Baseline Adenomas Research Articles

Structure of the Mucosal and Stool Microbiome in Lynch Syndrome

The gut microbiota has been associated with colorectal cancer (CRC), but causal alterations preceding CRC have not been elucidated. To prospectively assess microbiome changes prior to colorectal neoplasia, we investigated samples from 100 Lynch syndrome patients using 16S rRNA gene sequencing of colon biopsies, coupled with metagenomic and metatranscriptomic sequencing of feces. Colectomy and CRC history represented the largest effects on microbiome profiles. A subset of Clostridiaceae were depleted in stool corresponding with baseline adenomas, while Desulfovibrio was enriched both in stool and in mucosal biopsies. A classifier leveraging stool metatranscriptomes resulted in modest power to predict interval development of preneoplastic colonic adenoma. Predictive transcripts corresponded with a shift in flagellin contributors and oxidative metabolic microenvironment, potentially factors in local CRC pathogenesis. This suggests that the effectiveness of prospective microbiome monitoring for adenomas may be limited but supports the potential causality of these consistent, early microbial changes in colonic neoplasia.

232 Numerous Non-Advanced Adenomas Are Not Associated With Metachronous Advanced Neoplasia

INTRODUCTION: Studies using standard definition colonoscopes in the early 2000s demonstrated the risk of metachronous advanced neoplasia (MAN) was doubled in patients with >3 vs 1–2 small tubular adenomas. In the last decade, attention to the importance of adenoma detection rate and the use of high definition (HD) colonoscopes, increases small adenoma detection. We analyzed the association between baseline adenoma features, particularly multiplicity of non-advanced adenomas, on the risk of MAN in patients undergoing HD colonoscopy. METHODS: Patients undergoing first colonoscopy at age ≥50 in the era of HD colonoscopes (≥2006) and follow-up colonoscopy >24 months from baseline exam were identified from the electronic medical record. Exclusions included inflammatory bowel disease, history of colorectal cancer or colon surgery, incomplete colonoscopy, and inadequate bowel preparation. High risk adenoma (HRA) patients included those with an advanced adenoma (≥10 mm in size, adenoma with villous features/high-grade dysplasia) or ≥3 adenomas. Low risk adenoma (LRA) patients included those with 1–2, <10 mm tubular adenomas. The risk of MAN was calculated according to baseline adenoma features. Multivariable analysis compared the risk of MAN between individuals with LRA vs HRA on baseline HD colonoscopy adjusted for interval between first and follow-up colonoscopies. RESULTS: 159,273 patients underwent colonoscopy at age ≥50 in 2006 or later. After exclusions, 3,383 were included. Mean age was 60.5 ± 7.8 and 54.6% were females. The median time interval between the first and follow-up colonoscopy was 59.9 (42.5–66.7) months for the LRA group and 41.8 (36.3–52.2) months for the HRA group. The risk of MAN was 3.8% in individuals with no baseline adenomas; 4% with LRA; and 9.2% with HRA. The risk of MAN in individuals with >3 non-advanced adenomas was 6.3%; 6.1% with 3–4 and 7.4% with >5 non-advanced adenomas (Table 1). On multivariable analysis, the risk of MAN was not different between HRA and LRA based upon the number of non-advanced adenomas: >3 [OR 1.6, (0.7, 3.9)]; 3–4 [OR 1.6, (0.61, 4.0)] and >5 non-advanced adenomas [OR 2.2, (0.27, 17.0)] (Table 2). CONCLUSION: In the contemporary era of HD colonoscopy, compared to LRA patients, patients with ≥3 non-advanced adenomas are not at increased risk of MAN including patients with 3–4 and ≥5 non-advanced adenomas. These data support a longer colonoscopy interval (>5 years) in these individuals.

Can the Sum of Adenoma Diameters (Adenoma Bulk) on Index Examination Predict Risk of Metachronous Advanced Neoplasia?

Recent data suggest that adenoma size and number are more important predictors of metachronous colorectal neoplasia than advanced histology. Furthermore, there is poor reproducibility in diagnosing advanced histology; high-grade dysplasia and villous histology. Therefore we developed a new metric, adenoma bulk, the sum of diameters of all baseline adenomas, regardless of advanced features. Compare the predictive value for metachronous advanced neoplasia of adenoma bulk to conventional paradigm. Data were collected prospectively in a multicenter adenoma-chemoprevention trial (2004 to 2013). For the conventional paradigm, high-risk baseline findings were defined as ≥3 adenomas, large adenomas (≥1 cm) or adenomas with villous components or high-grade dysplasia. Adenoma bulk was examined across quartiles and as a continuous variable. Predictive characteristics (sensitivities, specificities, c-statistics) for metachronous advanced neoplasia using conventional criteria and adenoma bulk were calculated. receiver operator characteristic curves were computed using logistic regression. In total, 1948 adults had index and follow-up colonoscopies (mean follow-up, 45.2 mo). Those with an adenoma bulk ≥10 mm (4th quartile) had a higher metachronous advanced neoplasia risk (14.4% vs. 6.9-8.2% in lower 3 quartiles; P=0.0002). The c-statistics and sensitivities (specificity fixed at 0.73) for the adenoma bulk and conventional models were 0.587 and 0.563 (P=0.17) and 0.396 and 0.390, respectively. Categorizing sporadic adenoma patients as high versus low risk for metachronous advanced neoplasia by adenoma bulk of <versus ≥10 mm may be comparably predictive as conventional paradigm and simplifies risk stratification by obviating need for additional histology regarding extent of villous component or degree of dysplasia in resected polyps. The adenoma bulk metric and the 10 mm cutoff in particular would have to be validated in other populations before it can be used in clinical practice.

Expression of COX-2 and 15-PGDH in adenomas removed during pretreatment colonoscopy to predict chemopreventive efficacy of the selective COX-2 inhibitor, celecoxib.

524 Background: The APC trial showed that patients at high risk for colorectal adenoma development experienced a 33-45% reduction in post-polypectomy adenoma detection when treated with the selective cyclooxygenase-2 (cox-2) inhibitor, celecoxib. Unfortunately, this study also found a small increased risk of cardiovascular toxicity among celecoxib users, preventing broad use of this agent for chemoprevention. Celecoxib inhibits expression of prostaglandin E2 (PGE2), an inflammatory mediator produced by fatty acid metabolism via cyclooxygenases, and degraded through the activity of 15-prostaglandin dehydrogenase (15-PGDH). Methods: Adenomas collected from APC trial participants prior to treatment were examined using immunohistochemistry (IHC) to assess expression of cox-2 (high vs. low) and 15-PGDH (present vs. absent). A combined variable to estimate tumor PGE2 levels identified cases as PGE2 low (Cox-2 low/15-PGDH present) or PGE2 high (Cox-2 high/15-PGDH present; Cox-2 high/15-PGDH absent; or Cox-2 low/15-PGDH absent). Mantel–Cox test was used to evaluate whether markers of PGE2 expression in these adenomas predicted benefit from celecoxib treatment for the primary study outcome of adenoma detection. Results: Biomarker determinations were achieved for 1295 cases, or 71% of patients with available outcome data. Patients whose baseline adenomas demonstrated elevated Cox-2 achieved the greatest overall reduction in adenoma risk with celecoxib treatment (RR 0.37; p = 0.0001). This risk reduction was less significant in the low Cox-2 category (RR 0.64). Patients with low estimated tumor PGE2 did not benefit from celecoxib for adenoma prevention (RR 0.95; p = 0.83). This is compared to a 41% reduction in adenoma detection with celecoxib treatment for patients in the high PGE2 category (RR 0.59; p &lt; 0.0001). Conclusions: IHC to determine expression of target enzymes in pre-malignant adenomas provides significant prognostic and predictive information in patients treated with celecoxib for prevention of colorectal adenomas.

Predicting the risk of recurrent adenoma and incident colorectal cancer based on findings of the baseline colonoscopy.

Objectives:The decision tree underlying current practice guidelines for post polypectomy surveillance relies on risk stratification based on predictive attributes gleaned from adenomas removed on screening colonoscopy examination. Our primary aim was to estimate the magnitude of association between baseline adenoma attributes and the risk of adenoma recurrence and invasive colorectal adenocarcinoma (CRC). Our secondary aims were to estimate the adenoma detection rate (ADR) of surveillance compared with screening colonoscopies and describe time trends in preventive colonoscopy utilization.Methods:We used prospective analyses of retrospectively collected clinical data from electronic health records. A cohort of primary care patients eligible for colorectal cancer screening was assembled encompassing 110,452 subjects, of which 3,300 had adenomas removed on screening examination. Of those patients who had a follow-up surveillance colonoscopy (defined as a patient with a documented adenoma on prior colonoscopy) recorded during the study period, 537 had a recurrent adenoma.Results:Of those recurrent adenomas, 354 had a high-risk attributes. High-risk attributes were described at >3 adenomas, at least one adenoma >10 mm in size, high-grade dysplasia, or villous features. The risk of developing invasive CRC among post polypectomy patients was significantly higher if the baseline adenomas displayed any of the following attributes: more numerous than 3 (4.3-fold higher risk, 95% confidence interval (CI) low, high 1.4, 12.9), larger than 10 mm in size (5.2-fold higher risk, 95% CI low, high 1.8, 15.1), high-grade dysplasia (13.2-fold risk, 95% CI low, high 2.8, 62.1), or villous features (7.4-fold higher risk, 95% CI low, high 2.5, 21.5). These attributes combined added a net value of 22.8% to the probability of correctly predicting CRC. There was a threefold increase in surveillance utilization relative to screening from 2005 to 2011. The ADR of surveillance (34.1%) was 1.5-fold higher than that of screening (23.1%).Conclusions:These results emphasize the need to mitigate excessive risk by performing timely surveillance colonoscopies in patients with baseline adenomas displaying high-risk attributes as recommended in practice guidelines.

Abstract CT335: A clinical trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas

Abstract Considerable epidemiological and preclinical evidence suggests that high vitamin D status confers a lower risk of colorectal neoplasia. High calcium intake has also been associated with reduced risks, and trials using calcium have shown a reduction in the occurrence of adenomas. To study these issues, we conducted a randomized, double blind, placebo-controlled trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas. We hypothesized that subjects receiving Vitamin D supplementation would have a lower risk of metachronous adenomas than those given placebo, that those randomized to calcium would have a lower risk, and that subjects given calcium and vitamin D together would have a lower risk than those given calcium alone. Secondary hypotheses involved effects of study agents on advanced lesions. Methods: In 11 US centers, we recruited subjects recently diagnosed with at least one adenoma; with no known polyps remaining in the bowel; and with no known contraindication to, or need for, the study agents. In a modified 2 x 2 factorial design, 2259 subjects were randomized to vitamin D3 (1000 IU daily), calcium (1200 mg daily), both agents, or neither. Women could elect to be randomized only to vitamin D. Follow-up colonoscopy was planned by the subjects’ clinicians at either 3 or 5 years after the baseline exam. Every 6 months, subjects were queried about endoscopic procedures, major medical events, and compliance with study procedures. Intention to treat risk ratios (RRs) and 95% confidence intervals (CIs) were computed with adjustment for age, sex, study center, number of baseline adenomas, planned follow-up interval (3 or 5 years) and participation in calcium randomization. Results: Treatment arms were well balanced with regard to personal characteristics and risk factors for metachronous neoplasia. Treatment adherence was very good; 90% of subjects reported taking at least half their study tablets during the trial. About 93% of subjects had a follow-up colonoscopy at least 1 year after randomization; nearly all were complete examinations. Baseline 25-OH vitamin D levels were 24.6 ng/ml overall; by the end of study treatment, subjects given vitamin D had levels 7.8 ng/ml higher than those given placebo. Overall, 42% of subjects had one or more adenomas during follow-up (mean size 5 mm). The study treatments had no effect on adenoma outcomes. The RR for vitamin D vs. placebo was 0.97 (95% CI 0.88-1.08); for vitamin D plus calcium vs. calcium alone, 0.99 (95% CI 0.86-1.13); and for calcium alone, 0.95 (95% CI 0.85-1.06). RRs for advanced adenomas were similar. Numbers of subjects with major medical events were low, but study agents had no material effect on risk of cardiovascular endpoints, cancer or kidney stones. Conclusion: Despite previous evidence, we found supplemental vitamin D and calcium to be ineffective in reducing risk of metachronous colorectal adenomas over 3 - 5 years. Citation Format: John A. Baron, Elizabeth L. Barry, Dennis J. Ahnen, Carol A. Burke, Roberd M. Bostick, Robert S. Bresalier, Timothy R. Church, Marcia Cruz-Correa, Michael Goodman, Robert Haile, Anastasia Ivanova, Richard I. Rothstein, Robert S. Sandler, Dale Snover, Robert W. Summers. A clinical trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT335. doi:10.1158/1538-7445.AM2014-CT335

Risk of advanced lesions at first follow-up colonoscopy in high-risk groups as defined by the United Kingdom post-polypectomy surveillance guideline: data from a single U.S. center

The United Kingdom (U.K.) post-adenoma resection guidelines recommend earlier surveillance for patients with 5 or more adenomas or 3 to 4 adenomas of which one is 10 mm or larger compared with U.S. guidelines. To evaluate the effect of using the U.K. guideline on a U.S. cohort of adenoma patients. Single-center, retrospective study. Indiana University Hospital and an associated ambulatory surgery center. A total of 1414 patients with baseline adenoma findings belonging to one of 5 risk categories and with a follow-up colonoscopy more than 200 days later. Colonoscopy, polypectomy. Incidence of advanced lesions at follow-up colonoscopy. Advanced neoplasms at follow-up occurred in 16.3% of patients with 5 or more adenomas including 1 that was 10 mm or larger, 8.6% of patients with 3 or 4 adenomas including 1 that was 10 mm or larger, 5% of those with 5 or more adenomas all smaller than 10 mm, 1.8% of those with 3 or 4 adenomas all smaller than 10 mm, and 1.4% of those with 1 to 2 adenomas smaller than 10 mm. Logistic regression analyses showed that the rate of advanced lesions at first follow-up was increased in persons with 3 or more baseline adenomas and at least 1 that is 10 mm or larger compared with those with 1 to 4 small baseline adenomas. Single-center, retrospective study. Our results indicate the U.K. guideline predicts higher risk groups for advanced neoplasia at first follow-up. Our study had inadequate power to show better prediction of incident cancer. Additional study of other databases is warranted.

Colorectal Adenoma Stem-like Cell Populations: Associations with Adenoma Characteristics and Metachronous Colorectal Neoplasia

Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma ("recurrence"), has not been studied extensively. We evaluated the expression of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), a putative stem cell marker, in baseline adenomas from the placebo arm of chemoprevention trial participants with colonoscopic follow-up. An exploratory set of 20 baseline adenomas was analyzed by ALDH1A1 immunohistochemistry with morphometry, and a replication set of 89 adenomas from 76 high-risk participants was evaluated by computerized image analysis. ALDH1A1-labeling indices (ALI) were similar across patient characteristics and in advanced and nonadvanced adenomas. There was a trend toward higher ALIs in adenomas occurring in the right than left colon (P = 0.09). ALIs of synchronous adenomas were correlated (intraclass correlation coefficient 0.67). Participants in both sample sets who developed a metachronous adenoma had significantly higher ALIs in their baseline adenoma than participants who remained adenoma free. In the replication set, the adjusted odds for metachronous adenoma increased 1.46 for each 10% increase in ALIs (P = 0.03). A best-fit algorithm-based cutoff point of 22.4% had specificity of 75.0% and positive predictive value of 70.0% for metachronous adenoma development. A larger population of ALDH1A1-expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology. If confirmed, ALDH1A1 has potential as a novel biomarker in risk assessment and as a potential stem cell target for chemoprevention.

Abstract A56: Association between circulating 1,25(OH)2D concentration and recurrent colorectal adenoma

Abstract Cellular-level studies demonstrate that availability of the steroid hormone 1α,25-dihydroxyvitamin D (1,25(OH)2D) to colon cells induces anti-carcinogenic activities. Although epidemiological data are relatively sparse, suggestive inverse trends have been reported for circulating 1,25(OH)2D concentration and risk of colorectal neoplasia. Further, recent epidemiologic work has identified an inverse association between variation in circulating concentrations of 1,25(OH)2D and fibroblast growth factor 23 (FGF23), a hormone demonstrated to interfere with the anti-carcinogenic effects of 1,25(OH)2D, indicating that concentrations of 1,25(OH)2D may vary more widely than previously thought. We therefore conducted logistic regression analysis to evaluate the relationship between variation in serum 1,25(OH)2D concentrations and characteristics of baseline and recurrent colorectal adenomas among 1,151 participants from the Ursodeoxycholic Acid clinical trial. No relationship between 1,25(OH)2D and colorectal adenoma recurrence overall was observed. However, a statistically significant inverse association was observed between circulating 1,25(OH)2D concentration and odds of proximal colorectal adenoma recurrence, with an OR (95% CI) of 0.71 (0.52-0.98) for individuals in the highest tertile of circulating 1,25(OH)2D compared to those in the lowest (p-trend = 0.04). A significantly greater proportion of women were identified in the lowest 1,25(OH)2D tertile (p&amp;lt;0.01); however, gender did not modify the association between 1,25(OH)2D and proximal colorectal adenoma recurrence (LR-test p-value = 0.27). While there was no relationship overall between 1,25(OH)2D and recurrence of distal lesions, there was a significantly reduced odds for women in the highest tertile of 1,25(OH)2D compared to the lowest (OR=0.53; 95% CI 0.27-1.03; p-trend=0.05; p-interaction=0.08). No statistically significant associations were detected with any baseline colorectal adenoma characteristics or other classification of recurrent polyps. Associations with recurrent, as opposed to baseline lesions, may indicate that variation in circulating 1,25(OH)2D concentration influences progression of adenomas once the initiating event has occurred. The observed differences in associations with proximal and distal adenomas could indicate that delivery and activity of vitamin D metabolites in different anatomical sites in the colon may vary, particularly by gender. These results identify novel associations between 1,25(OH)2D and recurrent proximal and distal colorectal adenoma, which merit further epidemiologic studies. Citation Format: Elizabeth A. Hibler, Christine L. Sardo, Peter Lance, Peter Jurutka, Elizabeth T. Jacobs. Association between circulating 1,25(OH)2D concentration and recurrent colorectal adenoma. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A56.

Association between circulating concentrations of 25(OH)D and colorectal adenoma: A pooled analysis

The relationship between the biomarker of vitamin D status, 25(OH)D, and the risk for colorectal neoplasia is suggestive but equivocal. Questions remain regarding whether there are differential associations between 25(OH)D and colorectal adenoma by gender, colorectal subsite or features of baseline and recurrent adenomas. We sought to investigate the relationship between 25(OH)D and both baseline and recurrent adenoma characteristics. Our study was conducted among 2,074 participants in a pooled population of two clinical intervention trials of colorectal adenoma recurrence. A cross-sectional analysis of 25(OH)D and baseline adenoma characteristics and a prospective study of recurrent adenomas and their characteristics were conducted. There was a statistically significant inverse association between the concentrations of 25(OH)D and the presence of three or more adenomas at baseline. Compared to participants with 25(OH)D levels of <20 ng/mL, the adjusted odds ratios (ORs) (95% condifdence intervals [CIs]) were 0.99 (0.70-1.41) for those with concentrations of ≥20 and <30 ng/mL, and 0.73 (0.50-1.06) among participants with levels of ≥30 ng/mL (p-trend = 0.05). Baseline villous histology was also significantly inversely related to 25(OH)D levels (p-trend = 0.04). Conversely, 25(OH)D concentrations were not associated with overall colorectal adenoma recurrence, with ORs (95% CIs) of 0.91 (0.71-1.17) and 0.95 (0.73-1.24; p-trend = 0.85). These findings support the concept that the relationship between vitamin D and colorectal neoplasia may vary by stage of adenoma development.

Calcium, Magnesium, and Colorectal Cancer

To the Editor: High calcium consumption may confer a reduced risk of colorectal cancer.1,2 Dai and colleagues3 recently reported in a case-control study that intake of calcium may be associated with a decreased risk of colorectal adenoma only when the dietary calcium:magnesium intake ratio is low. This finding provides one possible interpretation for inconsistencies in previous studies of the association of calcium intake with risk of colorectal neoplasia.4 Belonging to the same family in the periodic table, calcium (Ca2+) and magnesium (Mg2+) share the same homeostatic control system and have the potential to antagonize each other physiologically.5 A high calcium intake reduces absorption of both magnesium and calcium,6 whereas moderate magnesium deprivation results in negative magnesium balance but increased calcium retention.7 Because of the potential competition between magnesium and calcium, we hypothesized that the dietary calcium:magnesium ratio may modify the effects of calcium supplementation on colorectal carcinogenesis. We sought to test this hypothesis using data from a randomized clinical trial of calcium supplementation (1200 mg/day), to prevent adenoma recurrence for a 4-year period. The outcome measure in this analysis was the recurrence of adenomas during the prespecified main risk period (ie, after a year-1 colonoscopy up to and including a year-4 examination).2 A validated semi-quantitative food frequency questionnaire (FFQ) was given at study entry to assess the usual diet. Consistent with our hypothesis,3 we found suggestions that the baseline dietary calcium:magnesium intake ratio modified the effect of calcium treatment on adenoma recurrence. Among subjects with the intake ratio above the median, calcium supplementation had no effect on the risk of one or more recurrent adenomas (relative risk [RR] = 0.98 [95% confidence interval (CI) = 0.75–1.28]) (Table). In contrast, among those with the baseline ratio less than or equal to the median, calcium treatment was associated with reduced risk (RR = 0.68 [95% CI = 0.52–0.90]; test for interaction, P = 0.075).Table: Effect of Calcium Supplementation on Recurrence of Total and Subtype Adenoma During Main Risk Period, Stratified by Median Baseline Calcium:Magnesium Intake RatioThe effect of calcium treatment did not differ by magnesium intake at baseline (test for interactions, P = 0.68). Previously, the study had shown that the effects of calcium supplementation on adenoma recurrence did not differ by baseline dietary intakes of calcium. We found no material change after adjustment for baseline dietary calcium intake. Thus, the suggestion of effect modification by the calcium:magnesium ratio cannot be attributed solely to the baseline dietary intake of either calcium or magnesium. Point estimates suggest that calcium reduces the risk of advanced adenoma regardless of the calcium:magnesium intake ratio level, a null finding that could be due to lack of statistical power. The effect of calcium on the risk of hyperplastic polyps did not differ by baseline calcium:magnesium intake ratio, but a protective effect of calcium on hyperplastic polyps was observed when baseline magnesium intake was below the median (test for interaction, P = 0.05) (eTable1, https://links.lww.com/EDE/A577). Although not entirely consistent, prospective studies conducted in Western societies have suggested that high intake of magnesium was associated with a reduced risk of colorectal cancer.8 Also, in a previous case-control study,3 polyp-free controls consumed substantially higher levels of magnesium than patients diagnosed with an initial colorectal adenoma. There are several possible reasons for the null magnesium finding in this study. It is possible that the association between magnesium intake and adenoma recurrence differs from that of an initial adenoma diagnosis. Also, baseline adenomas in participants with high dietary magnesium at entry may have occurred despite that intake, and so might develop adenoma recurrence along pathways unaffected by magnesium at that level. Future studies are needed to investigate the possibility that magnesium treatment among those with a high calcium:magnesium ratio at baseline could reduce the calcium:magnesium ratio and, in turn, reduce colorectal cancer risk. Qi Dai Department of Medicine Vanderbilt Epidemiology Center Vanderbilt-Ingram Cancer Center Vanderbilt School of Medicine Nashville, TN [email protected] Robert Sandler Department of Medicine University of North Carolina School of Medicine Chapel Hill, NC Elizabeth Barry Department of Community and Family Medicine Dartmouth Medical School Hanover, NH Robert Summers Department of Medicine University of Iowa Carver College of Medicine Iowa City, IA Maria Grau Department of Community and Family Medicine Dartmouth Medical School Hanover, NH John Baron Department of Medicine University of North Carolina School of Medicine Chapel Hill, NC Departments of Community and Family Medicine and of Medicine Dartmouth Medical School Hanover, NH

Adenoma incidence decreases under the effect of polypectomy

To investigate whether, under the influence of polypectomy, the incidence of adenoma decreases with age. Consecutive patients with colonic adenomas identified at index colonoscopy were retrospectively selected if they had undergone three or more complete colonoscopies, at least 24 mo apart. Patients who had any first-degree relative with colorectal cancer were excluded. Data regarding number of adenomas at each colonoscopy, their location, size and histological classification were recorded. The monthly incidence density of adenomas after the index examination was estimated for the study population, by using the person-years method. Baseline adenomas were excluded from incidence calculations but their characteristics were correlated with recurrence at follow-up, using the χ(2) test. One hundred and fifty-six patients were included (109 male, mean age at index colonoscopy 56.8 ± 10.3 years), with follow-up that ranged from 48 to 232 mo. No significant correlations were observed between the number, the presence of villous component, or the size of adenomas at index colonoscopy and the presence of adenomas at subsequent colonoscopies (P = 0.49, 0.12 and 0.78, respectively). The incidence of colonic adenomas was observed to decay from 1.4% person-months at the beginning of the study to values close to 0%, at 12 years after index colonoscopy. Our results suggest the sporadic formation of adenomas occurs within a discrete period and that, when these adenomas are removed, all neoplasia-prone clones may be extinguished.

Relationship of human rectal aberrant crypt foci and formation of colorectal polyp: One-year following up after polypectomy

To clarify the relationship of human rectal aberrant crypt foci and formation of colorectal polyp. Eighty-nine subjects were recruited from the population of Japanese individuals who underwent polypectomy at Yokohama City University Hospital. All patients had baseline adenomas removed at year 0 colonoscopy. Aberrant crypt foci (ACF) were defined as lesions in which the crypts were more darkly stained with methylene blue than normal crypts and had larger diameters, often with oval or slit-like lumens and a thicker epithelial lining. A total of 366 ACFs were identified in 89 patients; all had baseline adenomas removed at the first examination (year 0) colonoscopy and returned for the second (year 1). ACF in the lower rectum were assessed at year 0 and study group were divided into two groups depend on ACF numbers, 0-3 or over 3. All participants were examined in the number and maximum size of adenoma. There was no statistical difference in number and maximum size of ACF at year 0, however, maximum size of adenoma was larger in over 3 group than 0-3 group at year 1. The number of ACF may be a predictive factor of relatively large adenoma incidence in the pilot phase study.

Abstract B37: Relationship of human rectal aberrant crypt foci and formation of colorectal polyp

Abstract In experimental models of colonic carcinogenesis, aberrant crypt foci (ACF) are the earliest detectable abnormality and precede adenomas. Herein, we wanted to determine the adenoma incidence over a 1-year period after polypectomy. Eighty-nine subjects were recruited from the population of Japanese individuals who underwent polypectomy at Yokohama City University Hospital. All patients had baseline adenomas (&amp;gt; 6mm) removed at year 0 colonoscopy. ACF were defined as lesions in which the crypts were more darkly stained with methylene blue than normal crypts and had larger diameters, often with oval or slit-like lumens and a thicker epithelial lining. A total of 366 ACFs were identified in 89 patients; all had baseline adenomas (&amp;gt; 6mm) removed at the first examination (year 0) colonoscopy and returned for the second (year 1). ACF in the lower rectum were assessed at year 0 and study group were divided into two groups depend on ACF numbers, 0-3 or over 4. All participants were examined in the number and maximum size of adenoma. There was no statistical difference in number and maximum size of ACF at year 0, however, maximum size of adenoma was larger in over 4 group than 0-3 group at year 1. The meaning of the number of ACF is not elucidated; however, the number of ACF may be a predictive factor of relatively large adenoma incidence in the pilot phase study. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B37.

Abstract 2889: Folic acid for the prevention of colorectal adenomas: Combined analysis of randomized clinical trials

Abstract Studies have suggested that poor folate status is associated with a higher risk of colorectal adenomas and cancer. However, some epidemiological and animal studies have provided contradictory evidence. Data from a few randomized clinical trials of folic acid supplementation for the prevention of colorectal adenomas have been reported. Two small trials reported at least suggestions of benefit, but this was not observed in two much larger trials, the Aspirin/Folate Polyp Prevention Study (AFPPS) and the United Kingdom Colorectal Adenoma Prevention (ukCAP). Findings from Nurses’ Health Study/Health Professional Follow-Up Study (NHS/HPFS) showed no overall risk reduction, but some indications of decreased risks in selected subgroups of individuals. To obtain more precise clinical evidence on the effects of folic acid on incident adenoma occurrence, we conducted a collaborative pooled analysis of the largest trials: AFPPS, NHS/HPFS and the ukCAP trials, focusing on the treatment periods of the studies. To address the possibility that there may be subgroups of individuals who may be more susceptible to the effects of folic acid in the large bowel, we conducted a stratified analysis by selected patient characteristics and dietary exposures. Participants included 2,007 men and women with a recent history of adenomas randomized to 0.5 or 1.0 mg/day of folic acid (n=1,008) or placebo (n=999) who had a follow-up colonoscopy 6 to 42 months after randomization (mean=30.6 (SD=8.1) months). We used random-effects meta-analysis to estimate risk ratios (RR's) and 95% confidence intervals (CI). The RR comparing folic acid vs. placebo for the occurrence of at least one adenoma was 0.99 (95% CI=0.84−1.16). For advanced lesions, the RR was 1.05 (95% CI=0.80-1.39). There was a non-significant increased risk among individuals with two or more baseline adenomas (RR, 1.14; 95% CI=0.98 -1.33) and no association among those with only one adenoma at baseline (RR, 0.88; 95% CI=0.73-1.06, P-interaction=0.03). Folic acid supplementation was also associated with a non-significantly increased risk of adenomas for individuals in the highest tertile of baseline plasma folate (&amp;gt;25 nmol/L) (RR, 1.19; 95% CI=0.92-1.53), and a non-significantly lower risk in those in the lowest tertile (&amp;lt;13.5 nmol/L) (RR, 0.79; 95% CI=0.43-1.43, P-interaction=0.39). Among non-drinkers, there was a non-significant increase in risk of adenoma recurrence in the folic acid groups (RR=1.33, 95% CI=0.63-2.81), in contrast to a null effect among subjects who consumed one or more drinks per day (RR= 0.95, 95% CI=0.54-1.69, p-interaction=0.74). Similar results were observed for advanced lesions. Results from this pooled analysis suggest that during the first few years of folic acid use, there is no clear decrease or increase in the occurrence of new adenomas in patients with a recent adenoma history. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2889.

Does the Location of Adenoma At Baseline Predict the Location of Subsequent Recurrence? Evidence from the Polyp Prevention Trial

Background: Studies have suggested possible biological differences between proximal and distal colon neoplasia. There is limited prospective data on the role of location in colorectal carcinogenesis. Aim: To examine whether the baseline location of adenoma predict the location of subsequent recurrence. Methods: The Polyp Prevention Trial was a 4-year, multicenter, randomized control trial which evaluated the effect of a low fat, high fiber, fruits and vegetable diet on the risk of colorectal adenoma recurrence. A total of 1,864 participants had complete information on the location of their baseline adenomas and completed the trial. We examined the association between baseline adenoma location on subsequent distal (rectosigmoid to splenic flexure) and proximal (transverse colon to cecum) adenoma recurrence. We used multinomial regression models to estimate the Relative Risks (RR) and 95% confidence intervals (CI). Results: A total of 1,131 (60.7%) subjects did not have adenoma recurrence while 733 (39.3%) subjects had adenoma recurrence (228 distal only; 369 proximal only; and 136 in both distal and proximal colon). Overall, given adenoma recurrence, there was a tendency towards a proximal shift (Table). In multivariable analysis with adjustment for age, sex, body mass index, family history of colorectal cancer and use of non-steroidal anti-inflammatory drugs, subjects with only proximal adenoma at baseline were less likely to have only distal adenoma recurrence (RR = 0.69; 95% CI: 0.47-1.00), but were more likely to have proximal adenoma recurrence (RR = 1.58; 95% CI: 1.20-2.09). Participants with proximal and distal adenomas at baseline were more likely to have adenoma recurrence in both locations: (RR = 1.61; 95% CI: 1.11-2.33) for distal only and (RR = 2.11; 95% CI: 1.53-2.90) for proximal only adenoma recurrence. Conclusions: Our study suggests a proximal shift of metachronous adenomas and subjects with adenomas in both distal and proximal colon are at the highest risk of adenoma recurrence.

Hyperplastic Polyps and Risk for Adenomas

Recent studies evaluating whether patients with hyperplastic polyps might be at risk for subsequent development of adenomas have yielded inconsistent results. The current study used data from the Polyp Prevention Trial to test whether patients who had both hyperplastic polyps and adenomas had a higher risk for subsequent adenomas than those with only baseline adenomas. Participants …

A Pooled Analysis of Advanced Colorectal Neoplasia Diagnoses After Colonoscopic Polypectomy

Limited data exist regarding the actual risk of developing advanced adenomas and cancer after polypectomy or the factors that determine risk. We pooled individual data from 8 prospective studies comprising 9167 men and women aged 22 to 80 with previously resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer as well as identify factors associated with the development of advanced colorectal neoplasms during surveillance. During a median follow-up period of 47.2 months, advanced colorectal neoplasia was diagnosed in 1082 (11.8%) of the patients, 58 of whom (0.6%) had invasive cancer. Risk of a metachronous advanced adenoma was higher among patients with 5 or more baseline adenomas (24.1%; standard error, 2.2) and those with an adenoma 20 mm in size or greater (19.3%; standard error, 1.5). Risk factor patterns were similar for advanced adenomas and invasive cancer. In multivariate analyses, older age (P < .0001 for trend) and male sex (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.19-1.65) were associated significantly with an increased risk for metachronous advanced neoplasia, as were the number and size of prior adenomas (P < .0001 for trend), the presence of villous features (OR, 1.28; 95% CI, 1.07-1.52), and proximal location (OR, 1.68; 95% CI, 1.43-1.98). High-grade dysplasia was not associated independently with metachronous advanced neoplasia after adjustment for other adenoma characteristics. Occurrence of advanced colorectal neoplasia is common after polypectomy. Factors that are associated most strongly with risk of advanced neoplasia are patient age and the number and size of prior adenomas.

Association Between Body Size and Colorectal Adenoma Recurrence

Obesity has been associated with increased risk for colorectal adenoma, although its role as a risk factor after polypectomy for recurrence is unclear. Therefore, we sought to evaluate the effect of anthropometric measures of obesity on adenoma after polypectomy. Subjects with baseline adenomas (n = 2465) and follow-up colonoscopy data were drawn from 2 randomized trials designed to prevent adenoma recurrence. Over a mean follow-up period of 3.1 years presence of a body mass index (BMI) > or = 30 kg/m2 was associated with a nonsignificant 17% increase in the odds for any adenoma recurrence among all subjects (odds ratio [OR], 1.17; 95% confidence interval [CI], 0.92-1.48). This result was confined to men (OR, 1.36; 95% CI, 1.01-1.83) and not observed for women (OR, 0.90; 95% CI, 0.60-1.33). Results for waist circumference did not reach statistical significance, although trends were similar to those for BMI. Analyses of the effects of obesity on more clinically significant lesions demonstrated that high BMI was a slightly stronger risk factor for advanced adenoma recurrences in men (OR, 1.62; 95% CI, 1.04-2.53) when compared with non-advanced lesions (OR, 1.26; 95% CI, 0.91-1.75). In addition, we observed an association for obesity and odds of adenoma recurrence among participants reporting a family history of colorectal cancer (OR, 2.25; 95% CI, 1.32-3.84) but not for those without (OR, 1.00; 95% CI, 0.77 to 1.31; P(int) = P = .008). Our results support obesity as a risk factor for subsequent short-interval (mean follow-up time 3.1 years) development of colorectal adenomas, particularly among men and persons with a family history of colorectal cancer. Furthermore, obesity in men appears to be strongly associated with the development of clinically advanced lesions.

Gene-Specific Methylation and Subsequent Risk of Colorectal Adenomas among Participants of the Polyp Prevention Trial

Hypermethylation of tumor suppressor and other regulatory genes is thought to play an important role in colorectal neoplasia and tumorigenesis. This study examined the association between gene methylation status in baseline adenomas and subsequent adenoma recurrence in a randomized dietary intervention study, the Polyp Prevention Trial. The methylation status of four genes [CDKN2A (p16), PTGS2 (COX2), ESR1 (ER-alpha), and PGR(PR)] was determined by MethyLight in 284 baseline adenomas from 196 trial participants. The association of gene methylation with recurrence was determined using logistic regression models. Gene methylation was evaluated as percent of methylated reference, a measure of methylation of each gene relative to control DNA. ESR1methylation status was inversely associated with adenoma recurrence, odds ratio = 0.36 (95% confidence interval, 0.15-0.88; P = 0.02) for the highest compared with the lowest quartile of the ESR1methylation. Further, ESR1 methylation status was inversely associated with the recurrence of multiple adenomas, advanced adenomas, and the recurrence of adenomas in the proximal but not distal bowel. No association between CDKN2A, PTGS2, or PGR methylation and adenoma recurrence was observed. These data suggest that ESR1 methylation may play a role in subsequent adenoma recurrence.