962

Clinical Utility of Measuring Infliximab and Human Anti-Chimeric AntibodyLevels in Patients with Inflammatory Bowel DiseaseWaqqas Afif, Edward V. Loftus, William A. Faubion, Karen A. Hanson, William J.Sandborn

Background: Treatment with infliximab (IFX) can result in immunogenicity through theformation of human anti-chimeric antibodies (HACAs). These antibodies are associated witha decreased duration of response, whereas therapeutic levels of IFX are associated withdurable clinical response. We evaluated the clinical utility of measuring serum IFX andHACA levels. Methods: We retrospectively reviewed charts of patients with inflammatorybowel disease who had IFX drug and HACA levels measured over a three-year period from2005-2008. The clinical utility of these tests was assessed by determining whether theresult affected clinical management. The management and subsequent clinical response totherapeutic changes based on test results was evaluated. Fisher's exact test and log-rank testfor discontinuation were used for statistical analysis. Results: One hundred and fifty-fivepatients underwent IFX level and HACA status testing. The median time to initial testingafter IFX initiation was 50 weeks (IQR: 22.7-120). The main indications for testing were:loss of response to IFX (50.3%), partial response after initiation of IFX (22.6%) and possibleautoimmune/delayed hypersensitivity reaction (14.8%). HACAs were identified in 35 patients(22.6%) and therapeutic IFX levels were found in 51 (32.9%). Of 177 total tests assessed,the results impacted treatment decisions in 73.4% (95% CI: 66-80%). In those with positiveHACAs, change to another anti-TNF was associated with a complete or partial response in91.6% of patients whereas increasing the dose had a response of 16.7% (p<0.004). In thosewith sub-therapeutic levels, increasing the dose was associated with complete or partialclinical response in 86.2% of patients while changing to another anti-TNF resulted in aresponse of 40% (p<0.048). Patients with clinical symptoms and therapeutic IFX levelswere: continued at the same dose 70.8% of the time (95% CI: 49-87%) and had no evidenceof active inflammation by endoscopic/radiographic assessment 61.9 % of the time (95% CI,38-82%). In patients with therapeutic IFX levels who continued the same dose and thosewith non-therapeutic levels who were dose-escalated, the median time to discontinuationof IFX after the test date was similar at 51 weeks (IQR: 45-92). Conclusions: Measurementof IFX level and HACA status impacts management and is clinically useful. Increasing theIFX dose in patients who have HACAs is ineffective, whereas in patients with non-therapeuticIFX levels, this strategy may be more effective than changing to another anti-TNF agent.Changing treatment based on clinical symptoms alone may lead to inappropriate manage-ment.

963

Results from a Prospective Study Combining Infliximab, Surgery, andMethotrexate in Severe Fistulising Ano-Perineal Crohn's DiseasePauline Roumeguere, Dominique Bouchard, Francois Pigot, Frederic Juguet, AlainCastinel, Elise Chanteloup, Delphine Gaye, Maylis Capdepont, Frank Zerbib, DavidLaharie

Introduction: Infliximab (IFX) is effective in treating fistulising Crohn's disease (CD). How-ever, clinical recurrence may happen because of persistence of fistula tracks as observedwith MR-imaging. Initial IFX induction associated with an optimal surgical procedure, thenfollowed by a maintenance therapy should be evaluated regarding anatomic healing andprolonged clinical response. The aim of this open prospective study was to evaluate theshort- and long-term efficacy of a combined schedule comprising short course of IFX,associated with local optimal surgery, followed by long-term methotrexate (MTX) in patientswith severe fistulising ano-perineal CD. Patients and methods: From January 2006 to Nov-ember 2007, all consecutive patients with severe fistulising ano-perineal CD were prospect-ively included after primary abscess drainage. At inclusion, patients received MTX (25mg/week IM during all the study) and 3 IFX infusions (5mg/kg at weeks 0, 2, and 6). Duringsecond surgical step performed at week 4, all setons were removed and an optimal surgicalprocedure (including fistula laying out, fibrin glue injection, flap …) was done. IFX wasthen stopped and MTX continued as maintenance therapy. Clinical response was definedby a reduction in 50% or more of draining fistulas at two or more consecutive study visits.The primary end-point was clinical response at week 14. Secondary end-points were: i)time to loss of response for responders at week 14; ii) Perineal Disease Activity Index -PDAI-, and van Assche MR-imaging score at weeks 0, 14 and 50; iii) safety. Results: Thirty-fourCD patients (26W; mean age 38.5 years) were included. All had complex fistula, including9 recto-vaginal, and 10 ano-rectal stenosis. At week 14, 85% had clinical response, and itwas complete in 73.5%. Median time to loss of response was 69 weeks. Median PDAIdecreased from 11 to 3, and 0 (p<0.001), and median van Assche score decreased from 15to 9, and 6 (p≤0.001) at weeks 0, 14, and 50 respectively. Adverse events occurred in 62%of cases, with 15% severe infections. Conclusion: Treatment combining initial IFX induction,and two steps sphincter-sparing surgical procedure was very effective in achieving short-term response in severe fistulising ano-perineal CD. MTX as a maintenance therapy mayprovide long-term remission. MTX should be compared to IFX in maintenance therapy afteran optimised induction treatment.

964

Multiple Salivary Biomarkers for Pancreatic Cancer DetectionJames J. Farrell, Lei Zhang, M. Sugimoto, A. Hirayama, T. Soga, H. Zhou, David Elashoff,K. Gao, B. Paster, M. Tomita, David T. Wong

Background: Early detection of pancreatic cancer carries the best hope for improved survivalin this disease. Saliva offers great advantages for the non-invasive surveillance of humanhealth and detection of disease. This study explored the translational value of three discoveryplatforms (microbial, transcriptomic and metabolomic) to identify discriminatory salivarybiomarkers for pancreatic cancer detection. Methods: Three salivary biomarker discoverytechnologies were used to profile transcriptome and metabolome in saliva supernatant andmicrobiota in saliva pellet from an initial exploratory cohort including patients with pancreatic

A-147 AGA Abstracts

cancer, and chronic pancreatitis, and healthy controls. The Affymetrix U133 Plus 2.0 arraywas used to discover altered gene expression which were validated by RT-PCR. Differentiallypresent salivary metabolites were investigated using capillary electrophoresis with massspectrometry. The Human Oral Microbe Identification Microarray was used to investigatealtered microbial content in saliva pellet. Candidate biomarkers discovered from these studieswere then subjected to an independent clinical validation using a separate cohort of 30 earlypancreatic cancer (PC), 30 chronic pancreatitis (CP) and 30 healthy matched-control (H)saliva samples. Results: Three discriminatory panels of salivary biomarkers were discoveredand validated from the microbial, transcriptomic and metabolomic studies. The level of sixmicrobial biomarkers, eleven mRNA biomarkers and eight metabolites was found to besignificantly different between PC, CP and healthy controls (P<0.05). The combination offour biomarkers (mRNA biomarker MBD3L2, GLTSCR2; microbial biomarker Prevotellanigrescens, Neisseria elongata) yielded an ROC-plot AUC value of 0.94 (95% CI, 0.837 to0.984; P < 0.001) with sensitivity (89.3%) and specificity (89.3%) in distinguishing PCfrom healthy control. Additionally, these biomarkers could also distinguish PC from CP(ROC-plot AUC, 0.90) Conclusion: We have discovered and validated six microbial, elevenmRNA and eight metabolite biomarkers for pancreatic cancer detection in saliva. Combinationof multiple (4) salivary biomarkers can detect pancreatic cancer with strong discrimination.This is the first report demonstrating the value of multiple salivary biomarkers for thedetection of pancreatic cancer.

965

Comparative Yield of Endosonography and Magnetic Resonance Imaging inIndividuals At High-Risk for Pancreatic CancerFemme Harinck, Irma Kluijt, Jan-Werner Poley, Annemieke Cats, Cora M. Aalfs, Dirk J.Gouma, Chung Y. Nio, Paul Fockens, Marco Bruno

Introduction: Individuals at high-risk for pancreatic cancer (PC) are mutation carriers of PCprone hereditary syndromes and first-degree relatives of patients with PC from familial PCkindreds. Two non-invasive pre-cursor lesions are known: pancreatic intraepithelial neoplasia(PanIN) and intraductal papillary mucinous neoplasia (IPMN). A surveillance program mayimprove the prognosis of individuals at risk by detecting asymptomatic early cancers or,more preferably, precursor lesions. Endosonography (EUS) has been shown to be a potentiallyvaluable tool. Data for MRI are lacking. We present preliminary results of a comparativestudy between baseline EUS and MRI screening investigations in individuals entering a yearlysurveillance program.Methods: Asymptomatic high-risk individuals prospectively underwentEUS and MRI. Both investigations were carried out and scored according to predefinedcriteria. Investigators were blinded to the results of the alternative imaging modality. Results:Thirty-three individuals underwent both EUS and MRI. In 25 (76%) cases no focal lesionswere detected by either technique. In eight individuals (24%) focal lesions were detected,one with a mass lesion (11mm) and seven with cystic lesions. Focal lesions were detectedby both techniques in four individuals (12%), by MRI only in two (6%) and by EUS onlyin two (6%). Of the four individuals in whom both MRI and EUS detected lesions, lesionswere comparable in size, number and location in two cases. In the other two cases, thenumber varied from 5 reported by EUS to 11 by MRI. Cysts that were missed by EUSranged from 2-4mm and were predominantly located in the tail (4/6). In two individualsin whom only MRI suggested a focal lesion, these were classified as simple cysts, one locatedin the head (3mm) and one in the tail (4mm). The mass lesion was only detected by EUSand proven to be an adenocarcinoma. A small cyst (3mm) in the corpus was also onlydetected by EUS. Communication between cysts and the pancreatic duct (PD) was moreoften reported by EUS than MRI (4 vs 1). Conclusion: Based on these preliminary results,EUS and MRI seem complementary techniques to detect (pre)malignant lesions in individualsat high-risk for developing pancreatic cancer. MRI detected more cystic lesions, but EUSdetected communication between cyst and PD more often. The latter is valuable informationsince it differentiates a simple cyst from a side-branch IPMN. EUS detected one adenocarcin-oma in these 33 patients, which was missed by MRI.

966

Prevalence of Pancreatic Cysts in Individuals Undergoing Preventive MedicalExamination By Magnetic Resonance Imaging (MRI)Koen de Jong, Chung Y. Nio, John Hermans, Marcel G. Dijkgraaf, Dirk J. Gouma, CasperH. van Eijck, Eddy van Heel, Gunter Klaβ, Paul Fockens, Marco Bruno

Introduction: The true prevalence of pancreatic cysts (PCs) in the general population isunknown. Asymptomatic PCs are diagnosed with increasing frequency due to a more widespread use of diagnostic advanced cross-sectional imaging and the increased frequency atwhich individuals undergo preventive medical examinations. PC(s) may be identified as acoincidental finding with subsequent clinical management dilemmas. We investigated theprevalence of PCs in individuals undergoing screenings MRI performed at their own initiativeand cost. Aims & Methods: This study includes 3000 consecutive persons who underwentan abdominal MRI (non-secretin) as part of a preventive medical examination (Prescan,Rheine, Germany) between 3-2007 and 9-2008. All individuals had completed an applicationform with questions about medical history and presence of abdominal complaints. MRIreports and application forms were retrospectively reviewed. Primary endpoint was PCprevalence. Secondary endpoints were: age-, gender distribution, PC characteristics, presenceof liver- or kidney cysts, presence of abdominal complaints, and previous pancreatic disease.Results: Until the end of 11-2008, 1761 persons (M=1119) with a mean age of 51 years (SD,11.0; range, 21-86) have been investigated. PCs were reported in 38 persons, representing aprevalence of 2.2 per 100 persons (95% CI, 1.6-3.0). Mean age of individuals with PC(s)was 60 years (SD, 9.6). No difference in prevalence by sex was found (p=0.960). PC sizesranged from 2 to 54mm (median, 9mm; ≥30mm, n=2, 5.3%) and were solitary in 82% ofcases. 8% of PCs were multilocular. 36.8% of PCs were located in the tail. Communicationwith pancreatic duct was reported in 10%. PC presence correlated with increasing age, noPCs were identified <40 years, and prevalence of PCs from 70-80 years was 8.1% (95% CI,3.5-17.5). No other pancreatic MRI abnormalities were reported in any of the 1761 persons.Liver or kidney cyst(s) were present in 39% and 47% of cases with PCs as opposed to 25%and 35% in those without PCs (p=0.042; p=0.122). 5.3% of individuals with PC(s) had

AG

AA

bst

ract

s

AG

AA

bst

ract

sreported abdominal complaints as opposed to 7.6% of those without PC(s) (p = 0.589). Noneof the individuals with PC(s) had pancreatic disease in their medical history. Conclusion: Inindividuals undergoing preventive medical examination with MRI, the prevalence of PCswas 2.2%. Of these PCs, 5.3% were ≥30 mm, 8% were multilocular and in 10% of casesmay represent side-branch IPMN. Cyst presence correlated with increasing age, no differenceof prevalence by sex was found. Abdominal complaints did not correlate with PC presence.

967

Main-Duct and Combined IPMNs Are the Same Clinical Entity and Distinctfrom Branch-Duct IPMNsStefano Crippa, Carlos Fernandez del-Castillo, Roberto Salvia, Dianne M. Finkelstein,Claudio Bassi, Ismael Dominguez, Paola Capelli, Mari Mino-Kenudson, Gregory Y.Lauwers, Massimo Falconi, Sarah P. Thayer, Stefano Partelli, Paolo Pederzoli, Andrew L.Warshaw

Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreascomprise main-duct (MD), branch-duct (BD) and combined types. There is still no consensuswhether MD- and BD-IPMNs are different points on a spectrum or altogether differentdiseases, and where combined IPMNs fit. The aim of this study was to evaluate the clinico-epidemiological characteristics and prognosis of a large series of patients with IPMNs, toelucidate differences among the three types.Methods: 389 patients who underwent pancreaticresection for a histologically confirmed IPMN were identified. Surgical specimens were re-reviewed and eventually re-classified. The clinico-pathologic characteristics of the threesubtypes were contrasted. Results: 159 (41%) patients had BD- IPMNs, 149 (38%) combinedIPMNs, and 81 (21%) MD-IPMNs. MD- and combined IPMNs occurred more frequentlyin males (56%) while BD-IPMNs were seen more often in females (57%) (p<0.05). All IPMNssubtypes were generally located in the proximal pancreas with no age differences amongdifferent IPMNs. Incidental diagnosis was more common in BD-IPMNs (34.5%) than inMD- (13.5%) and combined (19%) ones (p=0.001), while jaundice and weight loss weresignificantly more frequent in MD- and combined-IPMNs (p<0.01). Adenoma was the mostcommon histological type in BD-IPMNs (44%) and its prevalence in MD- and combinedIPMNs was significantly lower (11% and 8%, p=0.0001). Conversely the rate of invasivecancer was 11% in BD-IPMNs and 42% and 48% in combined- and MD-IPMNs (p=0.0001).Patients with combined and MD-IPMNs with invasive cancer were older than those withnoninvasive tumors -suggesting tumor progression- while this age difference was not foundin BD-IPMNs. 5-year disease specific survival was 100% for patients with noninvasive BD-IPMNs and combined-IPMNs and 95% for patients with noninvasive MD-IPMNs (one patientwho underwent total pancreatectomy for in-situ-carcinoma had peritoneal recurrence); 5-year disease specific survival was 56%, 51%, and 64%, for BD-IPMNs, MD-IPMNs, andcombined-IPMNs with invasive cancer, respectively. Conclusion: BD-IPMNs have a specificprofile, likely representing an entity distinct from other IPMNs, and combined IPMNsshow close overlapping similarities with MD-IPMNs in regard to clinico-pathological andepidemiological characteristics. Combined IPMNs should be considered an extension of MD-IPMNs to the branch-ducts, and these two subtypes show a more aggressive biologicalbehavior compared to BD-IPMNs

968

Performance Characteristics of Cyst Fluid CEA Analysis for the Diagnosis ofMucinous Cysts of the PancreasSatish Nagula, Timothy J. Kennedy, Mark A. Schattner, Murray F. Brennan, Hans Gerdes,Arnold J. Markowitz, Laura H. Tang, Peter J. Allen

Background: Elevated cyst fluid CEA levels (>200 ng/ml) have been demonstrated to behighly diagnostic of mucinous cysts of the pancreas (intraductal papillary mucinous neoplasm- IPMN, and mucinous cystic neoplasm - MCN). Methods: A prospectively maintainedpancreatic cyst registry was reviewed and 191 patients with cystic neoplasms of the pancreaswere identifiedwho had undergone endoscopic ultrasound and fine needle aspiration between2001 and 2008. All patients had cyst fluid CEA measured. Patient demographics, imagingstudies, cyst characteristics, pathology, and treatment variables were recorded. Performancecharacteristics (sensitivity, specificity, positive predictive value [PPV], negative predictivevalue [NPV]) of elevated fluid CEA (>200 ng/ml) for detecting a mucinous cyst and detectingmalignancy (in situ or invasive adenocarcinoma) were calculated in those who had a patholo-gically proven diagnoses. The outcome of patients with an elevated cyst fluid CEA who didnot undergo resection was documented. Results: A pathologically proven diagnosis wasobtained in 63 patients (33%). Mucinous neoplasms were identified in 40/63 (64%): MCN,n=9; benign IPMN, n=27; malignant IPMN, n=4. Median cyst size was 3.3 cm for non-mucinous cysts (median CEA: 117 ng/ml) and 3.0 cm for mucinous cysts (median: CEA1272 ng/ml). A cyst fluid CEA > 200 had a sensitivity, specificity, PPV, and NPV of 85%,61%, 79%, 70%, respectively, for identifying a mucinous neoplasm. The extent to whichCEA was elevated was not associated with the presence of malignancy (mean fluid CEA:mucinous malignant 7025 ng/ml, mucinous non-malignant 4271 ng/ml; p=0.52). An addi-tional 128 patients were observed (mean follow-up 24 months, range 0-120 months); 23of these patients had a cyst fluid CEA > 200 ng/ml and were followed for more than 12months. None of these patients developed radiographic changes that resulted in surgicalresection. Cyst fluid CEA was not associated with cyst growth, even amongst the subset ofpatients with elevated cyst fluid CEA and extended followup. Conclusions: In this study,cyst fluid CEA > 200 ng/ml was found to have a PPV of 79% and NPV of 70% for identifyingmucinous neoplasms. In contrast to prior published reports, this registry contains a largenumber of IPMNs, and demonstrates that CEA has similar efficacy for the diagnosis of bothMCN and IPMN. Elevation of cyst fluid CEA was not associated with malignancy, or ahigher likelihood of cyst growth. Better markers for identifying dysplasia in mucinous cystsand predicting cyst behavior are needed to aid in management.

A-148AGA Abstracts

969

Proteomic Analysis of Cyst Fluid Mucin Expression Is Significantly MoreAccurate Than Conventional Cyst Fluid Analyses in the Clinical Assessmentof Pancreatic Cystic LesionsKarolina Sjöberg, Malin E. Johansson, Anders G. Hyltander, Evangelos Kalaitzakis,Morteza Shafazand, Jan Hansen, Henrik Sjovall, Gunnar C. Hansson, Riadh Sadik

The assessment of pancreatic cystic lesions (PCL) - the detection and staging of cystic/cyst-like tumors (CT) - is a clinical challenge. Mucin expression has been observed in mucinousand serous CTs and in ductal adenocarcinomas (that may appear cyst-like), but not inpseudocysts. Ductal adenocarcinomas exhibit MUC1 overexpression, which, when seen inmucinous CTs, supposedly indicates invasive disease. However, prospective studies arelacking, as are studies that use proteomics and thus avoid the diagnostic pitfall of differentialmucin glycosylation. AIMS: To explore the utility of proteomic analysis of cyst fluid mucinexpression, in the clinical assessment of PCLs. METHODS: Patients referred for endoscopicultrasound with fine needle aspiration of a PCL were prospectively included. Cytology withPAS diastase mucus stain, and cyst fluid CEA quantification were performed. Cyst fluidsamples (~20μl) were then run on a gel electrophoresis; high mass bands were cut out,trypsinized and analyzed by nanoLC-mass spectrometry and MS/MS on an FT mass spectro-meter. For peptide identification the Mascot software and an in-house mucin database wereused. Primary diagnostic endpoints: 1)Surgical pathology (n=8); 2)Follow-up includingimaging (n=12); 3)Preliminary diagnosis, based on all clinical data except proteomics results(blinded) (n=9). RESULTS: 13 females and 16 males were included, age range 36-86, median64. According to our primary diagnostic endpoints there were 19 CTs and 10 pseudocysts.We compared the sensitivity, specificity and accuracy for detection of CTs, for proteomicmucin expression analysis and cytology (Table 1). In line with earlier reports, 2/3 serousCTs expressed MUC6 alone, a pattern not seen for other PCLs. The diagnostic utility ofCEA was flawed by a lack of results for 10/29 PCLs due to low cyst fluid yield. For thecases with a surgical pathology, we compared the capacity for preoperative detection ofmalignancy, for proteomics (presence/absence of MUC1 expression) and cytology. Sensitivitywas 57% for proteomics and 13% for cytology; specificity 100% for both. CONCLUSION:Proteomic mucin expression analysis was significantly more accurate than standard cystfluid analyses in the clinical assessment of PCLs. MUC1 expression was more sensitive thancytology as a marker for malignancy.Minute amounts of cyst fluid are required for proteomics,whereas cyst fluid yield may restrict the diagnostic utility of CEA.Table 1

Cyst fluid CEA (cut-off 400ng/ml): Sensitivity:50% Specificity:89%

970

A 13-Nation Population Survey of Upper Gastrointestinal Symptoms: Age andGenderSebastian Haag, Jane M. Andrews, Judith D. Gapasin, Andreas Keller, Gerald Holtmann

Background: There is a lack of studies which assess and compare the prevalence of uppergastrointestinal (GI) symptoms contemporaneously in various countries using a uniform,standardised method. Previous data collected in separate studies using various differentsurvey instruments have suggested some variability in the prevalence of symptoms betweennations. Thus the aim of this study was to determine the prevalence of upper GI symptomsin 13 European countries (Austria, Belgium, Denmark, Finland, France, Germany, Hungary,Italy, Netherlands, Poland, Portugal, Spain, and Switzerland). Methods: A random sampleof 23000 population based subjects (aged 18-69 years) subjects participated in the survey.Results: The overall prevalence of any upper GI-symptoms (net-sum) was 38%, rangingfrom 24% in the Netherlands to 45% in Hungary. The prevalence of upper GI-symptomswas significantly higher in females (39%, 95%CI 38.4-39.6) vs. males (37%, 95%CI 36.4-37.6). Heartburn was reported by 24% (95%CI 23.4-24.6). Acidic reflux and acidic stomachcomplaints were reported by 14% (95%CI 13.6-14.4) and 13% (95%CI 12.6-13.4) respect-ively. Other upper GI complaints labelled as “gastritis” were reported by 12% (95%CI 11.6-12.4). There was no significant association between reported health-care seeking for theupper GI symptoms and perceived severity of symptoms. Stratified for age, significantlyfewer subjects between 50-69 years reported upper GI symptoms (33.4%, 95%CI 32.3-34.4) compared to the 18-29yr strata (42.8%, 95%CI 41.4-44.3), the 30-39yr strata (41.6%,95%CI 40.3-43.0) and the 40-49yr strata (37.4%, 95%CI 36.1-38.7). However, in the samestrata, the frequency of symptom episodes/ year reported is substantially higher (21.8 [50-69yr] vs. 11.3 [18-29yr]-17.4 [40-49yr], p=0.001). Summary: There are marked differencesin the country-specific prevalence of upper GI complaints. The reasons for this discrepancyare yet to be elucidated. In all countries, acidic reflux and heartburn are the most prevalentsymptoms. Symptoms are more prevalent in females. Overall, the prevalence of upper GIsymptoms decreases with age, although with age symptoms may be more frequent.

971

Abnormal Esophageal pH Study As Predictor of Treatment Response to ProtonPump Inhibitor (PPI) in Patients with Functional Dyspepsia (FD)Justin Wu, Pui Kuan Cheong, Yawen Chan, Sau Fong E. Lee, Larry Lai, Joseph J. Sung,Francis K. L. Chan

BACKGROUND: Results on the efficacy of PPI for treatment of FD are conflicting. It hasbeen postulated that PPI is only effective for dyspepsia related to gastroesophageal refluxdisease (GERD). AIM: To compare the efficacy of PPI for treatment of FD between patientswith and without abnormal esophageal pH study. METHODS: Consecutive patients whopresented with dyspeptic symptoms that fulfilled Rome II criteria were prospectively recruited