Risk Of Metachronous Adenomas Research Articles

Somatic Mutations in Exon 7 of the TP53 Gene in Index Colorectal Lesions Are Associated with the Early Occurrence of Metachronous Adenoma.

Simple SummaryIdentifying patients with an increased risk of early recurrence of colorectal lesions is still a problem. In our study, we focused on improving this identification by determining the mutation profile of index lesions. We found a statistically significant association between the mutation in exon 7 of the TP53 gene in the index lesion and the risk of early metachronous adenoma.(1) Background: this prospective study was focused on detailed analysis of the mutation heterogeneity in colorectal lesions removed during baseline (index) colonoscopy to identify patients at high risk of early occurrence of metachronous adenomas. (2) Methods: a total of 120 patients after endoscopic therapy of advanced colorectal neoplasia size ≥10 mm (index lesion) with subsequent surveillance colonoscopy after 10–18 months were included. In total, 143 index lesions and 84 synchronous lesions in paraffin blocks were divided into up to 30 samples. In each of them, the detection of somatic mutations in 11 hot spot gene loci was performed. Statistical analysis to correlate the mutation profiles and the degree of heterogeneity of the lesions with the risk of metachronous adenoma occurrence was undertaken. (3) Results: mutation in exon 7 of the TP53 gene found in the index lesion significantly correlated with the early occurrence of metachronous adenoma (log-rank test p = 0.003, hazard ratio 2.73, 95% confidence interval 1.14–6.56). We did not find an association between the risk of metachronous adenomas and other markers monitored. (4) Conclusions: the findings of this study could lead to an adjustment of existing recommendations for surveillance colonoscopies in a specific group of patients with mutations in exon 7 of the TP53 gene in an index lesion, where a shortening of surveillance interval may be warranted.

Fecal Fusobacterium nucleatum as a predictor for metachronous colorectal adenoma after endoscopic polypectomy.

Fusobacterium nucleatum is increasingly being recognized as an important risk factor in colorectal cancer and colorectal adenoma. Endoscopic polypectomy is associated with a decreased incidence of colorectal cancer; however, patients still suffer from a risk of metachronous adenoma. Currently, there are few effective non-invasive factors that may predict metachronous colorectal adenoma. Here, we evaluated the performance of F.nucleatum in predicting metachronous adenoma. Fecal samples and clinical information of patients before endoscopic polypectomy were collected from 367 patients in a retrospective cohort, and 238 patients in a prospective cohort. The abundance of fecal F.nucleatum was measured via quantitative polymerase chain reaction. Surveillance colonoscopies were conducted between 1 and 3years after polypectomy (average follow-up 27.07months for the retrospective cohort & 22.57months for the prospective cohort) to identify metachronous adenoma. Candidate predictive factors and cut-off value of F.nucleatum abundance were identified from the retrospective cohort and then validated in the prospective cohort. A high abundance of fecal F.nucleatum was found to be an independent risk factor for metachronous adenomas (odds ratio, 6.38; P<0.001) in the retrospective cohort and was validated in the prospective cohort with a specificity of 65.00%, and a sensitivity of 73.04%, and an overall performance with the area under the curve of 0.73. Fecal abundance of F.nucleatum may be a reliable predictor for metachronous adenoma after endoscopic polypectomy.

Family history of colorectal cancer in first-degree relatives and metachronous colorectal adenoma.

Little is known about the relationship between having a first-degree relative (FDR) with colorectal cancer (CRC) and risk for metachronous colorectal adenoma (CRA) following polypectomy. We pooled data from seven prospective studies of 7697 patients with previously resected CRAs to quantify the relationship between having a FDR with CRC and risk for metachronous adenoma. Compared with having no family history of CRC, a positive family history in any FDR was significantly associated with increased odds of developing any metachronous CRA (OR = 1.14; 95% CI = 1.01-1.29). Higher odds of CRA were observed among individuals with an affected mother (OR = 1.27; 95% CI = 1.05-1.53) or sibling (OR = 1.34; 95% CI = 1.11-1.62) as compared with those without, whereas no association was shown for individuals with an affected father. Odds of having a metachronous CRA increased with number of affected FDRs, with ORs (95% CIs) of 1.07 (0.93-1.23) for one relative and 1.39 (1.02-1.91) for two or more. Younger age of diagnosis of a sibling was associated with higher odds of metachronous CRA, with ORs (95% CIs) of 1.66 (1.08-2.56) for diagnosis at <54 years; 1.34 (0.89-2.03) for 55-64 years; and 1.10 (0.70-1.72) for >65 years (p-trend = 0.008). Although limited by sample size, results for advanced metachronous CRA were similar to those for any metachronous CRA. A family history of CRC is related to a modestly increased odds of metachronous CRA. Future research should explore whether having a FDR with CRC, particularly at a young age, should have a role in risk stratification for surveillance colonoscopy.

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

Role of obesity in a randomized placebo-controlled, double-blind trial of difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas.

374 Background: Chemoprevention with difluoromethylornithine (DFMO) plus sulindac markedly reduces risk of recurrence in colorectal adenoma (CRA) patients. Obesity is associated with risk of CRA and colorectal cancer (CRC). This study investigates how obesity influences CRA characteristics at baseline and risk of recurrence after treatment with DFMO plus sulindac vs. placebo. Methods: Our analysis included subjects enrolled in a phase III CRA prevention clinical trial investigating DFMO plus sulindac vs. placebo. Patients were classified by obesity (BMI &gt; 30 kg/m2) status at baseline. Pearson's χ2 statistic or Fisher's exact test and Mann-Whitney U test were used to compare baseline characteristics with regard to obesity status. Log-binomial regression analysis was used to determine the relative risk of metachronous adenoma, adenoma with advanced histology, or multiple adenomas, adjusted for covariates. Results: At baseline, obesity was associated with increased adenoma number (p =0.017), size (p =0.003), advanced histology (p =0.042), high-risk adenomas (p =0.0002), and distal adenomas (p =0.038). Obesity did not modify adenoma recurrence after treatment with DFMO plus sulindac or placebo (p =0.80). Conclusions: Our results provide supporting evidence for the association of obesity with high-risk adenoma features at baseline; however, obesity does not substantially modify CRA risk reduction after treatment with DFMO plus sulindac vs. placebo. [Table: see text] [Table: see text]

Role of dietary polyamines in a phase III clinical trial of DFMO and sulindac for prevention of metachronous colorectal adenomas.

1523 Background: Our group has previously demonstrated that polyamine-inhibitory regimen difluoromethylornithine (DFMO) plus sulindac vs. placebo has marked efficacy in preventing metachronous colorectal adenomas in a phase-III trial. Polyamines are synthesized endogenously but also obtained from diet. Here we investigate the role of dietary polyamines in the phase III placebo controlled colorectal adenoma prevention trial with DMFO + sulindac. Methods: Dietary polyamine data were available for 222 of 375 baseline study patients, and for 188 of 267 patients completing the study. A dietary questionnaire completed by each patient was collected at the initiation of the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and further categorized into highest (75%-100%) quartile group vs. a group with lower three quartiles (0-25, 25-50 and 50%-75%). Baseline tissue polyamine concentration was determined using HPLC methodology. Linear and logistic regression analyses were used for risk estimation. Results: A significant direct association was observed between dietary polyamine intake and tissue spermidine (p = 0.02) and spermine concentrations (p = 0.04) at baseline. Higher dietary polyamine group at baseline was associated with adenomas > 1 cm (43.6 % vs. 26.4 %; p = 0.01),high grade adenomas (32.7% vs. 20.4 %; p = 0.06) and advanced adenomas (52.7% vs. 35.9 %; p = 0.02). Among all patients, a significant interaction was observed between treatment, dietary polyamines and the risk of metachronous adenomas (p = 0.01). Therefore we stratified the final analyses (n = 188) by polyamine intake groups. We observed a significant risk reduction of metachronous adenomas from treatment with DFMO+sulindac in the lower dietary polyamine group (RR = 0.19 [0.09-0.40] p < 0.0001) and no benefit in the higher dietary polyamine group (RR = 1.04 [0.32-3.36] p = 0.94). Conclusions: Controlling dietary polyamines may be an effective strategy for preventing the occurrence of colorectal adenomas and colorectal cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cancer Prevention Pharmaceuticals Cancer Prevention Pharmaceuticals

W1983 The Risk of Metachronous Adenoma After Resection of Sporadic Colorectal Cancer with Microsatellite Instabiltiy

W1983 The Risk of Metachronous Adenoma After Resection of Sporadic Colorectal Cancer with Microsatellite Instabiltiy

Risk of advanced metachronous colorectal adenoma during long-term follow-up

According to the adenoma-carcinoma concept, all colorectal adenomas are to be removed and all patients have to undergo regular surveillance examinations. But there is still shortage on information on the long-term results of follow-up colonoscopy after polypectomy. Between 1978 and 2003, more than 20,000 polyps were prospectively documented at the Erlangen Registry of Colorectal Polyps. A total of 1,091 patients undergoing periodic surveillance examinations are studied for differences between initial and metachronous lesions of the colorectum. Statistical analysis using chi (2)-testing of adenoma characteristics found in four subsequent recurrence periods and calculation of the relative risk (RR) for the development of metachronous adenomas of advanced pathology was performed. In comparison with the initial findings, metachronous adenomas are, in general, significantly smaller ones (p < 0.00001), more frequently tubular lesions (p < 0.00001) and bearing less often high-grade dysplasia (p < 0.00001). Adenomas of advanced pathology were significantly less often found during follow-up than at baseline examination (p < 0.0001). These differences are found between the initial and four subsequent generations of metachronous adenomas. Patients with adenomas of advanced pathology at baseline have a significantly higher risk for metachronous adenomas of advanced pathology (RR 1.51; 95%CI 1.04-1.93) at the first recurrence. Metachronous adenomas show uniform characteristics of being small tubular lesions rarely bearing high-grade dysplasia. Thus, regular surveillance examinations can provide sufficient colorectal carcinoma prevention.

Predictors of metachronous colorectal neoplasms in sporadic adenoma patients

Our objective was to assess the overall risk of subsequent colorectal neoplasms (cancer or adenoma) in relation with the various characteristics of the index lesion in a cohort of patients who underwent endoscopic polypectomies of colorectal adenomas. A total of 1086 patients with adenomas of the large bowel were reported between 1979 and 1999 at the National Cancer Institute of Milan during a screening program for colorectal carcinoma. Data on patients who had colonoscopic examinations and treatments were collected prospectively. The relation between colorectal cancer (CRC) and adenoma features was assessed by computing the hazard ratio (HR) values and corresponding confidence intervals (95% CI) according to Cox proportional hazard models. Of the 1086 eligible patients (487 females, 579 males), 736 had single adenomas (67.7%) and 350 had multiple adenomas (32.3%). Histologic examination revealed 772 cases of tubular adenoma (73%), 205 cases of tubulovillous adenoma and 80 cases of villous adenoma (7.5%). Severe dysplasia was found in 3.3% of the cases. During the 11393 person-years of follow-up, with an average time of surveillance of 10.5 years, colorectal carcinomas developed in 10 patients (0.8%) and a new adenoma in 323 patients (29%). Multivariate analysis showed that male gender (HR 1.6; 95% CI 1.3-2.0), multiple polyps (HR 1.6; 95% CI 1.3-2.0), polyps larger than 2 cm (HR 1.5; 95% CI 1.1-2.1), tubulovillous and villous histology (HR 1.3; 95% CI 1.0-1.6 and HR 1.8; 95% CI 1.2-2.6, respectively) at index polypectomy were statistically significant risk factors for developing metachronous adenomatous polyps. The standardized incidence rates (SIR) for CRC was 0.52 (95% CI 0.25-0.95). The SIR was increased in subjects with severe dysplasia (2.8; 95% CI 0.34-1.02). Some features of large bowel adenomas are strongly correlated with an increased risk of metachronous adenomas and colorectal cancer. However, the endoscopic polypectomy is able to reduce by 50% the incidence of CRC in patients with large bowel adenomas.

Pathologic features of initial adenomas as predictors for metachronous adenomas of the rectum.

Colorectal cancer is the third most common cancer in the world, arising mostly from pre-existing adenomatous polyps (adenomas) of the large bowel. Patients with colorectal adenomas are at increased risk of colorectal cancer because of a high recurrence rate for adenomas. We followed a cohort of 1490 patients with rectal adenomas to determine whether recurrence might be related to pathologic characteristics of the initial adenomas. The patients were identified in Haining County, China, from 1977 through 1978 by means of examination with a 15-cm rigid sigmoidoscope. They were followed by endoscopic examination at years 2, 4, 6, 11, and 16 after their initial polypectomy. New adenomas in the rectum were identified in 280 patients in these follow-up examinations. Statistically significant twofold to threefold elevated risks of metachronous (recurrent) adenomas were observed for patients who had more than two initial adenomas or whose most advanced initial adenoma was more than 1.0 cm in size, was of villous/tubulovillous type, or showed moderate to severe dysplasia. Much stronger associations were observed for advanced metachronous neoplasms, which are defined as cancers or adenomas with severe dysplasia, with multivariate adjusted relative risks (95% confidence interval) of 4.2 (1.8-9.9) for a large initial adenoma (>1.0 cm), 8.1 (4.2-15.6) for villous/tubulovillous architecture, and 14.4 (5.0-41.3) for severe dysplasia. In particular, patients who had a large (>1.0 cm) adenoma with severe dysplasia at baseline had a relative risk of 37 (7.8-174.7) of developing advanced metachronous neoplasms compared with patients who had small adenoma(s) with mild dysplasia. The risk of metachronous adenomas is closely related to the pathology of initial adenomas, thus allowing identification of a high-risk group of adenoma patients for close surveillance after their initial polypectomy.

Prognostic value of K-ras-2 mutations in colorectal adenomas for the risk of metachronous adenomas

Prognostic value of K-ras-2 mutations in colorectal adenomas for the risk of metachronous adenomas

K-RAS-2 Gene Mutations as Predictors of Metachronous Colorectal Adenomas

Background: Mutations of K-RAS-2 gene and tumour suppressor genes have been found in both colorectal adenomas and carcinomas. The aim of this study was to investigate the prognostic value of K-RAS-2 gene mutations found in initial colorectal adenomas for predicting the risk of metachronous adenomas. Methods: Genomic DNA was extracted from formalin-fixed and paraffin-embedded adenomas larger than 5 mm in diameter removed at the initial total colonoscopy between 1980 and 1982. All patients underwent colonoscopic follow-up for at least 10 years. The sequence of exon 1 of the K-RAS-2 oncogene was amplified with the polymerase chain reaction technique and screened for mutation by single-strand conformation polymorphism analysis. All suspected mutations were confirmed by direct DNA sequencing. The predictive value of K-RAS-2 gene mutations for the risk of metachronous adenomas was assessed by chi-square testing and logistic regression analysis. Results: Of 54 patients 39 (72%) were male and 15 (28%) female. At the time the initial adenoma was removed, 31 (57%) patients were younger than 60, whereas 23 (43%) were 60 years or older. Point mutations of the K-RAS-2 oncogene were found in the index adenomas of 15 (27.7%) patients. Mutations were found more frequently in large (≥20mm) adenomas and in adenomas with severe dysplasia (P = 0.0011 and P = 0.0310, respectively). There were no significant associations between K-RAS-2 mutations and anatomic location, histologic type, or number of synchronous initial lesions. Mutations were found predominantly at codon 12 with transversions from GGT lo GTT (57%), from GGT to GAT (36%), and from GGT to TTT (one patient). The single mutation found at codon 13 showed a transversion from GGC to GAC. There were significant associations between size (≥20 mm) and K-RAS-2 mutation of the initial adenomas and the size (≥5 mm) of metachronous adenomas (P = 0.0259 and P = 0.0265, respectively). However, multivariate analysis showed that K-RAS-2 mutations did not provide a significant additional contribution to the prognostic value of the size of the initial adenoma (odds ratio, 7.62; 95% confidence interval (CI), 1.68-34.48) and the amount of villous structure (odds ratio, 0.22; 95% CI, 0.05-0.90) it contained. Conclusions: Patients with large (≥20 mm) adenomas and adenomas with K-RAS-2 mutations found at the initial examination have a significantly higher risk of developing large (≥5 mm) metachronous adenomas during surveillance. Multivariate analysis of initial adenoma characteristics showed that the risk of metachronous colorectal adenomas can be adequately estimated by the size and the histologic type of the largest initial adenoma and that K-RAS-2 mutations are of secondary importance only. Further studies based on a larger series will have to identify the adenoma characteristics that will help to improve follow-up strategies.

Epidemiology Of Gastrointestinal Polyps

Associations between polyps and cancer of the gastrointestinal tract have been fully documented for adenomatous polyps and cancer of the large bowel. The geographic, gender, and age distribution of colorectal adenomas parallels that of colorectal cancer incidence, and individuals with a history of adenomas are at increased risk for metachronous adenomas and cancer. Observational studies of risk factors for incident adenomas have found elevated risk associated with dietary variables including: high fat, low fiber, and low vegetable intake; family history; obesity; smoking; and other exposures, some of which also are associated with cancer. Dietary intervention trials with adenoma recurrence as an endpoint, however, have had little success. Screening with polypectomy has proved effective in reducing cancer incidence and may change the epidemiology of colorectal cancer.

Colorectal adenomas: morphologic features and the risk of developing metachronous adenomas and carcinomas in the colorectum.

The morphologic features of 307 colorectal adenomas among 159 patients are reviewed. Most adenomas (66.4%) were located in the sigmoid colon and the rectum, and the percentage decreased proximally to the right colon. The 307 adenomas comprised 244 (79.5%) tubular, 41 (13.3%) tubulovillous, and 22 (7.2%) villous adenomas. The epithelial dysplasia was graded as mild in 260 (84.7%) adenomas, moderate in 33 (10.7%), and severe in 14 (4.6%). The percentage of severe dysplasia was greater in villous adenomas than in tubular adenomas (p less than 0.05) and correlated with the increasing size (greater than 5 mm) of the adenomas (p less than 0.01). The risk of metachronous adenomas could be evaluated among 56 patients, 34 men and 22 women with a history of removed adenoma(s). Fourteen of 56 patients (25%) with 6:1 male to female ratio developed 18 new adenomas, after an average of 34.3 months (range, from 12 to 88 months). Eleven of the 14 patients had multiple adenomas at the initial examination. In addition, a carcinoma of the rectum was found in one male patient. Of the 48 patients, 17 men and 31 women, operated on for colorectal cancer 16 patients (34%) with 1.3:1 male to female ratio had 40 new adenomas after an average of 51.8 months (range, 12 to 252 months) after the surgical excision of their carcinomas. One patient had a recurrent carcinoma at the site of the anastomosis 22 months after anterior resection of his carcinoma. Our data suggest that a history of colorectal carcinoma, multiple adenomas, and male sex predict a higher risk of having future colorectal tumours.