Metachronous Adenomas Research Articles

Serrated Polyps in Inflammatory Bowel Disease Indicate a Similar Risk of Metachronous Colorectal Neoplasia as in the General Population.

The risk of metachronous advanced neoplasia after diagnosing serrated polyps in patients with IBD is poorly understood. A retrospective multicenter cohort study was conducted between 2010 and 2019 at three tertiary centers in Montreal, Canada. From pathology databases, we identified 1587 consecutive patients with serrated polyps (sessile serrated lesion, traditional serrated adenoma, or serrated epithelial change). We included patients aged 45-74 and excluded patients with polyposis, colorectal cancer, or no follow-up. The primary outcome was the risk of metachronous advanced neoplasia (advanced adenoma, advanced serrated lesion, or colorectal cancer) after index serrated polyp, comparing patients with and without IBD. 477 patients with serrated polyps were eligible (mean age 61years): 37 with IBD, totaling 45 serrated polyps and 440 without IBD, totaling 586 serrated polyps. The median follow-up was 3.4years. There was no difference in metachronous advanced neoplasia (HR 0.77, 95% CI 0.32-1.84), metachronous advanced adenoma (HR 0.54, 95% CI 0.11-2.67), and metachronous advanced serrated lesion (HR 0.76, 95% CI 0.26-2.18) risk. When comparing serrated polyps in mucosa involved or uninvolved with IBD, both groups had similar intervals from IBD to serrated polyp diagnosis (p > 0.05), maximal therapies (p > 0.05), mucosal inflammation, inflammatory markers, and fecal calprotectin (p > 0.05). The risk of metachronous advanced neoplasia after serrated polyp detection was similar in patients with and without IBD. Serrated polyps in IBD occurred independently of inflammation. This helps inform surveillance intervals for patients with IBD diagnosed with serrated polyps.

Abstract 4769: Phospho-YAP (Ser127) overexpression is associated with sporadic advanced adenomas: The Tennessee Colorectal Polyp Study

Abstract About 70-80% of sporadic colorectal cancers (CRCs) harbor APC mutations. Whether specific characteristics of APC mutation or APC-related signaling pathways contribute to tumor initiation, advanced progression, and recurrence in the precancerous lesions remain to be elucidated. This study included145 sporadic precancerous adenomas from the Tennessee Colorectal Polyp Study. Expression of six APC-related proteins (β-catenin, p-YAP, CtBP, EB1, Asef, and N-terminal APC) in adenoma and non-tumor tissues (n=22) were quantitatively detected by immunohistochemistry. Targeted sequencing of APC was done for 108 adenomas. Metachronous adenoma status was obtained from chart review. YAP-correlated genes and their functional enrichment analysis were conducted using gene expression data of 326 adenomas from the Gene Expression Omnibus database. We found that nuclear β-catenin and p-YAP overexpression only existed in adenoma tissue, correlated with each other (r=0.26, P=0.0018), and associated with APC mutations (P=0.05). P-YAP was strongly associated with odds of large adenomas (OR=14.25, 95%CI=3.32-61.18, P trend<0.0001), villous growth pattern (OR=58.71, 95%CI=10.49-328.61, P trend<0.0001) and advanced adenomas (OR=12.62, 95%CI 4.57-34.86, P trend<0.001), and showed a significant interaction with nuclear β-catenin on advanced tumor (OR=16.82, 95%CI 4.41-64.08, P<0.0001). After adjusting for selected covariates and mutually adjusting for biomarkers with P<0.20 in crude models, p-YAP overexpression remained significantly associated with advanced adenomas (OR=12.31, 95% CI=3.78-40.10, P trend<0.0001). YAP-correlated genes were significantly enriched in autophagy, unfolded protein response, and sirtuin pathways with predominantly pro-tumorigenic alterations. APC mutation and selected biomarkers were not significantly associated with metachronous adenoma. In conclusion, p-YAP overexpression might be a promising biomarker for high-risk sporadic adenoma. In addition to its synergistic effect with nuclear β-catenin, p-YAP may play tumorigenic roles through interaction with other cancer pathways in human sporadic adenoma. This study provided new evidence for oncogenic effects of p-YAP in human sporadic adenomas and shed light on the complex network of Hippo, Wnt, and other oncogenic signaling pathways. Citation Format: Lei Fan, Xingyi Guo, Mary Kay Washington, Jiajun Shi, Reid M. Ness, Qi Liu, Wanqing Wen, Xiao Liu, Qiuyin Cai, Wei Zheng, Robert J. Coffey, Martha J. Shrubsole, Timothy Su. Phospho-YAP (Ser127) overexpression is associated with sporadic advanced adenomas: The Tennessee Colorectal Polyp Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4769.

A152 THE RISK OF UNFAVORABLE HISTOLOGIC FEATURES, LYMPH NODE METASTASIS AND METACHRONOUS ADVANCED NEOPLASIA IN PATIENTS WITH COLORECTAL INTRAMUCOSAL CARCINOMA

Abstract Background Very few studies have described the risk of unfavorable histologic features (UHFs), lymph node involvement (LNI), distant metastasis (DM) and metachronous advanced neoplasia (MAN) after the detection of colorectal intramucosal carcinoma (IMC). Aims This study aimed to determine the risk of UHFs, LNI, DM and MAN in patients with IMC, compared to high-grade dysplasia (HGD) or T1 colorectal cancer (CRC). Methods A retrospective cohort study was conducted. Through a pathology database search, we identified all consecutive patients with HGD (epithelial) (n=908) or either IMC (lamina propria or muscularis mucosa) or T1 CRC (submucosa) (n=496) diagnosed between 2010 and 2019 at the University of Montreal Hospital Center. We excluded patients with age ampersand:003C40 or ampersand:003E90, IBD, hereditary CRC or post-neoadjuvant therapy. Primary outcome was the risk of UHF, LNI and DM in IMC vs T1. Secondary outcome was the risk of MAN (metachronous advanced adenoma or advanced serrated lesion or CRC) in the IMC group, compared to HGD and T1. Files were reviewed for demographics and index and follow-up findings. The metachronous analysis excluded follow-ups ampersand:003C6 months, no follow-up or previous CRC. Follow-up continued until MAN or last colonoscopy within 10 y. Variables were compared between groups using ANOVA, chi-squared tests or Kruskal-Wallis tests, followed by post-hoc tests. We performed multivariate Cox regressions, adjusting for age, sex, family history of CRC, main lesion location, villous histology, adenomas ≥10 mm, and number of adenomas. Results The primary cohort included 90 patients with IMC (mean age 69.4 y., 44.4% female) and 207 with T1 CRC (mean age 69.8 y., 43.5% female), as well as 797 with HGD. The rates of lymphatic invasion, vascular invasion, intermediate differentiation/grade and mucinous histology were 2/90, 1/90, 7/90 and 4/90 in the IMC group compared to respectively 30/207 (2.2% vs 14.5%, pampersand:003C0.01), 15/207 (1.1% vs 7.2%, p=0.06), 68/207 (7.7% vs 32.9%, pampersand:003C0.01) and 15/207 in the T1 group (4.4% vs 7.2%, p=0.52). No other UHFs were present. No patients with IMC had LNI or DM. In the metachronous outcomes analysis, 464 patients were eligible (mean age 67.1 y., 42.2% female, median follow-up 3.0 y.): 274 with HGD, 58 with IMC and 132 with T1 CRC. Compared to HGD, patients with IMC had a lower likelihood of MAN (HR 0.46, 0.22-0.96), and T1 CRC had a similar likelihood of MAN (HR 0.65, 0.41-1.02). Compared to IMC, T1 CRC had a similar likelihood of MAN (HR 1.39, 0.63-3.09). Conclusions Patients with colorectal IMC have a small risk of UHFs, but LNI and DM were not identified in this cohort study and have not been reported. Patients with IMC and T1 CRC do not have an increased risk of MAN compared to patients with HGD. Funding Agencies None

Metachronous Colorectal Adenomas Occur Close to the Index Lesion.

The aim of this study is to assess the spatial relationship between index and metachronous colorectal adenoma location. After the complete excision of a human sporadic colorectal adenoma, patients are at elevated risk of developing a further metachronous adenoma. Data regarding the occurrence site of a metachronous colorectal adenoma relative to the index adenoma are scarce. Prospectively maintained databases were interrogated to identify all colonoscopies and adenoma excisions performed over a 10-year period at a single university teaching hospital. Data for the colonic segments at which adenoma removal were reported at index and all subsequent colonoscopies were extracted and 2 allied data sets merged. A total of 15,121 colonoscopies and 4759 polyp events were recorded. Four hundred fifty-two patients [296 male, 156 female, median (range) age 75 (32 to 100) y] developed at least 1 metachronous adenoma at follow-up colonoscopy. When single index events only are considered (ie, synchronous adenoma cases excluded), over 61% of metachronous adenomas were recorded in the same or an adjacent colonic segment. When the full span of the colon is considered, metachronous adenomas were more likely to occur in a section of the colon proximal to that of the index adenoma (41%±5%) than the same (39%±5%) or distal segment (20%±5%; P=0.006; 1-way χ2 test). A metachronous human sporadic colorectal adenoma is more likely to be found in the same colonic segment to that of the index adenoma or 1 immediately adjacent. These data suggest a shared origin of metachronous adenoma with preceding lesions, supporting the existence of precancerous fields.

Elevated EVL Methylation Level in the Normal Colon Mucosa Is a Potential Risk Biomarker for Developing Recurrent Adenomas.

Individuals with adenomatous colorectal polyps undergo repeated colonoscopy surveillance to identify and remove metachronous adenomas. However, many patients with adenomas do not develop recurrent adenomas. Better methods to evaluate who benefits from increased surveillance are needed. We evaluated the use of altered EVL methylation as a potential biomarker for risk of recurrent adenomas. Patients with ≥1 colonoscopy had EVL methylation (mEVL) measured with an ultra-accurate methylation-specific droplet digital PCR assay on normal colon mucosa. The association between EVL methylation levels and adenoma or colorectal cancer was evaluated using three case/control definitions in three models: unadjusted (model 1), adjusting for baseline characteristics (model 2), and an adjusted model excluding patients with colorectal cancer at baseline (model 3). Between 2001 and 2020, 136 patients were included; 74 healthy patients and 62 patients with a history of colorectal cancer. Older age, never smoking, and baseline colorectal cancer were associated with higher levels of mEVL (P ≤ 0.05). Each log base 10 difference in mEVL was associated with an increased risk of adenoma(s) or cancer at/after baseline for model 1 [OR, 2.64; 95% confidence interval (CI), 1.09-6.36], and adenoma(s) or cancer after baseline for models 1 (OR, 2.01; 95% CI, 1.04-3.90) and model 2 (OR, 3.17; 95% CI, 1.30-7.72). Our results suggest that EVL methylation level detected in the normal colon mucosa has the potential to be a biomarker for monitoring the risk for recurrent adenomas. These findings support the potential utility of EVL methylation for improving the accuracy for assigning risk for recurrent colorectal adenomas and cancer.

Impact of cold snare versus cold forceps resection of diminutive adenomas on segmental incomplete resection rate.

Polypectomy technique, for diminutive lesion resection, is variable amongst colonoscopists using either cold snare (CSP) or cold forceps (CFP) polypectomy. While it is well described that CSP is a preferred technique to resect small lesions, there is little data evaluating the impact resection techniques have on metachronous adenoma burden. The study aim was to evaluate the rate of incomplete resection attributable to CSP and CFP of diminutive adenomas. This is a two-center retrospective cohort study evaluating the segmental incomplete resection rate (S-IRR) of diminutive tubular adenomas (TA). S-IRR was calculated by subtracting the segmental metachronous adenoma rate in a specific colonic segment without adenoma from segments with adenoma on index colonoscopy. The primary outcome was the S-IRR of diminutive TA resected by CSP or CFP on index colonoscopy. 1504 patients were included in the analysis: 1235 with TA <6 mm and 269 with TA 6-9 mm as the most advanced lesion. The S-IRR in a segment that had a <6 mm TA incompletely resected by CFP on index colonoscopy was 13%. The S-IRR in a segment which had a <6 mm TA incompletely resected by CSP was 0%. Among 12 included colonoscopists, the range of overall S-IRR was 1.1% - 24.4% with an average S-IRR of 10.3%. S-IRR was 13% higher with CFP resection of diminutive TA than with CSP. A proposed S-IRR metric of <5% is a target goal for all diminutive polyp resection, as 3/12 colonoscopists achieved this low rate. S-IRR can be utilized as a methodology to compare and quantify the difference in segmental metachronous adenoma burden across various polypectomy removal methods.

Chemoprevention of colorectal cancer in general population and high-risk population: a systematic review and network meta-analysis.

Many nutritional supplements and pharmacological agents have been reported to show preventive effects on colorectal adenoma and colorectal cancer (CRC). We performed a network meta-analysis to summarize such evidence and assess the efficacy and safety of these agents. We searched PubMed, Embase, and the Cochrane Library for studies published in English until October 31, 2021 that fit our inclusion criteria. We performed a systematic review and network meta-analysis to assess the comparative efficacy and safety of candidate agents (low-dose aspirin [Asp], high-dose Asp, cyclooxygenase-2 inhibitors [coxibs], calcium, vitamin D, folic acid, ursodeoxycholic acid [UDCA], estrogen, and progesterone, alone or in combination) for preventing colorectal adenoma and CRC. Cochrane risk-of-bias assessment tool was employed to evaluate the quality of each included study. Thirty-two randomized controlled trials (278,694 participants) comparing 13 different interventions were included. Coxibs significantly reduced the risk of colorectal adenoma (risk ratio [RR]: 0.59, 95% confidence interval [CI]: 0.44-0.79, six trials involving 5486 participants), advanced adenoma (RR: 0.63, 95% CI: 0.43-0.92, four trials involving 4723 participants), and metachronous adenoma (RR: 0.58, 95% CI: 0.43-0.79, five trials involving 5258 participants) compared with placebo. Coxibs also significantly increased the risk of severe adverse events (RR: 1.29, 95% CI: 1.13-1.47, six trials involving 7109 participants). Other interventions, including Asp, folic acid, UDCA, vitamin D, and calcium, did not reduce the risk of colorectal adenoma in the general and high-risk populations compared with placebo. Considering the balance between benefits and harms, regular use of coxibs for prevention of colorectal adenoma was not supported by the current evidence. Benefit of low-dose Asp for chemoprevention of colorectal adenoma still requires further evidence. PROSPERO, No. CRD42022296376.

Surveillance Colonoscopies of Synchronous Colorectal Cancer: What Should We Do?

The aim of this study is to investigate the occurrence of metachronous neoplasms at 2-year surveillance colonoscopy for synchronous colorectal cancer patients and the relative risk factors. Synchronous colorectal cancer patients who underwent surgery or endoscopic resection for colorectal cancer between January 2008 and December 2019 were enrolled. All patients underwent surveillance colonoscopies at least twice within 2 years after operation. Univariate and multivariate analyses were conducted to assess the risk factors for the metachronous neoplasms. Totally 38 patients (male/female: 26/12) were included, with an average age of 64.6 years (±11.5 years) and a mean surveillance interval of 23.47 ± 4.39 months. In 21 of 38 patients (55.3%), metachronous adenoma was detected, including 6 metachronous advanced adenomas. Two patients were detected with metachronous carcinomas. In univariate analysis, male sex, elderly age at diagnosis, and the presence of synchronous adenomas/synchronous advanced adenoma at baseline colonoscopy were associated with the development of metachronous adenoma (P = .037, .047, .013, .039), but not associated with metachronous advanced adenoma (P = 0.455, .746, .503, .269). Patients tends to occur less metachronous advanced adenoma if index colorectal tumors were treated by endoscopic resection (P = .010), but the tendency was not discovered in metachronous adenoma (P = .289). Tumor location (with/ without rectum cancer) was not associated with the development of metachronous lesions (P = .526, .382). On multivariate analysis, the presence of synchronous adenomas at baseline colonoscopy was an independent risk factor for MA during follow-up (odds ratio = 15.0; 95% CI: 1.55-145.22). For postoperative synchronous colorectal cancer patients, doctors should design individual surveillance strategies according to sex, baseline colonoscopy, and operative (or endoscopic) approach of resection.

Safety of pylorus-preserving gastrectomy for gastric cancer combined with antral high-risk lesions: a comparison with endoscopic submucosal dissection.

Pylorus-preserving gastrectomy (PPG) is a surgical treatment option for cT1N0M0 gastric cancer located in the middle third of the stomach. However, data for the long-term post-PPG clinical outcomes related to metachronous gastric neoplasms (mGNs) in the residual stomach are currently lacking. Therefore, we aimed to evaluate the safety of PPG by focusing on mGNs. In this single-center, retrospective study, we reviewed the data for 362 patients who underwent PPG with a 3-cm antral cuff and 139 who underwent endoscopic submucosal dissection (ESD) for middle-third gastric cancer between January 2013 and December 2015. The histopathologic features of the antrum in the ESD group, which could not be determined in the PPG group, were analyzed to investigate the risk factors for mGNs. The estimated and actual incidence of mGNs in the antrum were compared in the PPG group. The incidence of mGNs was 6.5% (9/139) in the ESD group. The presence of a synchronous adenoma (odds ratio [OR], 8.46; 95% confidence interval [CI], 1.55-46.34), carcinoma (OR, 15.71; 95% CI, 2.67-92.56) and moderate-to-severe intestinal metaplasia (OR, 9.77; 95% CI, 1.14-83.92) were associated with a higher risk of overall mGNs. However, when confined to the antrum, no significant association was observed between these factors and mGNs. In the ESD group, 2 of 9 mGNs (1.4%) were located at the 3-cm antral cuff. In the PPG group, both mGNs (0.6%) were located in the proximal remnant stomach. Pylorus-preserving gastrectomy was a safe therapeutic option with regard to the occurrence of metachronous adenomas or carcinomas in our series. Despite the low mGN incidence in the 3-cm antral cuff after PPG, the presence of synchronous neoplasms or moderate-to-severe intestinal metaplasia was a risk factor for mGNs in the ESD group; thus, further studies on longer antral cuffs with long-term follow-up are needed.

Genome-Wide Association Study of Metachronous Colorectal Adenoma Risk among Participants in the Selenium Trial

Genetic variants related to colorectal adenoma may help identify those who are at highest risk of colorectal cancer development or illuminate potential chemopreventive strategies. The purpose of this genome-wide association study was to identify genetic variants that are associated with risk of developing a metachronous colorectal adenoma among 1,215 study participants of European descent from the Selenium Trial. Associations of variants were assessed with logistic regression analyses and validated in an independent case-control study population of 1,491 participants from the Colorectal Cancer Study of Austria (CORSA). No statistically significant genome-wide associations between any variant and metachronous adenoma were identified after correction for multiple comparisons. However, an intron variant of FAT3 gene, rs61901554, showed a suggestive association (P = 1.10 × 10−6) and was associated with advanced adenomas in CORSA (P = 0.04). Two intronic variants, rs12728998 and rs6699944 in NLRP3 were also observed to have suggestive associations with metachronous lesions (P = 2.00 × 10−6) in the Selenium Trial and were associated with advanced adenoma in CORSA (P = 0.03). Our results provide new areas of investigation for the genetic basis of the development of metachronous colorectal adenoma and support a role for FAT3 involvement in the Wnt/β-catenin pathway leading to colorectal neoplasia. Trial Registration number: NCT00078897 (ClinicalTrials.gov).

Effect Modification of Selenium Supplementation by Intake and Serum Concentrations of Antioxidants on the Development of Metachronous Colorectal Adenoma

BackgroundSelenium (Se) is a trace element that has been investigated as a potential chemopreventive agent for colorectal cancer. Dietary intake of other antioxidant nutrients may modify the effect of Se.ObjectiveWe examined the association between intake and serum concentrations of retinol, β-carotene, β-cryptoxanthin, lycopene, lutein/zeaxanthin, and α- and γ-tocopherol and the development of metachronous colorectal adenoma, and if these nutrients modified the effect of Se.MethodsWe conducted a prospective study of 1874 participants from the Se Trial with data for antioxidant intake, as well as a subcohort of 508 participants with serum biomarker concentrations.ResultsStatistically significantly lower odds for the development of metachronous adenoma were observed for those participants in the highest tertile of intake for lutein/zeaxanthin compared to the lowest, with an OR (95% CI) of 0.72 (0.56-0.94). No effect modification for intake of any nutrient was observed. However, circulating concentrations of lycopene exhibited statistically significant effect modification of selenium supplementation (p < 0.06),ConclusionThese findings show that intake and circulating concentrations of antioxidant nutrients were not consistently associated with reduced odds for the development of metachronous lesions, although blood concentrations of lycopene may modify the effect of selenium supplementation.

Endoscopic Management of Adenomas in the Ileal Pouch and the Rectal Remnant after Surgical Treatment in Familial Adenomatous Polyposis.

In patients with familial adenomatous polyposis (FAP), adenomas and even carcinomas may develop in the rectal remnant and the ileal pouch after surgical treatment. The aim of this study was to evaluate the outcome of endoscopic management in patients with FAP. The main outcome measurements were the appearance of secondary cancer, complications, and the need for additional surgery. Thirty-four FAP patients with Kock’s continent ileostomy (Kock) (n = 3), ileorectal anastomosis (IRA) (n = 12), and ileal pouch-anal anastomosis (IPAA) (n = 19) were identified. The median follow-up period of endoscopic surveillance was 11.5 years for pouch patients (Kock + IPAA) and 21.7 years for IRA. Metachronous adenomas appeared in 32 patients (94.1%). In pouch patients, a total of 120 treatments were given to 20 patients, and 12 sessions of delayed bleeding (10%) occurred, which was significantly higher compared to IRA patients, with 0 sessions (p < 0.001). In IRA patients, a total of 169 treatments were given to 11 patients, with one case of perforation. No adenocarcinoma has developed since the start of endoscopic surveillance. Regular endoscopic surveillance and treatment are feasible and safe. However, in pouch patients, one must be cautious about delayed bleeding in the treatment of adenomas.

Abstract LB551: Critical role of necroptosis in colorectal carcinogenesis

Abstract Background: Unlike apoptosis, necroptosis, a programmed necrosis discovered in the past decade, elicits robust adaptive immune responses, including inflammatory cascade, against bacterial infection. However, no human study has yet examined the role of necroptosis in colorectal carcinogenesis. Methods: To compare the roles of necroptosis (TRPM7, pMLKL) with inflammation (COX-2), apoptosis (BAX, TUNEL) and cell proliferation (Ki67) biomarkers across the colorectal carcinogenesis spectrum, we evaluated the trends of biomarker levels from normal colorectal mucosa, to small adenoma, large adenomas and early stages of CRC in tissue microarray (TMA). Furthermore, we compared whether these biomarkers in rectal biopsies can predict the risk of developing metachronous polyp/adenoma. Results: In TMA, we revealed that levels of TRPM7, did not apparently change from normal mucosa (median=1.1) to small adenoma (median=0.8), but then substantially dropped in large adenoma (median=0.1) only to rise dramatically increased in early colorectal cancer (median=7.4) (P for trend=0.004). pMLKL, tended to decrease during carcinogenesis, although not significantly. Ki67 linearly and significantly increased during carcinogenesis (Ptrend=0.002). Similar to Ki67, levels of BAX and TUNEL increased significantly during carcinogenesis, but BAX started to drop in early carcinogenesis. Thus, compared to TRPM7, a necroptosis biomarker, BAX, an apoptosis biomarker, had an almost completely opposite trend during carcinogenesis. COX-2 intensity in the epithelium, but not the stroma, increased in carcinogenesis (Ptrend=0.01). Of 124/227 participants who had follow-up colonoscopy within 5 years, 69 (55.6%) were identified as having metachronous polyp/adenoma. For single biomarker analysis, overexpression of COX-2 was significantly associated with an increased risk of metachronous polyp OR=3.61 ( 95% CI: 1.05-2.47, Ptrend=0.02) and adenoma (OR=3.58, 95% CI 0.96-3.36, Ptrend=0.04). Higher expression of TRPM7 was associated with risk of recurrent polyp and adenoma in a dose-response manner although it did not reaching statistically significance. According to the results of single biomarker analysis and biological plausibility, we combined COX-2 with two necroptosis biomarkers, i.e., pMLKL, TRPM7 and two apoptosis biomarkers (BAX and TUNEL) to generate composite index scores using factor analysis. Several of these composite scores were strongly associated with a 3- to 5-fold increased of metachronous polyp and/or adenoma risk in the highest quartile including COX-2 with pMLKL, COX-2 and TRPM7, BAX and TRPM7 and COX-2 with BAX. The results were similar after the exclusion of recurrence within one year after the completion of the PPCCT. Conclusion: Necroptosis plays a key role in colorectal carcinogenesis. Combining necroptosis biomarkers with inflammation and apoptosis biomarkers can improve the prediction of risk of metachronous polyp/adenoma compared to using necroptosis, inflammation or apoptosis biomarkers alone. Citation Format: Xiangzhu Zhu, Timothy Su, Yong Li, Chang Yu, Xinqing Deng, Eugene Shubin, Wei Zheng, Harvey J. Murff, Reid M. Ness, Martha J. Shrubsole, Qi Dai. Critical role of necroptosis in colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB551.

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.

Sessile serrated lesions in patients with adenoma on index colonoscopy do not increase metachronous advanced adenoma risk.

Post-polypectomy surveillance intervals should be determined based on index colonoscopy findings. However, the risk of metachronous lesions, resulting from the coexistence of adenoma and sessile serrated lesions (SSLs), has rarely been addressed. We evaluated the impact of synchronous SSL on the risk of metachronous lesions within similar adenoma risk groups. We retrieved individuals with one or more adenomas on index colonoscopy in a single-center retrospective cohort and stratified them into four groups depending on the presence of SSL and low-risk/high-risk adenoma (LRA/HRA). Participants who underwent surveillance colonoscopies at least 12 months apart were included. We compared the risks of metachronous lesions including HRA, advanced adenoma (AA), or SSL within similar adenoma risk groups according to the presence of SSL. Overall 4493 individuals were included in the analysis. The risk of metachronous HRA/AA was not significantly higher in the adenoma with SSL group compared with the adenoma without SSL group, irrespective of LRA (HRA, 6/86 vs. 231/3297, P = 1.00; AA, 0/86 vs. 52/3297, P = 0.64) or HRA (HRA, 11/64 vs. 240/1046, P = 0.36; AA, 3/64 vs. 51/1046, P = 1.00). However, the risk of metachronous SSL in individuals with synchronous SSL was higher than that in those without SSL for both LRA (15/86 vs. 161/3297, P < 0.001) and HRA groups (11/64 vs. 61/1046, P = 0.002). The presence of synchronous SSL did not increase the risk of metachronous HRA/AA, compared with isolated adenoma, but increased the risk of metachronous SSL.

The necessity of intensive surveillance colonoscopy for patients with a remaining right colon after resection of colorectal cancer: a retrospective cohort study.

To clarify how often postoperative surveillance colonoscopy should be undertaken based on the risk factors for the development of metachronous cancer (MC) and advanced adenoma (AA) after surgery for colorectal cancer. We collected data of consecutive patients who underwent curative resection for primary colorectal cancer between 2005 and 2012, with preoperative colonoscopy and surveillance colonoscopy at 1year after surgery (406 patients, mean age: 69years, 59% male). The detection rates of AA (with villous features, > 10mm or high-grade dysplasia) and MC by surveillance colonoscopy were the primary outcomes. At 5years, colonoscopy was performed as postoperative surveillance an average of 3.2 times. AA and MC were detected in 57 (14.0%) and 18 patients (4.4%), respectively. Both lesions were more common in the right colon (n = 43) than in the left colon (n = 28). The detection rate did not differ to a statistically significant extent according to the number of colonoscopies performed for surveillance (p = 0.21). However, after left-sided colectomy, both types of lesions were more commonly detected in those who received ≥ 3 colonoscopies than in those with one or two colonoscopies (p = 0.04). A remaining right colon after left-sided colectomy was associated with a higher risk of developing AA and MC. Physicians should consider performing surveillance colonoscopy more frequently if the right colon remains after surgery.

Novel Methods of Risk Stratifying Patients for Metachronous, Pre-Malignant Colorectal Polyps: A Systematic Review.

Despite conventional measures of future polyp risk (histology, dysplasia, size, number), surveillance places a burden on patients and colonoscopy services. We aimed to review novel risk stratification techniques. A systematic literature review was performed for studies using genomics, transcriptomics, IHC or microbiome as markers of metachronous polyp risk. 4165 papers underwent title, 303 abstract and 215 full paper review. 25 papers were included. 49 mutations/ SNPs/ haplotypes in 23 genes/ chromosomal regions (KRAS, APC, EGFR, COX1/2, IL23R, DRD2, CYP2C9/24A1/7A1, UGT1A6, ODC, ALOX12/15, PGDH, SRC, IGSF5, KCNS3, EPHB1/ KY, FAM188b, 3p24.1, 9q33.2, 13q33.2) correlated with metachronous adenoma / advanced adenoma risk. Expression levels of 6 proteins correlated with metachronous adenoma (p53, β-catenin, COX2, Adnab-9, ALDH1A1) or sessile serrated polyp (ANXA10) risk. Although genomic and IHC markers correlated with metachronous polyp risk, it seems likely that a panel of novel markers will be required to refine this risk.

Oral Antibiotics and Risk of New Colorectal Adenomas During Surveillance Follow-up.

Antibiotics may increase colorectal neoplasia risk by modifying the gut microbiome. It is unknown whether use is associated with the risk of new colorectal adenomas among individuals with prior adenomas. We performed a secondary analysis of four randomized clinical trials for the chemoprevention of colorectal adenomas. Participants self-reported all currently used prescription drugs shortly after an initial colorectal adenoma diagnosis and two or three times a year thereafter over 3 to 5 years of follow-up. We estimated adjusted risk ratios (RR) with 95% confidence intervals (CI) for incident adenomas, analyzing the four trials together. Cumulatively, the four trials enrolled 5,174 participants (3,491 men and 1,683 women), of whom 4,769 (92%) completed ≥1 follow-up colonoscopy. A total of 763 (15%) participants reported using oral antibiotics on ≥2 occasions. Overall, 39% of those using oral antibiotics at least twice developed new colorectal adenomas compared with 40% of those with no use or a single report of use (RR, 0.99; 95% CI, 0.90-1.10). No statistically significant associations were found in study-specific analyses, and results were similar for high- and low-risk adenoma findings, antibiotic class, anatomic location of adenomas, and analyses excluding those with interim colorectal exams. Oral antibiotic use during colonoscopic surveillance after an initial adenoma diagnosis was not associated with risk of these polyps. Any changes to the gut microbiome as a consequence of oral antibiotic use during surveillance may not affect the development of metachronous colorectal adenomas.

Abstract 477: Elevated EVL methylation level in the normal colon mucosa is a potential risk biomarker for developing metachronous polyps

Abstract The purpose of this study is to evaluate the use of molecular markers for more accurately predicting the individual risk of metachronous polyps or cancer during colonoscopic surveillance. Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the United States. The risk of CRC varies among people; individuals who develop adenomas are at heightened risk of forming metachronous adenomas and interval cancer, compared to those without a personal history of adenoma or CRC. Yet, even in these high risk individuals, only 25-30% will develop subsequent adenomas. To date, few studies have evaluated the use of molecular markers for predicting the risk of metachronous lesions. We have demonstrated that aberrantly methylated mir342/EVL is present at a higher frequency in the normal colon of people with CRC compared to people with no colon cancer or polyps, suggesting it may indicate a field cancerization process. Further, we developed an ultra-sensitive quantitative Methylation-specific ddPCR (MS-ddPCR) assay to accurately determine the level of rare EVL methylation in the normal colon mucosa. To investigate the correlation of EVL methylation in normal mucosa and the risk of developing polyps during the follow-up colonoscopy, we conducted a retrospective cohort study (N=136 subjects) and EVL methylation status was determined in normal colon mucosa samples from these subjects. Among them, 71 subjects had polyps detected within 12 years of the index colonoscopy, and 11 subjects were polyp-free at all subsequent colonoscopic exams done within 8-16 years of the index colonoscopy (54 subjects did not meet the criteria for follow up, so were excluded from the following analysis). Applying the standard Inverse Probability Weighted Logistic Regression (IPWLR) model, we found that higher level of EVL methylation in the normal colon mucosa at the time of the index colonoscopy (which was when the tissue sample was collected) indicated an increased risk of having polyps detected within 12 years, compared to subjects with no polyps detected by colonoscopy done within 8-16 years (Odds Ratio (95% CI) = 4.35 (1.14, 16.60); p-value = 0.0317). Our results suggest that EVL methylation level in the normal colon mucosa can be used as a risk biomarker for metachronous adenomas. Citation Format: Ming Yu, Ting Wang, Kelly T. Carter, Kelsey Baker, Mary W. Redman, Kathy Vickers, Lynda Ann Dzubinski, Robert E. Schoen, William M. Grady. Elevated EVL methylation level in the normal colon mucosa is a potential risk biomarker for developing metachronous polyps [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 477.

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.