrelevant models of pancreatic cancer, in which the stromal compartment was not represented. Parallel studies ongoing in our group have identified a truncated C-terminal FGFR1 fragment of approximately 60kD that localizes to the nucleus of metastatic breast cancer cells, suggesting a novel mechanism by which FGF may regulate cell behavior. On profiling 30 pancreatic cancer patients, at least 80% showed nuclear localization of FGFR1 while 77% showed FGFR2 in the nucleus of the cancer cell. This is particularly apparent in peri-neural invasion and lymph node metastases and is not apparent in normal pancreatic duct. Preliminary results have also identified a 60 kDa truncated fragment that locates to the nucleus upon FGF 2 stimulation (in pancreatic cancer cell lines). Thus, FGFR appears to translocate to the nucleus upon FGF signaling in pancreatic cancer cells. The main focus of this research project will be identifying the mechanism underlying FGFR nuclear localization in pancreatic cancer cell lines. Determining the function and mechanism of FGFR1/2 sub cellular localization in different pancreatic cancer cell lines in 2D and 3D assays, together with interrogation of clinical samples representing the full spectrum of pancreatic cancer, will allow us to establish the functional, prognostic and therapeutic relevance of FGF signaling in pancreatic cancer.

AGA Abstracts

Mo2079 Branch Duct Intraductal Papillary Mucinous Neoplasms (BD-IPMN): Risk of Malignancy Still Present After 5 Years of Follow-up Wafaa Khannoussi, Marie-Pierre Vullierme, Frédérique Maire, Vinciane Rebours, Alain Sauvanet, Safi Dokmak, Anne Couvelard, Pascal Hammel, Philippe B. Ruszniewski, Philippe Levy In patients (pts) with BD-IPMN, the risk of malignant evolution is well described at shortand mid term. Few data beyond 5 years are available. Patients and Methods: Prospective study including all consecutive pts with BD-IPMN and a follow-up (F/U) > 5y to assess the risk of malignant evolution. All CT-scans and magnetic resonance cholangiopancreatographies performed every 1 or 2 y (depending on the maximum size of cyst) were read by the same radiologist. EUS +/- fine needle aspiration was performed in case of doubt (main pancreatic duct (MPD) dilation, appearance of a mural nodule > 5 mm, maximal diameter> 30 mm). Size increase was considered if diameter increase > 5 mm. Size variation, malignant criteria, surgery and pathology if available were recorded. Results: 53 pts were included (mean age at diagnosis: 59 y, median F/U: 6.7 y (range: 5-11 y) including 5 >10 y). Lesions were stable or size decreased in 31 pts (58%). Size increased in 15 (28%) by 10.5 (5-33)mm, median and ranges. A mural nodule appeared in 5 pts (9%). 1 pt had a 15 mm mural nodule with MPD involvement (surgery scheduled shortly), 4 had a mural nodule between 2-5mm. One of these underwent surgical enucleation (mild dysplasia). The 3 remaining are carefully followed-up. One pt with a BD size increasing 21 to 30 mm had surgery (low grade dysplasia). Invasive carcinoma occurred in 2 pts, both after 7 y F/U, less than 12

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