Patients with long-standing, extensive ulcerative colitis (UC) Progression to Colorectal Neoplasia in Ulcerative Colitis: Effect of Mesalamine

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:1225 1230 Progression to Colorectal Neoplasia in Ulcerative Colitis: Effect of Mesalamine THOMAS ULLMAN,* VICTORIA CROOG,* NOAM HARPAZ, SABERA HOSSAIN, ASHER KORNBLUTH,* CAROL BODIAN, and STEVEN ITZKOWITZ* *Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine; Division of Gastrointestinal Pathology, Department of Pathology; and the Department of Biomathematical Sciences, Mount Sinai School of Medicine, New York, New York See CME exam on page 1177. Background & Aims: Some studies have suggested that mesalamine can prevent the development of colorectal cancer in patients with ulcerative colitis (UC). The aim of this study was to compare rates of progression with advanced neoplasia in patient cohorts with UC taking low and high doses of mesalamine and to determine where in the process of neoplastic progression mesalamine might act. Methods: Three cohorts of UC patients were identified from an institutional database: 311 patients with no dysplasia (NoD), 56 with indefinite dysplasia (IND), and 26 with flat low-grade dysplasia (flgd). The impact of mesalamine exposure on the subsequent development of advanced neoplasia (high-grade dysplasia or colorectal cancer) was assessed using life-table methods. Results: Seventeen of 311 patients with NoD progressed to advanced neoplasia (5-year rate, 1.1%). This rate was lower than the 5-year rate for the IND (9%; P.02 vs NoD) and flgd (45%; P <.001 vs NoD and P.001 vs IND) cohorts. Among the NoD cohort, the hazard ratio for mesalamine users versus nonusers was 0.70 (95% confidence interval, 0.20 2.44), and for each 1 g/d increase in dose, the hazard ratio was 0.92 (95% confidence interval, 0.58 1.47). For patients with IND, no patients on greater than 2 g/d progressed versus 13.8% on low-dose mesalamine (P.11). For flgd, 62.5% on high dose progressed, versus 27.8% on low dose (P.054). Conclusions: In long-standing UC, patients with flgd have a higher rate of progression to advanced neoplasia than those with NoD or IND. However, at none of these stages of disease did mesalamine use show definitive chemopreventive activity. Patients with long-standing, extensive ulcerative colitis (UC) carry an increased risk for the development of colorectal cancer (CRC). 1 It is commonly believed that the development of neoplasia in UC is manifested by progressively severe histologic abnormalities classified as low-grade dysplasia (LGD), highgrade dysplasia (HGD), and, ultimately, invasive carcinoma. 1 Despite attempts to prevent CRC by a program of periodic colonoscopic surveillance, and because the precancerous changes do not necessarily progress in a sequential manner, CRC still may occur without the prior discovery of dysplasia. 1 This raises the question of whether other approaches such as chemoprevention should be used in conjunction with surveillance colonoscopy. Several studies have examined whether mesalamine is chemopreventive in UC. 1 9 Its effect within a surveillance cohort and on progression from early to more advanced neoplasia are unknown, as is its relative influence at different points in the colitis-dysplasia-carcinoma sequence. Because most previous studies used a case-control design, little is known about the possible impact of mesalamine dose changes over time. In the present study, we attempted to address these issues by using a retrospective cohort design. This design allowed us to analyze changes in mesalamine dose over time as well as at different points in the colitis-dysplasia-carcinoma sequence. Ultimately, we analyzed 3 cohorts of patients representing different stages of early neoplastic progression for the development of higher grades of dysplasia or CRC. Materials and Methods Identification of Subjects This study was conducted with the approval of the Mount Sinai School of Medicine Institutional Review Board, and in accordance with the Health Insurance Portability and Accountability Act regulations. All patients were identified using the Mount Sinai Gastrointestinal Pathology database. Patients with no dysplasia (NoD) and indefinite dysplasia (IND) were drawn from a query of UC surveillance colonoscopies performed on UC patients from January 1996 through December 1997. This time period was chosen to allow for sufficient follow-up evaluation. The cohort of UC patients with flat LGD (flgd) originally was identified as part of a previous institutional review board approved study conducted by our group in which we queried the Pathology database from January 1994 through December 2001. 10 Clinical Information By using the medical records of patients who were identified via the Gastrointestinal Pathology database query, a UC Surveillance Database was populated abstracting the following information: sex, date of birth, date of UC diagnosis Abbreviations used in this paper: CRC, colorectal cancer; flgd, flat low-grade dysplasia; HGD, high-grade dysplasia; IND, flat indefinite for dysplasia; LGD, low-grade dysplasia; NoD, no dysplasia; UC, ulcerative colitis. 2008 by the AGA Institute 1542-3565/08/$34.00 doi:10.1016/j.cgh.2008.05.020

1226 ULLMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 11 (based on the earlier of either symptom onset or diagnosis), and anatomic extent of disease. Extraintestinal manifestations and medication use were recorded. Pathology reports for all colonoscopies were reviewed, and, from these, the anatomic extent of inflammation and the location and number of all biopsies were tabulated. Endoscopy reports were reviewed and correlated with all pathology reports. Surgical reports and findings at colectomy both by the surgeon and the attending pathologist also were recorded. Other Inclusion and Exclusion Criteria Patients were included for a confirmed diagnosis of UC, and all colonoscopic examinations were considered to be for surveillance purposes if they were stated as such in the colonoscopy report, the pathology report, or if no specific reason for the examination was given and multiple biopsy specimens were taken in a patient with 7 or more years of disease. Patients were excluded if they had any previous colonic resection in an area of colitis, a diagnosis of Crohn s disease, a finding of IND or flgd outside of an area of colitis, a lack of endoscopic or surgical follow-up evaluation subsequent to inclusion, inadequate or absent information on mesalamine use, or inaccessible medical records. All clinical, endoscopic, and histologic diagnoses were recorded exactly as they were rendered in clinical practice; none were revised for the purpose of this study. In accordance with the retrospective nature of this study and consistent with the realities of routine clinical practice, the pathologist was unblinded to the patient s diagnosis, but was not made aware of any specifics of mesalamine use. Mesalamine Use The daily gram-equivalency of mesalamine was calculated as follows: one gram of sulfasalazine was considered equal to 0.4 g of mesalamine, one gram of balsalazide (Colazal; Salix Pharmaceuticals, Morrisville, NC) was equivalent to 0.356 g of mesalamine, mesalamine (Asacol; Proctor and Gamble Pharmaceuticals, Cincinnati, OH and Pentasa; Shire Pharmaceuticals, Wayne, PA) and olsalazine (Dipentum; Alaven Pharmaceutical, LLC, Marietta, GA) had one-to-one equivalency. For the purpose of this study, a dose of greater than 2.0 g/d was considered high dose, whereas an average daily dose of 2.0 g or less, including those patients who never took mesalamine, was designated low dose. Histologic Interpretation All biopsy specimens were classified as NoD, IND, LGD, HGD, or invasive cancer (CRC) based on the criteria of the Inflammatory Bowel Disease Morphology Study Group. 11 The diagnoses were rendered prospectively by expert faculty members of Mount Sinai s Division of Gastrointestinal Pathology and confirmed in intradepartmental conference by its director, a gastrointestinal pathologist highly experienced in evaluating inflammatory bowel disease associated dysplasia (N.H.). Diagnoses were not altered and specimens were not re-evaluated as part of this study, but rather reflected the real-time status of patients as understood by their gastroenterologists as part of routine practice. Subclassifications of IND were not used in this study. Biopsy specimens with LGD were subclassified as flgd when the respective histologic diagnosis was made in the absence of concomitant documentation of a mass or polypoid lesion at that biopsy site by the endoscopist in either the endoscopy note or on the pathology request form. Patients were entered into the study at the first colonoscopy that showed NoD, IND, or flgd. Patients were considered to have NoD if they had no documentation of concomitant or previous polypoid or flat dysplasia or CRC; IND if they had no documentation of concomitant or previous IND, polypoid or flat dysplasia, or CRC; and flgd if they had no documentation of concomitant or previous polypoid LGD, or polypoid or flat HGD or CRC. Study Definitions Advanced neoplasia was defined as HGD or CRC. Progression was defined as the development of advanced neoplasia either during surveillance or at colectomy. Time zero was defined as the date of the initial surveillance colonoscopy that found NoD, IND, or flgd. Patients were censored at the time of their last colonoscopy without progression or until colectomy. The follow-up period was the time from time zero to progression or censoring. Statistical Analysis Medians and ranges were calculated for continuous variables; proportions were calculate for binary variables. The outcome of interest was progression to advanced neoplasia. Crude proportions are shown for descriptive purposes only. Life-table analysis was used to describe the progression and to test for the influence of covariates known at entry, such as duration of disease, extent of disease, primary sclerosing cholangitis, and age at onset of disease. The influence of the primary variable of interest, mesalamine use, was not always constant during the follow-up period. To account for this variable s changing status during the follow-up Figure 1. At time zero (t 0 ) all patients begin. Every time a patient in the cohort develops advanced neoplasia, an event is registered by the model, and the mean daily dose of mesalamine is calculated for each patient in the model from t 0 to the time of the event. Here, patient A develops HGD, and event A is registered. Each patient s mean daily dose of mesalamine is calculated from t 0 to the time of event A. The next event in the cohort is the development of colon cancer in patient B. The mean daily dose of mesalamine is calculated for each patient still under surveillance from t 0 to the time of event B. This is performed for events in the model, and the variable in question, in this case mesalamine dose, is assessed for its impact.

November 2008 MESALAMINE AND COLORECTAL NEOPLASIA IN UC 1227 Table 1. Patient Characteristics Mesalamine status NoD a (n 311) IND (n 56) flgd (n 26) High dose Low dose High dose Low dose High dose Low dose n(%) 93 (30) 218 (70) 27 (48) 29 (52) 8 (31) 18 (69) No mesalamine exposure, % 18 10 28 Male, % 56 52 74 59 62 72 Median age at UC diagnosis (range), y 27 (6 59) 27 (6 69) 25 (7 60) 24 (11 54) 26 (7 59) 28 (13 54) Median duration of UC at t 0 (range), y 13 (7 37) 16 (8 48) 17 (10 57) 17 (10 33) 16 (10 60) 22 (9 45) Extensive disease, % 75 81 96 93 75 89 Primary sclerosing cholangitis, n (%) 0 (0) 3 (1) 1 (4) 5 (17) 0 (0) 0 (0) t 0, initial colonoscopy on record. a Mean taken over the course of each patient s surveillance history. The effect of the mesalamine dose was calculated as a time-changing covariate in this cohort, for which status above and below the 2 g/d equivalent could change during the follow-up period. period and to allow for assessment of its cumulative effect, it was analyzed as a time-changing covariate in a proportional hazards model (Cox regression) in the NoD cohort, 12 with values updated as follow-up evaluation proceeded (Figure 1). We have used this approach to study the effect of purine analog immunomodulator use on the progression to CRC in UC. 13 With the exception of the handling of mesalamine exposure as a time-changing covariate, there are no differences between this type of proportional hazards modeling and any other that examines the influence of independent variables on a timedependent outcome. In separate analyses, mesalamine use was characterized first by comparing those who ever used these medications with nonusers. Second, a cut-off level of 2 gramsequivalent per day mean exposure was assessed to evaluate for a greater than 0 threshold effect. Finally, dose effect over time was assessed by considering the cumulative average dose of mesalamine as a continuous variable. It turned out that no patients in the flgd cohort varied their dose across the 2 g/d threshold, and so analysis of this group was analyzed by comparing low- and high-dose users with mesalamine as a fixed, and not time-changing, covariate. In the IND cohort, this convention was used as well because only 2 patients crossed the 2 g/d threshold during the follow-up period. In addition to assessing the effect of mesalamine on progression in the 3 cohorts (NoD, IND, and flgd), we assessed the difference in rates of progression between the 3 cohorts themselves, using life-table analysis and log-rank testing. All analyses were performed using statistical software on a PC (SAS [SAS, Cary, NC] for NoD cohort analyses and SPSS [SPSS, Inc, Chicago, IL] for flgd and IND cohorts, as well as the analysis of progression between cohorts). Results Cohort Identification and Patient Characteristics From the UC Surveillance Database, 311 subjects met inclusion criteria for the NoD cohort, 56 for the IND cohort, and 26 for the flgd cohort. Fifty-nine patients were excluded because of incomplete information concerning mesalamine exposure. The clinical features of the subjects at the time of entry into the study are detailed in Table 1, and are classified according to patients mean daily dose of mesalamine averaged over the duration of their follow-up period. Between the cohorts, there were no significant differences in sex, age, and extent or duration of disease. There were, however, more patients with primary sclerosing cholangitis in the IND cohort on low-dose mesalamine (5 of 27; 17%) than high-dose mesalamine (1 of 29; 4%). Features of Patient Follow-Up Table 2 details the characteristics of surveillance among the 3 cohorts. The median time from entry into the study to the primary end point (advanced neoplasia or censoring at last colonoscopy without progression or surgery without progression) was nearly 7 years for the dysplasia-free group (initial NoD), but slightly less than half as long (3 years) for the groups with initial IND or flgd. Within each cohort, there were no important Table 2. Details of Patient Follow-Up Evaluation According to Dysplasia Status at Entry Into Study Mesalamine status NoD a (n 311) IND (n 56) flgd (n 26) High dose Low dose High dose Low dose High dose Low dose Follow-up duration, y 5.6 (0.2 14.5) 7.4 (0.6 15.5) 2.4 (0.5 9.1) 4.1 (0.3 10.5) 2.6 (0.1 8.4) 3.0 (0.1 13.5) Colonoscopies 5 (2 13) 5 (2 15) 3 (2 8) 5 (2 12) 4.5 (1 10) 4.5 (1 15) Surveillance interval, mo 17 (11 63) 20 (4 68) 12 (3 32) 13.1 (2 52) 13 (6 17) 9 (2 24) Specimen jars per colonoscopy 9 (3 12) 9 (4 12) 9 (7 14) 9 (7 11) 8 (5 11) 10 (7 15) Biopsy specimens per colonoscopy 14 (6 21) 13 (5 30) 16 (11 25) 14 (10 36) 18 (11 23) 16 (10 25) NOTE. All results are reported as median (range). t 0, initial colonoscopy on record. a The mean dose taken over the course of each patient s surveillance period. The effect of the mesalamine dose was calculated as a time-changing covariate in this cohort, for which status above and below the 2 g/d equivalent could change during the follow-up period.

1228 ULLMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 11 Table 3. Progression to Advanced Neoplasia in 3 Cohorts NoD (n 311) IND (n 56) flgd (n 26) Progressors, n 17 4 10 Cases of CRC, n 7 2 3 5-year rate of progression to advanced neoplasia (95% confidence interval) 1.1% (0% 2.3%) 9.0% (0% 19.2%) 44.9% (20.4% 69.4%) Low-dose mesalamine progressors, n 14/218 a 4/29 b 5/18 c High-dose mesalamine progressors, n 3/93 0/27 5/8 a See Table 4 for actuarial comparison of mesalamine use on progression to advanced neoplasia in the NoD cohort. b See Figure 3 for actuarial comparison of low- and high-dose mesalamine users. c See Figure 4 for actuarial comparison of low- and high-dose mesalamine users. differences in surveillance intensity between high-dose and lowdose groups. All patients had an average of 5 surveillance examinations during the follow-up period, which ranged from a median of 4.5 for the flgd cohort to 5 for the NoD cohort. The median time interval between surveillance examinations was longer for the NoD cohort (20 months) compared with the flgd cohort (12 months). Surveillance biopsy specimens were taken from a median of 8 to 10 sites throughout the colon, and the median number of biopsy specimens available for pathologic review ranged from 13 to 18 per examination. We first analyzed the overall rates of progression for each cohort (Table 3). Of the 311 patients in the NoD cohort, 17 progressed to advanced neoplasia; of these, 7 were CRCs. For the IND cohort, 4 of 56 subjects progressed (2 to CRC); 10 of the 26 flgd subjects progressed (3 to CRC). On an actuarial basis, the 5-year rate of progression to advanced neoplasia was 1%, 9%, and 45% for the NoD, IND, and flgd cohorts, respectively (Table 3, Figure 2). These rates were significantly different from each other: flgd showed a greater rate of progression compared with either the IND (P.001 by log-rank testing) or the NoD cohort (P.001 by log-rank testing); IND progressed at a greater rate than NoD (P.02 by log-rank testing). Of note, progression from NoD to advanced neoplasia did not appear linear; most events occurred 10 years after their first recorded surveillance examination. Progression in the IND and flgd cohorts occurred earlier (Figure 2). Effect of Mesalamine on Progression Dysplasia-free cohort. A proportional hazards analysis was performed on the NoD cohort coding mesalamine as a time-changing covariate and assessing its impact in 3 ways: (1) comparing those with mesalamine use at any time during surveillance with nonusers; (2) comparing those whose average dose was greater than 2 g/d with those with 2 g/d or less (with the mean dose calculated at each event as depicted in Figure 1); and (3) calculating the overall effect of mesalamine use for each 1-g increase in dose over the course of surveillance. By using this model, no statistically significant chemopreventive effect was shown comparing never users with any use of mesalamine, as well as comparing low- and high-dose users at the 2 g/d cut-off level (Table 4). In addition, for each 1-g increase in average daily mesalamine use, there was an 8% reduction in the hazard ratio estimate in our third analysis of this cohort; this estimate in reduction was not statistically significant. To determine whether known potential confounders altered the estimate of the effect of mesalamine use on subsequent neoplastic progression, we performed univariate assessment of these variables in a proportional hazards model, followed by multivariable testing for those variables whose P values were less than.10 (Cox regression). None of the potential confounders (sex, extent of disease, duration of disease, or age of onset) had a meaningful effect in univariate testing (data not shown; supplementary Table 1; see supplementary material online at www.cghjournal.org); testing was not performed on the primary sclerosing cholangitis group because so few patients in the NoD group had this diagnosis. In addition, none of these variables substantially modified the effect of mesalamine in multivariable analysis (data not shown). Indefinite dysplasia and low-grade dysplasia cohorts. Rates of progression to advanced neoplasia then were analyzed for the IND and LGD cohorts taking into account the Table 4. Effect of Mesalamine Use on Progression to Advanced Neoplasia in Proportional Hazards Model (Univariate) in Patients in NoD Cohort Any vs none Mesalamine use 2 vs 2 g/d For each 1-g/d increase in mesalamine vs none Figure 2. Progression to advanced neoplasia among patients in all cohorts. Hazard ratio 0.70 0.77 0.92 95% CI 0.20 2.44 0.22 2.67 0.58 1.47 CI, confidence interval.

November 2008 MESALAMINE AND COLORECTAL NEOPLASIA IN UC 1229 Figure 3. Progression to advanced neoplasia in the IND cohort. mean daily dose of mesalamine over the entirety of each individual s surveillance history, and coded in a binary fashion with 2 g/d equivalent again serving as the cut-off value (Table 3, Figures 3 and 4). Overall, 14 patients with IND progressed to LGD, HGD, or CRC during follow-up evaluation. Of note, in the IND cohort, none of the 27 patients in the high-dose group progressed to HGD or CRC, whereas 4 of the 29 subjects in the low-dose group did. Despite this rather marked difference actuarially (Figure 3), statistical significance was not achieved (P.11 by log-rank test). For the LGD cohort, 5 patients in both the high- and low-dose groups progressed over the course of surveillance (Table 3, Figure 4). Patients on high-dose mesalamine seemed to progress more rapidly, although the actuarial difference in progression rates was not statistically significant (P.054 by log-rank test). Discussion Previous studies have found evidence both to support 2,3,5 8 and refute 4,9,14,15 mesalamine-based agents as chemopreventive in colitis-associated neoplasia. The present cohort study enabled us to address not only whether, but where, in the colitisdysplasia-carcinoma sequence mesalamine compounds might exert a chemopreventive effect. Our methodology also allowed us to account for changes in mesalamine exposure over time, an underappreciated concept in the chemopreventive literature, in which some studies have defined exposure as just 3 months of continuous use at any time during the course of UC. We did not detect a significant chemopreventive effect for mesalamine, although point estimates slightly favored chemoprevention in the NoD and IND groups. In the NoD group, a mean daily dose of at least 2gof mesalamine resulted in a hazard ratio estimate of 0.77, but the upper boundary of the 95% confidence interval was greater than 1. Likewise, in the IND group, there were no progression events in the high-dose mesalamine group, whereas nearly 14% of patients in the low-dose group went on to develop advanced neoplasia. Overall, therefore, no chemopreventive effect was found, although the possibility of a weak effect remains. One possible reason why we were unable to achieve statistical significance using the proportional hazards model is that there were very few progression events in the NoD group. Before undertaking our study, little information was available regarding rates of progression among individuals with dysplasia-free screening examinations. By simultaneously performing an analysis of the natural history of neoplastic progression within each cohort, we found strikingly different 5-year actuarial rates of progression to advanced neoplasia between patients with initial NoD (1%), IND (9%), and flgd (45%). Because event rates drive the sample size calculations, we calculate that given the hazard ratio observed, we would have needed approximately 3000 patients with an initial surveillance finding of NoD to reach statistical significance. Another corollary to the low event rate stems from the probability that dysplasia surveillance works by identifying those at greatest risk at the initial (screening) examination. Our observed event rate for the NoD cohort is less than half of what would have been expected based on the Eaden et al 7 meta-analysis, and suggests that the so-called natural history of patients in a surveillance program is different from the natural history of UC patients overall. Recent evidence from a case-control study supports the concept that exposure to colonoscopy reduces the risk of CRC in longstanding colitis independent of exposure to anti-inflammatory medications. 16 It is quite possible, therefore, that the absolute risk reduction of mesalamine (or any putative chemopreventive agent) is small in the context of a surveillance program in which an initial examination decreases the hazard for those who are dysplasia-free by greater than half. The flgd group showed a fairly high rate of progression to advanced neoplasia, regardless of mesalamine dose. Although the flgd cohort was created in a similar fashion to the IND and NoD cohorts, the calendar time band of inclusion was somewhat greater, with 8 of the 26 flgd patients having all of their examinations before or after 1996 1997, the requirement for inclusion in the IND or NoD cohorts. It is doubtful, however, that this subtle difference introduced any selection biases because neither the indications for colectomy nor the histologic interpretation of dysplasia by our expert gastrointestinal pathologists changed during these time periods. Curiously, high-dose mesalamine use after flgd appeared to increase the risk of progression in this small cohort. This lack of chemopreventive activity for mesalamine in the flgd group is not surprising because we previously reported a substantial risk of synchronous or metachronous advanced neoplasia once flgd was found. 10 It is noteworthy that the actuarial progression of IND patients in our study was intermediate between the NoD and LGD groups. Figure 4. Progression to advanced neoplasia in the flgd cohort.

1230 ULLMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 11 Our findings suggest that despite the heterogeneity and inherent uncertainty of this category, patients diagnosed with IND may represent a subgroup that might be useful in future chemoprevention studies. Little is known about the natural history of IND, and some have questioned whether this histologic category is clinically meaningful. Our results showed that a finding of IND at surveillance carries a risk intermediate to that of flgd and NoD. A potential limitation of our study was that we created and analyzed results from a single-center, nonprotocolized, retrospective, surveillance system database. Although the single-center orientation of the study raises some concerns about the external validity of our findings, it is hard to imagine that mesalamine exposure somehow exerted a different effect at our center than would have been seen in subjects at another center, in a multi-institutional study, or in a population-based cohort. Another potential limitation to the validity of our findings was a result of our nonprotocolized surveillance system. This might have resulted in less regimented surveillance intervals or insufficient biopsy sampling than would be seen in a protocol-based system. Although these features could have affected our findings, we found that surveillance frequency and biopsy practices were similar between low-dose and high-dose mesalamine users. Actually, varied surveillance may improve the external validity of our results because most clinicians in practice perform dysplasia surveillance outside the confines of a clinical trial, and are free to perform examinations at varied intervals with varied biopsy practices. Also, the fact that all slides were interpreted by a single group of gastrointestinal pathologists and reviewed by one expert may explain why we were able to discern distinct natural history curves for the NoD, IND, and LGD groups. Although this single-group:one-expert paradigm may limit the generalizability of our findings, there is no accepted manner to broker disagreements between old reports and updated reinterpretations; we therefore elected not to have specimens re-read. Of note, pathologists were blind to mesalamine doses. As for the retrospective nature of our study, we doubt that this orientation biased our results because much of the data collected antedated the first positive studies for mesalamine as a chemopreventive agent, and no meaningful changes in prescribing habits were observed after these publications. It is doubtful that our colleagues were sufficiently prescient to have altered their mesalamine prescribing habits in advance of these initial works. In conclusion, our findings failed to show chemoprevention for mesalamines in colitis-related CRC for patients enrolled in a surveillance program. Although there still remains the possibility that mesalamine compounds play a chemopreventive role for CRC in UC, a rather large cohort would be needed to show such an effect in a statistically significant way. Further studies are required to elucidate the role of chemopreventive agents in UC patients under surveillance. 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Long-term therapy with sulphasalazine protects against colorectal cancer in ulcerative colitis: a retrospective study of colorectal cancer risk and compliance with treatment in Leicestershire. Eur J Gastroenterol Hepatol 1996;8:1179 1183. 6. Pinczowski D, Ekbom A, Baron J, et al. Risk factors for colorectal cancer in patients with ulcerative colitis: a case-control study. Gastroenterology 1994;107:117 120. 7. Eaden J, Abrams K, Ekbom A, et al. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 2000;14:145 153. 8. Rubin DT, LoSavio A, Yadron N, et al. Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis. Clin Gastroenterol Hepatol 2006;4:1346 1350. 9. Terdiman JP, Steinbuch M, Blumentals WA, et al. 5-Aminosalicylic acid therapy and the risk of colorectal cancer among patients with inflammatory bowel disease. Inflamm Bowel Dis 2007;13:367 371. 10. Ullman T, Croog V, Harpaz N, et al. Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003;125:1311 1319. 11. Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983;14:931 968. 12. Cox DR. Regression models and life tables. J R Stat Soc Ser B Method 1972;34:187 220. 13. Matula S, Croog V, Itzkowitz S, et al. Chemoprevention of colorectal neoplasia in ulcerative colitis: the effect of 6-mercaptopurine. Clin Gastroenterol Hepatol 2005;3:1015 1021. 14. Lashner BA, Heidenreich PA, Su GL, et al. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study. Gastroenterology 1989; 97:255 259. 15. Lashner BA, Provencher KS, Seidner DL, et al. The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterology 1997;112:29 32. 16. Velayos FS, Loftus EV Jr, Jess T, et al. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study. Gastroenterology 2006;130:1941 1949. Address requests for reprints to: Thomas A. Ullman, MD, Gastrointestinal Division, Box 1069, Mount Sinai School of Medicine, One Gustave Levy Place, New York, New York 10029. e-mail: thomas. ullman@msnyuhealth.org; fax: (212) 426-5099. Supported by grants from Procter and Gamble Pharmaceuticals, The American College of Gastroenterology, and the National Institutes of Health (K-08-DK069393). In addition to sponsorship, speakers bureau support was received from Procter and Gamble (T.U., A.K., S.I.), Shire Pharmaceuticals (T.U., A.K.), and Salix Pharmaceuticals (A.K.), and T.U., A.K., S.I. were consultants for Procter and Gamble, and T.U. was a consultant for Shire Pharmaceuticals. The authors would like to acknowledge and thank the many faculty members of the Dr. Henry D. Janowitz Division of Gastroenterology who shared their charts and wisdom with us, and without whom this effort would not have been possible.