cancer diagnosis and therapeutic strategies for the management of patients after tumordiagnosis were collected. A possible association between IBD therapy and malignancy risk,and the treatment and evolution of cancer were also reviewed. Results: Ninety six IBDpatients (47 Crohn's disease, 47 ulcerative colitis, 2 unclassified colitis) and 107 tumorswere studied. Mean age was 58±14 years, 57% males, 38% smokers, 25% with family historyof cancer. Seventeen tumors (15.9%) were diagnosed in patients receiving treatment withthiopurines, 3 in patients on methotrexate (2.8%), 2 during anti-TNF- α therapy (1.9%),and 11 were identified in patients on combined therapy with an immunosuppressive (9thiopurines and 2 methotrexate) and an anti-TNF- α drug (10.3%). The median durationof treatment was: 72 months for thiopurines (IQR 6-102) and 6 months for adalimumabor infliximab (IQR 2-13). After the diagnosis of cancer, IBD treatment was maintained in8 (47.1%) patients on thiopurines and in 1 (11.1%) patient with combined therapy. In theremaining patients on immunosuppressive and/or anti-TNF- α drug (n=24), the treatmentwas withdrawn, and in 5 (20.8%) of these cases the therapy was reintroduced later inagreement with the Oncology team. We could not find an association between thiopurines/anti-TNF- α drugs and malignancy risk. Regarding the evolution of cancer, 55 tumors(51.4%) were managed only with oncological surgery, 9 (8.4%) with chemotherapy, 2 (1.9%)with radiotherapy and 33 tumors (30.8%) with combined therapy. Of these therapies, 82.5%were curative and 17.5% were palliative intent treatments. Patients were followed-up for amedian of 39 months (IQR 24-57) from tumor diagnosis. During this period, 15 patientsdied (15.6%) due to cancer (mean age= 66±13 years), 4 (4.2%) had tumor recurrenceand 77 (80.2%) patients remained in remission. Conclusions: 1.) Thiopurine treatment ismaintained in approximately half of IBD patients after a cancer diagnosis. In contrast, anti-TNF- α drugs are withdrawn in most cases. 2.) An association between these drugs and ahigher cancer risk was not found in our series; these findings support the subsequentreintroduction of these therapies in selected patients, always in agreement with the oncolo-gist's recommendations.

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A Pilot Study of Optimized Monotherapy With Infliximab for Patients WithInflammatory Bowel DiseaseByron P. Vaughn, Manuel Martínez˜˜-Vazquez, Vilas Patwardhan, Alan C. Moss, William J.Sandborn, Adam S. Cheifetz

Background: Combination therapy with infliximab (IFX) and an immunomodulator hasbeen shown to be superior to IFX monotherapy for patients with inflammatory bowel disease(IBD). Presumably much of the benefit of combination therapy is decreased immunogenicityof IFX, which has been associated with secondary loss of response. IFX trough concentrationtesting is not routinely performed for patients who have responded to IFX. We describeour experience of optimizing IFX monotherapy through proactive measurement of IFXtrough concentration and titration. Methods: In 2009, one of the authors (ASC) beganproactively measuring IFX trough concentrations in patients with IBD who were in clinicalremission with the intent to optimize the trough to a detectable concentration. In 2010 thegoal trough concentration was changed to 5-10ug/ml. Patients on IFX monotherapy whohad a trough concentration drawn over this time period with the intent of titrating to atarget trough range were included. Charts were reviewed to ensure the intent of the IFXconcentration was to optimize the IFX dose. Paired Wilcoxon Signed Rank test was utilizedto assess for changes between initial and follow-up trough concentrations (p<0.05 consideredsignificant). Results: Thirty-one patients met the criteria for "optimized monotherapy" withIFX. Crohn's disease was the predominant indication for IFX (84%). Twenty-six percent (8/31) were initially on combination therapy but deescalated to IFX monotherapy. Seven ofthose patients had an IFX concentration after stopping combination therapy and 4 weredeemed low requiring an increase of IFX dose. Two patients developed transient low-levelantibody to IFX (<10ug/ml), with resolved after dose escalation. The median duration onIFX was 175 week (IQR: 116, 304). The median first IFX trough concentration was 6ug/ml (IQR: 3.2, 10.2). Thirty-five percent (11/31) underwent an escalation of IFX therapyafter their initial trough concentration. Twenty patients had a follow-up IFX trough concentra-tion (nine of whom underwent a dose escalation) allowing for a paired analysis. Of thosepatients, the median initial IFX concentration was 4.2ug/ml compared to the follow-upconcentration of 7.6ug/ml (paired Wilcoxon Signed Rank test, p=0.02, Figure 1). All patientswere eventually titrated to an IFX trough concentration of > 3ug/ml and 83% (26/31)achieved a trough concentration of > 5ug/ml. None of the 31 patients stopped IFX therapy.Conclusion: Prospectively optimized monotherapy may be an alternative to combinationtherapy for patients with IBD on IFX. Our data suggests that patients who have routinetrough concentration monitoring and dose adjustment to optimize IFX dose, can have asustained response to IFX. This approach should be further evaluated in a prospectivelycontrolled trial as an alternative to combination therapy for patients with IBD.

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Serum CRP Is a Better Early Marker for Response to Infliximab InductionTherapy Than Fecal Calprotectin in Patients With Moderate to SevereUlcerative ColitisJohannan F. Brandse, Jeroen M. Jansen, Paul A. Baars, M. Lowenberg, Cyriel Ponsioen,Gijs R. van den Brink, Geert R. D'Haens

Background: Serum CRP and fecal calprotectin are established makers for response toinfliximab (IFX) maintenance therapy in Ulcerative Colitis (UC). However early measurementand its predictive value for response to IFX induction in UC remain uncertain. We aimedto define the optimal timing of measurement and compare both markers for response totherapy. Methods: In this multicenter prospective observational study UC patients startingon IFX were included. Serum CRP and albumin and fecal calprotectin (Bühlmann ELISA)were measured at day 0,1,4,7,11,14,18,21,28,42 during the first 6 weeks of inductiontherapy and Clinical Colitis Activity Index was monitored weekly. Absence of response wasdefined as the need for higher dose infusion during induction or colectomy within 3 months.Endoscopic response was defined as improvement at week 6-8 endoscopy. Results: FifteenUC patients (5/15 left-sided, 10/15 pancolitis and 14/15 Mayo endoscopic score 3) wereincluded. All but one patients received IFX according to the regular induction regime of5mg/kg at week 0,2,6 and 7/15 with concomitant thiopurines. Median (IQR) baseline serumCRP was 36 (3-96) mg/L, albumin 38 (30-41) g/L and fecal calprotectin 1800ug/g (647-1800). Median (IQR) serum CRP at day 4 was 59 (30-96) mg/l for patient with absence ofresponse (n=3) compared to 3.8 (1.3-11.3) for responders (n=12), P=0.01. Median (IQR)CRP at day 7 was 15.3 (2-35) mg/l for endoscopic non-responders (n=8) compared to 1.6(0.8-3.4) mg/l for endoscopic responders (n=7), P=0.06. CRP of >25mg/l at day 4 seemedto be an optimal cut-off OR:175 ( 95%CI:2.9-10520, P<0.01) for predicting absence ofresponse. A cut-off for serum CRP of >5mg/l at day 7 had an OR:23 (95%CI:0.99-556, P=0.02) for predicting lack of endoscopic response. Both serum albumin and fecal calprotectindiscriminated less or later between clinical and endoscopic response. Analysis of fecal sampleswas however limited by the upper detection limit of the test (1800ug/g). Conclusions: SerumCRP is a better early marker for response to infliximab therapy compared to fecal calprotectinor serum albumin in patients with Ulcerative Colitis. Optimal timing for measuring serumCRP seems to be day 4 and day 7 in order to predict absence of clinical or endoscopicresponse, with cut-off values of 25mg/l and 5mg/ml respectively. Larger numbers of patientsare needed to confirm these findings.Markers that significantly discriminate between absence of response and response or endo-scopic response or non-response

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225

A Risk Stratification Strategy for Colorectal Cancer Screening: SequentialApplication of Two Clinical Prediction RulesThomas F. Imperiale, Patrick O. Monahan, Timothy E. Stump, Elizabeth A. Glowinski,David F. Ransohoff

Background: Risk stratification for average-risk colorectal (CRC) screening could improvescreening uptake and efficiency. We previously presented two clinical prediction rules (CPRs)(DDW and ACG 2013) that stratify risk for advanced neoplasia (AN) (CRC and advanced,precancerous lesions): a 5-variable "short model" and a 12-variable "long model". Objective:Determine the extent of risk stratification and degree of discrimination when the modelsare applied sequentially. Methods: Both models were derived and internally validated onaverage-risk, 50-80 year old persons who underwent first-time screening colonoscopybetween 2004 and 2011. We measured socio-demographic and physical features, medical andfamily history, and lifestyle factors and linked these variables to endoscopic and pathologicalfindings. On 2/3s of the sample, we first applied the short model, which categorized personsinto low, intermediate, and high-risk groups, and calculated the proportion allocated to andprevalence of AN in each group. To the short-model's intermediate risk group, we appliedthe long model, and quantified both the proportion of subjects reclassified as low or highrisk and the prevalence of AN in each final risk group. We then tested this sequentialapplication of the two models on the remaining 1/3 of the sample. Results: Among 2859persons in the derivation set (mean age 57.3 ± 6.5 years; 52% women), AN prevalence was9.2% (including 25 cancers). The short model categorized 53% as low-risk, 31% as intermedi-ate risk, and 15% as high-risk, with respective AN risks of 4.6%, 9.5%, and 25.1% (P<0.001).Applying the long model to the 896 intermediate-risk persons resulted in reclassification of55 (6%) persons as low-risk, none of whom had AN, and 203 (23%) as high-risk group,46 (23%) of whom had AN, for final risk categories of 55% (low), 22% (intermediate), and22% (high), and with AN risks of 4.4%, 6.1%, and 24%, respectively (P<0.001). In thelow-risk group of 1580 there were 5 distal CRCs and 65 advanced adenomas, 46 (71%) ofwhich would have been detected by sigmoidoscopy with colonoscopy for any distal polyp.In the high-risk group the number needed to screen (NNS) with colonoscopy to detect oneperson with AN was 4.1 (95% CI, 3.6-4.7). Results were comparable among 1402 personsin the validation set. In the final low-risk group of 779 there were 26 ANs (no CRCs), 22(85%) detectable by sigmoidoscopy. NNS to detect one person with AN in the high-riskgroup was 4.2 (CI, 3.4-5.2). Conclusion: Sequential application of short and long clinicalprediction rules stratified risk for 77-78% of an average-risk cohort, resulting in a high-riskgroup in which colonoscopy had a high-yield for AN, and a low-risk group that could bescreened less invasively. If validated in independent cohorts, this strategy could improvethe efficiency and uptake of CRC screening.

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The Comparative Cost-Effectiveness of Faecal Immunochemical Tests vs.Screening Colonoscopy in the Detection of Neoplastic LesionsMartin C. Wong, Jessica Ching, Victor C. Chan, Thomas Y. Lam, Arthur K. Luk, Siew C.Ng, Simon S. Ng, Joseph J. Y. Sung

BACKGROUND: Faecal immunochemical tests (FITs) and colonoscopy are two commonscreening tools for colorectal cancer (CRC). Most cost-effectiveness studies focused onsurvival as the outcome variable, and were based on modeling techniques instead of realworld observational data. OBJECTIVE: This study evaluated the cost-effectiveness of thesetwo tests to detect colorectal neoplastic lesions based on data from a territory-wide communityscreening service. METHODS: We included all asymptomatic subjects aged 50-70 years whounderwent CRC screening in a community centre between 2008 and 2012 in Hong Kong.They received either a yearly FIT for up to 4 years, or one direct colonoscopy. Participantswho had any one FIT being positive received a colonoscopy. The incremental cost-effective-ness ratio (ICER) was assessed based on the detection rates of neoplastic lesions, and costsincluding screening compliance, polypectomy, colonoscopy complications, and staging ofCRC detected. There were 1,838,916 citizens aged between 50 to 70 years in the HongKong population in 2011. This population was assigned into our two screening schemesbased on the proportion of the study participants choosing FIT vs. colonoscopy in theprogramme. RESULTS: 5,863 patients received yearly FIT and 4,869 received colonoscopy.The compliance rates with yearly FIT were 97.3%, 82.8%, 84.6% and 77.7%, respectively,in the first four years of follow-up. The positivity rates of FIT in the first four years were97.3%, 82.8%, 84.6% and 77.7%, respectively. Among those who chose colonoscopy, 90.7%attended for the procedure (n=4,418); whereas 89.8% of participants in the FIT groupwho had positive faecal test results completed colonoscopy (n=343). Compared with FIT,colonoscopy detected significantly more neoplastic lesions (23.6% vs. 1.6%) and advancedlesions or cancer (4.2% vs. 1.2%). The cost of finding a colorectal neoplasia was US$16,085by FIT and US$4,719 by colonoscopy. The cost of detecting an advanced neoplasia wasUS$26,712 by FIT and US$28,913 by colonoscopy. FIT (US$149,590) was more cost-effective in finding colorectal cancer than colonoscopy (US$388,268). Using FIT scheme asa control, the incremental Cost-Effectiveness Ratio (iCER) of screening colonoscopy wasUS$3,721, US$29,847 and US$984,120 to detect one adenoma, advanced neoplasia andCRC, respectively. CONCLUSIONS: FIT is more cost-effective in screening for both advancedneoplasia and CRC than a direct colonoscopy. FIT screening is cost-effective at detectingadvanced lesions, which is coherent with the purpose of using FIT to detect malignancy.Cost to detect one colorectal neoplasia in the Hong Kong population according to screen-ing modality

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Evaluation of a 2-Gene (IKZF1 and BCAT1) DNA Blood Test for Detection ofColorectal CancerGraeme P. Young, Susanne K. Pedersen, Evelien Dekker, Stephen R. Cole, Joanne M.Osborne, Erin L. Symonds, Rosalie C. Mallant-Hent, Aidan McEvoy, Rohan Baker,Snigdha Gaur, David H. Murray, Lawrence C. LaPointe

Background: Two genes, BCAT1 and IKZF1, are frequently hypermethylated in colorectaladenoma and cancer (CRC) tissues. Since tumour-derived aberrant DNA can be detectablein blood, and blood tests have the potential to improve screening participation rates, weassessed the accuracy of a blood test comprising detection of methylated BCAT1 and IKZF1across the spectrum of benign and neoplastic conditions encountered in the colon/rectum.Methods: Subjects comprised volunteers from an Australian and a Dutch hospital who werescheduled for colonoscopy for any reason, or for resection of colonic neoplasia. Circulatingcell-free DNA was extracted from 4mL plasma samples (phenotype blinded to processoperator) and bisulphite converted. Levels of recovered DNA and methylated BCAT1 andIKZF1 DNA were simultaneously determined using multiplexed qPCR. A plasma samplewas defined as positive if amplified target sequence signal above background fluorescencewas present in any of 3 replicates in the BCAT1 or IKZF1 qPCR assay. Sensitivity andspecificity for neoplasia were estimated as the primary outcome measures. Results: Of the2187 volunteers (mean age 62 years, 52% male) who met enrolment criteria and providedsufficient plasma, the test was run successfully on 2139 plasma specimens including 30sample pairs taken pre- and post-surgical removal of neoplastic lesions. The 2-gene bloodtest (i.e. BCAT1 and/or IKZF1 positive) successfully identified 85 of 130 CRC cases (sensitivityof 65%, 95% CI: 56-73). For UICC CRC Stages I-IV, respective positivity rates were 29%(95% CI: 14-51), 68% (54-80), 77% (60-88) and 89% (51-99). For T element of TNMstaging, respective rates were pT1 - 43%, pT2 - 58%, pT3 - 70%, pT4 - 71%. The resultsfor the individual markers are shown in the Table. There was no correlation of BCAT1/IKZF1 positivity with smoking, gender, age or family history of CRC. The twelve BCAT1/IKZF1 methylation-positive CRC subjects with paired pre- and post-surgery plasma showedreduction in methylation signal after surgery, with complete disappearance of signal in 10subjects. Sensitivity for advanced adenoma (n= 232) was 7% (95% CI: 4.5-11.7). Specificitywas 94.2% (95% CI: 92.8-95.4) in all non-neoplastic cases (n=1283) and 94.9% (92.4-96.7) in those with a normal colon (n=454). Conclusions: The sensitivity for cancer of thistwo-marker panel justifies prospective evaluation in a true screening population. However,if it is to be used for population screening, it would be advantageous to show improvedparticipation rates relative to established methods and/or better sensitivity than we have