Expression and significance of pigment epithelium-derived factor and vascular endothelial growth factor in colorectal adenoma and cancer

BACKGROUND The incidence and mortality of colorectal cancer(CRC)are among the highest in the world,and its occurrence and development are closely related to tumor neovascularization.When the balance between pigment epithelium-derived factors(PEDF)that inhibit angiogenesis and vascular endothelial growth factors(VEGF)that stimulate angiogenesis is broken,angiogenesis is out of control,resulting in tumor development.Therefore,it is very necessary to find more therapeutic targets for CRC for early intervention and later treatment.AIM To investigate the expression and significance of PEDF,VEGF,and CD31-stained microvessel density values(CD31-MVD)in normal colorectal mucosa,adenoma,and CRC.METHODS In this case-control study,we collected archived wax blocks of specimens from the Digestive Endoscopy Center and the General Surgery Department of Chengdu Second People's Hospital from April 2022 to October 2022.Fifty cases of specimen wax blocks were selected as normal intestinal mucosa confirmed by electronic colonoscopy and concurrent biopsy(normal control group),50 cases of specimen wax blocks were selected as colorectal adenoma confirmed by electronic colonoscopy and pathological biopsy(adenoma group),and 50 cases of specimen wax blocks were selected as CRC confirmed by postoperative pathological biopsy after inpatient operation of general surgery(CRC group).An immunohistochemical staining experiment was carried out to detect PEDF and VEGF expression in three groups of specimens,analyze their differences,study the relationship between the two and clinicopathological factors in CRC group,record CD31-MVD in the three groups,and analyze the correlation of PEDF,VEGF,and CD31-MVD in the colorectal adenoma group and the CRC group.The F test or adjusted F test is used to analyze measurement data statistically.Kruskal-Wallis rank sum test was used between groups for ranked data.The chi-square test,adjusted chi-square test,or Fisher's exact test were used to compare the rates between groups.All differences between groups were compared using the Bonferroni method for multiple comparisons.Spearman correlation analysis was used to test the correlation of the data.The test level(α)was 0.05,and a two-sided P<0.05 was considered statistically significant.RESULTS The positive expression rate and expression intensity of PEDF were gradually decreased in the normal control group,adenoma group,and CRC group(100%vs 78%vs 50%,χ^(2)=34.430,P<0.001;++~++vs+~++vs-~+,H=94.059,P<0.001),while VEGF increased gradually(0%vs 68%vs 96%,χ^(2)=98.35,P<0.001;-vs-~+vs++~+++,H=107.734,P<0.001).In the CRC group,the positive expression rate of PEDF decreased with the increase of differen-tiation degree,invasion depth,lymph node metastasis,distant metastasis,and TNM stage(χ^(2)=20.513,4.160,5.128,6.349,5.128,P<0.05);the high expression rate of VEGF was the opposite(χ^(2)=10.317,13.134,17.643,21.844,17.643,P<0.05).In the colorectal adenoma group,the expression intensity of PEDF correlated negatively with CD31-MVD(r=-0.601,P<0.001),whereas VEGF was not significantly different(r=0.258,P=0.07).In the CRC group,the expression intensity of PEDF correlated negatively with the expression intensity of CD31-MVD and VEGF(r=-0.297,P<0.05;r=-0.548,P<0.05),while VEGF expression intensity was positively related to CD31-MVD(r=0.421,P=0.002).CONCLUSION It is possible that PEDF can be used as a new treatment and prevention target for CRC by upregulating the expression of PEDF while inhibiting the expression of VEGF.

Standard-definition White-light,High-definition White-light versus Narrow-band Imaging Endoscopy for Detecting Colorectal Adenomas:A Multicenter Randomized Controlled Trial

Objective This study aimed to compare the performance of standard-definition white-light endoscopy(SD-WL),high-definition white-light endoscopy(HD-WL),and high-definition narrow-band imaging(HD-NBI)in detecting colorectal lesions in the Chinese population.Methods This was a multicenter,single-blind,randomized,controlled trial with a non-inferiority design.Patients undergoing endoscopy for physical examination,screening,and surveillance were enrolled from July 2017 to December 2020.The primary outcome measure was the adenoma detection rate(ADR),defined as the proportion of patients with at least one adenoma detected.The associated factors for detecting adenomas were assessed using univariate and multivariate logistic regression.Results Out of 653 eligible patients enrolled,data from 596 patients were analyzed.The ADRs were 34.5%in the SD-WL group,33.5%in the HD-WL group,and 37.5%in the HD-NBI group(P=0.72).The advanced neoplasm detection rates(ANDRs)in the three arms were 17.1%,15.5%,and 10.4%(P=0.17).No significant differences were found between the SD group and HD group regarding ADR or ANDR(ADR:34.5%vs.35.6%,P=0.79;ANDR:17.1%vs.13.0%,P=0.16,respectively).Similar results were observed between the HD-WL group and HD-NBI group(ADR:33.5%vs.37.7%,P=0.45;ANDR:15.5%vs.10.4%,P=0.18,respectively).In the univariate and multivariate logistic regression analyses,neither HD-WL nor HD-NBI led to a significant difference in overall adenoma detection compared to SD-WL(HD-WL:OR 0.91,P=0.69;HD-NBI:OR 1.15,P=0.80).Conclusion HD-NBI and HD-WL are comparable to SD-WL for overall adenoma detection among Chinese outpatients.It can be concluded that HD-NBI or HD-WL is not superior to SD-WL,but more effective instruction may be needed to guide the selection of different endoscopic methods in the future.Our study’s conclusions may aid in the efficient allocation and utilization of limited colonoscopy resources,especially advanced imaging technologies.

Long-term impact of artificial intelligence on colorectal adenoma detection in high-risk colonoscopy

BACKGROUND Improved adenoma detection rate(ADR)has been demonstrated with artificial intelligence(AI)-assisted colonoscopy.However,data on the real-world appli-cation of AI and its effect on colorectal cancer(CRC)screening outcomes is limited.AIM To analyze the long-term impact of AI on a diverse at-risk patient population undergoing diagnostic colonoscopy for positive CRC screening tests or sympt-oms.METHODS AI software(GI Genius,Medtronic)was implemented into the standard proced-ure protocol in November 2022.Data was collected on patient demographics,procedure indication,polyp size,location,and pathology.CRC screening outcomes were evaluated before and at different intervals after AI introduction with one year of follow-up.RESULTS We evaluated 1008 colonoscopies(278 pre-AI,255 early post-AI,285 established post-AI,and 190 late post-AI).The ADR was 38.1%pre-AI,42.0%early post-AI(P=0.77),40.0%established post-AI(P=0.44),and 39.5%late post-AI(P=0.77).There were no significant differences in polyp detection rate(PDR,baseline 59.7%),advanced ADR(baseline 16.2%),and non-neoplastic PDR(baseline 30.0%)before and after AI introduction.CONCLUSION In patients with an increased pre-test probability of having an abnormal colonoscopy,the current generation of AI did not yield enhanced CRC screening metrics over high-quality colonoscopy.Although the potential of AI in colonoscopy is undisputed,current AI technology may not universally elevate screening metrics across all situations and patient populations.Future studies that analyze different AI systems across various patient populations are needed to determine the most effective role of AI in optimizing CRC screening in clinical practice.

Advancing Early Detection of Colorectal Adenomatous Polyps via Genetic Data Analysis: A Hybrid Machine Learning Approach

In this study, a hybrid machine learning (HML)-based approach, incorporating Genetic data analysis (GDA), is proposed to accurately identify the presence of adenomatous colorectal polyps (ACRP) which is a crucial early detector of colorectal cancer (CRC). The present study develops a classification ensemble model based on tuned hyperparameters. Surpassing accuracy percentages of early detection approaches used in previous studies, the current method exhibits exceptional performance in identifying ACRP and diagnosing CRC, overcoming limitations of CRC traditional methods that are based on error-prone manual examination. Particularly, the method demonstrates the following CRP identification accuracy data: 97.7 ± 1.1, precision: 94.3 ± 5, recall: 96.0 ± 3, F1-score: 95.7 ± 4, specificity: 97.3 ± 1.2, average AUC: 0.97.3 ± 0.02, and average p-value: 0.0425 ± 0.07. The findings underscore the potential of this method for early detection of ACRP as well as clinical use in the development of CRC treatment planning strategies. The advantages of this approach are highly expected to contribute to the prevention and reduction of CRC mortality.

Helicobacter pylori infection concomitant with metabolic syndrome further increase risk of colorectal adenomas

AIM: To investigate the association of colorectal adenomas with both Helicobacter pylori (H. pylori) infection and metabolic syndrome. METHODS: Using a cross-sectional hospital-based study, we analyzed physical examination data from 9311 healthy subjects with overnight physical examinations performed between January 2004 and December 2006. Examined data included gender, age, life style, anthropometric measurements, blood pressure, biochemical and hematological studies, H. pylori infection detected by esophagogastroduodenoscopy and biopsy urease tests, and colorectal adenomas detected with a complete total colonoscopy. RESULTS: The prevalence values for H. pylori infection, metabolic syndrome, and colorectal adenoma were39.2%, 18.7%, and 20.7%, respectively. Colorectal adenoma risk factors included male gender [odd ratio (OR): 2.005, 95% conf idence interval (CI): 1.740-2.310, P < 0.001], advanced age (OR: 1.046, 95% CI: 1.040-1.052, P < 0.001), smoking (OR: 1.377, 95% CI: 1.146-1.654, P = 0.001), increased body fat (OR: 1.016, 95% CI: 1.007-1.026, P = 0.001), higher white blood cell count (OR: 1.038, 95% CI: 1.005-1.073, P = 0.025), H. pylori infection (OR: 1.366, 95% CI: 1.230-1.517, P < 0.001), and metabolic syndrome (OR: 1.408, 95% CI: 1.231-1.610, P < 0.001). In addition, concomitant H. pylori infection with metabolic syndrome further increased the probability of colorectal adenomas. CONCLUSION: Our study revealed H. pylori infection with concomitant metabolic syndrome might further increase the risk of colorectal adenomas.

Development and validation of a risk score for advanced colorectal adenoma recurrence after endoscopic resection

AIM: To develop and validate a risk score for advanced colorectal adenoma(ACA) recurrence after endoscopic polypectomy.METHODS: Out of 3360 patients who underwent colon polypectomy at University of Foggia between 2004 and 2008, data of 843 patients with 1155 ACAs was retrospectively reviewed. Surveillance intervals were scheduled by guidelines at 3 years and primary endpoint was considered 3-year ACA recurrence. Baseline clinical parameters and the main features of ACAs were entered into a Cox regression analysis and variables with P < 0.05 in the univariate analysis were then tested as candidate variables into a stepwise Cox regression model(conditional backward selection). The regression coefficients of the Cox regression model were multiplied by 2 and rounded in order to obtain easy to use point numbers facilitating the calculation of the score. To avoid overoptimistic results due to model fitting and evaluation in the same dataset, we performed an internal 10-fold cross-validation by means of bootstrap sampling. RESULTS: Median lesion size was 16 mm(12-23) while median number of adenomas was 2.5(1-3), whereof the number of ACAs was 1.5(1-2). At 3 years after polypectomy, recurrence was observed in 229 ACAs(19.8%), of which 157(13.5%) were metachronous neoplasms and 72(6.2%) local recurrences. Multivariate analysis, after exclusion of the variable "type of resection" due to its collinearity with other predictive factors, confirmed lesion size, number of ACAs and grade of dysplasia as significantly associated to the primary outcome. The score was then built by multiplying the regression coefficients times 2 and the cut-off point 5 was selected by means of a Receiver Operating Characteristic curve analysis. In particular, 248 patients with 365 ACAs fell in the higher-risk group(score ≥ 5) where 3-year recurrence was detected in 174 ACAs(47.6%) whereas the remaining 595 patients with 690 ACAs were included in the low-risk group(score < 5) where 3-year recurrence rate was 7.9%(55/690 ACAs). Area under the curve of the model was 0.81(0.72-0.86) with an overall classification error rate of 0.09. The model was finally validated by means of 10-fold cross validation.CONCLUSION: Our study provides support for the use of a novel risk score as a clinical predictor of ACA recurrence after colon polypectomy.

Calcium supplementation for the prevention of colorectal adenomas: a systematic review and meta-analysis of randomized controlled trials

AIM: To determine the efficacy of calcium supplementation in reducing the recurrence of colorectal adenomas.METHODS: We conducted a systematic review and meta-analysis of published studies. We searched PubMed, Scopus, the Cochrane Library, the WHO International Clinical Trials Registry Platform, and the ClinicalTrials.gov website, through December 2015. Randomized, placebo-controlled trials assessing supplemental calcium intake for the prevention of recurrence of adenomas were eligible for inclusion. Two reviewers independently selected studies based on predefined criteria, extracted data and outcomes (recurrence of colorectal adenomas, and advanced or &#x0201c;high-risk&#x0201d; adenomas), and rated each trial&#x02019;s risk-of-bias. Between-study heterogeneity was assessed, and pooled risk ratio (RR) estimates with their 95% confidence intervals (95%CI) were calculated using fixed- and random-effects models. To express the treatment effect in clinical terms, we calculated the number needed to treat (NNT) to prevent one adenoma recurrence. We also assessed the quality of evidence using GRADE.RESULTS: Four randomized, placebo-controlled trials met the eligibility criteria and were included. Daily doses of elemental calcium ranged from 1200 to 2000 mg, while the duration of treatment and follow-up of participants ranged from 36 to 60 mo. Synthesis of intention-to-treat data, for participants who had undergone follow-up colonoscopies, indicated a modest protective effect of calcium in prevention of adenomas (fixed-effects, RR = 0.89, 95%CI: 0.82-0.96; random-effects, RR = 0.87, 95%CI: 0.77-0.98; high quality of evidence). The NNT was 20 (95%CI: 12-61) to prevent one colorectal adenoma recurrence within a period of 3 to 5 years. On the other hand, the association between calcium treatment and advanced adenomas did not reach statistical significance (fixed-effects, RR = 0.92, 95%CI: 0.75-1.13; random-effects, RR = 0.92, 95%CI: 0.71-1.18; moderate quality of evidence).CONCLUSION: Our results suggest a modest chemopreventive effect of calcium supplements against recurrent colorectal adenomas over a period of 36 to 60 mo. Further research is warranted.

Micro RNA-320 family is downregulated in colorectal adenoma and affects tumor proliferation by targeting CDK6

AIM: To investigate the microR NA(miR NA) expression during histological progression from colorectal normal mucosa through adenoma to carcinoma within a lesion. METHODS: Using microarray, the sequential changes in miR NA expression profiles were compared in colonic lesions from matched samples; histologically, nonneoplastic mucosa, adenoma, and submucosal invasive carcinoma were microdissected from a tissue sample. Cell proliferation assay was performed to observe the effect of miR NA, and its target genes were predicted using bioinformatics approaches and the expression profile of SW480 transfected with the miR NA mimics. mR NA and protein levels of the target gene in colon cancer cell lines with a mimic control or miR NA mimics were measured using qR TPCR and Western blotting. The expression levels of miR NA and target gene in colorectal tissue samples were also measured.RESULTS: Microarray analysis identified that the miR-320 family, including miR-320 a, miR-320 b, miR-320 c, miR-320 d and miR-320 e, were differentially expressed in adenomaand submucosal invasive carcinoma. The mi R-320 family, which inhibits cell proliferation, is frequently downregulated in colorectal adenoma and submucosal invasive carcinoma tissues. Seven genes including CDK6 were identified to be common in the results of gene expression array and bioinformatics analyses performed to find the target gene of the miR-320 family. We confirmed that mR NA and protein levels of CDK6 were significantly suppressed in colon cancer cell lines with miR-320 family mimics. CDK6 expression was found to increase from non-neoplastic mucosa through adenoma to submucosal invasive carcinoma tissues and showed an inverse correlation with miR-320 family expression.CONCLUSION: MiR-320 family affects colorectal tumor proliferation by targeting CDK6, plays important role in its growth, and is considered to be a biomarker for its early detection.

Current and future molecular diagnostics in colorectal cancer and colorectal adenoma

Colorectal cancer(CRC)is one of the most prevalent cancers in developed countries.On the other hand,CRC is also one of the most curable cancers if it is detected in early stages through regular colonoscopy or sigmoidoscopy.Since CRC develops slowly from precancerous lesions,early detection can reduce both the incidence and mortality of the disease.Fecal occult blood test is a widely used non-invasive screening tool for CRC.Although fecal occult blood test is simple and cost-effective in screening CRC,there is room for improvement in terms of the accuracy of the test.Genetic dysregulations have been found to play an important role in CRC development.With better understanding of the molecular basis of CRC,there is a growing expectation on the development of diagnostic tests based on more sensitive and specific molecular markers and those tests may provide a breakthrough to the limitations of current screening tests for CRC.In this review,the molecular basis of CRC development,the characteristics and applications of different non-invasive molecular biomarkers,as well as the technologies available for the detection were discussed.This review intended to provide a summary on the current and future molecular diagnostics in CRC and its pre-malignant state,colorectal adenoma.

Endoscopic mucosal resection of colorectal adenomas > 20 mm: Risk factors for recurrence

AIM: To evaluate risk factors for local recurrence after endoscopic mucosal resection of colorectal adenomas > 20 mm.METHODS: Retrospective data analysis of 216 endoscopic mucosal resections for colorectal adenomas > 20 mm in 179 patients(40.3% female; median age 68 years; range 35-91 years). All patients had at least 1 follow-up endoscopy with a minimum control interval of 2 mo(mean follow-up 6 mo/2.0-43.4 mo). Possible factors associated with local recurrence were analyzed by univariate and multivariate analysis. RESULTS: Median size of the lesions was 30 mm(20-70 mm),69.0% were localized in the right-sided(cecum,ascending and transverse) colon. Most of the lesions(85.6%) showed a non-pedunculated morphology and the majority of resections was in piecemeal technique(78.7%). Histology showed carcinoma or high-grade intraepithelial neoplasia in 51/216(23.6%) lesions including 4 low risk carcinomas(pT1 a,L0,V0,R0- G1/G2). Histologically proven recurrence was observed in 33/216 patients(15.3%). Patient age>65 years,polyp size>30 mm,non-pedunculated morphology,localization in the right-sided colon,piecemeal resection and tubular-villous histology were found as associated factors in univariate analysis. On multivariate analysis,only localization in the rightsided colon(HR = 6.842/95%CI:1.540-30.394; P=0.011),tubular-villous histology(HR = 3.713/95%CI: 1.617-8.528;P=0.002) and polyp size>30 mm(HR=2.563/95%CI:1.179-5.570; P=0.017) were significantly associated risk factors for adenoma recurrence. CONCLUSION: Meticulous endoscopic follow-up is warranted after endoscopic mucosal resection of adenomas localized in the right-sided colon larger than > 30 mm,with tubular-villous histology.

Diabetes mellitus increases risk for colorectal adenomas in younger patients

AIM: To determine if diabetes mellitus (DM) is associated with increased risk of colorectal adenomas in younger subjects.

Hypertriglyceridemia is positively correlated with the development of colorectal tubular adenoma in Japanese men

AIM： To determine the real association between serum lipid levels and colonic polyp formation. METHODS： We performed a large scale retrospective study to analyze the correlation between the incidence of colorectal adenoma or carcinoma and the fasting serum levels of total cholesterol （TC） and triglycerides （TG） in patients who underwent total colonoscopy for screening for colon cancer. RESULTS： Both levels were significantly elevated in patients with adenomas as compared with patients without any neoplastic lesion （TC 207.6 ± 29.5 vs 199.5 ±34.3, n= 4883, p〈 0.001; TG 135.0 ± 82.2 vs 108.7± 71.5, n= 4874, p〈 0.001）. The difference was significant in patients with tubular adenoma but not in those with villous or serrated adenoma. Multiple logistic regression analysis including age and sex revealed that TG was an independent correlation factor in male （p〈0.01）, but not in female patients. The level of TG in patients with invasive carcinoma did not show a significant elevation from that in patients with adenoma. These findings suggest that hypertriglyceridemia is an independent risk factor for colonic adenoma in men. CONCLUSION： Although a high level of serum triglyceride does not appear to be mechanically involved in the development of carcinoma, reduction of serum TG and intensive surveillance with total colonoscopy may have benefit in men with hypertriglyceridemia.

Helicobacter pylori infection with atrophic gastritis: An independent risk factor for colorectal adenomas

BACKGROUND The significance of Helicobacter pylori(H.pylori)infection and atrophic gastritis(AG)in the prevalence of colorectal adenomas has been examined in a limited number of studies.However,these studies reported disputed conclusions.AIM To investigate whether H.pylori infection,AG,and H.pylori-related AG increase the risk of colorectal adenomas.METHODS This retrospective cross-sectional study included 6018 health-check individuals.The relevant data for physical examination,laboratory testing,13C-urea breath testing,gastroscopy,colonoscopy and histopathological examination of gastric and colorectal biopsies were recorded.Univariate and multivariate logistic regression analyses were performed to determine the association between H.pylori-related AG and colorectal adenomas.RESULTS Overall,1012 subjects(16.8%)were diagnosed with colorectal adenomas,of whom 143(2.4%)had advanced adenomas.Among the enrolled patients,the prevalence of H.pylori infection and AG was observed as 49.5%(2981/6018)and 10.0%(602/6018),respectively.Subjects with H.pylori infection had an elevated risk of colorectal adenomas(adjusted odds ratio[OR]of 1.220,95%confidence interval(CI):1.053-1.413,P=0.008)but no increased risk of advance adenomas(adjusted OR=1.303,95%CI:0.922-1.842,P=0.134).AG was significantly correlated to an increased risk of colorectal adenomas(unadjusted OR=1.668,95%CI:1.352-2.059,P<0.001;adjusted OR=1.237,95%CI:0.988-1.549,P=0.064).H.pylori infection accompanied by AG was significantly associated with an increased risk of adenomas(adjusted OR=1.491,95%CI:1.103-2.015,P=0.009)and advanced adenomas(adjusted OR=1.910,95%CI:1.022-3.572,P=0.043).CONCLUSION H.pylori-related AG was associated with a high risk of colorectal adenomas and advanced adenomas in Chinese individuals.

CYP1A1 , GSTM1 , GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

AIM: To investigate the role of functional genetic poly-morphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied wereCYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other life-style factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1 . A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There was no measurable effect modification of smoking even regarding the combination of the genetic polymorphisms of the phaseⅠ and phase Ⅱ enzymes. CONCLUSION: Combination of the CYP1A1*2C and NQO1 609CC genotypes was associated with a decreased risk of colorectal adenomas regardless of smoking status.

Risk factors associated with missed colorectal flat adenoma: A multicenter retrospective tandem colonoscopy study

AIM: To determine the miss rate for colorectal flat adenomas during colonoscopy and the risk factors.

Folic acid supplementation inhibits recurrence of colorectal adenomas:A randomized chemoprevention trial

AIM: To determine whether folic acid supplementation will reduce the recurrence of colorectal adenomas, the precursors of colorectal cancer, we performed a double-blind placebo-controlled trial in patients with adenomatous polyps. METHODS: In the current double-blind, placebo-controlled trial at this VA Medical Center, patients with colorectal adenomas were randomly assigned to receive either a daily 5 mg dose of folic acid or a matched identical placebo for 3 years. All polyps were removed at baseline colonoscopy and each patient had a follow up colonoscopy at 3 years. The primary endpoint was a reduction in the number of recurrent adenomas at 3 years. RESULTS: Of 137 subjects, who were eligible after confirmation of polyp histology and run-in period to conform compliance, 94 completed the study; 49 in folic acid group and 45 in placebo group. Recurrence of adenomas at 3-year was compared between the two groups. The mean number of recurrent polyps at 3-year was 0.36 (SD, 0.69) for folic acid treated patients compared to 0.82 (SD, 1.17) for placebo treated subjects, resulting in a 3-fold increase in polyp recurrence in the placebo group. Patients below 70 years of age and those with left-sided colonicadenomas or advanced adenomas responded better to folic acid supplementation. CONCLUSION: High dose folic acid supplementation is associated with a signif icant reduction in the recurrence of colonic adenomas suggesting that folic acid may be an effective chemopreventive agent for colorectal neoplasia.

Low-grade slightly elevated and polypoid colorectal adenomas display differential β-catenin-TCF/LEF activity, c-Myc, and cyclin D1 expression

AIM To comparatively investigate the cellular and molecular characteristics of low-grade slightly elevated adenomas and polypoid adenomas.METHODS Colorectal tumors were collected from 24 patients with slightly elevated adenomas and 23 patients with polypoid adenomas. five commonly mutated genes(APC, BRAf, KRAS, NRAS, and PIK3CA) were selected for mutational analysis. Paraffin-embedded tumor sections were used to calculate the apoptotic index(AI) and Ki-67 labeling index(KLI). Two pure colorectal epithelial cell lines were created by pooling the slightly elevated and polypoid tumors. western blots, luciferase assays for β-catenin-T-cell factor protein/β-cateninlymphoid enhancer factor(β-catenin-TCf/LEf)-driven transcriptional activity, and caspase activity assays were conducted on the two cell lines.RESULTS Slightly elevated lesions showed a significantly lower APC mutational frequency and a significantly higher KRAS mutational frequency(both P < 0.05). Slightly elevated lesions showed a significantly lower AI(P < 0.05). β-catenin and β-catenin-TCf/LEf-driven transcriptional activity was significantly upregulated in slightly elevated lesions(both P < 0.05). In slightly elevated lesions, c-Myc was significantly downregulated, while cyclin D1 was significantly upregulated(both P < 0.05). β-catenin-TCf/LEf-driven transcriptional activity was negatively correlated with c-Myc(ρ =-0.78). Slightly elevated lesions displayed significant Bcl-2 and Bcl-x L upregulation(both P < 0.05) along with significant decreases in caspase-9 and caspase-3 activity(both P < 0.05). c-Myc was negatively correlated with Bcl-2 and Bcl-x L(ρ =-0.74 and-0.78, respectively).CONCLUSION The lower apoptotic activity of low-grade slightly elevated adenomas can be partly attributed to upregulated β-catenin pathway activity and downregulated c-Myc expression.

Aging related methylation influences the gene expression of key control genes in colorectal cancer and adenoma

AIM To analyze colorectal carcinogenesis and age-related DNA methylation alterations of gene sequences associated with epigenetic clock CpG sites. METHODS In silico DNA methylation analysis of 353 epigenetic clock Cp G sites published by Steve Horvath was performed using methylation array data for a set of 123 colonic tissue samples [64 colorectal cancer(CRC), 42 adenoma, 17 normal; GEO accession number: GSE48684]. Among the differentially methylated agerelated genes, secreted frizzled related protein 1(SFRP1) promoter methylation was further investigated in colonic tissue from 8 healthy adults, 19 normal children, 20 adenoma and 8 CRC patients using bisulfite-specific PCR followed by methylation-specific high resolution melting(MS-HRM) analysis. m RNA expression of age-related "epigenetic clock" genes was studied using Affymetrix HGU133 Plus2.0 whole transcriptome data of 153 colonic biopsy samples(49 healthy adult, 49 adenoma, 49 CRC, 6 healthy children)(GEO accession numbers: GSE37364, GSE10714, GSE4183, GSE37267). Whole promoter methylation analysis of genes showing inverse DNA methylationgene expression data was performed on 30 colonic samples using methyl capture sequencing.RESULTS Fifty-seven age-related Cp G sites including hypermethylated PPP1R16 B, SFRP1, SYNE1 and hypomethylated MGP, PIPOX were differentially methylated between CRC and normal tissues(P < 0.05, ?β≥ 10%). In the adenoma vs normal comparison, 70 CpG sites differed significantly, including hypermethylated DKK3, SDC2, SFRP1, SYNE1 and hypomethylated CEMIP, SPATA18(P < 0.05, ?β≥ 10%). In MS-HRM analysis, the SFRP1 promoter region was significantly hypermethylated in CRC(55.0% ± 8.4 %) and adenoma tissue samples(49.9% ± 18.1%) compared to normal adult(5.2% ± 2.7%) and young(2.2% ± 0.7%) colonic tissue(P < 0.0001). DNA methylation of SFRP1 promoter was slightly, but significantly increased in healthy adults compared to normal young samples(P < 0.02). This correlated with significantly increased SFRP1 m RNA levels in children compared to normal adult samples(P < 0.05). In CRC tissue the mR NA expression of 117 agerelated genes were changed, while in adenoma samples 102 genes showed differential expression compared with normal colonic tissue(P < 0.05, logF C > 0.5). The change of expression for several genes including SYNE1, CLEC3 B, LTBP3 and SFRP1, followed the same pattern in aging and carcinogenesis, though not for all genes(e.g., MGP). CONCLUSION Several age-related DNA methylation alterations can be observed during CRC development and progression affecting the m RNA expression of certain CRC- and adenoma-related key control genes.

Colon adenoma features and their impact on risk of future advanced adenomas and colorectal cancer

AIMTo review the evidence on the association between specific colon adenoma features and the risk of future colonic neoplasia [adenomas and colorectal cancer (CRC)]. METHODSWe performed a literature search using the National Library of Medicine through PubMed from 1/1/2003 to 5/30/2015. Specific Medical Subject Headings terms (colon, colon polyps, adenomatous polyps, epidemiology, natural history, growth, cancer screening, colonoscopy, CRC) were used in conjunction with subject headings/key words (surveillance, adenoma surveillance, polypectomy surveillance, and serrated adenoma). We defined non-advanced adenomas as 1-2 adenomas each 25% villous histology or high-grade dysplasia. A combined endpoint of advanced neoplasia included advanced adenomas and invasive CRC. RESULTSOur search strategy identified 592 candidate articles of which 8 met inclusion criteria and were relevant for assessment of histology (low grade vs high grade dysplasia, villous features) and adenoma size. Six of these studies met the accepted quality indicator threshold for overall adenoma detection rate > 25% among study patients. We found 254 articles of which 7 met inclusion criteria for the evaluation of multiple adenomas. Lastly, our search revealed 222 candidate articles of which 6 met inclusion criteria for evaluation of serrated polyps. Our review found that villous features, high grade dysplasia, larger adenoma size, and having &ge; 3 adenomas at baseline are associated with an increased risk of future colonic neoplasia in some but not all studies. Serrated polyps in the proximal colon are associated with an increased risk of future colonic neoplasia, comparable to having a baseline advanced adenoma. CONCLUSIONData on adenoma features and risk of future adenomas and CRC are compelling yet modest in absolute effect size. Future research should refine this risk stratification.

Markers of systemic inflammation and colorectal adenoma risk: Meta-analysis of observational studies

To perform a meta-analysis of observational studies on inflammatory markers levels and occurrence of colorectal adenoma.METHODSPubMed and EMBASE databases were searched until March 2016 for the articles reporting on the circulating levels of inflammatory markers, including: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) and risk of colorectal adenoma. Random-effects models were used to calculate summary odds ratios (ORs) with 95%CIs for the highest vs lowest category of exposure. Heterogeneity was assessed by using the Q test and I2 statistic. Subgroup analyses were also performed to test for potential source of heterogeneity.RESULTSA total of 14 case-control studies were included. Ten studies on CRP including a total of 3350 cases and 4168 controls showed non-significant summary (OR = 1.23, 95%CI: 0.98-1.54; I2 = 54%, Pheterogeneity = 0.01) in the general analysis, but significant increased odds when considering only advanced adenoma (OR = 1.59, 95%CI: 1.09-2.32; I2 = 44%, Pheterogeneity = 0.15). Subgroup and stratified analyses revealed a potential influence of smoking status and aspirin use on the association between CRP levels and colorectal adenoma. Five studies examined the association between circulating levels of TNF-α and colorectal adenoma risk, including a total of 1,568 cases and 2,832 controls. The summary OR for the highest vs the lowest category of exposure was 1.00 (95%CI: 0.77-1.29). The relationship between circulating IL-6 levels and colorectal adenoma risk was investigated in 7 studies including a total of 1936 cases and 3611 controls. The summary OR for the highest vs the lowest category of exposure was 1.19 (95%CI: 0.92-1.55).CONCLUSIONSummary of current evidence suggests a positive association of CRP levels and advanced colorectal adenoma risk. The role of potential confounding factors should be further evaluated.