Alexander Lee

Fecal Immunochemical Test Program Performance Over 4 Rounds of Annual Screening: A Retrospective Cohort Study

Context The fecal immunochemical test is an effective way to screen for colorectal cancer, but we know more about how well it does the first time it is used and less about how well it does in later years with repeated testing. Contribution The researchers show that, after 4 years of repeated testing, patients continued to use the test and it continued to identify colorectal cancer. Caution This study did not measure whether identification of cancer changed outcomes. Implication The fecal immunochemical test is acceptable and effective for repeated testing. Colorectal cancer (CRC) is the second leading cause of cancer death in the United States (13), and screening with fecal occult blood tests (FOBTs) reduces CRC incidence and mortality (46). In randomized trials (711), annual or biennial guaiac-based FOBTs reduced CRC incidence by 17% to 20% and CRC mortality by 15% to 33%. Thus, the U.S. Preventive Services Task Force (4) and U.S. Multi-Society Task Force on Colorectal Cancer (12) recommend annual FOBT as an option for CRC screening for average-risk patients, defined as those aged 50 to 75 years with no history of CRC or adenoma, with no first-degree relatives with CRC, and who are not up to date with CRC screening according to other methods (that is, sigmoidoscopy within 5 years or colonoscopy within 10 years). Annual highly sensitive FOBTs are believed to be as effective as screening colonoscopy performed every 10 years if levels of adherence are high (13), although colonoscopy is recommended for those with a family history of CRC. Fecal blood tests are noninvasive and can be delivered by mail (14). In contrast to guaiac-based stool tests, fecal immunochemical test (FIT) screening can be done without dietary or medication restrictions, which allows it to achieve higher patient acceptance in organized CRC screening programs (15). This test also has higher detection rates for CRC and advanced adenomas than guaiac-based stool tests (1517). In a recent meta-analysis (18), the sensitivity of a single FIT application was 79% for CRC diagnosed within 2 years of testing; however, little is known about performance characteristics over several rounds of annual screening, particularly in community practice. The present study was conducted to evaluate FIT sensitivity for CRC and other performance characteristics over 4 rounds of annual testing in a U.S. community-based CRC screening program. Methods Study Population This retrospective longitudinal study was performed in a fixed cohort of Kaiser Permanente Northern California (KPNC) and Southern California (KPSC) health plan members. These integrated health care delivery organizations serve approximately 7 million persons in urban, suburban, and semirural regions throughout California. Kaiser Permanente health plan membership in California is diverse and similar in socioeconomic characteristics to the regions census demographics (1921). Study Oversight The study was approved by the institutional review boards of KPNC and KPSC, both of which waived the requirement for informed consent. The listed authors had sole responsibility for the study design, data collection, decision to submit the manuscript for publication, and drafting of the manuscript. This study was conducted within the National Cancer Institutefunded Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium, which conducts multisite, coordinated, transdisciplinary research to evaluate and improve cancer-screening processes. Organized CRC Screening Program The KPNC and KPSC initiated similar organized FIT screening programs between 2006 and 2008; the KPNC program has been described previously (14). Briefly, each year, the programs mail a FIT kit to eligible health plan members aged 50 to 75 years without a record of a colonoscopy within 10 years, sigmoidoscopy within 5 years, or fecal blood test within the prior year. The kit includes the FIT (OC FIT-CHEK; Polymedco), a standardized letter from the patients primary care provider, directions for completing and mailing the test, and a preprinted laboratory requisition order form. Outreach includes in-person, mail, secure e-mail, and telephone reminders as needed. The kits are returned by mail to regional laboratories and analyzed on or shortly after the return date using an OC-Sensor Diana automated system (Polymedco) with a cutoff level of 20 g of hemoglobin/g of buffer for a positive result. Patients with a positive FIT result are referred for follow-up colonoscopy. Study Eligibility Criteria and Participant Tracking The study cohort included CRC screening program participants aged 50 to 70 years on the date an initial kit was mailed to them in 2007 or 2008. Patients were excluded if they had been enrolled in the health plan for less than 1 year before the round 1 FIT mail date (to allow for the recording of prior out-of-system endoscopy procedures). They were also excluded if they were mailed a kit but subsequently had sigmoidoscopy or colonoscopy, were diagnosed with CRC, died, or terminated membership in the health plan before returning the initial FIT or within 1 year after their round 1 mail date if no FIT was returned. A total of 670841 health plan members was mailed the initial kit in 2007 or 2008 and met the study eligibility criteria; 323349 (48.2%) returned a FIT within 1 year after the mail date (Figure). The analytic cohort comprised these round 1 participants who were tracked from their baseline mail date (cohort entry) through up to 4 rounds of testing for mail dates; result dates; results (positive or negative); whether follow-up colonoscopy was performed within 1 year after a positive FIT result; and diagnoses of adenoma, adenoma with advanced histology, and CRC. Cohort members were followed for CRC through the follow-up screening rounds, even if they subsequently became ineligible for screening because of sigmoidoscopy or colonoscopy. Patients were censored at the time of CRC diagnosis, death, or termination of membership in the health plan if they did not rejoin. Figure. Study flow diagram.* The figure includes 1192 patients with CRC who were screened by FIT the year before diagnosis. Further, there were 118 additional patients with CRC diagnosed more than 1 y beyond the FIT screening date and 101 additional patients diagnosed with CRC who either crossed over to endoscopy in subsequent rounds or terminated health plan membership but then rejoined. CRC = colorectal cancer; FIT = fecal immunochemical test. * Shading indicates where patients were censored or became ineligible for subsequent FIT screening. Patients were eligible for the initial FIT mailing if they were aged 50 to 70 y and had 1 y of membership. See Methods section for exclusions. Number censored because of CRC and includes patients with CRC diagnosed within 1 y after their FIT result. Defining Annual Screening Episodes For each patient, the initial kit mail date in 2007 or 2008 was the anchor date for round 1 and for each subsequent round of testing. However, because subsequent mailing dates varied each round, mail dates within 3 months before to 12 months after each subsequent rounds anchor date were counted as having been distributed during that specific round. For example, a patient with a round 1 mail date of 15 March 2007 had subsequent anchor dates of 15 March for rounds 2 through 4 (2008, 2009, and 2010, respectively). If their next FIT was mailed on 15 January 2008, the test was considered to be distributed in round 2 because the second mail date occurred within 3 months of the round 2 anchor date. The FIT results recorded within 1 year of each mail date, and colonoscopies performed and adenomas or CRC diagnosed within 1 year after FIT results, were considered part of a single screening episode for the round when the FIT was distributed. Among round 1 participants, FITs with no recorded mail dates returned in rounds 2 through 4 were assumed to be distributed through in-reach methods (such as a clinic visit) and were counted in the follow-up round returned. In general, the first result per patient was counted in any given round. The earliest possible date of cohort entry (first mail date) was 1 January 2007, and the last possible date of follow-up was 31 December 2013 (12 months after the last possible FIT result date of 31 December 2012). Data Sources The FIT-related dates and results were obtained from the CRC screening program and laboratory databases for each region, respectively. Endoscopy procedures were identified using Current Procedural Terminology codes (22). Adenoma diagnoses used Systematized Nomenclature of Medicine codes. Prior validation studies have confirmed high levels of sensitivity and accuracy for capture of colonoscopy examinations and assignment of adenoma status (23). Colorectal adenocarcinomas and disease stage were obtained from the KPNC and KPSC cancer registries, which report to the SEER (Surveillance, Epidemiology, and End Results) registry. Cancer databases capture more than 98% of cancer diagnoses within the KPNC and KPSC populations. Advanced-stage cancer was defined as stage III (regional disease with spread to regional lymph nodes only) or stage IV (distant metastasis) according to the American Joint Committee on Cancer staging system; for patients who did not have such staging, advanced-stage cancer was defined as code 3 (disease in the regional lymph nodes), code 4 (regional disease with direct extension and spread to regional lymph nodes), or code 7 (distant metastasis) according to the SEER Program Coding and Staging Manual 2013 (24). Data Analysis The following performance characteristics were calculated for each round of screening and overall: 1) participation (percentage of eligible patients who were distributed and completed a FIT within 1 year of their mailing date), 2) FIT positivity (percentage of participants who completed FITs and had positive results), 3) follow-up colonoscopy (per

Queue Position in the Endoscopic Schedule Impacts Effectiveness of Colonoscopy

OBJECTIVES:Endoscopist fatigue potentially impacts colonoscopy. Fatigue is difficult to quantitate, but polyp detection rates between non-fatigued and fatigued time periods could represent a surrogate marker. We assessed whether timing variables impacted polyp detection rates at a busy tertiary care endoscopy suite.METHODS:Consecutive patients undergoing colonoscopy were retrospectively identified. Indications, clinical demographics, pre-procedural, and procedural variables were extracted from chart review; colonoscopy findings were determined from the procedure reports. Three separate timing variables were assessed as surrogate markers for endoscopist fatigue: morning vs. afternoon procedures, start times throughout the day, and queue position, a unique variable that takes into account the number of procedures performed before the colonoscopy of interest. Univariate and multivariate analyses were performed to determine whether timing variables and other clinical, pre-procedural, and procedural variables predicted polyp detection.RESULTS:During the 4-month study period, 1,083 outpatient colonoscopy procedures (57.5±0.5 years, 59.5% female) were identified, performed by 28 endoscopists (mean 38.7 procedures/endoscopist), with a mean polyp detection rate of 0.851/colonoscopy. At least, one adenoma was detected in 297 procedures (27.4%). A 12.4% reduction in mean detected polyps was detected between morning and afternoon procedures (0.90±0.06 vs. 0.76±0.06, P=0.15). Using start time on a continuous scale, however, each elapsed hour in the day was associated with a 4.6% reduction in polyp detection (P=0.005). When queue position was assessed, a 5.4% reduction in polyp detection was noted with each increase in queue position (P=0.016). These results remained significant when controlled for each individual endoscopist.CONCLUSIONS:Polyp detection rates decline as time passes during an endoscopists schedule, potentially from endoscopist fatigue. Queue position may be a novel surrogate measure for operator fatigue.

Influence of Crohn's disease risk alleles and smoking on disease location.

OBJECTIVE: Our objective is to assess the effect of genetic and environmental factors on Crohns disease location. DESIGN: We identified 628 patients with Crohns disease within the Washington University database (April 2005 through February 2010) that had complete information on 31 Crohns disease-associated genotypes and clinical information on disease location (L1 to L4), smoking, sex, race, and age at diagnosis. For statistical reasons, the 3 major NOD2 alleles (rs2066844, rs2066845, and rs2066847) were grouped together. Logistic regression incorporating all of the genotypes and clinical covariates, including smoking, was performed with stepwise variable selection and by best subset selection. RESULTS: Stepwise variable selection selected 3 major covariates, composite NOD2 genotype, smoking, and TNFSF15 genotype, which are also the 3 covariates selected by the best subset method. Whereas the NOD2 genotype and smoking are positively associated with ileal (L1 + L3) disease, the TNFSF15 genotype is positively associated with isolated colonic (L2) disease. LIMITATIONS: The ability to detect disease site associations in this single-center study may be limited by the population size, low allelic frequency, and/or low odds ratio of certain Crohns disease risk alleles. CONCLUSION: These results indicate that NOD2 genotype, smoking status, and TNFSF15 genotype should be included as covariates in assessing the effect of genetic and environmental factors on Crohns disease site location.

IDO1 and IDO2 Non-Synonymous Gene Variants: Correlation with Crohn's Disease Risk and Clinical Phenotype

Background Crohns disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Genetic polymorphisms can confer CD risk and influence disease phenotype. Indoleamine 2,3 dioxygenase-1 (IDO1) is one of the most over-expressed genes in CD and mediates potent anti-inflammatory effects via tryptophan metabolism along the kynurenine pathway. We aimed to determine whether non-synonymous polymorphisms in IDO1 or IDO2 (a gene paralog) are important either as CD risk alleles or as modifiers of CD phenotype. Methods Utilizing a prospectively collected database, clinically phenotyped CD patients (n = 734) and non-IBD controls (n = 354) were genotyped for established IDO1 and IDO2 non-synonymous single nucleotide polymorphisms (SNPs) and novel genetic variants elucidated in the literature. Allelic frequencies between CD and non-IBD controls were compared. Genotype-phenotype analysis was conducted. IDO1 enzyme activity was assessed by calculating the serum kynurenine to tryptophan ratio (K/T). Results IDO1 SNPs were rare (1.7% non-IBD vs 1.1% CD; p = NS) and not linked to Crohns disease diagnosis in this population. IDO1 SNPs did however associate with a severe clinical course, presence of perianal disease, extraintestinal manifestations and a reduced serum K/T ratio during active disease suggesting lower IDO1 function. IDO2 minor allele variants were common and one of them, rs45003083, associated with reduced risk of Crohns disease (p = 0.025). No IDO2 SNPs associated with a particular Crohns disease clinical phenotype. Conclusions This work highlights the functional importance of IDO enzymes in human Crohns disease and establishes relative rates of IDO genetic variants in a US population.

The impact of opiate pain medications and psychoactive drugs on the quality of colon preparation in outpatient colonoscopy.

BACKGROUND Suboptimal colon preparation is a significant barrier to quality colonoscopy. The impact of pharmacologic agents associated with gastrointestinal dysmotility on quality of colon preparation has not been well characterized. AIMS Evaluate impact of opiate pain medication and psychoactive medications on colon preparation quality in outpatients undergoing colonoscopy. METHODS Outpatients undergoing colonoscopy at a single medical centre during a 6-month period were retrospectively identified. Demographics, clinical characteristics and pharmacy records were extracted from electronic medical records. Colon preparation adequacy was evaluated using a validated composite colon preparation score. RESULTS 2600 patients (57.3 ± 12.9 years, 57% female) met the inclusion and exclusion criteria. 223 (8.6%) patients were regularly using opioids, 92 antipsychotics, 83 tricyclic antidepressants and 421 non-tricyclic antidepressants. Opioid use was associated with inadequate colon preparation both with low dose (OR = 1.4, 95%CI 1.0-2.1, p = 0.05) and high dose opioid users (OR = 1.7, 95%CI 1.1-2.9, p = 0.039) in a dose dependent manner. Other significant predictors of inadequate colon preparation included use of tricyclics (OR = 1.9, 95%CI 1.1-3.0, p = 0.012), non-tricyclic antidepressants (OR = 1.5, 95%CI 1.1-2.0, p = 0.013), and antipsychotic medications (OR = 2.2, 95%CI 1.4-3.4, p = 0.001). CONCLUSIONS Opiate pain medication use independently predicts inadequate quality colon preparation in a dose dependent fashion; furthermore psychoactive medications have even more prominent effects and further potentiates the negative impact of opiates with concurrent use.

Tu1034 Impact of Fatigue on Colonoscopic Adenoma Detection in a Large Community-Based Managed Healthcare System

national pathology database (PALGA) and the Netherlands Cancer Registry. Patients with hereditary forms of CRC or inflammatory bowel disease were excluded. We defined mCRCs as second primary colorectal adenocarcinomas, diagnosed at least 6 months after the primary CRC. We characterized the CRCs according to location, size, shape and clinical stage. Using a modified algorithm for ascribing the potential etiology, we classified the mCRCs into cancers due to non-compliance with surveillance recommendations, inadequate examination (incomplete or suboptimal bowel prep), incomplete resection (CRC in same segment as previous advanced adenoma), missed lesions, or newly developed cancers (Pabby et al, Gastrointest Endosc, 2005). Results: We included a total of 5,157 CRC patients with 5,357 CRCs (mean age 70.0 yrs; 53.7% males). Of these, 93 (1.8%) patients with 98 mCRCs were examined (mean age at index CRC diagnosis: 67.3 yrs, range 36-88). Metachronous CRCs were diagnosed on average (range) 81 (7-356) months after the initial CRC diagnosis, of which 40.8% were diagnosed within 3 years. Of the mCRCs, 43.0% were attributable to non-compliance with surveillance guidelines, 3.2% to inadequate examination, 5.4% to incompletely resected lesions, 43.0% to missed lesions, and 5.4% to newly developed cancers (Figure). Logistic regression analyses, adjusting for age and gender showed that mCRCs were significantly smaller in size (OR 0.8, 95%CI 0.7-0.9) and had more often a flat macroscopic appearance (OR 1.8, 95%CI 1.2-2.7) than sporadic CRCs. No significant differences were found between mCRCs and sporadic CRCs with regard to location and stage of tumor at the time of diagnosis. Similar rates of mCRCs were found across hospitals. Conclusion: In our experience, mCRCs accounted for 1.8% of all CRCs and the vast majority could be explained by missed lesions or non-compliance with surveillance recommendations. Our findings highlight potential targets for quality improvements in post-CRC surveillance by colonoscopy.

315 The Effect of Ambient Temperature on the Performance of Mailed Fecal Immunochemical Tests for Population-Based Screening

FIT tests within two weeks, the lifetime incidence of CRCwas 35.5 cases per 1,000 individuals screened (figure). Of these cancers, 18.5, 9.1, 4.7 and 3.2 were diagnosed in stage I-IV, respectively, and CRC deaths occurred in 7.8 per 1,000 patients. The incidence of CRC increased when diagnostic follow-up was delayed. In a scenario with 12-month delays, there were 37.0 cases per 1,000 (relative risk (RR) 1.04), of which fewer cases (17.1 per 1,000) were diagnosed in stage I, and more cases (19.9 per 1,000) were diagnosed in stages II-IV. Further, the delays led to an increased incidence and risk of colorectal deaths -8.0 per 1,000 (RR 1.03), 8.2 per 1,000 (RR 1.06), and 8.7 per 1,000 (RR 1.12) for 3-, 6and 12month delays, respectively. CONCLUSION: Delaying the diagnostic follow-up of a positive FIT decreases the likelihood that colorectal cancer is detected in an early, more treatable stage. This could increase colorectal cancer deaths by more than 10% compared to no delays.

956 The Effect of an Organized Screening Program on Racial and Ethnic Disparities and Choice of Colorectal Cancer Screening Test

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third most common cause of cancer deaths in both men and women in the United States. Blacks have been reported to have a higher incidence and mortality and a more proximal anatomic distribution of CRC compared to whites and Hispanics. However, it is unclear whether this is due to biological differences in the pathology of adenomatous polyps or lower screening rates. Existing data consisting of retrospective studies and one single center prospective study indicate that factors such as access to health care and modifiable risk factors may be responsible for these racial disparities as opposed to biological differences. Methods: In 2003, the New York City Department of Health and Mental Hygiene (NYC DOHMH) implemented the Colonoscopy Patient Navigator Program (CPNP). Ten New York City Hospital Sites, five public and five private, participated in the study. Through a one to one relationship, PN helped to bridge disparities by scheduling appointments, educating regarding bowel preparation and addressing obstacles. Data were prospectively collected from 2005 through the first quarter of 2012 from centers with at least three consecutive years of reporting while using PN. Patient information including name, contact information, gender, date of birth, ethnicity and insurance information was collected by each PN during the initial contact after the patient was referred for screening colonoscopy (sCo). Adenoma and cancer detection rates, pathology and location were recorded and stratified by patient demographic characteristics including age, gender, and race. Results: With the assistance of PN, 29,711 individuals ages 50 and older underwent complete sCo. A total of 6226 adenomas and 35 cancers were found. The prevalence of adenomas was higher among white patients than black patients (27.45% versus 19.35%, p value < 0.05) (See tables 1 and 2). With the exception of the hepatic flexure, whites had a statistically significant higher prevalence of adenomas, segment by segment, than blacks and Hispanics. Conclusion: This is a prospective multicenter center study of a large urban cohort investigating the prevalence of adenomas in blacks versus whites and Hispanics using a PN program. Preliminary data do not show that blacks have an increased risk of adenomas compared to whites and Hispanics. This suggests that the higher incidence and mortality from CRC in blacks that was reported in other studies aremore likely a function of access to colonoscopy as opposed to biologic factors. Table 1: Results of completed screening colonoscopy exams cross-tabulated by patient race (age ≥ 50)

W1234 Non-Synonymous Polymorphisms in the Tryptophan Catabolism Pathway: Correlation to Crohn's Disease Risk and Phenotype

Background. Clinical data support the existence of discrete subsets of Crohns disease (CD) patients by disease location. Previous genotype-phenotype analyses have linked the NOD2 and ATG16L1 risk alleles with ileal disease location. Aim. To elucidate novel genotypesubphenotype correlations between 28 established CD risk alleles and disease location (Montreal classification).Methods. We reviewed our established inflammatory bowel disease relational genotypic-phenotypic database. We identified 600 CD patients that had been genotyped for 28 established CD risk alleles that were selected based on previous genome wide association studies [Barrett et al. Nature Genetics 2008; 40:955]. Genotyping was conducted using Taqman allelic discrimination and Sequenom MassARRAY®. The patients were classified as risk (at least one risk allele) or non-risk (no risk allele). In addition, the three major NOD2 risk alleles (Leu1007fs, R702W and G908R) were combined as a single superallele where the NOD2 risk group harbored at least one of the three risk alleles and the NOD2 non-risk group had none of the three risk alleles. The patients were subphenotyped with respect to their maximal disease location using the Montreal classification. Genotypesubphenotype analysis was carried out usingmultinomial logistic regression analysis.Results. The distribution of disease locations were 274 for L1 (ileal), 126 for L2 (colonic), 187 for L3 (ileocolonic), and 3 for L4 (upper small bowel). Five CD risk alleles were significantly associated with disease location (L1 vs L2 vs L3, P<0.05, see Table 1). We detected no effect of gender, race or smoking on disease location. Conclusions. These results support the concept that there is a genetic basis for CD subphenotypes by disease location. Although both NOD2 and ATG16L1 have been associated with ileal disease, harboring a NOD2 risk allele is associated with L1 disease location, whereas harboring the ATG16L1T300A risk allele is associated with L3 disease location. The TNSF15 risk allele is associated with L2 disease location, whereas the X21q21 risk allele is associated with L3 disease location. Table 1. Significant CD risk alleles