Serum Interleukin-6, insulin, and HOMA-IR in male individuals with colorectal adenoma.

PubMed

Sasaki, Yu; Takeda, Hiroaki; Sato, Takeshi; Orii, Tomohiko; Nishise, Shoichi; Nagino, Ko; Iwano, Daisuke; Yaoita, Takao; Yoshizawa, Kazuya; Saito, Hideki; Tanaka, Yasuhisa; Kawata, Sumio

2012-01-15

It is widely acknowledged that chronic low-grade inflammation plays a key role in the development of obesity-related insulin resistance and type 2 diabetes. The level of circulating interleukin-6 (IL-6), one of the major proinflammatory adipokines, is correlated with obesity and insulin resistance, which are known to be risk factors for colorectal adenoma. We examined the association between the circulating level of IL-6 and the presence of colorectal adenoma. In a total colonoscopy-based cross-sectional study conducted between January and December 2008, serum levels of IL-6 were measured in samples of venous blood obtained from 336 male participants attending health checkups (118 individuals with colorectal adenoma and 218 age-matched controls) after an overnight fast. In the colorectal adenoma group, the median levels of serum IL-6 (1.24 vs. 1.04 pg/mL; P = 0.01), triglyceride, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were to be significantly higher than those in the control group. When restricted to individuals with adenoma, levels of IL-6 were positively correlated with body mass index, insulin, and HOMA-IR. Multiple logistic analyses adjusted to include insulin or HOMA-IR showed that high levels of IL-6 were associated with the presence of colorectal adenoma. There was no significant interaction of IL-6 with HOMA-IR to modify this association. Our findings suggest that increased serum levels of IL-6 are positively associated with the presence of colorectal adenoma in men, independently of insulin and HOMA-IR. ©2011 AACR.

Colorectal adenoma stem-like cell populations: associations with adenoma characteristics and metachronous colorectal neoplasia.

PubMed

Bartley, Angela N; Parikh, Nila; Hsu, Chiu-Hsieh; Roe, Denise J; Buckmeier, Julie A; Corley, Lynda; Phipps, Ron A; Gallick, Gary; Lance, Peter; Thompson, Patricia A; Hamilton, Stanley R

2013-11-01

Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma ("recurrence"), has not been studied extensively. We evaluated the expression of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), a putative stem cell marker, in baseline adenomas from the placebo arm of chemoprevention trial participants with colonoscopic follow-up. An exploratory set of 20 baseline adenomas was analyzed by ALDH1A1 immunohistochemistry with morphometry, and a replication set of 89 adenomas from 76 high-risk participants was evaluated by computerized image analysis. ALDH1A1-labeling indices (ALI) were similar across patient characteristics and in advanced and nonadvanced adenomas. There was a trend toward higher ALIs in adenomas occurring in the right than left colon (P = 0.09). ALIs of synchronous adenomas were correlated (intraclass correlation coefficient 0.67). Participants in both sample sets who developed a metachronous adenoma had significantly higher ALIs in their baseline adenoma than participants who remained adenoma free. In the replication set, the adjusted odds for metachronous adenoma increased 1.46 for each 10% increase in ALIs (P = 0.03). A best-fit algorithm-based cutoff point of 22.4% had specificity of 75.0% and positive predictive value of 70.0% for metachronous adenoma development. A larger population of ALDH1A1-expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology. If confirmed, ALDH1A1 has potential as a novel biomarker in risk assessment and as a potential stem cell target for chemoprevention. ©2013 AACR

Colorectal adenoma stem-like cell populations: Associations with adenoma characteristics and metachronous colorectal neoplasia

PubMed Central

Bartley, Angela N.; Parikh, Nila; Hsu, Chiu-Hsieh; Roe, Denise J.; Buckmeier, Julie A.; Corley, Lynda; Phipps, Ron A.; Gallick, Gary; Lance, Peter; Thompson, Patricia A.; Hamilton, Stanley R.

2014-01-01

Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma (“recurrence”), have not been studied extensively. We evaluated the expression of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), a putative stem cell marker, in baseline adenomas from the placebo arm of chemoprevention trial participants with colonoscopic follow-up. An exploratory set of 20 baseline adenomas was analyzed by ALDH1A1 immunohistochemistry with morphometry, and a replication set of 89 adenomas from 76 high-risk participants was evaluated by computerized image analysis. ALDH1A1 labeling indices (ALIs) were similar across patient characteristics and in advanced and non-advanced adenomas. There was a trend toward higher ALIs in adenomas occurring in the right than left colon (p=0.09). ALIs of synchronous adenomas were correlated (intraclass correlation coefficient 0.67). Participants in both sample sets who developed a metachronous adenoma had significantly higher ALIs in their baseline adenoma than participants who remained adenoma-free. In the replication set, the adjusted odds for metachronous adenoma increased 1.46 for each 10% increase in ALIs (p=0.03). A best-fit algorithm-based cut-point of 22.4% had specificity of 75.0% and positive predictive value of 70.0% for metachronous adenoma development. A larger population of ALDH1A1-expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology. If confirmed, ALDH1A1 has potential as a novel biomarker in risk assessment and as a potential stem-cell target for chemoprevention. PMID:24008128

Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.

PubMed

Cheng, Timothy H T; Gorman, Maggie; Martin, Lynn; Barclay, Ella; Casey, Graham; Saunders, Brian; Thomas, Huw; Clark, Sue; Tomlinson, Ian

2015-02-01

The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10(-7)). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

Advanced colorectal adenoma related gene expression signature may predict prognostic for colorectal cancer patients with adenoma-carcinoma sequence.

PubMed

Li, Bing; Shi, Xiao-Yu; Liao, Dai-Xiang; Cao, Bang-Rong; Luo, Cheng-Hua; Cheng, Shu-Jun

2015-01-01

There are still no absolute parameters predicting progression of adenoma into cancer. The present study aimed to characterize functional differences on the multistep carcinogenetic process from the adenoma-carcinoma sequence. All samples were collected and mRNA expression profiling was performed by using Agilent Microarray high-throughput gene-chip technology. Then, the characteristics of mRNA expression profiles of adenoma-carcinoma sequence were described with bioinformatics software, and we analyzed the relationship between gene expression profiles of adenoma-adenocarcinoma sequence and clinical prognosis of colorectal cancer. The mRNA expressions of adenoma-carcinoma sequence were significantly different between high-grade intraepithelial neoplasia group and adenocarcinoma group. The biological process of gene ontology function enrichment analysis on differentially expressed genes between high-grade intraepithelial neoplasia group and adenocarcinoma group showed that genes enriched in the extracellular structure organization, skeletal system development, biological adhesion and itself regulated growth regulation, with the P value after FDR correction of less than 0.05. In addition, IPR-related protein mainly focused on the insulin-like growth factor binding proteins. The variable trends of gene expression profiles for adenoma-carcinoma sequence were mainly concentrated in high-grade intraepithelial neoplasia and adenocarcinoma. The differentially expressed genes are significantly correlated between high-grade intraepithelial neoplasia group and adenocarcinoma group. Bioinformatics analysis is an effective way to study the gene expression profiles in the adenoma-carcinoma sequence, and may provide an effective tool to involve colorectal cancer research strategy into colorectal adenoma or advanced adenoma.

Effects of polymorphisms in ERCC1, ASE-1 and RAI on the risk of colorectal carcinomas and adenomas: a case control study.

PubMed

Skjelbred, Camilla F; Saebø, Mona; Nexø, Bjørn A; Wallin, Håkan; Hansteen, Inger-Lise; Vogel, Ulla; Kure, Elin H

2006-07-03

The risk of sporadic colorectal cancer is mainly associated with lifestyle factors and may be modulated by several genetic factors of low penetrance. Genetic variants represented by single nucleotide polymorphisms in genes encoding key players in the adenoma carcinoma sequence may contribute to variation in susceptibility to colorectal cancer. In this study, we aimed to evaluate whether the recently identified haplotype encompassing genes of DNA repair and apoptosis, is associated with increased risk of colorectal adenomas and carcinomas. We used a case-control study design (156 carcinomas, 981 adenomas and 399 controls) to test the association between polymorphisms in the chromosomal region 19q13.2-3, encompassing the genes ERCC1, ASE-1 and RAI, and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (CI) were estimated by binary logistic regression model adjusting for age and gender. The ASE-1 polymorphism was associated with an increased risk of adenomas, OR of 1.39 (95% CI 1.06-1.81), which upon stratification was apparent among women only, OR of 1.66 (95% CI 1.15-2.39). The RAI polymorphism showed a trend towards risk reduction for both adenomas (OR of 0.70, 95% CI 0.49-1.01) and carcinomas (OR of 0.49, 95% CI 0.21-1.13) among women, although not significant. Women who were homozygous carriers of the high risk haplotype had an increased risk of colorectal cancer, OR of 2.19 (95% CI 0.95-5.04) compared to all non-carriers although the estimate was not statistically significant. We found no evidence that the studied polymorphisms were associated with risk of adenomas or colorectal cancer among men, but we found weak indications that the chromosomal region may influence risk of colorectal cancer and adenoma development in women.

[Expression of CD10 in tumor-associated fibroblast of cancerized or recurrent colorectal adenomas].

PubMed

Zheng, Jiangjiang; Zhu, Yin; Li, Changshui; Li, Yinya; Nie, Qianqian; Zhu, Ziling; Deng, Hong

2016-05-25

Objective: To investigate the expression of CD10 in tumor-associated fibroblasts (TAF) in colorectal adenomas and its relation to cancerization and recurrence of adenoma. Methods: Tissue samples of low-grade adenoma ( n =50), high-grade adenoma ( n =50) and colorectal adenocarcinoma ( n =50) were collected, and tissue samples at the distal margin of corresponding colorectal lesions were taken as controls. The expression of CD10 in the stromal TAFs, and the expressions of β-catenin, Ki-67, p53 and CyclinD1 in tumor cells were detected by immunohistochemistry (Envision). The correlation of CD10 expression in stromal TAFs with the expressions of β-catenin, Ki-67, p53 and CyclinD1 in tumor cells was analyzed by Spearmen. One hundred samples of low-grade colorectal adenoma were collected, including 57 non-recurrent cases and 43 recurrent cases (16 cases of recurrent adenoma and 27 cases of recurrent adenocarcinoma); the expression of stromal TAF CD10 were determined and compared among groups. Results: There was no TAF in normal colorectal mucosa. The expression rates of TAF CD10 in low-grade adenoma, high-grade adenoma and colorectal adenocarcinoma were 22%, 50% and 78%, respectively (all P <0.05). The expression of Ki-67 and β-catenin in low-grade adenoma, high-grade adenoma, colorectal adenocarcinoma was on a rising trend (all P <0.01). The expression of CyclinD1 in high-grade adenoma was higher than that in colorectal adenocarcinoma and low-grade adenoma (all P >0.05). The expression of p53 in colorectal adenocarcinoma and high-grade adenoma was higher than that in low grade adenoma (all P <0.01). The expression of TAF CD10 was correlated with the expression of p53, Ki-67 and β-catenin-nucleus( r =0.264、0.307、0.320, all P <0.01),but not correlated with CyclinD1 and β-catenin-membrane ( r =0.012、-0.073, all P >0.05). The TAF CD10 level was significantly higher in low-grade adenoma with recurrence than that in those without recurrence ( P <0.05).The expression of CD10 in recurrent colorectal adenocarcinoma was higher than that in recurrent adenoma ( P <0.05). Conclusion: The expression of TAF CD10 is increased gradually in the process of adenoma-cancer, indicating that it may play an important role in the canceration of adenoma. Adenomas with high expression of CD10 TAF are likely to be recurrent and cancerized, and detection of TAF CD10 combined with p53, Ki-67 and β-catenin may be of value in predicting canceration or recurrence of colorectal adenoma.

Blood free-circulating DNA testing by highly sensitive methylation assay to diagnose colorectal neoplasias.

PubMed

Suehiro, Yutaka; Hashimoto, Shinichi; Higaki, Shingo; Fujii, Ikuei; Suzuki, Chieko; Hoshida, Tomomi; Matsumoto, Toshihiko; Yamaoka, Yuko; Takami, Taro; Sakaida, Isao; Yamasaki, Takahiro

2018-03-30

Although methylated TWIST1 is a biomarker of colorectal neoplasia, its detection from serum samples is very difficult by conventional bisulfite-based methylation assays. Therefore, we have developed a new methylation assay that enables counting of even one copy of a methylated gene in a small DNA sample amount without DNA bisulfite treatment. We performed this study to evaluate the sensitivity and specificity of serum DNA testing by the new methylation assay in combination with and without the fecal immunochemical test for hemoglobin for the detection of colorectal neoplasia. This study comprised 113 patients with colorectal neoplasia and 25 control individuals. For the new methylation assay, DNA was treated in two stages with methylation-sensitive restriction enzymes, followed by measurement of copy numbers of hTERT and methylated TWIST1 by multiplex droplet digital PCR. The fecal immunochemical test had a sensitivity of 8.0% for non-advanced adenoma, 24.3% for advanced adenoma, and 44.4% for colorectal cancer, and a specificity of 88.0%. The new assay had a sensitivity of 36.0% for non-advanced adenoma, 30.0% for advanced adenoma, and 44.4% for colorectal cancer, and a specificity of 92.0%. Combination of the both tests increased the sensitivity to 40.0%, 45.7%, and 72.2% for the detection of non-advanced adenoma, advanced adenoma, and colorectal cancer, respectively, and resulted in a specificity of 84.0%. Combination of both tests may provide an alternative screening strategy for colorectal neoplasia including potentially precancerous lesions and colorectal cancer.

Overexpression of the obesity hormone leptin in human colorectal cancer

PubMed Central

Koda, Mariusz; Sulkowska, Mariola; Kanczuga‐Koda, Luiza; Surmacz, Eva; Sulkowski, Stanislaw

2007-01-01

Background Leptin is an adipocyte‐derived neurohormone, high levels of which are found in obese individuals. Leptin controls energy expenditure, acting in the brain, and regulates different processes in peripheral organs. Recent studies have suggested that leptin may be involved in cancer development and progression. Aims To analyse leptin expression in human colorectal cancer as well as in colorectal mucosa and colorectal adenomas. Methods Leptin expression was assessed by immunohistochemistry in 166 colorectal cancers, 101 samples of colorectal mucosa and 41 adenomas. Leptin concentration in colorectal cancer was correlated with selected clinicopathological features. Results Immunoreactivity for leptin was observed in 51.2% (85/166) of primary colorectal cancers. In adenomas leptin expression was observed in 14.6% (6/41) of studied cases. In normal mucosa, leptin was present at low levels, except in tumour bordering areas where its concentration appeared to reflect levels in the adjacent cancer tissue. Leptin expression in colorectal cancer significantly correlated with tumour G2 grade (p = 0.002) as well as with histological type (adenocarcinoma) of tumours (p = 0.044). Conclusions Results indicate that leptin is overexpressed in human colorectal cancer, which suggests that the hormone might contribute to colorectal cancer development and progression. PMID:17660334

The prevalence of colorectal adenomas in asymptomatic Korean men and women.

PubMed

Yang, Moon Hee; Rampal, Sanjay; Sung, Jidong; Choi, Yoon-Ho; Son, Hee Jung; Lee, Jun Haeng; Kim, Young-Ho; Chang, Dong Kyung; Rhee, Poong-Lyul; Rhee, Jong Chul; Guallar, Eliseo; Cho, Juhee

2014-03-01

Colorectal cancer incidence is rapidly rising in many Asian countries, with rates approaching those of Western countries. This study aimed to evaluate the prevalence and trends of colorectal adenomas by age, sex, and risk strata in asymptomatic Koreans. Cross-sectional study of 19,372 consecutive participants aged 20 to 79 years undergoing screening colonoscopy at the Center for Health Promotion of the Samsung Medical Center in Korea from January 2006 to June 2009. Among participants at average risk, those without a history of colorectal polyps or a family history of colorectal cancer, the prevalence of colorectal adenomas and advanced adenomas were 34.5% and 3.1%, respectively, in men and 20.0% and 1.6%, respectively, in women. The prevalence of adenomas increased with age in both men and women, with a more marked increase for advanced adenoma. Participants with a family history of colorectal cancer or with a history of colorectal polyps had significantly higher prevalence of adenomas compared with participants of average risk (36.9% vs. 26.9%; age- and sex-adjusted prevalence ratio = 1.16; 95% confidence interval, 1.09-1.22). The prevalence of adenomas increased annually in both men and women. In this large study of asymptomatic Korean men and women participating in a colonoscopy screening program, the prevalence of colorectal adenomas was comparable and possibly higher than previously reported in Western countries. Cost-effectiveness studies investigating the optimal age for starting colonoscopy screening and etiological studies to identify the reasons for the increasing trend in colorectal adenomas in Koreans are needed. ©2014 AACR.

[Relationships between the enrichment of ETBF, Fn, Hp in intestinal and colorectal cancer].

PubMed

Zhang, J; Lu, X L; Zhao, G; Shi, H T; Geng, Y; Zhong, W T; Dong, L

2018-02-23

Objective: To explore relationships between the enrichment of ETBF, Fn, Hp in feces, tissues and colorectal cancer. Methods: Feces, lesion tissue and adjacent tissue from 24 patients with colorectal cancer and 31 patients with adenomas were collected, and we collected Feces and tissue of 20 healthy control persons. Then the copy numbers of enterotoxigenic B. fragilis (ETBF), Fusobacterium nucleatum (Fn) and Helicobacter pylori (Hp) were determined by quantitative real-time PCR. Immunohistochemical method was used to examine the expression intensity of EGFR and p53, and the relationships between different expression intensity of EGFR, p53 and the numbers of three bacterias. Results: In the feces, copy numbers of ETBF and Fn were as follous: colorectal cancer group>adenomas group>healthy control group ( P <0.05). Copy numbers of Hp were as follous: colorectal cancer group>healthy control group ( P <0.01); adenomas group>healthy control group ( P <0.01). In the tissue, copy numbers of ETBF, Fn were as follows: colorectal cancer group>adenomas group>healthy control group ( P <0.05). Copy numbers of Hp were as follows: colorectal cancer group>healthy control group ( P <0.01); adenomas group>healthy control group ( P <0.01). Copy numbers of those three bacteria in the lesion tissue and the adjacent tissue had no significant difference. This happened both in colorectal cancer group and adenomas group. The different expression intensity of EGFR, p53 and the number of three bacteria showed no obviously statistical correlation( P >0.05). Conclusion: Adenomatous polyp and colorectal cancer patients show high enrichment of ETBF, Fn and Hp in both feces and tissues. ETBF, Fn and Hp probably contribute to the development of adenomatous polyp and colorectal cancer. Trial registration Chinese Clinical Trial Registry, ChiCTR-BOC-17012509.

Adenomas - Genetic factors in colorectal cancer prevention.

PubMed

Witold, Kycler; Anna, Kubiak; Maciej, Trojanowski; Jakub, Janowski

2018-01-01

Colorectal cancer is the second most common type of cancer both in Europe and Poland. During the last 30 years more than a 3-fold increase has been observed in Poland due to environmental and genetic factors. Almost all colorectal malignancies are related to the formation and malignant transformation of colorectal dysplasia and adenoma. Efforts aiming to decrease the number of colorectal cancer deaths are focused on the disease early detection. Genetic diagnosis for hereditary syndromes predisposing to colorectal cancer has been developed and is a part of the routine treatment. Most cancers are sporadic. They often develop from polyps in the colon. In addition to the genetic events described in the 1990s, showing the adenoma transformation into carcinoma that has been a prime example of malignant transformation for a long time, there are also other possibilities of neoplastic transformation. The recognition of colorectal cancer risk factors make sense as their nature is lifestyle- and diet-related. In this review paper those risk factors are presented and the prevention of colorectal cancer is discussed taking into account genetic factors.

Endoscopic management of colorectal adenomas.

PubMed

Meier, Benjamin; Caca, Karel; Fischer, Andreas; Schmidt, Arthur

2017-01-01

Colorectal adenomas are well known precursors of invasive adenocarcinoma. Colonoscopy is the gold standard for adenoma detection. Colonoscopy is far more than a diagnostic tool, as it allows effective treatment of colorectal adenomas. Endoscopic resection of colorectal adenomas has been shown to reduce the incidence and mortality of colorectal cancer. Difficult resection techniques are available, such as endoscopic mucosal resection, endoscopic submucosal dissection and endoscopic full-thickness resection. This review aims to provide an overview of the different endoscopic resection techniques and their indications, and summarizes the current recommendations in the recently published guideline of the European Society of Gastrointestinal Endoscopy.

Endoscopic management of colorectal adenomas

PubMed Central

Meier, Benjamin; Caca, Karel; Fischer, Andreas; Schmidt, Arthur

2017-01-01

Colorectal adenomas are well known precursors of invasive adenocarcinoma. Colonoscopy is the gold standard for adenoma detection. Colonoscopy is far more than a diagnostic tool, as it allows effective treatment of colorectal adenomas. Endoscopic resection of colorectal adenomas has been shown to reduce the incidence and mortality of colorectal cancer. Difficult resection techniques are available, such as endoscopic mucosal resection, endoscopic submucosal dissection and endoscopic full-thickness resection. This review aims to provide an overview of the different endoscopic resection techniques and their indications, and summarizes the current recommendations in the recently published guideline of the European Society of Gastrointestinal Endoscopy. PMID:29118553

Adult weight gain and colorectal adenomas-a systematic review and meta-analysis.

PubMed

Schlesinger, S; Aleksandrova, K; Abar, L; Vieria, A R; Vingeliene, S; Polemiti, E; Stevens, C A T; Greenwood, D C; Chan, D S M; Aune, D; Norat, T

2017-06-01

Colorectal adenomas are known as precursors for the majority of colorectal carcinomas. While weight gain during adulthood has been identified as a risk factor for colorectal cancer, the association is less clear for colorectal adenomas. We conducted a systematic review and meta-analysis to quantify the evidence on this association. We searched Medline up to September 2016 to identify observational (prospective, cross-sectional and retrospective) studies on weight gain during adulthood and colorectal adenoma occurrence and recurrence. We conducted meta-analysis on high weight gain versus stable weight, linear and non-linear dose-response meta-analyses to analyze the association. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using a random effects model. For colorectal adenoma occurrence, the summary OR was 1.39 (95% CI: 1.17-1.65; I2: 43%, N = 9 studies, cases = 5507) comparing high (midpoint: 17.4 kg) versus stable weight gain during adulthood and with each 5 kg weight gain the odds increased by 7% (2%-11%; I2: 65%, N = 7 studies). Although there was indication of non-linearity (Pnon-linearity < 0.001) there was an increased odds of colorectal adenoma throughout the whole range of weight gain. Three studies were identified investigating the association between weight gain and colorectal adenoma recurrence and data were limited to draw firm conclusions. Even a small amount of adult weight gain was related to a higher odds of colorectal adenoma occurrence. Our findings add to the benefits of weight control in adulthood regarding colorectal adenoma occurrence, which might be relevant for early prevention of colorectal cancer. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Genetic variation in SLC7A2 interacts with calcium and magnesium intakes in modulating the risk of colorectal polyps.

PubMed

Sun, Pin; Zhu, Xiangzhu; Shrubsole, Martha J; Ness, Reid M; Hibler, Elizabeth A; Cai, Qiuyin; Long, Jirong; Chen, Zhi; Li, Guoliang; Hou, Lifang; Smalley, Walter E; Edwards, Todd L; Giovannucci, Edward; Zheng, Wei; Dai, Qi

2017-09-01

Solute carrier family 7, member 2 (SLC7A2) gene encodes a protein called cationic amino acid transporter 2, which mediates the transport of arginine, lysine and ornithine. l-Arginine is necessary for cancer development and progression, including an important role in colorectal cancer pathogenesis. Furthermore, previous studies found that both calcium and magnesium inhibit the transport of arginine. Thus, calcium, magnesium or calcium:magnesium intake ratio may interact with polymorphisms in the SLC7A2 gene in association with colorectal cancer. We conducted a two-phase case-control study within the Tennessee Colorectal Polyps Study. In the first phase, 23 tagging single-nucleotide polymorphisms in the SLC7A2 gene were included for 725 colorectal adenoma cases and 755 controls. In the second phase conducted in an independent set of 607 cases and 2113 controls, we replicated the significant findings in the first phase. We observed that rs2720574 significantly interacted with calcium:magnesium intake ratio in association with odds of adenoma, particularly multiple/advanced adenoma. In the combined analysis, among those with a calcium:magnesium intake ratio below 2.78, individuals who carried GC/CC genotypes demonstrated higher odds of adenoma [OR (95% CI):1.36 (1.11-1.68)] and multiple/advanced adenoma [OR (95% CI): 1.68 (1.28, 2.20)] than those who carried the GG genotype. The P values for interactions between calcium:magnesium intake ratio and rs2720574 were .002 for all adenomas and <.001 for multiple/advanced adenoma. Among those with the GG genotype, a high calcium:magnesium ratio was associated with increased odds of colorectal adenoma [OR (95% CI): 1.73 (1.27-2.36)] and advanced/multiple adenomas [1.62 (1.05-2.50)], whereas among those with the GC/CC genotypes, high calcium:magnesium ratio was related to reduced odds of colorectal adenoma [0.64 (0.42-0.99)] and advanced/multiple adenomas [0.55 (0.31-1.00)]. Copyright © 2017 Elsevier Inc. All rights reserved.

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer.

PubMed

Galamb, Orsolya; Kalmár, Alexandra; Péterfia, Bálint; Csabai, István; Bodor, András; Ribli, Dezső; Krenács, Tibor; Patai, Árpád V; Wichmann, Barnabás; Barták, Barbara Kinga; Tóth, Kinga; Valcz, Gábor; Spisák, Sándor; Tulassay, Zsolt; Molnár, Béla

2016-08-02

The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2'-deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, β-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.

PUFA levels in erythrocyte membrane phospholipids are differentially associated with colorectal adenoma risk.

PubMed

Rifkin, Samara B; Shrubsole, Martha J; Cai, Qiuyin; Smalley, Walter E; Ness, Reid M; Swift, Larry L; Zheng, Wei; Murff, Harvey J

2017-06-01

Dietary intake of PUFA has been associated with colorectal neoplasm risk; however, results from observational studies have been inconsistent. Most prior studies have utilised self-reported dietary measures to assess fatty acid exposure which might be more susceptible to measurement error and biases compared with biomarkers. The purpose of this study was to determine whether erythrocyte phospholipid membrane PUFA percentages are associated with colorectal adenoma risk. We included data from 904 adenoma cases and 835 polyp-free controls who participated in the Tennessee Colorectal Polyp Study, a large colonoscopy-based case-control study. Erythrocyte membrane PUFA percentages were measured using GC. Conditional logistic regression was used to calculate adjusted OR for risk of colorectal adenomas with erythrocyte membrane PUFA. Higher erythrocyte membrane percentages of arachidonic acid was associated with an increased risk of colorectal adenomas (adjusted OR 1·66; 95 % CI 1·05, 2·62, P trend=0·02) comparing the highest tertile to the lowest tertile. The effect size for arachidonic acid was more pronounced when restricting the analysis to advanced adenomas only. Higher erythrocyte membrane EPA percentages were associated with a trend towards a reduced risk of advanced colorectal adenomas (P trend=0·05). Erythrocyte membrane arachidonic acid percentages are associated with an increased risk of colorectal adenomas.

Application of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry technology for the diagnosis of colorectal adenoma.

PubMed

Zhou, Zhong-Yin; Tao, DI-DI; Cao, Ji-Wang; Luo, He-Sheng

2013-06-01

The aim of the present study was to identify a specific biological marker for the diagnosis of colorectal adenomas through the analysis of variations in serum protein profiling in colorectal adenoma patients. The study was conducted at the Renmin Hospital of Wuhan University (Wuhan, China) between September 2011 and May 2012. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was performed to compare the serum protein profiles of 50 patients with colorectal adenoma and 50 healthy individuals. The obtained protein profiles were analyzed using Biomarker Wizard software. Twenty protein peaks were identified to exhibit differences in average intensity between colorectal adenomas compared with normal controls, including peaks 8,565.84, 8,694.51 and 5,910.50 Da, in which the intensity between the patients and control individuals was significantly different. Two peaks, 8,565.84 and 8,694.51 Da, were observed to be highly expressed in the colorectal adenomas, however, expression was low in the control samples. By contrast, 5,910.50 Da expression was low in the colorectal adenomas and high in the controls. The results of the current study indicate that the three protein peaks may represent specific biomarkers for colorectal adenomas.

[Early flat colorectal cancer].

PubMed

Castelletto, R H; Chiarenza, C; Ottino, A; Garay, M L

1991-01-01

We report three cases of flat early colorectal carcinoma which were detected during the examination of 51 surgical specimens of colorectal resection. Two of them were endoscopically diagnosed, but the smallest one was not seen in the luminal instrumental examination. From the bibliographic analysis and our own experience we deduce the importance of flat lesions in the development of early colorectal carcinoma, either originated from pre-existent adenoma or de novo. Flat variants of adenoma, and presumably flush or depressed ones, must be considered as important factors in the early sequence adenoma-cancer. An appropriate endoscopic equipment with employment of additional staining techniques (such as carmine indigo and methylene blue) and the correct investigation during inflation-deflation procedures facilitates the identification of small lesions, their eradication and prevention from advanced forms of colorectal carcinoma.

Meat, meat cooking methods and preservation, and risk for colorectal adenoma.

PubMed

Sinha, Rashmi; Peters, Ulrike; Cross, Amanda J; Kulldorff, Martin; Weissfeld, Joel L; Pinsky, Paul F; Rothman, Nathaniel; Hayes, Richard B

2005-09-01

Cooking meat at high temperatures produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Processed meats contain N-nitroso compounds. Meat intake may increase cancer risk as HCAs, PAHs, and N-nitroso compounds are carcinogenic in animal models. We investigated meat, processed meat, HCAs, and the PAH benzo(a)pyrene and the risk of colorectal adenoma in 3,696 left-sided (descending and sigmoid colon and rectum) adenoma cases and 34,817 endoscopy-negative controls. Dietary intake was assessed using a 137-item food frequency questionnaire, with additional questions on meats and meat cooking practices. The questionnaire was linked to a previously developed database to determine exposure to HCAs and PAHs. Intake of red meat, with known doneness/cooking methods, was associated with an increased risk of adenoma in the descending and sigmoid colon [odds ratio (OR), 1.26; 95% confidence interval (95% CI), 1.05-1.50 comparing extreme quintiles of intake] but not rectal adenoma. Well-done red meat was associated with increased risk of colorectal adenoma (OR, 1.21; 95% CI, 1.06-1.37). Increased risks for adenoma of the descending colon and sigmoid colon were observed for the two HCAs: 2-amino-3,8-dimethylimidazo[4,5]quinoxaline and 2-amino-1-methyl-6-phenylimidazo[4,5]pyridine (OR, 1.18; 95% CI, 1.01-1.38 and OR, 1.17, 95% CI, 1.01-1.35, respectively) as well as benzo(a)pyrene (OR, 1.18; 95% CI, 1.02-1.35). Greater intake of bacon and sausage was associated with increased colorectal adenoma risk (OR, 1.14; 95% CI, 1.00-1.30); however, total intake of processed meat was not (OR, 1.04; 95% CI, 0.90-1.19). Our study of screening-detected colorectal adenomas shows that red meat and meat cooked at high temperatures are associated with an increased risk of colorectal adenoma.

OCCURRENCE OF COLORECTAL ADENOMAS IN YOUNGER ADULTS: AN EPIDEMIOLOGIC NECROPSY STUDY

PubMed Central

Pendergrass, Cheryl J.; Edelstein, Daniel L.; Hylind, Linda M.; Phillips, Blaine T.; Iacobuzio-Donahue, Christine; Romans, Katharine; Griffin, Constance A.; Cruz-Correa, Marcia; Tersmette, Anne C.; Offerhaus, G. Johan A.; Giardiello, Francis M.

2009-01-01

Background and Aims The colorectal adenoma is the precursor lesion in virtually all colorectal cancers. Occurrence of colorectal adenomas has been studied in older adults but analysis in younger adults is lacking. Methods The prevalence by age, sex, race, and location, and the number of colorectal adenomas detected was investigated using epidemiologic necropsy in 3558 persons aged 20–89 autopsied from 1985 to 2004 at the Johns Hopkins Hospital. Results were standardized to the general population. Younger adults 20–49 years old were compared to older adults 50 to 89 years old. Results The prevalence of colorectal adenomas in younger adults increased from 1.72% to 3.59% from the 3rd to 5th decade of life and then sharply increased after age 50. In younger adults, adenomas were more prevalent in men than women (RR= 1.09, CI 1.07–1.11) and whites than blacks (RR=1.28, CI 1.26–1.31). Overall, both younger and older adults had predominately left-sided adenomas, but blacks in both age groups had more right-sided adenomas. Occurrence of two or more adenomas in younger adults and five or more in older adults was greater than 2 standard deviations from the mean. Conclusions Colorectal adenomas infrequently occur in younger adults and are more prevalent in the left colon. Irrespective of age, blacks have more right-sided adenomas suggesting need for screening the entire colorectum. Two or more adenomas in younger adults and five or more in older adults represents polyp burden outside the normal expectation. PMID:18558514

Colorectal Adenomas in Participants of the SELECT Randomized Trial of Selenium and Vitamin E for Prostate Cancer Prevention

PubMed Central

Lance, Peter; Alberts, David S.; Thompson, Patricia A.; Fales, Liane; Wang, Fang; Jose, Jerilyn San; Jacobs, Elizabeth T.; Goodman, Phyllis J.; Darke, Amy K.; Yee, Monica; Minasian, Lori; Thompson, Ian M.; Roe, Denise J.

2017-01-01

Selenium and vitamin E micronutrients have been advocated for the prevention of colorectal cancer. Colorectal adenoma occurrence was used as a surrogate for colorectal cancer in an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT) for prostate cancer prevention. The primary objective was to measure the effect of selenium (as selenomethionine) on colorectal adenomas occurrence, with the effect of vitamin E (as alpha tocopherol) supplementation on colorectal adenoma occurrence considered as a secondary objective. Participants who underwent lower endoscopy while in SELECT were identified from a subgroup of the 35,533 men randomized in the trial. Adenoma occurrence was ascertained from the endoscopy and pathology reports for these procedures. Relative risk (RR) estimates and 95% confidence intervals (CI) of adenoma occurrence were generated comparing those randomized to selenium versus placebo and to vitamin E versus placebo based on the full factorial design. Evaluable endoscopy information was obtained for 6,546 participants, of whom 2,286 had 1+ adenomas. Apart from 21 flexible sigmoidoscopies, all the procedures yielding adenomas were colonoscopies. Adenomas occurred in 34.2% and 35.7%, respectively, of participants whose intervention included or did not include selenium. Compared with placebo, the RR for adenoma occurrence in participants randomized to selenium was 0.96 (95% CI, 0.90–1.02; P = 0.194). Vitamin E did not affect adenoma occurrence compared to placebo (RR = 1.03, 95% CI, 0.96–1.10; P = 0.38). Neither selenium nor vitamin E supplementation can be recommended for colorectal adenoma prevention. PMID:27777235

Dietary Intakes of Red Meat, Poultry, and Fish During High School and Risk of Colorectal Adenomas in Women

PubMed Central

Nimptsch, Katharina; Bernstein, Adam M.; Giovannucci, Edward; Fuchs, Charles S.; Willett, Walter C.; Wu, Kana

2013-01-01

Adolescent diet may be etiologically relevant for colorectal carcinogenesis. We examined the association between meat and fish intakes during adolescence and the risk of colorectal adenomas later in life among 19,771 women participating in the Nurses' Health Study II. Subjects had completed a validated food frequency questionnaire in 1998 (when aged 34–51 years) about their diets during high school and subsequently underwent at least 1 lower-bowel endoscopy during the study period (1998–2007). During this period, 1,494 subjects were diagnosed with colorectal adenomas. Intake of red meat during adolescence was not associated with colorectal adenoma risk when comparing those in the highest versus lowest category of intake (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.81, 1.35). Similarly, intake of fish during adolescence was not associated with colorectal adenoma risk (OR = 0.96, 95% CI: 0.78, 1.17). Intake of poultry during adolescence was associated with a lower risk of total colorectal (OR = 0.80, 95% CI: 0.64, 0.99), distal (OR = 0.71, 95% CI: 0.51, 0.99), rectal (OR = 0.51, 95% CI: 0.29, 0.90), and advanced (OR = 0.60, 95% CI: 0.38, 0.93) adenomas. Replacement of 1 serving per day of red meat with 1 serving per day of poultry or fish was associated with 41% and 35% decreased risks for rectal adenomas and advanced adenomas, respectively. Our findings do not suggest an association between red meat intake during adolescence and colorectal adenomas later in life, but higher poultry intake during this time was associated with a lower risk of colorectal adenomas. PMID:23785116

Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: Self-Defense Forces Health Study.

PubMed

Hirose, Maho; Kono, Suminori; Tabata, Shinji; Ogawa, Shinsaku; Yamaguchi, Keizo; Mineshita, Masamichi; Hagiwara, Tomoko; Yin, Guang; Lee, Kyong-Yeon; Tsuji, Akiko; Ikeda, Noriaki

2005-08-01

Methylenetetrahydrofolate reductase is a key enzyme in folate metabolism, which affects DNA synthesis and methylation and is possibly linked to colorectal carcinogenesis. Alcohol and acetaldehyde have an adverse effect on folate metabolism. This study investigated the relationship of functional MTHFR C677T and ALDH2 polymorphisms to colorectal adenomas with reference to alcohol consumption in a case-control study of male officials in the Self-Defense Forces (SDF) who received a preretirement health examination at two SDF hospitals. The study subjects were 452 cases of colorectal adenoma and 1050 controls with no polyp who underwent total colonoscopy. Genotypes were determined by the PCR-RFLP method using genomic DNA extracted from the buffy coat. Statistical adjustment was made for age, hospital, rank in the SDF, body mass index, cigarette-years and alcohol intake. Neither MTHFR C677T nor ALDH2 showed a measurable association with colorectal adenoma. While high alcohol consumption was associated with a moderately increased risk of colorectal adenoma, neither of the two polymorphisms showed a significant effect on the association between alcohol and colorectal adenoma. Individuals with the variant alleles ALDH2*2 and MTHFR 677T had a decreased risk of colorectal adenomas, showing adjusted odds ratios of 0.70 (95% confidence interval 0.49-1.00) for all adenomas and 0.57 (0.34-0.95) for large adenomas (> or = 5 mm), as compared to individuals with ALDH2*1/1 and MTHFR 677CC genotypes combined. The findings may be interpreted as suggesting that folate inhibits the growth of colorectal adenomas, but further confirmation is needed.

Sedentary behavior is associated with colorectal adenoma recurrence in men

PubMed Central

Molmenti, Christine L. Sardo; Hibler, Elizabeth A.; Ashbeck, Erin L.; Thomson, Cynthia A.; Garcia, David O.; Roe, Denise; Harris, Robin B.; Lance, Peter; Cisneroz, Martin; Martinez, Maria Elena; Thompson, Patricia A.; Jacobs, Elizabeth T.

2014-01-01

Purpose The association between physical activity and colorectal adenoma is equivocal. This study was designed to assess the relationship between physical activity and colorectal adenoma recurrence. Methods Pooled analyses from two randomized, controlled trials included 1,730 participants who completed the Arizona Activity Frequency Questionnaire at baseline, had a colorectal adenoma removed within 6 months of study registration, and had a follow-up colonoscopy during the trial. Logistic regression modeling was employed to estimate the effect of sedentary behavior, light-intensity physical activity, and moderate-vigorous physical activity on colorectal adenoma recurrence. Results No statistically significant trends were found for any activity type and odds of colorectal adenoma recurrence in the pooled population. However, males with the highest levels of sedentary time experienced 47% higher odds of adenoma recurrence. Compared to the lowest quartile of sedentary time, the ORs (95% CIs) for the second, third, and fourth quartiles among men were 1.23 (0.88, 1.74), 1.41 (0.99, 2.01), and 1.47 (1.03, 2.11) respectively (P trend=0.03). No similar association was observed for women. Conclusions This study suggests that sedentary behavior is associated with a higher risk of colorectal adenoma recurrence among men, providing evidence of detrimental effects of a sedentary lifestyle early in the carcinogenesis pathway. PMID:25060482

Temporal and spatial changes of cells positive for stem-like markers in different compartments and stages of human colorectal adenoma-carcinoma sequence

PubMed Central

Cui, Guanglin; Xu, Gang; Zhu, Li; Pang, Zhigang; Zheng, Wei; Li, Zhenfeng; Yuan, Aping

2017-01-01

Considerable evidence supports the idea that stem-like cells may play an essential role during the development of colorectal cancer (CRC). To accomplish this aim, we use immunohistochemistry (IHC) and double IHC with different potential stem-like markers, anti-musashi (Msi), anti-CD133, anti- LGR5 and anti-ALDH1 to examine the presentation of stem-like cells in different compartments including adenoma/CRC epithelium, transitional crypts and tumor stroma in colorectal adenoma and CRC. The results showed that cells positive for stem-like markers were remarkably increased in number and frequently observed in the adenoma/CRC epithelium, transitional crypts and tumor stroma. Notably, the population of cells positive for stem-liker markers was expanded from the base to the middle part of the transitional crypt in both adenoma and CRC tissues, reflecting that stem-like cells are likely involved in the process of colorectal tumorigenesis. Counting results showed that the grading scores of cells positive for LGR5 and ALDH1 in the adenoma/CRC epithelium were significantly increased relative with the control epithelium, and associated with the degree of dysplasia in the adenoma and node involvement in the CRC (all P < 0.05). In addition, the density of cells positive for stem–like markers in the adenomatous/cancerous stroma was also increased and paralleled an increase in the density of proliferative stromal cells labeled by PCNA, which were primarily identified as vimentin positive fibroblasts. Our results have revealed a changed temporal and spatial presentation of stem-like markers in different stages of human colorectal adenoma-carcinoma sequence, which might be a hallmark of the adenoma-carcinoma transition. PMID:28484082

Colorectal Adenomas in Participants of the SELECT Randomized Trial of Selenium and Vitamin E for Prostate Cancer Prevention.

PubMed

Lance, Peter; Alberts, David S; Thompson, Patricia A; Fales, Liane; Wang, Fang; San Jose, Jerilyn; Jacobs, Elizabeth T; Goodman, Phyllis J; Darke, Amy K; Yee, Monica; Minasian, Lori; Thompson, Ian M; Roe, Denise J

2017-01-01

Selenium and vitamin E micronutrients have been advocated for the prevention of colorectal cancer. Colorectal adenoma occurrence was used as a surrogate for colorectal cancer in an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT) for prostate cancer prevention. The primary objective was to measure the effect of selenium (as selenomethionine) on colorectal adenomas occurrence, with the effect of vitamin E (as α-tocopherol) supplementation on colorectal adenoma occurrence considered as a secondary objective. Participants who underwent lower endoscopy while in SELECT were identified from a subgroup of the 35,533 men randomized in the trial. Adenoma occurrence was ascertained from the endoscopy and pathology reports for these procedures. Relative Risk (RR) estimates and 95% confidence intervals (CI) of adenoma occurrence were generated comparing those randomized to selenium versus placebo and to vitamin E versus placebo based on the full factorial design. Evaluable endoscopy information was obtained for 6,546 participants, of whom 2,286 had 1+ adenomas. Apart from 21 flexible sigmoidoscopies, all the procedures yielding adenomas were colonoscopies. Adenomas occurred in 34.2% and 35.7%, respectively, of participants whose intervention included or did not include selenium. Compared with placebo, the RR for adenoma occurrence in participants randomized to selenium was 0.96 (95% CI, 0.90-1.02; P = 0.194). Vitamin E did not affect adenoma occurrence compared with placebo (RR = 1.03; 95% CI, 0.96-1.10; P = 0.38). Neither selenium nor vitamin E supplementation can be recommended for colorectal adenoma prevention. Cancer Prev Res; 10(1); 45-54. ©2016 AACR. ©2016 American Association for Cancer Research.

Karyometry of the colonic mucosa.

PubMed

Alberts, David S; Einspahr, Janine G; Krouse, Robert S; Prasad, Anil; Ranger-Moore, James; Hamilton, Peter; Ismail, Ayaaz; Lance, Peter; Goldschmid, Steven; Hess, Lisa M; Yozwiak, Michael; Bartels, Hubert G; Bartels, Peter H

2007-12-01

The study summarizes results of karyometric measurements in epithelial cells of the colorectal mucosa to document evidence of a field effect of preneoplastic development among patients with colorectal adenocarcinoma or adenoma. Karyometric analyses were done on high-resolution images of histologic sections from 48 patients with colorectal adenocarcinomas and 44 patients with adenomas and on images from matching normal-appearing mucosa directly adjacent to such lesions, at a 1-cm and 10-cm distance from the lesions or from the rectal mucosa of adenoma patients, as well as from 24 healthy normal controls with no family history of colonic disease. The nuclei recorded in the histologically normal-appearing mucosa of patients with either colorectal adenoma or adenocarcinoma exhibited differences in karyometric features in comparison with nuclei recorded in rectal mucosa from patients who were free of a colonic lesion. These differences were expressed to the same extent in tissue adjacent to the lesions and in normal-appearing tissue as distant as the rectum. The nuclear chromatin pattern may serve as an integrating biomarker for a preneoplastic development. The field effect might provide an end point in chemopreventive intervention trials.

Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis.

PubMed

Sekine, Shigeki; Mori, Taisuke; Ogawa, Reiko; Tanaka, Masahiro; Yoshida, Hiroshi; Taniguchi, Hirokazu; Nakajima, Takeshi; Sugano, Kokichi; Yoshida, Teruhiko; Kato, Mamoru; Furukawa, Eisaku; Ochiai, Atsushi; Hiraoka, Nobuyoshi

2017-08-01

Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins. Sequencing analyses identified APC or CTNNB1 mutations in the majority of sporadic adenomas (58/84, 69%) and MMR-proficient Lynch syndrome-associated adenomas (13/18, 72%). However, MMR-deficient Lynch syndrome-associated adenomas had less APC or CTNNB1 mutations (25/68, 37%) and frequent frameshift RNF43 mutations involving mononucleotide repeats (45/68, 66%). Furthermore, frameshift mutations affecting repeat sequences constituted 14 of 26 APC mutations (54%) in MMR-deficient adenomas whereas these frameshift mutations were rare in MMR-proficient adenomas in patients with Lynch syndrome (1/12, 8%) and in sporadic adenomas (3/52, 6%). Lynch syndrome-associated adenocarcinomas exhibited mutation profiles similar to those of MMR-deficient adenomas. Considering that WNT pathway activation sufficiently drives colorectal adenoma formation, the distinct mutation profiles of WNT pathway genes in Lynch syndrome-associated adenomas suggest that MMR deficiency commonly precedes adenoma formation.

Risk of colorectal adenomas in patients with celiac disease: a systematic review and meta-analysis.

PubMed

Lasa, J; Rausch, A; Zubiaurre, I

Whether celiac disease increases the risk of presenting with colorectal adenoma or not, has not been extensively evaluated. This question becomes relevant when considering early screening methods in patients with the disease. The aim of our article was to determine the risk of colorectal adenomas in celiac disease patients. A computer-assisted search of the MEDLINE-Pubmed, EMBASE, LILACS, Cochrane Library, and Google Scholar databases was carried out, encompassing the time frame of 1966 to December 2016. The search strategy consisted of the following MESH terms: 'celiac disease' OR 'celiac sprue' AND 'colorectal' OR 'colorectal neoplasia' OR 'colorectal adenoma'. A fixed-effect model was used for the analyses. The first analysis dealt with the prevalence of all presentations of colorectal adenoma in patients with celiac disease and the second was on the prevalence of advanced adenomas. The outcomes were described as odds ratios (OR) with their 95% confidence intervals. The search identified 480 bibliographic citations, 17 of which were chosen for evaluation. Fourteen of those studies were rejected, leaving a final total of three for the analysis. Those studies included 367 cases of celiac disease and 682 controls. No significant heterogeneity was observed (I 2 =26%). There was no increased prevalence of colorectal adenomas in the celiac disease patients, when compared with the controls (OR: 0.94 [0.65-1.38]), and no significant difference was observed when assessing the prevalence of advanced adenomas (OR: 0.97 [0.48-1.97]). Celiac disease was not associated with an increased risk of colorectal adenomas. However, due to the limited evidence available, more studies are necessary to determine whether there is an actual association. Copyright © 2018 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.

Molecular markers of carcinogenesis for risk stratification of individuals with colorectal polyps: a case-control study.

PubMed

Gupta, Samir; Sun, Han; Yi, Sang; Storm, Joy; Xiao, Guanghua; Balasubramanian, Bijal A; Zhang, Song; Ashfaq, Raheela; Rockey, Don C

2014-10-01

Risk stratification using number, size, and histology of colorectal adenomas is currently suboptimal for identifying patients at increased risk for future colorectal cancer. We hypothesized that molecular markers of carcinogenesis in adenomas, measured via immunohistochemistry, may help identify high-risk patients. To test this hypothesis, we conducted a retrospective, 1:1 matched case-control study (n = 216; 46% female) in which cases were patients with colorectal cancer and synchronous adenoma and controls were patients with adenoma but no colorectal cancer at baseline or within 5 years of follow-up. In phase I of analyses, we compared expression of molecular markers of carcinogenesis in case and control adenomas, blind to case status. In phase II of analyses, patients were randomly divided into independent training and validation groups to develop a model for predicting case status. We found that seven markers [p53, p21, Cox-2, β-catenin (BCAT), DNA-dependent protein kinase (DNApkcs), survivin, and O6-methylguanine-DNA methyltransferase (MGMT)] were significantly associated with case status on unadjusted analyses, as well as analyses adjusted for age and advanced adenoma status (P < 0.01 for at least one marker component). When applied to the validation set, a predictive model using these seven markers showed substantial accuracy for identifying cases [area under the receiver operation characteristic curve (AUC), 0.83; 95% confidence interval (CI), 0.74-0.92]. A parsimonious model using three markers performed similarly to the seven-marker model (AUC, 0.84). In summary, we found that molecular markers of carcinogenesis distinguished adenomas from patients with and without colorectal cancer. Furthermore, we speculate that prospective studies using molecular markers to identify individuals with polyps at risk for future neoplasia are warranted. ©2014 American Association for Cancer Research.

Dietary patterns and risk of colorectal adenoma: a systematic review and meta-analysis of observational studies.

PubMed

Godos, J; Bella, F; Torrisi, A; Sciacca, S; Galvano, F; Grosso, G

2016-12-01

Current evidence suggests that dietary patterns may play an important role in colorectal cancer risk. The present study aimed to perform a systematic review and meta-analysis of observational studies exploring the association between dietary patterns and colorectal adenomas (a precancerous condition). Pubmed and EMBASE electronic databases were systematically searched to retrieve eligible studies. Only studies exploring the risk or association with colorectal adenomas for the highest versus lowest category of exposure to a posteriori dietary patterns were included in the quantitative analysis. Random-effects models were applied to calculate relative risks (RRs) of colorectal adenomas for high adherence to healthy or unhealthy dietary patterns. Statistical heterogeneity and publication bias were explored. Twelve studies were reviewed. Three studies explored a priori dietary patterns using scores identifying adherence to the Mediterranean, Paleolithic and Dietary Approaches to Stop Hypertension (DASH) diet and reported an association with decreased colorectal adenoma risk. Two studies tested the association with colorectal adenomas between a posteriori dietary patterns showing lower odds of disease related to plant-based compared to meat-based dietary patterns. Seven studies identified 23 a posteriori dietary patterns and the analysis revealed that higher adherence to healthy and unhealthy dietary patterns was significantly associated risk of colorectal adenomas (RR = 0.81, 95% confidence interval = 0.71, 0.94 and RR = 1.24, 95% confidence interval = 1.13, 1.35, respectively) with no evidence of heterogeneity or publication bias. The results of this systematic review and meta-analysis indicate that dietary patterns may be associated with the risk of colorectal adenomas. © 2016 The British Dietetic Association Ltd.

The association between cecal insertion time and colorectal neoplasm detection

PubMed Central

2013-01-01

Background Information on the impact of cecal insertion time on colorectal neoplasm detection is limited. Our objective was to determine the association between cecal insertion time and colorectal neoplasm detection rate in colonoscopy screening. Methods We performed a cross-sectional study of 12,679 consecutive subjects aged 40–79 years undergoing screening colonoscopy in routine health check-ups at the Center for Health Promotion of the Samsung Medical Center from December 2007 to June 2009. Fixed effects logistic regression conditioning on colonoscopist was used to eliminate confounding due to differences in technical ability and other characteristics across colonoscopists. Results The mean cecal insertion time was 5.9 (SD, 4.4 minutes). We identified 4,249 (33.5%) participants with colorectal neoplasms, of whom 1,956 had small single adenomas (<5 mm), 595 had medium single adenomas (5–9 mm), and 1,699 had multiple adenomas or advanced colorectal neoplasms. The overall rates of colorectal neoplasm detection by quartiles of cecal insertion time were 36.8%, 33.4%, 32.7%, and 31.0%, respectively (p trend <0.001).The odds for small single colorectal adenoma detection was 16% lower (adjusted OR 0.84; 95% CI 0.71 to 0.99) in the fourth compared to the first quartile of insertion time (p trend 0.005). Insertion time was not associated with the detection rate of single adenomas ≥5 mm, multiple adenomas or advanced colorectal neoplasms. Conclusion Shorter insertion times were associated with increased rates of detection of small colorectal adenomas <5 mm. Cecal insertion time may be clinically relevant as missed small colorectal adenomas may progress to more advanced lesions. PMID:23915303

Calcium/magnesium intake ratio, but not magnesium intake, interacts with genetic polymorphism in relation to colorectal neoplasia in a two-phase study

PubMed Central

Zhu, Xiangzhu; Shrubsole, Martha J.; Ness, Reid M.; Hibler, Elizabeth A; Cai, Qiuyin; Long, Jirong; Chen, Zhi; Li, Guoliang; Ming, Jiang; Hou, Lifang; Kabagambe, Edmond K.; Zhang, Bing; Smalley, Walter E.; Edwards, Todd L.; Giovannucci, Edward L.; Zheng, Wei; Dai, Qi

2016-01-01

Background Some studies suggest that the calcium to magnesium ratio intakes modifies the associations of calcium or magnesium with risk of colorectal adenoma, adenoma recurrence and cancer. Parathyroid hormone (PTH) plays a key role in the regulation of homeostasis for both calcium and magnesium. We hypothesized that polymorphisms in PTH and 13 other genes may modify the association between the calcium/magnesium intake ratio and colorectal neoplasia risk. Methods We conducted a two-phase study including 1,336 cases and 2,891 controls from the Tennessee Colorectal Polyp Study. Results In Phase I, we identified 19 SNPs that significantly interacted with the calcium/magnesium intake ratio in adenoma risk. In Phase II, rs11022858 in PTH was replicated. In combined analysis of phases I and II, we found high calcium/magnesium intake ratio tended to be associated with a reduced risk of colorectal adenoma (p for trend, 0.040) among those who carried the TT genotype in rs11022858. In stratified analyses, calcium intake (≥1000 mg/day) was significantly associated with 64% reduced adenoma risk (OR=0.36 (95% CI: 0.18–0.74)) among those homozygous for the minor allele (TT genotype) (p for trend, 0.012), but not associated with risk in other genotypes (CC/TC). Conversely, we found highest magnesium intake was significantly associated with 27% reduced risk (OR=0.73 (95% CI: 0.54–0.97)) of colorectal adenoma (p for trend, 0.026) among those who possessed the CC/TC genotypes, particularly among those with the TC genotype; whereas magnesium intake was not linked to risk among those with the TT genotype. Conclusions These findings, if confirmed, will help for the development of personalized prevention strategies for colorectal cancer. PMID:26333203

Association of meat intake and meat-derived mutagen exposure with the risk of colorectal polyps by histologic type

PubMed Central

Fu, Zhenming; Shrubsole, Martha J.; Smalley, Walter E.; Wu, Huiyun; Chen, Zhi; Shyr, Yu; Ness, Reid M.; Zheng, Wei

2011-01-01

Background The association of meat intake and meat-derived mutagens with colorectal tumor risk remains unclear. We evaluated this hypothesis in a large colonoscopy-based case-control study. Methods Included in the study were 2,543 polyp patients [(1,881 with adenomas, and 622 with hyperplastic polyp (HPP)] and 3,764 polyp-free controls. Surveys obtained information about meat intake by cooking methods and doneness levels plus other suspected or known risk factors for colorectal tumors. Unconditional logistic regression was used to derive odds ratios (ORs) after adjusting for potential confounders. Results High intake of red meat and processed meat (P-trend < 0.05), particularly red meat cooked using high-temperature cooking methods (P-trend ≤ 0.01), was associated with an elevated risk for colorectal polyps. A significant positive association between exposures to meat-derived heterocyclic amines and risk of polyps was found for both adenomas and hyperplastic polyps. Furthermore, the positive association with red-meat intake and heterocyclic amine exposure was stronger for multiple adenomas than single adenoma and serrated than non-serrated adenomas. Conclusion This study supports a role for red meat and meat-derived mutagen exposure in the development of colorectal tumor. PMID:21803984

The human gut microbiome as a screening tool for colorectal cancer.

PubMed

Zackular, Joseph P; Rogers, Mary A M; Ruffin, Mack T; Schloss, Patrick D

2014-11-01

Recent studies have suggested that the gut microbiome may be an important factor in the development of colorectal cancer. Abnormalities in the gut microbiome have been reported in patients with colorectal cancer; however, this microbial community has not been explored as a potential screen for early-stage disease. We characterized the gut microbiome in patients from three clinical groups representing the stages of colorectal cancer development: healthy, adenoma, and carcinoma. Analysis of the gut microbiome from stool samples revealed both an enrichment and depletion of several bacterial populations associated with adenomas and carcinomas. Combined with known clinical risk factors of colorectal cancer (e.g., BMI, age, race), data from the gut microbiome significantly improved the ability to differentiate between healthy, adenoma, and carcinoma clinical groups relative to risk factors alone. Using Bayesian methods, we determined that using gut microbiome data as a screening tool improved the pretest to posttest probability of adenoma more than 50-fold. For example, the pretest probability in a 65-year-old was 0.17% and, after using the microbiome data, this increased to 10.67% (1 in 9 chance of having an adenoma). Taken together, the results of our study demonstrate the feasibility of using the composition of the gut microbiome to detect the presence of precancerous and cancerous lesions. Furthermore, these results support the need for more cross-sectional studies with diverse populations and linkage to other stool markers, dietary data, and personal health information. ©2014 American Association for Cancer Research.

Anatomical distribution and detection rate of colorectal neoplasms according to age in the colonoscopic screening of a Korean population.

PubMed

Lee, Suk-Young; Song, Wan Hee; Oh, Sang Cheul; Min, Byung-Wook; Lee, Sun Il

2018-01-01

Because data as a basis for the determination of proper age and modality for screening of colorectal neoplasms is lacking, we evaluated detection rates and anatomical distribution of colorectal neoplasms according to age in healthy individuals who underwent total colonoscopy for health checkup. A total of 16,100 cases that had received the colonoscopic examination from January to December in 2014 were analyzed. The total number of individuals who received total colonoscopy were divided by the number of individuals harboring colorectal adenoma to calculate the detection rate of colorectal adenoma. Individuals ≤50 years old were classified as young-age group and aged >50 were old-age group. Differences in anatomical locations of colorectal neoplasms were analyzed in the 2 age groups by chi-square test. Risk factors for colorectal adenoma in each age group were analyzed using univariate and multivariate logistic regression analyses. Detection rates of colorectal adenoma were 13.7% in all cases and 12.8% for those in their 40's. The main anatomical location of colorectal adenoma was proximal colon in both age groups (P < 0.001). Hyperplastic polyp was mainly distributed to the distal colon in both age groups (P < 0.001). Distal colon was the major site for colorectal cancer in the old-age group (P = 0.001). Proximal location of neoplasms was a risk factor for colorectal adenoma in both age groups with multivariate analysis. These data could be the bases for earlier initiation of screening for colorectal neoplasms with total colonoscopy to detect clinically significant colorectal polyps.

Chemoprevention with special reference to inherited colorectal cancer.

PubMed

Lynch, Patrick M

2008-01-01

Familial Adenomatous Polyposis (FAP) is a model for the adenoma-carcinoma sequence in several respects. One important area in which FAP serves as a model is chemoprevention. Early prevention trials mainly utilized micronutrients and were largely unsuccessful in preventing or causing regression of adenomas. A new era was ushered in by the recognition that antiarthritic doses of a nonsteroidal anti-inflammatory agent (NSAID), sulindac, could actually induce regression of colorectal adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal adenomas, but sulindac appears to lack significant benefit in regressing duodenal adenomas or preventing initial occurrence of adenomas in APC mutation carriers. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some duodenal activity as well. Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of NSAID research in chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic adenoma prevention trials. Whether NSAIDs will have a significant future in FAP chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial adenomas, a problem with even greater societal impact. The historical development of chemoprevention in FAP will be presented, with an emphasis on issues of trial design.

Dietary Choline and Betaine and the Risk of Distal Colorectal Adenoma in Women

PubMed Central

Cho, Eunyoung; Willett, Walter C.; Colditz, Graham A.; Fuchs, Charles S.; Wu, Kana; Chan, Andrew T.; Zeisel, Steven H.; Giovannucci, Edward L.

2008-01-01

Background Choline and betaine are involved in methyl-group metabolism as methyl-group donors; thus, like folate, another methyl-group donor, they may be associated with a reduced risk of colorectal adenomas. No epidemiologic study has examined the association of intake of these nutrients and colorectal adenoma risk. Methods We investigated the relationship between intakes of choline and betaine and risk of colorectal adenoma in US women enrolled in the Nurses' Health Study. Dietary intake was measured by food-frequency questionnaires, and individual intakes of choline and betaine were calculated by multiplying the frequency of consumption of each food item by its choline and betaine content and summing the nutrient contributions of all foods. Logistic regression models were used to calculate adjusted odds ratios (as approximations for relative risks) and 95% confidence intervals (CIs) of colorectal adenoma. All statistical tests were two-sided. Results Among 39 246 women who were initially free of cancer or polyps and who had at least one endoscopy from 1984 through 2002, 2408 adenoma cases were documented. Increasing choline intake was associated with an elevated risk of colorectal adenoma; the multivariable relative risks (95% CIs) for increasing quintiles of intake, relative to the lowest quintile, were 1.03 (0.90 to 1.18), 1.01 (0.88 to 1.16), 1.23 (1.07 to 1.41), and 1.45 (1.27 to 1.67; Ptrend<.001). Betaine intake had a nonlinear inverse association with colorectal adenoma; the multivariable relative risks (95% CIs) for increasing quintiles of intake were 0.94 (0.83 to 1.07), 0.85 (0.75 to 0.97), 0.86 (0.75 to 0.98), and 0.90 (95% CI = 0.78 to 1.04; Ptrend = .09). Among individual sources of choline, choline from phosphatidylcholine and from sphingomyelin were each positively related to adenoma risk. Conclusions Our findings do not support an inverse association between choline intake and risk of colorectal adenoma. The positive association between choline intake and colorectal adenoma that we observed could represent effects of other components in the foods from which choline was derived and should be investigated further. PMID:17686825

ASSOCIATION BETWEEN URINARY MUTAGENICITY AND RISK OF COLORECTAL ADENOMAS IN A CLINIC-BASED CASE-CONTROL STUDY

EPA Science Inventory

ASSOCIATION BETWEEN URINARY MUTAGENICITY AND RISK OF COLORECTAL ADENOMAS IN A CLINIC-BASED CASE-CONTROL STUDY

Humans are exposed to a variety of mutagens from diet, smoking, or occupation. To explore if exposure to mutagens was related to the risk of colorectal adenomas i...

Altered expression of cytokeratin 7 and CD117 in transitional mucosa adjacent to human colorectal cancer.

PubMed

Kigasawa, Hideaki; Fujiwara, Masachika; Ishii, Jun; Chiba, Tomohiro; Terado, Yuichi; Shimoyamada, Hiroaki; Mochizuki, Makoto; Kitamura, Osamu; Kamma, Hiroshi; Ohkura, Yasuo

2017-07-01

The multi-step progression of colorectal cancer through precancerous lesions (adenoma and dysplasia) is associated with cumulative molecular alterations, a number of which have also been demonstrated to be present in morphologically normal transitional mucosa adjacent to colorectal cancer. The cytoskeletal protein cytokeratin 7 (CK7) and the receptor tyrosine kinase, KIT proto-oncogene receptor tyrosine kinase (CD117), encoded by the proto-oncogene c-Kit, are lacking in normal colorectal crypt epithelium and are aberrantly expressed in a subset of colorectal cancer. The aim of the present study was to evaluate the expression of CK7 and CD117 in morphologically normal transitional mucosa adjacent to colorectal cancer. Immunohistochemical staining for CK7 and CD117 was performed in the mucosa adjacent to five groups of surgically resected colorectal tumors [low-grade adenoma, high-grade adenoma, mucosal adenocarcinoma, small-sized invasive adenocarcinoma (≤2 cm) and large-sized invasive adenocarcinoma (>2 cm)]. CK7 was expressed in the mucosa adjacent to a subset of colorectal tumors, and the positivity ratio increased according to tumor grade from low-grade adenoma up to small-sized invasive adenocarcinoma (61.2%). However, the positivity ratio of CK7 in the mucosa adjacent to the large-sized invasive adenocarcinoma (25.0%) was significantly lower compared with that of the next lower grade. CD117 was also expressed in the mucosa adjacent to a subset of colorectal tumors. In contrast to CK7, the positivity ratio of CD117 increased according to tumor grade from low-grade adenoma all the way through to the large-sized invasive adenocarcinoma (45.0%). Based on these results, the mechanism of CK7 and CD117 expression in the transitional mucosa adjacent to colorectal cancer may be different, and analysis of their individual expression may provide novel insights into the development and progression of colorectal cancer.

Altered expression of cytokeratin 7 and CD117 in transitional mucosa adjacent to human colorectal cancer

PubMed Central

Kigasawa, Hideaki; Fujiwara, Masachika; Ishii, Jun; Chiba, Tomohiro; Terado, Yuichi; Shimoyamada, Hiroaki; Mochizuki, Makoto; Kitamura, Osamu; Kamma, Hiroshi; Ohkura, Yasuo

2017-01-01

The multi-step progression of colorectal cancer through precancerous lesions (adenoma and dysplasia) is associated with cumulative molecular alterations, a number of which have also been demonstrated to be present in morphologically normal transitional mucosa adjacent to colorectal cancer. The cytoskeletal protein cytokeratin 7 (CK7) and the receptor tyrosine kinase, KIT proto-oncogene receptor tyrosine kinase (CD117), encoded by the proto-oncogene c-Kit, are lacking in normal colorectal crypt epithelium and are aberrantly expressed in a subset of colorectal cancer. The aim of the present study was to evaluate the expression of CK7 and CD117 in morphologically normal transitional mucosa adjacent to colorectal cancer. Immunohistochemical staining for CK7 and CD117 was performed in the mucosa adjacent to five groups of surgically resected colorectal tumors [low-grade adenoma, high-grade adenoma, mucosal adenocarcinoma, small-sized invasive adenocarcinoma (≤2 cm) and large-sized invasive adenocarcinoma (>2 cm)]. CK7 was expressed in the mucosa adjacent to a subset of colorectal tumors, and the positivity ratio increased according to tumor grade from low-grade adenoma up to small-sized invasive adenocarcinoma (61.2%). However, the positivity ratio of CK7 in the mucosa adjacent to the large-sized invasive adenocarcinoma (25.0%) was significantly lower compared with that of the next lower grade. CD117 was also expressed in the mucosa adjacent to a subset of colorectal tumors. In contrast to CK7, the positivity ratio of CD117 increased according to tumor grade from low-grade adenoma all the way through to the large-sized invasive adenocarcinoma (45.0%). Based on these results, the mechanism of CK7 and CD117 expression in the transitional mucosa adjacent to colorectal cancer may be different, and analysis of their individual expression may provide novel insights into the development and progression of colorectal cancer. PMID:28693143

Immunohistochemical Expression of PCNA and CD34 in Colorectal Adenomas and Carcinomas Using Specified Automated Cellular Image Analysis System: A Clinicopathologic Study

PubMed Central

Qasim, Ban J.; Ali, Hussam H.; Hussein, Alaa G.

2012-01-01

Background/Aim: To evaluate the immunohistochemical expression of proliferating cell nuclear antigen (PCNA) and CD34 in colorectal adenomas and carcinomas, and to correlate this expression with different clinicopathologic parameters. Materials and Methods: The study was retrospectively designed. A total of 86 tissue samples, including 33 paraffin blocks from patients with colorectal adenomas, 33 paraffin blocks from patients with colorectal adenocarcinomas, and a control group of 20 samples of nontumerous colonic tissue, were included in the study. From each block, 3 sections of 5 ΅m thickness were taken, 1 section was stained with hematoxylin and eosin (H and E) and the other 2 sections were stained immunohistochemically for PCNA and CD34. Scoring of the immunohistochemical staining was performed using a specified automated cellular image analysis system (Digimizer). Results: PCNA expression was significantly increased in a sequence of normal mucosa–adenoma–carcinoma. It was significantly higher in adenomas ≥ 1 cm and those with severe dysplasia, and it showed a significant positive correlation with grade and lymph node involvement in colorectal carcinoma. CD34 showed significantly higher expression in carcinoma than adenoma and in adenoma than in the control group. CD34 expression showed a significant correlation with adenomas carrying severe dysplasia and large-sized adenomas (≥1cm). It was significantly correlated with tumor grade, lymphovascular invasion, and lymph node involvement in colorectal carcinoma. Conclusion: PCNA plays an important role in colorectal neoplastic progression and can be utilized as ancillary marker for the risk of malignant transformation in colorectal adenomas as it correlates with high grade dysplasia and size. Intratumoral quantification of the mean (A and N) of CD34 in colorectal carcinoma reflects the grade of tumors and can predict lymph node involvement and lymphovascular invasion, to make a useful additional prognostic factor. PMID:22824771

Prevalence and features of colorectal lesions among Hispanics: A hospital-based study.

PubMed

Ashktorab, Hassan; Laiyemo, Adeyinka O; Lee, Edward; Cruz-Correa, Marcia; Ghuman, Amita; Nouraie, Mehdi; Brim, Hassan

2015-12-14

To evaluate the prevalence and characteristics of colorectal adenoma and carcinoma in an inner city Hispanic population. We reviewed the reports of 1628 Hispanic patients who underwent colonoscopy at Howard University from 2000 to 2010. Advanced adenoma was defined as adenoma ≥ 1 cm in size, adenomas with villous histology, high grade dysplasia and/or invasive cancer. Statistical analysis was performed using χ(2) statistics and t-test. The median age of the patients was 54 years, 64.2% were females. Polyps were observed in 489 (30.0%) of patients. Adenoma prevalence was 16.8% (n = 273), advanced adenoma 2.4% (n = 39), and colorectal cancer 0.4% (n = 7). Hyperplastic polyps were seen in 6.6% of the cohort (n = 107). Adenomas predominantly exhibited a proximal colonic distribution (53.7%, n = 144); while hyperplastic polyps were mostly located in the distal colon (70%, n = 75). Among 11.7% (n = 191) patients who underwent screening colonoscopy, the prevalence of colorectal lesions was 21.4% adenoma, 2.6% advanced adenoma; and 8.3% hyperplastic polyps. Our data showed low colorectal cancer prevalence among Hispanics in the Washington DC area. However, the pre-neoplastic pattern of colonic lesions in Hispanics likely points toward a shift in this population that needs to be monitored closely through large epidemiological studies.

Body mass index increases risk of colorectal adenomas in men with Lynch syndrome: the GEOLynch cohort study.

PubMed

Botma, Akke; Nagengast, Fokko M; Braem, Marieke G M; Hendriks, Jan C M; Kleibeuker, Jan H; Vasen, Hans F A; Kampman, Ellen

2010-10-01

High body mass index (BMI) is an established risk factor for sporadic colorectal cancer. Still, the influence of BMI on hereditary colorectal cancer (eg, Lynch syndrome [LS]), is unknown. The objective of this study was to assess whether BMI is associated with colorectal adenoma occurrence in persons with LS. A prospective cohort study of 486 patients with LS was conducted. Cox regression models with robust sandwich estimates controlling for age, sex, extent of colon surgery, smoking, and alcohol intake were used to evaluate associations between BMI, height, weight, weight change, and risk of colorectal adenomas. Analyses were performed separately for those without (incident cohort; n = 243) and those with (prevalent cohort; n = 243) a history of colorectal cancer neoplasms at baseline. A statistically significant association between current overweight (≥ 25 kg/m(2)) and developing colorectal adenomas was seen among men in the incident cohort (overweight v normal weight hazard ratio [HR], 8.72; 95% CI, 2.06 to 36.96). This association was not observed among women (overweight v normal weight HR, 0.75; 95% CI, 0.19 to 3.07), nor was it observed in the prevalent cohort. In the incident cohort, height was statistically significantly associated with a decreased risk of adenomatous polyps among men (per 5 cm HR, 0.43; 95% CI, 0.23 to 0.83), but the association between weight and adenomatous polyps among men was of marginal significance (per 5 kg HR, 1.17; 95% CI, 1.00 to 1.37). No statistically significant associations were observed among women in either the incident cohort or the prevalent cohort. Excess body weight increased the risk of incident colorectal adenomas in people with LS. This increased risk was seen only in men.

Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma.

PubMed

Kim, Tae-Min; An, Chang Hyeok; Rhee, Je-Keun; Jung, Seung-Hyun; Lee, Sung Hak; Baek, In-Pyo; Kim, Min Sung; Lee, Sug Hyung; Chung, Yeun-Jun

2015-09-29

Although the colorectal adenoma-to-carcinoma sequence represents a classical cancer progression model, the evolution of the mutational landscape underlying this model is not fully understood. In this study, we analyzed eight synchronous pairs of colorectal high-grade adenomas and carcinomas, four microsatellite-unstable (MSU) and four-stable (MSS) pairs, using whole-exome sequencing. In the MSU adenoma-carcinoma pairs, we observed no subclonal mutations in adenomas that became fixed in paired carcinomas, suggesting a 'parallel' evolution of synchronous adenoma-to-carcinoma, rather than a 'stepwise' evolution. The abundance of indel (in MSU and MSS pairs) and microsatellite instability (in MSU pairs) was noted in the later adenoma- or carcinoma-specific mutations, indicating that the mutational processes and functional constraints operative in early and late colorectal carcinogenesis are different. All MSU cases exhibited clonal, truncating mutations in ACVR2A, TGFBR2, and DNA mismatch repair genes, but none were present in APC or KRAS. In three MSS pairs, both APC and KRAS mutations were identified as both early and clonal events, often accompanying clonal copy number changes. An MSS case uniquely exhibited clonal ERBB2 amplification, followed by APC and TP53 mutations as carcinoma-specific events. Along with the previously unrecognized clonal origins of synchronous colorectal adenoma-carcinoma pairs, our study revealed that the preferred sequence of mutational events during colorectal carcinogenesis can be context-dependent.

Matrix metalloproteinase-13 expression in the progression of colorectal adenoma to carcinoma : Matrix metalloproteinase-13 expression in the colorectal adenoma and carcinoma.

PubMed

Foda, Abd Al-Rahman Mohammad; El-Hawary, Amira K; Abdel-Aziz, Azza

2014-06-01

Most colorectal carcinomas (CRCs) are considered to arise from conventional adenoma based on the concept of the adenoma-carcinoma sequence. Matrix metalloproteinases (MMPs) are known to be overexpressed as normal mucosa progresses to adenomas and carcinomas. There has been little previous investigation about MMP-13 expression in adenoma-carcinoma sequence. In this study, we aimed to investigate the immunohistochemical expression of MMP-13 in colorectal adenoma and CRC specimens using tissue microarray (TMA) technique. A total of 40 cases of CRC associated with adenoma were collected from files of the Pathology laboratory at Mansoura Gastroenterology Center between January 2007 and January 2012. Sections from TMA blocks were prepared and stained for MMP-13. Immunoreactivity to MMP-13 staining was localized to the cytoplasm of mildly, moderately, and severely dysplatic cells of adenomas and CRC tumor cells that were either homogenous or heterogeneous. There was no significant difference in MMP-13 expression between adenomas and CRCs either non-mucinous or mucinous. Adenomas with high MMP-13 expression were significantly associated with moderate to marked degree of inflammatory cellular infiltrate and presence of familial adenomatous polyps. In conclusion, MMP-13 may be a potential biological marker of early tumorigenesis in the adenoma-carcinoma sequence.

Gender Modifies the Effect of Ursodeoxycholic Acid (UDCA) in a Randomized Controlled Trial in Colorectal Adenoma Patients

PubMed Central

Thompson, Patricia A.; Wertheim, Betsy C.; Roe, Denise J.; Ashbeck, Erin L.; Jacobs, Elizabeth T.; Lance, Peter; Martínez, María Elena; Alberts, David S.

2014-01-01

Background Ursodeoxycholic acid (UDCA) was one of the earliest agents investigated as a drug for colorectal cancer prevention. However, UDCA failed to demonstrate efficacy to prevent the development of colorectal adenomas in a large phase III randomized controlled trial. We re-evaluated the effect of UDCA in men and women separately, based on sex-specific differences in bile acid metabolism and suspected variation in etiologic factors contributing to colorectal cancer risk. Method We conducted a secondary analysis of the efficacy of UDCA to prevent colorectal adenoma in men (n = 804) and women (n = 388). Results We found no reduction in risk of any metachronous adenoma with UDCA treatment in men or women. However, UDCA treatment significantly lowered the odds of advanced lesions (OR = 0.62, 95% CI = 0.43 to 0.89) in men, but not women. We also observed significantly higher odds of advanced lesions with UDCA treatment in women who were younger (age < 65 y; OR = 3.24, 95% CI = 1.10 to 9.56), obese (body mass index ≥ 30 kg/m2; OR = 5.45, 95% CI = 1.42 to 20.9), or in the highest tertile of total dietary fat (≥ 56.2 g/day; OR = 3.48, 95% CI = 1.35 to 8.95). The interactive effect of fat intake accounted for the modulating effects of age and BMI in women. Conclusion Our findings support the use of UDCA for preventing advanced colorectal adenomas in men. The increased odds of adenoma among women with high fat intake suggest a previously unrecognized harm that warrants further study, especially given some patients’ chronic exposure to UDCA for the treatment of primary biliary cirrhosis and the rising investigational use of this drug for several other conditions. PMID:19952360

Meat consumption and the risk of incident distal colon and rectal adenoma

PubMed Central

Ferrucci, L M; Sinha, R; Huang, W-Y; Berndt, S I; Katki, H A; Schoen, R E; Hayes, R B; Cross, A J

2012-01-01

Background: Most studies of meat and colorectal adenoma have investigated prevalent events from a single screening, thus limiting our understanding of the role of meat and meat-related exposures in early colorectal carcinogenesis. Methods: Among participants in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who underwent baseline and follow-up sigmoidoscopy (n=17 072), we identified 1008 individuals with incident distal colorectal adenoma. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between meat and meat-related components and incident distal colorectal adenoma using multivariate logistic regression. Results: We observed suggestive positive associations for red meat, processed meat, haeme iron, and nitrate/nitrite with distal colorectal adenoma. Grilled meat (OR=1.56, 95% CI=1.04–2.36), well or very well-done meat (OR=1.59, 95% CI=1.05–2.43), 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) (OR=1.75, 95% CI=1.17–2.64), benzo[a]pyrene (OR=1.53, 95% CI=1.06–2.20), and total mutagenic activity (OR=1.57, 95% CI=1.03–2.40) were positively associated with rectal adenoma. Total iron (diet and supplements) (OR=0.69, 95% CI=0.56–0.86) and iron from supplements (OR=0.65, 95% CI=0.44–0.97) were inversely associated with any distal colorectal adenoma. Conclusion: Our findings indicate that several meat-related components may be most relevant to early neoplasia in the rectum. In contrast, total iron and iron from supplements were inversely associated with any distal colorectal adenoma. PMID:22166801

Increased tumor necrosis factor receptor 1 expression in human colorectal adenomas

PubMed Central

Hosono, Kunihiro; Yamada, Eiji; Endo, Hiroki; Takahashi, Hirokazu; Inamori, Masahiko; Hippo, Yoshitaka; Nakagama, Hitoshi; Nakajima, Atsushi

2012-01-01

AIM: To determine the expression statuses of tumor necrosis factor (TNF)-α, its receptors (TNF-R) and downstream effector molecules in human colorectal adenomas. METHODS: We measured the serum concentrations of TNF-α and its receptors in 62 colorectal adenoma patients and 34 healthy controls. The protein expression of TNF-α, TNF-R1, TNF-R2 and downstream signals of the TNF receptors, such as c-Jun N-terminal kinase (JNK), nuclear factor-κ B and caspase-3, were also investigated in human colorectal adenomas and in normal colorectal mucosal tissues by immunohistochemistry. Immunofluorescence confocal microscopy was used to investigate the consistency of expression of TNF-R1 and phospho-JNK (p-JNK). RESULTS: The serum levels of soluble TNF-R1 (sTNF-R1) in adenoma patients were significantly higher than in the control group (3.67 ± 0.86 ng/mL vs 1.57 ± 0.72 ng/mL, P < 0.001). Receiver operating characteristic analysis revealed the high diagnostic sensitivity of TNF-R1 measurements (AUC was 0.928) for the diagnosis of adenoma, and the best cut-off level of TNF-R1 was 2.08 ng/mL, with a sensitivity of 93.4% and a specificity of 82.4%. There were no significant differences in the serum levels of TNF-α or sTNF-R2 between the two groups. Immunohistochemistry showed high levels of TNF-R1 and p-JNK expression in the epithelial cells of adenomas. Furthermore, a high incidence of co-localization of TNF-R1 and p-JNK was identified in adenoma tissue. CONCLUSION: TNF-R1 may be a promising biomarker of colorectal adenoma, and it may also play an important role in the very early stages of colorectal carcinogenesis. PMID:23082052

Shifts in the Fecal Microbiota Associated with Adenomatous Polyps.

PubMed

Hale, Vanessa L; Chen, Jun; Johnson, Stephen; Harrington, Sean C; Yab, Tracy C; Smyrk, Thomas C; Nelson, Heidi; Boardman, Lisa A; Druliner, Brooke R; Levin, Theodore R; Rex, Douglas K; Ahnen, Dennis J; Lance, Peter; Ahlquist, David A; Chia, Nicholas

2017-01-01

Adenomatous polyps are the most common precursor to colorectal cancer, the second leading cause of cancer-related death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas. We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n = 233) and without (n = 547). Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, proinflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Our findings were consistent with previously reported shifts in the gut microbiota of colorectal cancer patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism. These data hint that increased sugar, protein, and lipid metabolism along with increased bile acid production could promote a colonic environment that supports the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio In turn, these microbes may produce genotoxic or inflammatory metabolites such as H 2 S and secondary bile acids, which could play a role in catalyzing adenoma development and eventually colorectal cancer. This study suggests a plausible biological mechanism to explain the links between shifts in the microbiota and colorectal cancer. This represents a first step toward resolving the complex interactions that shape the adenoma-carcinoma sequence of colorectal cancer and may facilitate personalized therapeutics focused on the microbiota. Cancer Epidemiol Biomarkers Prev; 26(1); 85-94. ©2016 AACR. ©2016 American Association for Cancer Research.

Effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs on the incidence of recurrent colorectal adenomas: a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials.

PubMed

Veettil, Sajesh K; Lim, Kean Ghee; Ching, Siew Mooi; Saokaew, Surasak; Phisalprapa, Pochamana; Chaiyakunapruk, Nathorn

2017-11-14

Beneficial effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) against recurrent colorectal adenomas have been documented in systematic reviews; however, the results have not been conclusive. Uncertainty remains about the appropriate dose of aspirin for adenoma prevention. The persistence of the protective effect of NSAIDs against recurrent adenomas after treatment cessation is yet to be established. Our objective was to update and systematically evaluate the evidence for aspirin and other NSAIDs on the incidence of recurrent colorectal adenomas taking into consideration the risks of random error and to appraise the quality of evidence using GRADE (The Grading of Recommendations, Assessment, Development and Evaluation) approach. Retrieved trials were evaluated using Cochrane risk of bias instrument. Meta-analytic estimates were calculated with random-effects model and random errors were evaluated with trial sequential analysis (TSA). In patients with a previous history of colorectal cancer or adenomas, low-dose aspirin (80-160 mg/day) compared to placebo taken for 2 to 4 years reduces the risk of recurrent colorectal adenomas (relative risk (RR), 0.80 [95% CI (confidence interval), 0.70-0.92]). TSA indicated a firm evidence for this beneficial effect. The evidence indicated moderate GRADE quality. Low-dose aspirin also reduces the recurrence of advanced adenomas (RR, 0.66 [95% CI, 0.44-0.99]); however, TSA indicated lack of firm evidence for a beneficial effect. High-dose aspirin (300-325 mg/day) did not statistically reduce the recurrent adenomas (RR, 0.90 [95% CI, 0.68-1.18]). Cyclooxygenase-2 (COX-2) inhibitors (e.g. celecoxib 400 mg/day) were associated with a significant decrease in the recurrence of both adenomas (RR, 0.66 [95% CI, 0.59-0.72]) and advanced adenomas (RR, 0.45 [95% CI, 0.33-0.57]); however, this association did not persist and there was a trend of an increased risk of recurrent adenomas observed 2 years after the withdrawal. Our findings confirm the beneficial effect of low-dose aspirin on recurrence of any adenomas; however, effect on advanced adenomas was inconclusive. COX-2 inhibitors seem to be more effective in preventing recurrence of adenomas; however, there was a trend of an increased risk of recurrence of adenomas observed after discontinuing regular use.

Microsatellite Instability of Gastric and Colorectal Cancers as a Predictor of Synchronous Gastric or Colorectal Neoplasms.

PubMed

Kim, Young Beak; Lee, Sun-Young; Kim, Jeong Hwan; Sung, In-Kyung; Park, Hyung Seok; Shim, Chan Sup; Han, Hye Seung

2016-03-01

Microsatellite instability (MSI) plays a crucial role in gastrointestinal carcinogenesis. The aim of this study was to clarify whether MSI is a useful marker for predicting synchronous gastric and colorectal neoplasms. Consecutive patients who underwent both esophagogastroduodenoscopy and colonoscopy before the resection of gastric or colorectal cancers were included. MSI was analyzed using two mononucleotide and three dinucleotide markers. In total, 434 gastric cancers (372 microsatellite stability [MSS], 21 low incidence of MSI [MSI-L], and 41 high incidence of MSI [MSI-H]) and 162 colorectal cancers (138 MSS, 9 MSI-L, and 15 MSI-H) were included. Patients with MSI gastric cancer had a higher prevalence of synchronous colorectal cancer, colorectal adenoma, and gastric adenoma than those with MSS gastric cancers (4.8% vs 0.5%, p=0.023; 11.3% vs 3.2%, p=0.011; 3.2% vs 1.2%, p=0.00, respectively). The prevalence of synchronous colorectal adenomas was highest in MSI-L gastric cancers (19.0%), compared with MSI-H (7.3%) or MSS (3.2%) gastric cancers (p=0.002). In addition, there were no significant differences in the prevalence rates of synchronous colorectal adenoma among the MSI-H (13.3%), MSI-L (11.1%), and MSS (12.3%) colorectal cancers (p=0.987). The presence of MSI in gastric cancer may be a predictor of synchronous gastric and colorectal neoplasms, whereas MSI in colorectal cancer is not a predictor of synchronous colorectal adenoma.

Diabetes Mellitus and Colorectal Neoplasia.

PubMed

Acevedo, Alejandro; Diaz, Yaritza; Perez, Cynthia M; Garau, Maria; Baron, John; Cruz-Correa, Marcia

2012-11-01

Many studies have provided evidence for an association between obesity, physical inactivity, and western diet as risk factors for colorectal cancer (CRC). Few studies directly address the association between type 2 Diabetes Mellitus (DM) and the risk of colorectal lesions at specific anatomic locations. 2,663 subjects with a previous history of adenoma(s) and removal of all current adenomas at study entry were followed for a mean time of three years across three different chemoprevention clinical trials. The primary endpoint was colorectal adenoma recurrence and number of lesions during the treatment phase; the secondary endpoints were presence of advanced colorectal neoplasia (CRN) and location of CRN. Using log linear regression, the effect of DM status on the relative risk (RR) of CRN recurrence, advanced CRN, and location of CRN was assessed. DM status was not significantly associated with incidence of colorectal adenomas, incidence of advanced colorectal lesions, or left-sided colorectal neoplastic lesions. Subjects with DM had a marginally increased risk of right-sided (p= 0.06) colorectal adenomas and a significant increased risk of multiple right-sided adenomas (p=0.03) in the unadjusted model; this association was not significant after adjusting for age and other potential confounders (RR=1.22, 95% CI: 0.85-1.76). We did not observe a statistically significant increased risk in CRN recurrence for overall neoplasia, advanced neoplasia or location of neoplasia in individuals with DM compared to non-DM individuals. However, given the patterns observed in this investigation, future studies with longer follow-up time and longer DM exposure, incorporating objective measurements of type 2 DM might help elucidate the risk of CRN among individuals with DM.

Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study.

PubMed

Shimizu, Masahito; Fukutomi, Yasushi; Ninomiya, Mitsuo; Nagura, Kazuo; Kato, Tomohiro; Araki, Hiroshi; Suganuma, Masami; Fujiki, Hirota; Moriwaki, Hisataka

2008-11-01

Experimental studies indicate the chemopreventive properties of green tea extract (GTE) on colorectal cancer. Epidemiologically, green tea consumption of > 10 cups daily reduced colorectal cancer risk in Japanese. Because colorectal adenomas are the precursors to most sporadic colorectal cancers, we conducted a randomized trial to determine the preventive effect of GTE supplements on metachronous colorectal adenomas by raising green tea consumption in the target population from an average of 6 cups (1.5 g GTE) daily to > or = 10 cups equivalent (2.5 g GTE) by supplemental GTE tablets. We recruited 136 patients, removed their colorectal adenomas by endoscopic polypectomy, and 1 year later confirmed the clean colon (i.e., no polyp) at the second colonoscopy. The patients were then randomized into two groups while maintaining their lifestyle on green tea drinking: 71 patients supplemented with 1.5 g GTE per day for 12 months and 65 control patients without supplementation. Follow-up colonoscopy was conducted 12 months later in 125 patients (65 in the control group and 60 in the GTE group). The incidence of metachronous adenomas at the end-point colonoscopy was 31% (20 of 65) in the control group and 15% (9 of 60) in the GTE group (relative risk, 0.49; 95% confidence interval, 0.24-0.99; P < 0.05). The size of relapsed adenomas was also smaller in the GTE group than in the control group (P < 0.001). No serious adverse events occurred in the GTE group. GTE is an effective supplement for the chemoprevention of metachronous colorectal adenomas.

Prevalence and features of colorectal lesions among Hispanics: A hospital-based study

PubMed Central

Ashktorab, Hassan; Laiyemo, Adeyinka O; Lee, Edward; Cruz-Correa, Marcia; Ghuman, Amita; Nouraie, Mehdi; Brim, Hassan

2015-01-01

AIM: To evaluate the prevalence and characteristics of colorectal adenoma and carcinoma in an inner city Hispanic population. METHODS: We reviewed the reports of 1628 Hispanic patients who underwent colonoscopy at Howard University from 2000 to 2010. Advanced adenoma was defined as adenoma ≥ 1 cm in size, adenomas with villous histology, high grade dysplasia and/or invasive cancer. Statistical analysis was performed using χ2 statistics and t-test. RESULTS: The median age of the patients was 54 years, 64.2% were females. Polyps were observed in 489 (30.0%) of patients. Adenoma prevalence was 16.8% (n = 273), advanced adenoma 2.4% (n = 39), and colorectal cancer 0.4% (n = 7). Hyperplastic polyps were seen in 6.6% of the cohort (n = 107). Adenomas predominantly exhibited a proximal colonic distribution (53.7%, n = 144); while hyperplastic polyps were mostly located in the distal colon (70%, n = 75). Among 11.7% (n = 191) patients who underwent screening colonoscopy, the prevalence of colorectal lesions was 21.4% adenoma, 2.6% advanced adenoma; and 8.3% hyperplastic polyps. CONCLUSION: Our data showed low colorectal cancer prevalence among Hispanics in the Washington DC area. However, the pre-neoplastic pattern of colonic lesions in Hispanics likely points toward a shift in this population that needs to be monitored closely through large epidemiological studies. PMID:26673447

Colorectal adenoma recurrence rates among post-polypectomy patients in the placebo-controlled groups of randomized clinical trials: a meta-analysis

PubMed Central

Shi, Xin; Yang, Zhiping; Wu, Qiong; Fan, Daiming

2017-01-01

Background Evidence regarding the benefit of therapy to prevent the post-polypectomy recurrence of colorectal adenoma is limited. Endoscopic recurrence is the main outcome according to an evaluation of trials involving recurrence prevention. Aim To estimate the recurrence rates of post-polypectomy colorectal adenoma in placebo-controlled arms of randomized clinical trials and to identify the prognostic factors influencing these rates. Methods We combined data from all randomized controlled trials evaluating therapies for colorectal adenoma using placebo from 1988 to 2016. The data were combined in a random-effects model. Primary outcomes were endoscopic adenoma and advanced adenoma recurrence of colorectal adenoma. Results The pooled estimates of the adenoma recurrence rates were 37% (95% confidence interval [CI], 33%-41%; range, 33%-52%) at 1 year, 47% (95% CI, 41%-54%; range, 46%-51%) at 2 years, 41% (95% CI, 33%-48%; range, 20%-61%) at 3 years, 48% (95% CI, 38%-57%; range, 37%-53%) at 4 years, and 60% (95% CI, 52%-68%; range, 48%-68%) at 5 years. The pooled estimates of the advanced adenoma recurrence rates were 10% (95% CI, 6%-15%; range, 7%-13%) at 1 year, 12% (95% CI, 8%-16%; range, 3%-19%) at 3 years, 14% (95% CI, 10%-18%; range, 13%-16%) at 4 years, and 14% (95% CI, 10%-19%; range, 9%-21%) at 5 years. Significant heterogeneity among the randomized clinical trials (P < 0.001) was observed for each recurrence rate. Conclusions This meta-analysis confirms the heterogeneity of recurrence rates among post-polypectomy colorectal adenoma patients who received placebo. No single design variable was identified that might explain the heterogeneity. PMID:28977952

Calcium/magnesium intake ratio, but not magnesium intake, interacts with genetic polymorphism in relation to colorectal neoplasia in a two-phase study.

PubMed

Zhu, Xiangzhu; Shrubsole, Martha J; Ness, Reid M; Hibler, Elizabeth A; Cai, Qiuyin; Long, Jirong; Chen, Zhi; Li, Guoliang; Jiang, Ming; Hou, Lifang; Kabagambe, Edmond K; Zhang, Bing; Smalley, Walter E; Edwards, Todd L; Giovannucci, Edward L; Zheng, Wei; Dai, Qi

2016-10-01

Some studies suggest that the calcium to magnesium ratio intakes modify the associations of calcium or magnesium with risk of colorectal adenoma, adenoma recurrence, and cancer. Parathyroid hormone (PTH) plays a key role in the regulation of homeostasis for both calcium and magnesium. We hypothesized that polymorphisms in PTH and 13 other genes may modify the association between the calcium/magnesium intake ratio and colorectal neoplasia risk. We conducted a two-phase study including 1336 cases and 2891 controls from the Tennessee Colorectal Polyp Study. In Phase I, we identified 19 SNPs that significantly interacted with the calcium/magnesium intake ratio in adenoma risk. In Phase II, rs11022858 in PTH was replicated. In combined analysis of phases I and II, we found high calcium/magnesium intake ratio tended to be associated with a reduced risk of colorectal adenoma (P for trend, 0.040) among those who carried the TT genotype in rs11022858. In stratified analyses, calcium intake (≥ 1000 mg/d) was significantly associated with 64% reduced adenoma risk (OR = 0.36 (95% CI : 0.18-0.74)) among those homozygous for the minor allele (TT genotype) (P for trend, 0.012), but not associated with risk in other genotypes (CC/TC). Conversely, we found that highest magnesium intake was significantly associated with 27% reduced risk (OR = 0.73 (95% CI : 0.54-0.97)) of colorectal adenoma (P for trend, 0.026) among those who possessed the CC/TC genotypes, particularly among those with the TC genotype, whereas magnesium intake was not linked to risk among those with the TT genotype. These findings, if confirmed, will help for the development of personalized prevention strategies for colorectal cancer. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomas

PubMed Central

2013-01-01

Background Recent studies suggest that bacterial endotoxins may be associated with various chronic diseases, including colorectal adenomas and cancer. Given the evidence linking inflammation and colorectal cancer, we sought to determine if plasma endotoxin concentrations are associated with indicators of systemic or local inflammation and colorectal adenomas. Methods This cross-sectional study consisted of participants who underwent screening colonoscopies and included adenoma cases (n=138) and non-adenoma controls (n=324). Plasma concentrations of endotoxin were measured with Limulus Amebocyte Lysate (LAL) assay. We quantified concentrations of inflammatory cytokines, interleukin-4 (IL-4), IL-6, IL-8, IL-10, IL-12, tumor necrosis factor-alpha (TNF-α), and interferon-γ (IFN-γ) in plasma by ELISA and mRNA expression levels in rectal mucosal biopsies by quantitative RT-PCR. Interleukin-17 was evaluated only in the rectal mucosa. Results Compared to subjects with low plasma endotoxin concentrations, those with higher concentrations were more likely to have adenomas (OR 1.4, 95% CI 1.0-2.1). Among subjects with adenomas, those with villous histology were more likely to have higher endotoxin concentrations (5.4 vs. 4.1EU/mL, p=0.05) and lower plasma IFN-γ (0 vs. 1.64 pg/mL, p=0.02) compared to those with only tubular adenomas. Cases showed a trend of having higher plasma TNF-α levels than controls (p=0.06), but none of the other plasma or rectal mucosal cytokine levels differed between cases and controls. Elevated mucosal IL-12 levels were associated with having multiple adenomas (p=0.04). Higher concentrations of plasma endotoxin predicted increased plasma IL-12 levels (OR 1.5, 95% CI 1.0-2.2) and rectal mucosal IL-12 (OR 1.9, 95% CI 1.0-3.7) and IL-17 gene expression (OR 2.2, 95% CI 1.0-4.6). Conclusions These findings suggest that interactions between elevated plasma endotoxin concentrations and inflammatory cytokines may be relevant to the development of colorectal adenomas. PMID:23442743

Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans.

PubMed

Sanapareddy, Nina; Legge, Ryan M; Jovov, Biljana; McCoy, Amber; Burcal, Lauren; Araujo-Perez, Felix; Randall, Thomas A; Galanko, Joseph; Benson, Andrew; Sandler, Robert S; Rawls, John F; Abdo, Zaid; Fodor, Anthony A; Keku, Temitope O

2012-10-01

Differences in the composition of the gut microbial community have been associated with diseases such as obesity, Crohn's disease, ulcerative colitis and colorectal cancer (CRC). We used 454 titanium pyrosequencing of the V1-V2 region of the 16S rRNA gene to characterize adherent bacterial communities in mucosal biopsy samples from 33 subjects with adenomas and 38 subjects without adenomas (controls). Biopsy samples from subjects with adenomas had greater numbers of bacteria from 87 taxa than controls; only 5 taxa were more abundant in control samples. The magnitude of the differences in the distal gut microbiota between patients with adenomas and controls was more pronounced than that of any other clinical parameters including obesity, diet or family history of CRC. This suggests that sequence analysis of the microbiota could be used to identify patients at risk for developing adenomas.

Increased expression of interleukin-21 along colorectal adenoma-carcinoma sequence and its predicating significance in patients with sporadic colorectal cancer.

PubMed

Cui, Guanglin; Yuan, Aping; Zhu, Li; Florholmen, Jon; Goll, Rasmus

2017-10-01

The role and significance of interleukin (IL)-21 in the development of sporadic CRC have not been well defined. The aim of this study is therefore to investigate the dynamics of the IL-21 along colorectal adenoma-carcinoma sequence and to evaluate the impact of IL-21 on clinicopathological parameters and CRC prognosis. The real-time PCR results showed that the level of IL-21 in adenomas (n=50) and sporadic CRC (n=50) were significantly higher than that in normal controls (n=18), which were predominately observed in the adenoma/CRC stroma. Analysis revealed that IL-21 level was correlated with the overall survival time in CRC patients. Double immunofluorescence observations confirmed that IL-21 positive cells were mostly natural killer cells and T lymphocytes in the tumor stroma. These results indicate that significant increased IL-21 expression present within the adenoma/CRC microenvironment might have a potential predicating significance for survival time in patients with CRC. Copyright © 2017 Elsevier Inc. All rights reserved.

Helicobacter pylori infection with intestinal metaplasia: An independent risk factor for colorectal adenomas

PubMed Central

Yan, Ye; Chen, Yi-Na; Zhao, Qian; Chen, Chao; Lin, Chun-Jing; Jin, Yin; Pan, Shuang; Wu, Jian-Sheng

2017-01-01

AIM To explore the association between Helicobacter pylori (H. pylori) infection status, intestinal metaplasia (IM), and colorectal adenomas. METHODS We retrospectively reviewed 1641 individuals aged ≥ 40 years who underwent physical examination, laboratory testing, 13C-urea breath testing, gastroscopy, colonoscopy, and an interview to ascertain baseline characteristics and general state of health. Histopathological results were obtained by gastric and colorectal biopsies. RESULTS The prevalence of H. pylori infection and adenomas was 51.5% (845/1641) and 18.1% (297/1641), respectively. H. pylori infection was significantly correlated with an increased risk of colorectal adenomas (crude OR = 1.535, 95%CI: 1.044-1.753, P = 0.022; adjusted OR = 1.359, 95%CI: 1.035-1.785, P = 0.028). Individuals with IM had an elevated risk of colorectal adenomas (crude OR = 1.664, 95%CI: 1.216-2.277, P = 0.001; adjusted OR = 1.381, 95%CI: 0.998-1.929, P = 0.059). Stratification based on H. pylori infection stage and IM revealed that IM accompanied by H. pylori infection was significantly associated with an increased risk of adenomas (crude OR = 2.109, 95%CI: 1.383-3.216, P = 0.001; adjusted OR = 1.765, 95%CI: 1.130-2.757, P = 0.012). CONCLUSION H. pylori-related IM is associated with a high risk of colorectal adenomas in Chinese individuals. PMID:28293091

Microsatellite Instability of Gastric and Colorectal Cancers as a Predictor of Synchronous Gastric or Colorectal Neoplasms

PubMed Central

Kim, Young Beak; Lee, Sun-Young; Kim, Jeong Hwan; Sung, In-Kyung; Park, Hyung Seok; Shim, Chan Sup; Han, Hye Seung

2016-01-01

Background/Aims Microsatellite instability (MSI) plays a crucial role in gastrointestinal carcinogenesis. The aim of this study was to clarify whether MSI is a useful marker for predicting synchronous gastric and colorectal neoplasms. Methods Consecutive patients who underwent both esophagogastroduodenoscopy and colonoscopy before the resection of gastric or colorectal cancers were included. MSI was analyzed using two mononucleotide and three dinucleotide markers. Results In total, 434 gastric cancers (372 microsatellite stability [MSS], 21 low incidence of MSI [MSI-L], and 41 high incidence of MSI [MSI-H]) and 162 colorectal cancers (138 MSS, 9 MSI-L, and 15 MSI-H) were included. Patients with MSI gastric cancer had a higher prevalence of synchronous colorectal cancer, colorectal adenoma, and gastric adenoma than those with MSS gastric cancers (4.8% vs 0.5%, p=0.023; 11.3% vs 3.2%, p=0.011; 3.2% vs 1.2%, p=0.00, respectively). The prevalence of synchronous colorectal adenomas was highest in MSI-L gastric cancers (19.0%), compared with MSI-H (7.3%) or MSS (3.2%) gastric cancers (p=0.002). In addition, there were no significant differences in the prevalence rates of synchronous colorectal adenoma among the MSI-H (13.3%), MSI-L (11.1%), and MSS (12.3%) colorectal cancers (p=0.987). Conclusions The presence of MSI in gastric cancer may be a predictor of synchronous gastric and colorectal neoplasms, whereas MSI in colorectal cancer is not a predictor of synchronous colorectal adenoma. PMID:26087787

Ethnic disparities in the risk of colorectal adenomas associated with lipid levels: a retrospective multiethnic study.

PubMed

Davis-Yadley, Ashley H; Lipka, Seth; Shen, Huafeng; Devanney, Valerie; Swarup, Supreeya; Barnowsky, Alex; Silpe, Jeff; Mosdale, Josh; Pan, Qinshi; Fridlyand, Svetlana; Sreeharshan, Suhas; Abraham, Albin; Viswanathan, Prakash; Krishnamachari, Bhuma

2015-03-01

Although data exists showing that uncontrolled lipid levels in white and black patients is associated with colorectal adenomas, there are currently no studies looking only at the Hispanic population. With the rapid increase in the Hispanic population, we aimed to look at their risk of colorectal adenomas in association with lipid levels. We retrospectively analyzed 1473 patients undergoing colonoscopy from 2009 to 2011 at a community hospital. Statistical analysis was performed using Chi-squared for categorical variables and t test for continuous variables with age-, gender-, and race-adjusted odds ratios. Unconditional logistic regression model was used to estimate 95 % confidence intervals (CI). SAS 9.3 software was used to perform all statistical analysis. In our general population, there was an association with elevated triglyceride levels greater than 150 and presence of multiple colorectal adenomas with odds ratio (OR) 1.60 (1.03, 2.48). There was an association with proximal colon adenomas and cholesterol levels between 200 and 239 with OR 1.57 (1.07, 2.30), and low-density lipoprotein (LDL) levels of greater than 130 with OR 1.54 (1.04, 2.30). There was no association between high-density lipoproteins (HDL) levels and colorectal adenomas. The Hispanic population showed no statistical correlation between elevated triglycerides, cholesterol, or LDL with the presence, size, location, or multiplicity of colorectal adenomas. We found a significant correlation between elevated lipid levels and colorectal adenomas in white and black patients; however, there was no such association in the Hispanic population. This finding can possibly be due to environmental factors such as dietary, colonic flora, or genetic susceptibility, which fosters further investigation and research.

Development of new non-invasive tests for colorectal cancer screening: the relevance of information on adenoma detection.

PubMed

Haug, Ulrike; Knudsen, Amy B; Lansdorp-Vogelaar, Iris; Kuntz, Karen M

2015-06-15

Researchers are actively pursuing the development of a new non-invasive test (NIT) for colorectal cancer (CRC) screening as an alternative to fecal occult blood tests (FOBTs). The majority of pilot studies focus on the detection of invasive CRC rather than precursor lesions (i.e., adenomas). We aimed to explore the relevance of adenoma detection for the viability of an NIT for CRC screening by considering a hypothetical test that does not detect adenomas beyond chance. We used the Simulation Model of Colorectal Cancer (SimCRC) to estimate the effectiveness of CRC screening and the lifetime costs (payers' perspective) for a cohort of US 50-years-old persons to whom CRC screening is offered from age 50-75. We compared annual screening with guaiac and immunochemical FOBTs (with sensitivities up to 70 and 24% for CRC and adenomas, respectively) to annual screening with a hypothetical NIT (sensitivity of 90% for CRC, no detection of adenomas beyond chance, specificity and cost similar to FOBTs). Screening with the NIT was not more effective, but was 29-44% more costly than screening with FOBTs. The findings were robust to varying the screening interval, the NIT's sensitivity for CRC, adherence rates favoring the NIT, and the NIT's unit cost. A comparative modelling approach using a model that assumes a shorter adenoma dwell time (MISCAN-COLON) confirmed the superiority of the immunochemical FOBT over an NIT with no ability to detect adenomas. Information on adenoma detection is crucial to determine whether a new NIT is a viable alternative to FOBTs for CRC screening. Current evidence thus lacks an important piece of information to identify marker candidates that hold real promise and deserve further (large-scale) evaluation. © 2014 UICC.

Immunohistochemical Expression of Matrix Metalloproteinase-7 in Human Colorectal Adenomas Using Specified Automated Cellular Image Analysis System: A Clinicopathological Study

PubMed Central

Qasim, Ban J.; Ali, Hussam H.; Hussein, Alaa G.

2013-01-01

Background/Aim: To evaluate the immunohistochemical expression of matrix metalloproteinase-7 (MMP-7) in colorectal adenomas, and to correlate this expression with different clinicopathological parameters. Patients and Methods: The study was retrospectively designed. Thirty three paraffin blocks from patients with colorectal adenoma and 20 samples of non-tumerous colonic tissue taken as control group were included in the study. MMP-7 expression was assessed by immunohistochemistry method. The scoring of immunohistochemical staining was conducted utilizing a specified automated cellular image analysis system (Digimizer). Results: The frequency of positive immunohistochemical expression of MMP-7 was significantly higher in adenoma than control group (45.45% versus 10%) (P value < 0.001). Strong MMP-7 staining was mainly seen in adenoma cases (30.30%) in comparison with control (0%) the difference is significant (P < 0.001). The three digital parameters of MMP-7 immunohistochemical expression (Area (A), Number of objects (N), and intensity (I)) were significantly higher in adenoma than control. Mean (A and I) of MMP-7 showed a significant correlation with large sized adenoma (≥ 1cm) (P < 0.05), also a significant positive correlation of the three digital parameters (A, N, and I) of MMP-7 expression with villous configuration and severe dysplasia in colorectal adenoma had been identified (P < 0.05). Conclusion: MMP-7 plays an important role in the growth and malignant conversion of colorectal adenomas as it is more likely to be expressed in advanced colorectal adenomatous polyps with large size, severe dysplasia and villous histology. The use of automated cellular image analysis system (Digmizer) to quantify immunohistochemical staining yields more consistent assay results, converts semi-quantitative assay to a truly quantitative assay, and improves assay objectivity and reproducibility. PMID:23319034

Interobserver agreement in the histologic diagnosis of colorectal polyps. the experience of the multicenter adenoma colorectal study (SMAC).

PubMed

Costantini, Massimo; Sciallero, Stefania; Giannini, Augusto; Gatteschi, Beatrice; Rinaldi, Paolo; Lanzanova, Giuseppe; Bonelli, Luigina; Casetti, Tino; Bertinelli, Elisabetta; Giuliani, Orietta; Castiglione, Guido; Mantellini, Paola; Naldoni, Carlo; Bruzzi, Paolo

2003-03-01

Current clinical practice guidelines for patients with colorectal polyps are mainly based on the histologic characteristics of their lesions. However, interobserver variability in the assessment of specific polyp characteristics was evaluated in very few studies. The purpose of this study was to evaluate the interobserver agreement of four pathologists in the diagnosis of histologic type of colorectal polyps and in the degree of dysplasia and of infiltrating carcinoma in adenomas. A stratified random sample of 100 polyps was obtained from the 4,889 polyps resected within the Multicentre Adenoma Colorectal Study (SMAC), and the slides were blindly reviewed by the four pathologists. Agreement was analyzed using kappa statistics. A median kappa of 0.89 (range 0.79-1.0) was estimated for the interobserver agreement for the diagnosis of hyperplastic polyp vs. adenoma. The agreement in the diagnosis of tubular, tubulovillous, and villous type, was given by median kappa values of 0.50, 0.15, and 0.36, respectively. The median kappa for the diagnosis of infiltrating carcinoma was 0.78 (range 0.73-0.84). Agreement on diagnosis of adenoma histologic subtypes, degrees of dysplasia, or infiltrating carcinoma in adenoma was moderate. A simpler classifications might help to better identify patients at different risk of colorectal cancer.

Dietary meat intake in relation to colorectal adenoma in asymptomatic women.

PubMed

Ferrucci, Leah M; Sinha, Rashmi; Graubard, Barry I; Mayne, Susan T; Ma, Xiaomei; Schatzkin, Arthur; Schoenfeld, Philip S; Cash, Brooks D; Flood, Andrew; Cross, Amanda J

2009-05-01

No previous study has concurrently assessed the associations between meat intake, meat-cooking methods and doneness levels, meat mutagens (heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons), heme iron, and nitrite from meat and colorectal adenoma in asymptomatic women undergoing colonoscopy. Of the 807 eligible women in a cross-sectional multicenter colonoscopy screening study, 158 prevalent colorectal adenoma cases and 649 controls satisfactorily completed the validated food frequency and meat questionnaires. Using an established meat mutagen database and new heme iron and nitrite databases, we comprehensively investigated the components of meat that may be involved in carcinogenesis. Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) within quartiles of meat-related variables. Red meat was associated positively with colorectal adenoma (OR fourth vs. first quartile = 2.02; 95% CI = 1.06-3.83; P trend = 0.38). Intake of pan-fried meat (OR = 1.72; 95% CI = 0.96-3.07; P trend = 0.01) and the HCA: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (OR = 1.90; 95% CI = 1.05-3.42; P trend = 0.07) were also associated with an increased risk of colorectal adenoma. The new databases yielded lower estimates of heme iron and nitrite than previous assessment methods, although the two methods were highly correlated for both exposures. Although not statistically significant, there were positive associations between iron and heme iron from meat and colorectal adenoma. In asymptomatic women undergoing colonoscopy, colorectal adenomas were associated with high intake of red meat, pan-fried meat, and the HCA MeIQx. Other meat-related exposures require further investigation.

Serrated pathway in colorectal carcinogenesis

PubMed Central

Yamane, Letícia; Scapulatempo-Neto, Cristovam; Reis, Rui Manuel; Guimarães, Denise Peixoto

2014-01-01

Serrated adenocarcinoma is a recently described subset of colorectal cancer (CRC), which account for about 10% of all CRCs and follows an alternative pathway in which serrated polyps replace the traditional adenoma as the precursor lesion to CRC. Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps (HPs), sessile serrated adenoma (SSA), traditional serrated adenoma (TSA) and mixed polyps. HPs are the most common serrated polyp followed by SSA and TSA. This distinct histogenesis is believed to have a major influence in prevention strategies, patient prognosis and therapeutic impact. Genetically, serrated polyps exhibited also a distinct pattern, with KRAS and BRAF having an important contribution to its development. Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype. In the present review we will address the current knowledge of serrated polyps, clinical pathological features and will update the most recent findings of its molecular pathways. The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development. PMID:24627599

Correlation of Ki-67, p53, and Adnab-9 immunohistochemical staining and ploidy with clinical and histopathologic features of severely dysplastic colorectal adenomas.

PubMed

Sheikh, Rafiq A; Min, Byung Hee; Yasmeen, Shagufta; Teplitz, Raymond; Tesluk, Henry; Ruebner, Boris Henry; Tobi, Martin; Hatfield, James; Fligiel, Suzanne; Lawson, Michael J

2003-01-01

Variations of Ki-67, p53, and Adnab-9 monoclonal antibody reactions in colonic adenomas may be associated with colonic cancer risk. We studied the predictive value of these markers for adverse behavior in severely dysplastic colorectal adenomas, such as an associated carcinoma, multiplicity of adenomas, and subsequent development of adenomas. For this purpose we compared theclinical, gross, and histologic characteristics of highly dysplastic index polyps in 42 patients with Ki 67, p53, and Adnab-9 immunostaining and other molecular markers. Polyps were removed endoscopically, and severely dysplastic polyps were stained immunohistochemically with Ki-67, Adnab-9, and p53 protein by the avidin biotin conjugate (ABC) technique. Quantitative DNA (QDNA) was analyzed by computer-assisted image analysis. Ki-67 immunohistochemistry showed reversal of normal distribution of nuclear staining from the normal basal position to the upper third of the colonic crypts. This abnormality of immunostaining in dysplastic adenomas was the earliest detected by the panel we used. A statistically significant correlation was seen between invasiveness of carcinoma in the index polyp and polyp size (P = 0.003), sessile morphology (P = 0.037), and villous or tubulovillous histology (P = 0.019). In the index adenoma, p53 positivity was correlated with multiplicity at initial examination (P = 0.053), villous histology (P = 0.053), invasiveness of carcinoma (P < 0.003), and recurrence of colorectal adenomas (P = 0.025). Although p53 positivity and aneuploidy were correlated with invasiveness of carcinoma in the index polyp (P = 0.025), Adnab-9 positivity was not. However, Adnab-9 positivity in the index polyp was associated with multiplicity of adenomas (P = 0.04) as well as recurrence of adenomas (P < 0.024). In conclusion, in addition to the morphologic and histologic markers already known, Ki-67, Adnab-9 antibody, and p53 protein may be prognostic indicators useful in follow-up of patients with severely dysplastic colorectal adenomas. Adnab-9 antibody may identify a field defect in above-average-risk adenoma-bearing patients.

The inflammatory microenvironment in colorectal neoplasia.

PubMed

McLean, Mairi H; Murray, Graeme I; Stewart, Keith N; Norrie, Gillian; Mayer, Claus; Hold, Georgina L; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N Ashley G; Drew, Janice E; El-Omar, Emad M

2011-01-07

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

Meat intake and risk of colorectal polyps: results from a large population-based screening study in Germany.

PubMed

Carr, Prudence R; Holleczek, Bernd; Stegmaier, Christa; Brenner, Hermann; Hoffmeister, Michael

2017-06-01

Background: Red and processed meats have been shown to be associated with colorectal adenomas in many, but not all, studies, and the association according to the type of colorectal adenoma or the location in the colorectum is unclear. Objectives: We investigated the association of meat intake in relation to colorectal polyps and further investigated the association according to histologic subtypes and subsites in a large population-based screening study in Germany. Design: In this cross-sectional study, 15,950 participants aged ≥55 y underwent a screening colonoscopy. We calculated prevalence ratios (PRs) and 95% CIs for associations between meat intake and the most-advanced findings from a colonoscopy with the use of log binomial regression. Results: Overall, 3340 participants (20.4%) had nonadvanced adenomas, 1643 participants (10.0%) had advanced adenomas, and 189 participants (1.2%) had colorectal cancer. We observed no statistically significant association between red or processed meat consumption and the prevalence of any adenomas or advanced adenomas [highest compared with lowest: red meat, PR: 1.07 (95% CI: 0.83, 1.37); processed meat, PR: 1.11 (95% CI: 0.91, 1.36)]. In site-specific analyses, although no dose-response relation was observed, processed meat was positively associated with the prevalence of advanced adenomas in the rectum only (multiple times per day compared with <1 time/wk, PR: 1.87; 95% CI: 1.19, 2.95). Poultry intake was not associated with any outcome. Conclusions: On the basis of this large colonoscopy-based study, there are no significant associations between red or processed meat intake and the prevalence of any adenomas or advanced adenomas. However, processed meat may be positively associated with the prevalence of advanced adenomas in the rectum, but prospective cohort studies are needed to further clarify this association. There is no association between poultry consumption and the prevalence of colorectal polyps in this study. © 2017 American Society for Nutrition.

Role of supplemental calcium in the recurrence of colorectal adenomas: a metaanalysis of randomized controlled trials.

PubMed

Shaukat, Aasma; Scouras, Nicole; Schünemann, Holger J

2005-02-01

Colorectal adenomas are neoplastic growths that are important targets for chemoprevention. Dietary calcium is thought to play an important role in chemoprevention. However, the role of calcium supplementation for preventing recurrence of adenomas is controversial. We performed a systematic review and meta-analysis to study the role of calcium supplementation in preventing recurrence of adenomas. We searched electronic bibliographic databases (Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, CINAHL, EMBASE, and MEDLINE) and contacted authors to identify potentially eligible studies. We identified three trials including 1,485 subjects with previously removed adenomas who were randomized to calcium versus placebo supplementation. The study endpoint was recurrence of adenomas at the end of 3-4 yr in 1,279 patients who completed the trials. We found that the recurrence of adenomas was significantly lower in subjects randomized to calcium supplementation (RR: 0.80, CI: 0.68, 0.93; p-value = 0.004). This systematic review and meta-analysis suggest that calcium supplementation prevents recurrent colorectal adenomas.

A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma

USDA-ARS?s Scientific Manuscript database

Background: Evidence from observational studies suggests that inadequate folate status enhances colorectal carcinogenesis, but results from some randomized trials do not support this hypothesis. Objective: To assess the effect of folic acid supplementation on recurrent colorectal adenoma, we conduc...

CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas.

PubMed

Sun, Lifeng; Guzzetta, Angela A; Fu, Tao; Chen, Jinming; Jeschke, Jana; Kwak, Ruby; Vatapalli, Rajita; Baylin, Stephen B; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Ahuja, Nita

2014-05-01

CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance.

CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas

PubMed Central

Sun, Lifeng; Guzzetta, Angela A; Fu, Tao; Chen, Jinming; Jeschke, Jana; Kwak, Ruby; Vatapalli, Rajita; Baylin, Stephen B; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Ahuja, Nita

2014-01-01

CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance. PMID:24518818

Fusobacterium and colorectal cancer: causal factor or passenger? Results from a large colorectal cancer screening study.

PubMed

Amitay, Efrat L; Werner, Simone; Vital, Marius; Pieper, Dietmar H; Höfler, Daniela; Gierse, Indra-Jasmin; Butt, Julia; Balavarca, Yesilda; Cuk, Katarina; Brenner, Hermann

2017-08-01

Colorectal cancer is a leading cause of morbidity and mortality worldwide in both men and women. The gut microbiome is increasingly recognized as having an important role in human health and disease. Fusobacterium has been identified in former studies as a leading gut bacterium associated with colorectal cancer, but it is still not clear if it plays an oncogenic role. In the current study, fecal samples were collected prior to bowel preparation from participants of screening colonoscopy in the German BliTz study. Using 16S rRNA gene analysis, we examined the presence and relative abundance of Fusobacterium in fecal samples from 500 participants, including 46, 113, 110 and 231 individuals with colorectal cancer, advanced adenomas, non-advanced adenomas and without any neoplasms, respectively. We found that the abundance of Fusobacterium in feces was strongly associated with the presence of colorectal cancer (P-value < 0.0001). This was confirmed by PCR at the species level for Fusobacterium nucleatum. However, no association was seen with the presence of advanced adenomas (P-value = 0.80) or non-advanced adenomas (P-value = 0.80), nor were there any associations observed with dietary or lifestyle habits. Although a causal role cannot be ruled out, our observations, based on fecal microbiome, support the hypothesis that Fusobacterium is a passenger that multiplies in the more favorable conditions caused by the malignant tumor rather than a causal factor in colorectal cancer development. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

PubMed Central

Jaszewski, Richard; Misra, Sabeena; Tobi, Martin; Ullah, Nadeem; Naumoff, Jo Ann; Kucuk, Omer; Levi, Edi; Axelrod, Bradley N; Patel, Bhaumik B; Majumdar, Adhip PN

2008-01-01

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 colonic adenomas or advanced adenomas responded better to folic acid supplementation. CONCLUSION: High dose folic acid supplementation is associated with a significant reduction in the recurrence of colonic adenomas suggesting that folic acid may be an effective chemopreventive agent for colorectal neoplasia. PMID:18680228

Dietary meat intake in relation to colorectal adenoma in asymptomatic women

PubMed Central

Ferrucci, Leah M.; Sinha, Rashmi; Graubard, Barry I.; Mayne, Susan T.; Ma, Xiaomei; Schatzkin, Arthur; Schoenfeld, Philip S.; Cash, Brooks D.; Flood, Andrew; Cross, Amanda J.

2009-01-01

Introduction No previous study has concurrently assessed the association between meat intake, meat cooking methods and doneness levels, meat mutagens (heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons), heme iron, and nitrite from meat and colorectal adenoma in asymptomatic women undergoing colonoscopy. Methods Of 807 eligible women in a cross-sectional multi-center colonoscopy screening study, 158 prevalent colorectal adenoma cases and 649 controls satisfactorily completed validated food frequency and meat questionnaires. Using an established meat mutagen database and new iron and nitrite databases, we comprehensively investigated components of meat that may be involved in carcinogenesis. Using logistic regression we estimated odds ratios (OR) and 95% confidence intervals (CI) within quartiles of meat-related variables. Results Red meat was positively associated with colorectal adenoma (OR fourth versus first quartile = 2.02; 95% CI = 1.06–3.83; P trend = 0.38). Intake of pan fried meat (OR = 1.72; 95% CI = 0.96–3.07; P trend = 0.01) and the HCA: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (OR = 1.90; 95% CI = 1.05–3.42; P trend = 0.07) were also associated with increased risk of colorectal adenoma. The new databases yielded lower estimates of heme iron and nitrite than previous assessment methods, although the two methods were highly correlated for both exposures. Although not statistically significant, there were positive associations between iron and heme iron from meat and colorectal adenoma. Conclusions In asymptomatic women undergoing colonoscopy, colorectal adenomas were associated with high intake of red meat, pan fried meat, and the HCA MeIQx. Other meat-related exposures require further investigation. PMID:19367270

MLH1-deficient Colorectal Carcinoma With Wild-type BRAF and MLH1 Promoter Hypermethylation Harbor KRAS Mutations and Arise From Conventional Adenomas.

PubMed

Farchoukh, Lama; Kuan, Shih-Fan; Dudley, Beth; Brand, Randall; Nikiforova, Marina; Pai, Reetesh K

2016-10-01

Between 10% and 15% of colorectal carcinomas demonstrate sporadic DNA mismatch-repair protein deficiency as a result of MLH1 promoter methylation and are thought to arise from sessile serrated adenomas, termed the serrated neoplasia pathway. Although the presence of the BRAF V600E mutation is indicative of a sporadic cancer, up to 30% to 50% of colorectal carcinomas with MLH1 promoter hypermethylation will lack a BRAF mutation. We report the clinicopathologic and molecular features of MLH1-deficient colorectal carcinoma with wild-type BRAF and MLH1 promoter hypermethylation (referred to as MLH1-hypermethylated BRAF wild-type colorectal carcinoma, n=36) in comparison with MLH1-deficient BRAF-mutated colorectal carcinoma (n=113) and Lynch syndrome-associated colorectal carcinoma (n=36). KRAS mutations were identified in 31% of MLH1-hypermethylated BRAF wild-type colorectal carcinomas compared with 0% of MLH1-deficient BRAF-mutated colorectal carcinomas and 37% of Lynch syndrome-associated colorectal carcinomas. When a precursor polyp was identified, MLH1-hypermethylated BRAF wild-type colorectal carcinomas arose from precursor polyps resembling conventional tubular/tubulovillous adenomas in contrast to MLH1-deficient BRAF-mutated colorectal carcinomas, which arose from precursor sessile serrated adenomas (P<0.001). Both MLH1-hypermethylated BRAF wild-type colorectal carcinoma and MLH1-deficient BRAF-mutated colorectal carcinoma had a predilection for the right colon compared with Lynch syndrome-associated colorectal carcinoma (86% vs. 92% vs. 49%, P<0.001). There was no significant difference in mucinous differentiation, tumor-infiltrating lymphocytes, Crohn-like reaction, and medullary differentiation between the 3 tumor groups. Using Kaplan-Meier survival functions, there was no significant difference in disease-specific survival between the 3 patient groups (P>0.05). In conclusion, our results indicate that MLH1-hypermethylated BRAF wild-type colorectal carcinomas can harbor KRAS mutations and arise from precursor polyps resembling conventional tubular/tubulovillous adenomas.

Three molecular pathways model colorectal carcinogenesis in Lynch syndrome.

PubMed

Ahadova, Aysel; Gallon, Richard; Gebert, Johannes; Ballhausen, Alexej; Endris, Volker; Kirchner, Martina; Stenzinger, Albrecht; Burn, John; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Kloor, Matthias

2018-07-01

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR-deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR-deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome. © 2018 UICC.

Polymorphisms in heterocyclic aromatic amines metabolism-related genes are associated with colorectal adenoma risk

PubMed Central

Eichholzer, Monika; Rohrmann, Sabine; Barbir, Aline; Hermann, Silke; Teucher, Birgit; Kaaks, Rudolf; Linseisen, Jakob

2012-01-01

Colorectal adenoma (CRA) and colorectal cancer (CRC) risks have been linked to the intake of red and processed meat. Heterocyclic aromatic amines (HCA) formed herein during high temperature cooking, are metabolized by a variety of enzymes, and allelic variation in the coding genes could influence individual CRA risk. Associations of polymorphisms in NAT1, NAT2, GSTA1, SULT1A1, CYP1A2, UGT1A7, UGT1A9, GSTP1 genes with colorectal adenoma risk were investigated in a nested case-control study of the EPIC-Heidelberg cohort including 428 cases matched by age, sex and year of recruitment with one or two controls (n=828) with negative colonoscopy per case. Genoyping was preformed with the Sequenom MassArray system and the LightCycler 480. Conditional logistic regression was used to compute odds ratios (OR) and corresponding 95% confidence intervals (CI). For rs15561 (NAT1) and rs1057126 (NAT1), the rarer allel was significantly inversely associated with adenoma risk OR=0.80 (95% CI 0.65-0.97) and (OR=0.81 (95% CI 0.65-0.99) and, respectively). For the combined NAT2 alleles encoding for enzymes with medium (versus slow) activity we also observed a significantly inverse association with adenoma risk (OR=0.75; 95% CI 0.85-0.97). In addition, homozygous carriers of the A allele of rs3957357 (GSTA1), i.e., those with a decreased enzyme activity, had a decreased risk of colorectal adenoma with an OR of 0.68 (95% CI 0.50-0.92; AA versus GG/GA). Polymorphisms in the other tested genes did not modify the risk of colorectal adenomas. In conclusion, polymorphisms in NAT1, NAT2, and GSTA1 are related to colorectal adenoma risk in this German cohort. PMID:22724046

Polymorphisms in heterocyclic aromatic amines metabolism-related genes are associated with colorectal adenoma risk.

PubMed

Eichholzer, Monika; Rohrmann, Sabine; Barbir, Aline; Hermann, Silke; Teucher, Birgit; Kaaks, Rudolf; Linseisen, Jakob

2012-01-01

Colorectal adenoma (CRA) and colorectal cancer (CRC) risks have been linked to the intake of red and processed meat. Heterocyclic aromatic amines (HCA) formed herein during high temperature cooking, are metabolized by a variety of enzymes, and allelic variation in the coding genes could influence individual CRA risk. Associations of polymorphisms in NAT1, NAT2, GSTA1, SULT1A1, CYP1A2, UGT1A7, UGT1A9, GSTP1 genes with colorectal adenoma risk were investigated in a nested case-control study of the EPIC-Heidelberg cohort including 428 cases matched by age, sex and year of recruitment with one or two controls (n=828) with negative colonoscopy per case. Genoyping was preformed with the Sequenom MassArray system and the LightCycler 480. Conditional logistic regression was used to compute odds ratios (OR) and corresponding 95% confidence intervals (CI). For rs15561 (NAT1) and rs1057126 (NAT1), the rarer allel was significantly inversely associated with adenoma risk OR=0.80 (95% CI 0.65-0.97) and (OR=0.81 (95% CI 0.65-0.99) and, respectively). For the combined NAT2 alleles encoding for enzymes with medium (versus slow) activity we also observed a significantly inverse association with adenoma risk (OR=0.75; 95% CI 0.85-0.97). In addition, homozygous carriers of the A allele of rs3957357 (GSTA1), i.e., those with a decreased enzyme activity, had a decreased risk of colorectal adenoma with an OR of 0.68 (95% CI 0.50-0.92; AA versus GG/GA). Polymorphisms in the other tested genes did not modify the risk of colorectal adenomas. In conclusion, polymorphisms in NAT1, NAT2, and GSTA1 are related to colorectal adenoma risk in this German cohort.

The Inflammatory Microenvironment in Colorectal Neoplasia

PubMed Central

McLean, Mairi H.; Murray, Graeme I.; Stewart, Keith N.; Norrie, Gillian; Mayer, Claus; Hold, Georgina L.; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N. Ashley G.; Drew, Janice E.; El-Omar, Emad M.

2011-01-01

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified. PMID:21249124

Cell-of-Origin DNA Methylation Signatures Are Maintained during Colorectal Carcinogenesis.

PubMed

Bormann, Felix; Rodríguez-Paredes, Manuel; Lasitschka, Felix; Edelmann, Dominic; Musch, Tanja; Benner, Axel; Bergman, Yehudit; Dieter, Sebastian M; Ball, Claudia R; Glimm, Hanno; Linhart, Heinz G; Lyko, Frank

2018-06-12

Colorectal adenomas are precursor lesions of colorectal cancers and represent clonal amplifications of single cells from colonic crypts. DNA methylation patterns specify cell-type identity during cellular differentiation and, therefore, provide opportunities for the molecular analysis of tumors. We have now analyzed DNA methylation patterns in colorectal adenomas and identified three biologically defined subclasses that describe different intestinal crypt differentiation stages. Importantly, colorectal carcinomas could be classified into the same methylation subtypes, reflecting their shared cell types of origin with adenomas. Further data analysis also revealed significantly reduced overall survival for one of the subtypes. Our results provide a concept for understanding the methylation patterns observed in colorectal cancer and provide opportunities for tumor subclassification and patient stratification. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Cyclooxygenase-2 expression and recurrence of colorectal adenomas: effect of aspirin chemoprevention.

PubMed

Benamouzig, Robert; Uzzan, Bernard; Martin, Antoine; Deyra, Jacques; Little, Julian; Girard, Bernard; Chaussade, Stanislas

2010-05-01

Low-dose aspirin reduces the incidence of colorectal cancer and recurrence of adenomas. Cyclooxygenase-2 (COX-2), one of its main target enzymes, is reportedly over-expressed in colorectal adenomas. To assess COX-2 expression, in relation to adenoma recurrence and the protective effect of aspirin, in a large series of colorectal adenomas, recruited from a double-blind randomised controlled trial comparing recurrences after low-dose aspirin or placebo. Follow-up colonoscopies were performed after 1 and 4 years to assess adenoma recurrence. COX-2 expression was assessed by immunohistochemistry for each adenoma obtained at baseline colonoscopy, separately for epithelium, deep stroma and overall. Architecture, grade of dysplasia, K-ras mutation, p53 and cyclin D1 expression were studied. COX-2 expression could be assessed in 219 adenomas from 136 128 adenomas (58%) from 59 patients strongly expressed COX-2. Strong COX-2 expression predominated in adenomas larger than 10 mm (84/129 vs 44/90; p=0.02) and in adenomas showing high-grade dysplasia (22/29 vs 104/188; p=0.04). Deep stromal but not epithelial initial expression of COX-2 predicted adenoma recurrence in the whole population (30/72 patients or 42% strongly expressed deep stromal COX-2 compared with 16/64 or 25% without recurrent adenoma; p=0.04). The protective effect of aspirin was mainly observed in patients in whom COX-2 initial expression was low (RR for recurrence in patients taking aspirin with low COX-2 expression: 0.59; 95% CI 0.39 to 0.90; p=0.02). There was no significant effect of aspirin at the end of the trial. Over-expression of COX-2 was frequent and predominated in large and high-grade dysplasia adenomas. Deep stromal but not epithelial initial expression of COX-2 predicted recurrence of adenomas. Aspirin did not act preferentially on patients whose initial adenomas strongly expressed COX-2.

Polymorphisms in genes related to inflammation and obesity and colorectal adenoma risk.

PubMed

Huang, Brian Z; Tsilidis, Konstantinos K; Smith, Michael W; Hoffman-Bolton, Judith; Visvanathan, Kala; Platz, Elizabeth A; Joshu, Corinne E

2018-05-26

We previously investigated the association between single nucleotide polymorphisms (SNPs) in genes related to obesity and inflammation and colorectal cancer in the CLUE II cohort. However, the relationships between these SNPs and colorectal adenomas have not been well evaluated. In a nested case-control study of 135 incident adenoma cases and 269 matched controls in the CLUE II cohort (1989-2000), we genotyped 17 candidate SNPs in 12 genes (PPARG, TCF7L2, ADIPOQ, LEP, IL10, CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and 19 tagSNPs in three genes (IL10, CRP, and TLR4). Conditional logistic regression was used to calculate odds ratios (OR) for adenomas (overall and by size, histology, location, number). Polymorphisms in the inflammatory-related genes CRP, ADIPOQ, IL6, and TLR4 were observed to be associated with adenoma risk. At rs1205 in CRP, T (minor allele) carriers had a higher risk (OR 1.67, 95%CI 1.07-2.60; reference: CC) of adenomas overall and adenomas with aggressive characteristics. At rs1201299 in ADIPOQ, the AC genotype had a higher risk (OR 1.58, 95%CI 1.00-2.49) of adenomas, while the minor AA genotype had a borderline inverse association (OR 0.44, 95%CI 0.18-1.08; reference: CC). At rs1800797 in IL6, the AA genotype had a borderline inverse association (OR 0.53, 95%CI 0.27-1.05; reference: GG). Three TLR4 tagSNPs (rs10116253, rs1927911, rs7873784) were associated with adenomas among obese participants. None of these SNPs were associated with colorectal cancer in our prior study in CLUE II, possibly suggesting a different genetic etiology for early colorectal neoplasia. © 2018 Wiley Periodicals, Inc.

Rotating night shift work, sleep, and colorectal adenoma in women.

PubMed

Devore, Elizabeth E; Massa, Jennifer; Papantoniou, Kyriaki; Schernhammer, Eva S; Wu, Kana; Zhang, Xuehong; Willett, Walter C; Fuchs, Charles S; Chan, Andrew T; Ogino, Shuji; Giovannucci, Edward; Wei, Esther K

2017-07-01

This study aims to investigate the associations of rotating night shift work history and sleep duration with risk of colorectal adenoma. We evaluated 56,275 cancer-free participants of the Nurses' Health Study II, who had their first colonoscopy or sigmoidoscopy between 1991 and 2011; rotating night shift work and sleep duration were reported by mailed questionnaire. Multivariable-adjusted logistic regression was used to estimate relative risks (RR) of colorectal adenoma, with 95% confidence intervals (CI), across categories of rotating night shift work history (none, 1-4, 5-9, and ≥10 years) and sleep duration (≤5, 6, 7, 8, and ≥9 h/day). We found no association between duration of rotating night shift work and occurrence of colorectal adenoma (p-trend across shift work categories = 0.5). Women with the longest durations of rotating night shift work (≥10 years) had a similar risk of adenoma compared to women without a history of rotating night shift work (multivariable-adjusted RR = 0.96, 95% CI = 0.83-1.11). Similarly, there were no associations of shorter or longer sleep durations with adenoma risk (p-trend = 0.2 across sleep durations of ≤5 through 7 h/day and p-trend = 0.5 across sleep durations of 7 through ≥9 h/day). Results were similar when we examined associations according to adenoma location and subtype. Our results do not support an association between rotating night shift work or sleep duration and risk of colorectal adenoma in women.

Associations Between Markers of Colorectal Cancer Stem Cells and Adenomas Among Ethnic Groups

PubMed Central

Leavell, Bonita J.; Van Buren, Eric; Antaki, Fadi; Axelrod, Bradley N.; Rambus, Mary Ann; Majumdar, Adhip P. N.

2013-01-01

Background and Purposes Most colorectal tumors develop from adenomatous polyps, which are detected by colonoscopy. African Americans (AAs) have higher incidence of colorectal cancer (CRC) and greater mortality from this disease than Caucasian Americans (CAs). We investigated whether differences in predisposition to CRC and its surrogate (colonic adenomas) between these ethnic groups were related to numbers of cancer stem or stem-like cells (CSCs) in colonocytes. Methods We analyzed colonic effluent from 11 AA and 14 CA patients who underwent scheduled colonoscopy examinations at the John D. Dingell Veterans Affairs Medical Center. We determined proportions of cells that expressed the CSC markers CD44 and CD166 by flow cytometry. Results The proportion of colonocytes that were CD44+CD166– in effluent from patients with adenomas was significantly greater than from patients without adenomas (P = 0.01); the proportion of CD44+CD166+ colonocytes was also greater (P = 0.07). Effluent from AAs with adenomas had 60 % more CD44+166– colonocytes than from CAs with adenomas. Using cutoff values of 8 % for AAs and 3 % for CAs, the proportion of CD44+166– colonocytes that had positive predictive value for detection of adenomas was 100 % for AAs and CAs, determined by receiver operator characteristic curve analysis. Conclusion The proportion of CD44+166– colonocytes in colonic effluent can be used to identify patients with adenoma. AAs with adenomas have a higher proportion of CD44+166– colonocytes than CA. The increased proportion of CSCs in colonic tissue from AA might be associated with the increased incidence of CRC in this population. PMID:22562538

Supplemental calcium in the chemoprevention of colorectal cancer: a systematic review and meta-analysis.

PubMed

Carroll, Christopher; Cooper, Katy; Papaioannou, Diana; Hind, Daniel; Pilgrim, Hazel; Tappenden, Paul

2010-05-01

The aim of the review was to assess the evidence for the effectiveness of calcium in reducing the recurrence of adenomas and the occurrence of colorectal cancer among populations at high, intermediate, and low risk of the disease. A systematic review of randomized controlled trials (RCTs) was performed to compare calcium alone, and with other agents, versus placebo. Nine databases (Cochrane Library, MEDLINE, PreMEDLINE, CINAHL, EMBASE, Web of Science, Biological Abstracts, the National Research Register, and Current Controlled Trials) were searched for published and unpublished trials. Searches were not restricted by either language or date of publication. All searches were completed in January 2010. Database thesaurus and free text terms for calcium and adenomas or colorectal cancer were used to search for trial reports; additional terms were used to search for other agents of interest, such as NSAIDs and folic acid. Search terms consisted of a combination of terms for colorectal cancer (eg, colon or colorectal and neoplasm or cancer or adenoma) and terms for calcium and RCTs. The initial searches were conducted in June 2008, with update searches in January 2010 to identify more recent studies. The reference lists of relevant studies were also searched for additional papers not identified by the search of electronic databases. Studies had to satisfy the following criteria to be included: RCTs about calcium, with or without other chemopreventive agents, in adults with familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer, or a history of colorectal adenomas, or with no increased baseline risk of colorectal cancer. Meta-analysis was performed. For discrete and numerical outcomes, relative risks (RRs) and risk differences were reported with 95% CIs. The random-effects model was used to account for clinical and methodologic variations between trials. The original and update searches of electronic databases produced 3835 citations, of which 6 studies (8 papers) met the inclusion criteria. Supplemental calcium had no effect on the number of adenomas in 1 small trial of patients with FAP. Meta-analysis of 3 trials in individuals with a history of adenomas showed a statistically significant reduction in the RR for adenoma recurrence (RR = 0.80 [95% CI, 0.69-0.94], P = 0.006) for those receiving calcium 1200 to 2000 mg/d, but no effect was seen in advanced adenoma (RR = 0.77 [95% CI, 0.501.17], P = NS). Meta-analysis of 2 trials in populations with no increased baseline risk for colorectal cancer suggested that calcium, with or without vitamin D, had no effect on the RR for colorectal cancer (RR = 0.62 [95% CI, 0.11-3.40], P = NS). Published reports indicated that supplemental calcium was effective for the prevention of adenoma recurrence in populations with a history of adenomas, but no similar effect was apparent in populations at higher or lower risk. Copyright 2010 Excerpta Medica Inc. All rights reserved.

Effect of combined folic acid, Vitamin B6, and Vitamin B12 on colorectal adenoma

USDA-ARS?s Scientific Manuscript database

Folic acid, vitamin B(6), and vitamin B(12) act in concert in the one-carbon metabolism and may protect against colorectal neoplasia. We examined the effect of combined B-vitamin treatment on the occurrence of colorectal adenoma. The Women's Antioxidant and Folic Acid Cardiovascular Study was a rand...

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

PubMed Central

Hamachi, Tadamichi; Tajima, Osamu; Uezono, Kousaku; Tabata, Shinji; Abe, Hiroshi; Ohnaka, Keizo; Kono, Suminori

2013-01-01

AIM: To investigate the role of functional genetic polymorphisms 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 were CYP1A1*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 lifestyle 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 phase I 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. PMID:23840148

Optical coherence tomography imaging of colonic crypts in a mouse model of colorectal cancer

NASA Astrophysics Data System (ADS)

Welge, Weston A.; Barton, Jennifer K.

2016-03-01

Aberrant crypt foci (ACF) are abnormal epithelial lesions that precede development of colonic polyps. As the earliest morphological change in the development of colorectal cancer, ACF is a highly studied phenomenon. The most common method of imaging ACF is chromoendoscopy using methylene blue as a contrast agent. Narrow- band imaging is a contrast-agent-free modality for imaging the colonic crypts. Optical coherence tomography (OCT) is an attractive alternative to chromoendoscopy and narrow-band imaging because it can resolve the crypt structure at sufficiently high sampling while simultaneously providing depth-resolved data. We imaged in vivo the distal 15 mm of colon in the azoxymethane (AOM) mouse model of colorectal cancer using a commercial swept-source OCT system and a miniature endoscope designed and built in-house. We present en face images of the colonic crypts and demonstrate that different patterns in healthy and adenoma tissue can be seen. These patterns correspond to those reported in the literature. We have previously demonstrated early detection of colon adenoma using OCT by detecting minute thickening of the mucosa. By combining mucosal thickness measurement with imaging of the crypt structure, OCT can be used to correlate ACF and adenoma development in space and time. These results suggest that OCT may be a superior imaging modality for studying the connection between ACF and colorectal cancer.

A randomized controlled trial of eicosapentaenoic acid and/or aspirin for colorectal adenoma prevention during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme (The seAFOod Polyp Prevention Trial): study protocol for a randomized controlled trial.

PubMed

Hull, Mark A; Sandell, Anna C; Montgomery, Alan A; Logan, Richard F A; Clifford, Gayle M; Rees, Colin J; Loadman, Paul M; Whitham, Diane

2013-07-29

The naturally-occurring omega (ω)-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) reduces colorectal adenoma (polyp) number and size in patients with familial adenomatous polyposis. The safety profile and potential cardiovascular benefits associated with ω-3 PUFAs make EPA a strong candidate for colorectal cancer (CRC) chemoprevention, alone or in combination with aspirin, which itself has recognized anti-CRC activity. Colorectal adenoma number and size are recognized as biomarkers of future CRC risk and are established as surrogate end-points in CRC chemoprevention trials. The seAFOod Polyp Prevention Trial is a randomized, double-blind, placebo-controlled, 2×2 factorial 'efficacy' study, which will determine whether EPA prevents colorectal adenomas, either alone or in combination with aspirin. Participants are 55-73 year-old patients, who have been identified as 'high risk' (detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter) at screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Exclusion criteria include the need for more than one repeat endoscopy within the three-month BCSP screening period, malignant change in an adenoma, regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs, regular use of fish oil supplements and concomitant warfarin or anti-platelet agent therapy. Patients are randomized to either EPA-free fatty acid 1 g twice daily or identical placebo AND aspirin 300 mg once daily or identical placebo, for approximately 12 months. The primary end-point is the number of participants with one or more adenomas detected at routine one-year BCSP surveillance colonoscopy. Secondary end-points include the number of adenomas (total and 'advanced') per patient, the location (left versus right colon) of colorectal adenomas and the number of participants re-classified as 'intermediate risk' for future surveillance. Exploratory end-points include levels of bioactive lipid mediators such as ω-3 PUFAs, resolvin E1 and PGE-M in plasma, urine, erythrocytes and rectal mucosa in order to gain insights into the mechanism(s) of action of EPA and aspirin, alone and in combination, as well as to discover predictive biomarkers of chemopreventive efficacy. The recruitment target is 904 patients. Current Controlled Trials ISRCTN05926847.

Helicobacter pylori infection is an independent risk factor of early and advanced colorectal neoplasm.

PubMed

Kim, Tae Jun; Kim, Eun Ran; Chang, Dong Kyung; Kim, Young-Ho; Baek, Sun-Young; Kim, Kyunga; Hong, Sung Noh

2017-06-01

The role of Helicobacter pylori (H. pylori) in the development of colorectal neoplasm remains controversial. We examined the association between H. pylori infection and colorectal neoplasm in a large sample of healthy participants who underwent screening colonoscopy. A cross-sectional study of 8916 men, who participated in a regular health-screening examination that included an H. pylori-specific immunoglobulin G antibody test and colonoscopy, was conducted to evaluate the association between H. pylori and colorectal neoplasm. Multivariable analyses adjusted for age, body mass index, smoking status, alcohol intake, regular exercise, regular aspirin use, and family history of colorectal cancer showed that the odds ratio (OR) (95% confidence interval [CI]) for any adenoma and advanced neoplasm was 1.32 (1.07-1.61) and 1.90 (1.05-3.56) in participants with H. pylori infection and without H. pylori infection, respectively. The association persisted after further adjustment for inflammatory markers or metabolic variables including fasting blood glucose, triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol. Regarding the location, a positive association was confined to cases with proximal adenomas and was observed similarly in all the evaluated subgroups. In a large-scale study, carefully controlled for confounding factors, involving asymptomatic participants without a history of colonoscopy, H. pylori infection was significantly associated with the risk of any colorectal adenoma and advanced colorectal neoplasm. Prospective studies are necessary to determine whether H. pylori eradication can reduce this risk. © 2017 John Wiley & Sons Ltd.

URINARY MUTAGENICITY AND COLORECTAL ADENOMA RISK

EPA Science Inventory

Abstract

We investigated urinary mutagenicity and colorectal adenoma risk in a clinic-based, case-control study of currently nonsmoking cases (n = 143) and controls (n = 156). Urinary organics were extracted by C18/methanol from 12-h overnight urine samples, and mutagenici...

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

PubMed

Bonovas, Stefanos; Fiorino, Gionata; Lytras, Theodore; Malesci, Alberto; Danese, Silvio

2016-05-14

To determine the efficacy of calcium supplementation in reducing the recurrence of colorectal adenomas. 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 "high-risk" adenomas), and rated each trial'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. 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). 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.

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

PubMed Central

Bonovas, Stefanos; Fiorino, Gionata; Lytras, Theodore; Malesci, Alberto; Danese, Silvio

2016-01-01

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 “high-risk” adenomas), and rated each trial’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. PMID:27182169

Loss of insulin-like growth factor-II imprinting and the presence of screen-detected colorectal adenomas in women.

PubMed

Woodson, Karen; Flood, Andrew; Green, Lisa; Tangrea, Joseph A; Hanson, Jeffrey; Cash, Brooks; Schatzkin, Arthur; Schoenfeld, Phillip

2004-03-03

Loss of imprinting (LOI) of insulin-like growth factor-II (IGF-II) may be an inherited epigenetic trait that is polymorphic in the population, and its presence may predispose an individual to the development of colorectal cancer. We evaluated the association between LOI of IGF-II in normal colonic mucosal samples and adenomas in women participating in a colonoscopy screening study. Among 40 participants, 11 (27.5%) had LOI of IGF-II in their normal colonic mucosal tissue. After adjusting for body mass index and family history of colorectal cancer, LOI status was associated with a fivefold increased risk of adenoma formation (odds ratio = 5.2, 95% confidence interval = 1.0 to 26.7). On average, IGF-II expression was more than threefold higher among women with LOI of IGF-II than among women with normal imprinting status. Our findings support the hypothesis that LOI of IGF-II is an epigenetic trait polymorphic in the population and suggest that LOI of IGF-II may play a role in colorectal cancer. These findings are intriguing and need to be confirmed in larger studies.

Genetic biomarkers for neoplastic colorectal cancer in peripheral lymphocytes.

PubMed

Ionescu, Mirela; Ciocirlan, Mihai; Ionescu, Cristina; Becheanu, Gabriel; Gologan, Serban; Teiusanu, Adriana; Arbanas, Tudor; Mircea, Diculescu

2011-04-01

Loss of genomic stability appears as a key step in colorectal carcinogenesis. Micronucleus (MN) designates a chromosome fragment or an entire chromosme which lags behind mitosis. MN may be noticed as an additional nucleus within the cytoplasm cell during the intermediate mitosis phases. We tested the hypothesis that MN and its related anomalies may be associated with the presence of neoplastic colorectal lesions. Peripheral blood lymphocytes were cultured and microscopically examined. The frequency of micronuclei (FMN) and the presence of nucleoplasmic bridges (NPB) in binucleated cells were compared in patients with of without colorectal neoplastic lesions. We included 45 patients undergoing colonoscopy, 23 males and 22 females, with a median age of 59. 17 patients had polyps, 11 colorectal cancer (CRC) and 17 had a normal colonoscopy. The FMN was significantly higher in women than in men (8.14 vs 4.17, p=0.008); NPB were significantly less frequent in patients with advanced adenomas (>10mm or vilous) or CRC (p=0.044) when compared with patients with normal colonoscopy, hiperplastic polyps or non-advanced adenomas. Micronuclei are more frequent in women, but its frequency was not significantly different in patients with advanced adenomas or CRC. Null or low frequency values for nucleoplasmic bridges presence in peripheral lymphocyte may be predictive for advanced adenomas and colorectal cancer.

Understanding the potential and challenges of adenoma treatment as a prevention opportunity: insights from the BeWEL formative study.

PubMed

Stead, Martine; Caswell, Stephen; Craigie, Angela M; Eadie, Douglas; Anderson, Annie S

2012-01-01

To explore prevention opportunities presented by colorectal adenoma diagnosis and inform engagement strategies for the BeWEL study (body weight and physical activity lifestyle intervention for colorectal cancer screening participants who have undergone adenoma removal). Qualitative study comprising 4 purposively sampled focus groups conducted in urban and rural areas in Tayside, Scotland, with different deprivation levels. Participants were men and women (n=17) aged 50-74 with BMI>25 kg/m(2) with removal of adenoma detected by colorectal cancer screening. Adenoma diagnosis presents both opportunities and challenges for prevention. Some patients perceived adenoma as minor and not sufficiently motivating to act as a 'teachable moment'. Patients had low awareness of the relationship between adenoma and lifestyle factors, and received little information on prevention during screening and treatment. Consequently they interpreted post-treatment 'all clear' messages as validation of existing lifestyles, and did not see the relevance of prevention advice. Receptiveness increased when the association between lifestyle, adenoma recurrence and other illness was explained. The study illustrates the value of exploratory research into patient understanding to improve communications and health services. Without unduly worrying patients, professionals should explain how to reduce risk of adenoma, cancer and other diseases, particularly through diet, physical activity and weight reduction. Copyright © 2011 Elsevier Inc. All rights reserved.

Comparison of the clinicopathological features of flat and polypoid colorectal adenomas that are smaller than or equal to five millimeters.

PubMed

Yener, Neşe Arzu; Midi, Ahmet; Ataizi Çelikel, Ciğdem

2014-02-01

Colorectal flat adenomas (FAs) may represent a different histogenesis, since their malignant potential is thought to be higher than polypoid adenomas of the same size. In this study, we classified FAs of ≤5 mm into three subgroups-superficially elevated adenomas (SEAs), completely flat adenomas (CFAs), and depressed adenomas (DAs)-based on their low microscopic shapes and compared their clinicopathological features with polypoid tubular adenomas (pTAs) with the same size. One hundred one pTAs and 46 FAs with tubular morphology with the same size (≤5 mm) were studied. The percentages of high-grade dysplasia in FAs and pTAs were 19.56% and 12.87%, respectively. The percentages of the high-grade dysplasia were 28.57%, 13.63%, and 20.00% in the DA, SEA, and CFA subgroups, respectively. FAs had a significantly higher number of normal epithelium at the basal crypts of the lesion than the pTAs (p=0.001). The presence of pericryptal mesenchymal cells was higher in pTAs than the FAs (78.21% vs 10.86%) (p<0.001). Flat adenoma represents a distinct type of colorectal adenoma with special histopathological properties-existence of a normal epithelium at the basal crypts, lack of pericryptal mesenchymal cells, and a high percentage of high-grade dysplasia-especially when it has a depressed shape at low magnification.

[A systematic review of worldwide natural history models of colorectal cancer: classification, transition rate and a recommendation for developing Chinese population-specific model].

PubMed

Li, Z F; Huang, H Y; Shi, J F; Guo, C G; Zou, S M; Liu, C C; Wang, Y; Wang, L; Zhu, S L; Wu, S L; Dai, M

2017-02-10

Objective: To review the worldwide studies on natural history models among colorectal cancer (CRC), and to inform building a Chinese population-specific CRC model and developing a platform for further evaluation of CRC screening and other interventions in population in China. Methods: A structured literature search process was conducted in PubMed and the target publication dates were from January 1995 to December 2014. Information about classification systems on both colorectal cancer and precancer on corresponding transition rate, were extracted and summarized. Indicators were mainly expressed by the medians and ranges of annual progression or regression rate. Results: A total of 24 studies were extracted from 1 022 studies, most were from America ( n =9), but 2 from China including 1 from the mainland area, mainly based on Markov model ( n =22). Classification systems for adenomas included progression risk ( n =9) and the sizes of adenoma ( n =13, divided into two ways) as follows: 1) Based on studies where adenoma was risk-dependent, the median annual transition rates, from ' normal status' to ' non-advanced adenoma', 'non-advanced' to ' advanced' and ' advanced adenoma' to CRC were 0.016 0 (range: 0.002 2-0.020 0), 0.020 (range: 0.002-0.177) and 0.044 (range: 0.005-0.063), respectively. 2) Median annual transition rates, based on studies where adenoma were classified by sizes, into <10 mm and ≥10 mm ( n =7), from ' normal' to adenoma <10 mm, from adenoma <10 mm to adenoma ≥10 mm and adenoma ≥ 10 mm to CRC, were 0.016 7 (range: 0.015 0-0.037 0), 0.020 (range: 0.015-0.035) and 0.040 0 (range: 0.008 5-0.050 0), respectively. 3) Median annual transition rates, based on studies where adenoma, were classified by sizes into diminutive (≤5 mm), small (6-9 mm) and large adenoma (≥10 mm) ( n =6), from ' normal' to diminutive adenoma,'diminutive' to ' small','small' to ' large', and large adenoma to CRC were 0.013 (range: 0.009-0.019), 0.043 (range: 0.020-0.085), 0.044 (range: 0.020-0.125) and 0.033 5 (range: 0.030-0.040), respectively. Staging system of CRC mainly included LRD (localized/regional/distant, n =10), Dukes' ( n =7) and TNM ( n =3). When using the LRD classification, the median annual transition rates from ' localized' to ' regional' and ' regional' to 'distant' were 0.28 (range: 0.20-0.33) and 0.40 (range: 0.24-0.63), respectively. Under the Dukes' classification, the median annual transition rates appeared as 0.583 (range: 0.050-0.910), 0.656 (range: 0.280-0.720) and 0.830 (range: 0.630-0.865) from Dukes' A to B, B to C and C to Dukes' D, respectively. Again, when using the TNM classification, very limited transition rate was reported. Serrated pathway was only described in one study. Conclusions: Studies on the natural history model of colorectal cancer was still limited worldwide. Adenoma seemed the most common status setting for precancer model, and the risk-dependent classification for adenoma was consistent with the most commonly used system in clinical practice as well as major cancer screening programs in China. Since the staging systems of cancers varied, and shortage of transition rates based on TNM classification (commonly used in China), there will be a challenge for building Chinese population-specific natural history model of colorectal cancer, information from other classification systems could be conditionally applied.

Television watching and risk of colorectal adenoma

PubMed Central

Cao, Y; Keum, N N; Chan, A T; Fuchs, C S; Wu, K; Giovannucci, E L

2015-01-01

Background: Prolonged TV watching, a major sedentary behaviour, is associated with increased risk of obesity and diabetes and may involve in colorectal carcinogenesis. Methods: We conducted a cross-sectional analysis among 31 065 men with ⩾1 endoscopy in the Health Professionals Follow-up Study (1988–2008) to evaluate sitting while watching TV and its joint influence with leisure-time physical activity on risk of colorectal adenoma. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Prolonged sitting while watching TV was significantly associated with increased risk of colorectal adenoma (n=4280), and adjusting for physical activity or a potential mediator body mass index did not change the estimates. The ORs (95% CIs) across categories of TV watching (0–6, 7–13, 14–20, and 21+ h per week) were 1.00 (referent), 1.09 (1.01–1.17), 1.16 (1.06–1.27), and 1.10 (0.97–1.25) (OR per 14-h per week increment=1.11; 95% CI: 1.04–1.18; Ptrend=0.001). Compared with the least sedentary (0–6 h per week of TV) and most physically active (highest quintile) men, the most sedentary (14+ h per week) and least active (lowest quintile) men had a significant increased risk of adenoma (OR=1.25; 95% CI: 1.05–1.49), particularly for high-risk adenoma. Conclusions: Prolonged TV viewing is associated with modest increased risk of colorectal adenoma independent of leisure-time physical activity and minimally mediated by obesity. PMID:25590667

Moderate Alcohol Consumption is Protective Against Colorectal Adenomas in Smokers

PubMed Central

Galanko, Joseph A.; Martin, Christopher F.; Sandler, Robert S.

2009-01-01

Background Although some studies have shown an association between alcohol consumption and colorectal adenomas, the effect of moderate alcohol consumption is not well-defined, nor is the interaction between alcohol and smoking. Aim To investigate the relationship between different levels of alcohol consumption and colorectal adenomas and to determine whether smoking modifies this relationship. Methods Eligible patients who underwent a complete colonoscopy were included (179 cases and 466 controls). Alcohol consumption was obtained from a lifestyle questionnaire. Patients were divided into three groups: 1) Abstainers: 0 drinks/week; 2) Moderate drinkers: >0-<7 drinks/week; 3) Heavy drinkers: >=7 drinks/week. Odds ratios (OR) were calculated using logistic regression, controlling for gender, age, body mass index, use of non-steroidal anti-inflammatory medications. Results were stratified by the number of years smoked. Results The proportion of patients with adenomas was 29.6% in abstainers, 22.1% in moderate drinkers, and 36.7% in heavy drinkers. There was significant modification of the relationship between alcohol consumption and colorectal adenomas by smoking. For individuals who had never smoked, heavy drinkers were at significantly increased odds of having an adenoma compared to moderate drinkers (OR 3.08; 95% CI: 1.50-6.32), while no difference was seen for abstainers (OR 0.99; 95% CI: 0.52-1.89). Similarly, among individuals who had smoked 1-14 years, heavy drinkers were at increased odds of having an adenoma compared to moderate drinkers (OR 2.61; 95% CI: 1.04-6.51), and no difference was seen for abstainers (OR 1.02; 95% CI: 0.33-3.10). Somewhat unexpectedly, among individuals who had smoked for 15 or more years, abstainers were at increased odds of having an adenoma compared to moderate drinkers (OR 2.04; 95% CI: 0.91-4.59), while heavy drinkers were not at increased odds of having an adenoma (OR 0.73; 95% CI: 0.27-1.97). Conclusions Consumption of less than seven alcohol drinks per week does not increase the risk of having a colorectal adenoma. We found evidence in this study that moderate alcohol consumption among long-term smokers may potentially decrease the risk of an adenoma compared to abstainers. PMID:17510802

Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution

PubMed Central

Humphries, Adam; Cereser, Biancastella; Gay, Laura J.; Miller, Daniel S. J.; Das, Bibek; Gutteridge, Alice; Elia, George; Nye, Emma; Jeffery, Rosemary; Poulsom, Richard; Novelli, Marco R.; Rodriguez-Justo, Manuel; McDonald, Stuart A. C.; Wright, Nicholas A.; Graham, Trevor A.

2013-01-01

The genetic and morphological development of colorectal cancer is a paradigm for tumorigenesis. However, the dynamics of clonal evolution underpinning carcinogenesis remain poorly understood. Here we identify multipotential stem cells within human colorectal adenomas and use methylation patterns of nonexpressed genes to characterize clonal evolution. Numerous individual crypts from six colonic adenomas and a hyperplastic polyp were microdissected and characterized for genetic lesions. Clones deficient in cytochrome c oxidase (CCO−) were identified by histochemical staining followed by mtDNA sequencing. Topographical maps of clone locations were constructed using a combination of these data. Multilineage differentiation within clones was demonstrated by immunofluorescence. Methylation patterns of adenomatous crypts were determined by clonal bisulphite sequencing; methylation pattern diversity was compared with a mathematical model to infer to clonal dynamics. Individual adenomatous crypts were clonal for mtDNA mutations and contained both mucin-secreting and neuroendocrine cells, demonstrating that the crypt contained a multipotent stem cell. The intracrypt methylation pattern was consistent with the crypts containing multiple competing stem cells. Adenomas were epigenetically diverse populations, suggesting that they were relatively mitotically old populations. Intratumor clones typically showed less diversity in methylation pattern than the tumor as a whole. Mathematical modeling suggested that recent clonal sweeps encompassing the whole adenoma had not occurred. Adenomatous crypts within human tumors contain actively dividing stem cells. Adenomas appeared to be relatively mitotically old populations, pocketed with occasional newly generated subclones that were the result of recent rapid clonal expansion. Relative stasis and occasional rapid subclone growth may characterize colorectal tumorigenesis. PMID:23766371

Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution.

PubMed

Humphries, Adam; Cereser, Biancastella; Gay, Laura J; Miller, Daniel S J; Das, Bibek; Gutteridge, Alice; Elia, George; Nye, Emma; Jeffery, Rosemary; Poulsom, Richard; Novelli, Marco R; Rodriguez-Justo, Manuel; McDonald, Stuart A C; Wright, Nicholas A; Graham, Trevor A

2013-07-02

The genetic and morphological development of colorectal cancer is a paradigm for tumorigenesis. However, the dynamics of clonal evolution underpinning carcinogenesis remain poorly understood. Here we identify multipotential stem cells within human colorectal adenomas and use methylation patterns of nonexpressed genes to characterize clonal evolution. Numerous individual crypts from six colonic adenomas and a hyperplastic polyp were microdissected and characterized for genetic lesions. Clones deficient in cytochrome c oxidase (CCO(-)) were identified by histochemical staining followed by mtDNA sequencing. Topographical maps of clone locations were constructed using a combination of these data. Multilineage differentiation within clones was demonstrated by immunofluorescence. Methylation patterns of adenomatous crypts were determined by clonal bisulphite sequencing; methylation pattern diversity was compared with a mathematical model to infer to clonal dynamics. Individual adenomatous crypts were clonal for mtDNA mutations and contained both mucin-secreting and neuroendocrine cells, demonstrating that the crypt contained a multipotent stem cell. The intracrypt methylation pattern was consistent with the crypts containing multiple competing stem cells. Adenomas were epigenetically diverse populations, suggesting that they were relatively mitotically old populations. Intratumor clones typically showed less diversity in methylation pattern than the tumor as a whole. Mathematical modeling suggested that recent clonal sweeps encompassing the whole adenoma had not occurred. Adenomatous crypts within human tumors contain actively dividing stem cells. Adenomas appeared to be relatively mitotically old populations, pocketed with occasional newly generated subclones that were the result of recent rapid clonal expansion. Relative stasis and occasional rapid subclone growth may characterize colorectal tumorigenesis.

[The expression and significance of CD(276) and CD(133) in colorectal cancer and precancerous lesions].

PubMed

Lu, G F; Huang, L N; Ren, J L; Hu, G M; Zheng, Z H; Wu, J X; Zhu, Y P; Tang, F A

2018-06-01

In order to study the significance of CD(276) and CD(133) in the development and progression of colorectal cancer (CRC), the expression of CD(276) and CD(133) was detected by immunohistochemistry in CRC and precancerous lesions. The results showed that the intensity of CD(276) and CD(133) in CRC samples was higher than that in adenoma group and non-adenoma group. CD(276) and CD(133) single and double positive expression were significantly correlated with CRC lymph node metastasis, distant metastasis and survival. CD(276) and CD(133) are significantly correlated to the development and progression of CRC and associated with poor prognosis.

URINARY MUTAGENICITY AS A BIOMARKER OF COOKED-MEAT-ASSOCIATED MUTAGENS AND RISK FOR COLORECTAL ADENOMA

EPA Science Inventory

Urinary Mutagenicity as a Biomarker of Cooked-Meat-Associated Mutagens and Risk for Colorectal Adenoma

In a controlled feeding study involving 60 subjects, we have investigated urinary mutagenicity as a biomarker of exposure to cooked-meat-associated mutagens. In a separa...

A randomized controlled trial of eicosapentaenoic acid and/or aspirin for colorectal adenoma prevention during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme (The seAFOod Polyp Prevention Trial): study protocol for a randomized controlled trial

PubMed Central

2013-01-01

Background The naturally-occurring omega (ω)-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) reduces colorectal adenoma (polyp) number and size in patients with familial adenomatous polyposis. The safety profile and potential cardiovascular benefits associated with ω-3 PUFAs make EPA a strong candidate for colorectal cancer (CRC) chemoprevention, alone or in combination with aspirin, which itself has recognized anti-CRC activity. Colorectal adenoma number and size are recognized as biomarkers of future CRC risk and are established as surrogate end-points in CRC chemoprevention trials. Design The seAFOod Polyp Prevention Trial is a randomized, double-blind, placebo-controlled, 2 × 2 factorial ‘efficacy’ study, which will determine whether EPA prevents colorectal adenomas, either alone or in combination with aspirin. Participants are 55–73 year-old patients, who have been identified as ‘high risk’ (detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter) at screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Exclusion criteria include the need for more than one repeat endoscopy within the three-month BCSP screening period, malignant change in an adenoma, regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs, regular use of fish oil supplements and concomitant warfarin or anti-platelet agent therapy. Patients are randomized to either EPA-free fatty acid 1 g twice daily or identical placebo AND aspirin 300 mg once daily or identical placebo, for approximately 12 months. The primary end-point is the number of participants with one or more adenomas detected at routine one-year BCSP surveillance colonoscopy. Secondary end-points include the number of adenomas (total and ‘advanced’) per patient, the location (left versus right colon) of colorectal adenomas and the number of participants re-classified as ‘intermediate risk’ for future surveillance. Exploratory end-points include levels of bioactive lipid mediators such as ω-3 PUFAs, resolvin E1 and PGE-M in plasma, urine, erythrocytes and rectal mucosa in order to gain insights into the mechanism(s) of action of EPA and aspirin, alone and in combination, as well as to discover predictive biomarkers of chemopreventive efficacy. The recruitment target is 904 patients. Trial Registration Current Controlled Trials ISRCTN05926847 PMID:23895505

Selenium supplementation and colorectal adenomas: an analysis of the nutritional prevention of cancer trial.

PubMed

Reid, Mary E; Duffield-Lillico, Anna J; Sunga, Annette; Fakih, Marwan; Alberts, David S; Marshall, James R

2006-04-01

Selenium status has been inversely associated with colorectal cancers (CRC) and adenomas. This investigation evaluates the association between selenium supplementation and prevalent and incident colorectal adenomas and CRC detected during the Nutritional Prevention of Cancer trial follow-up. Of the 1,312 randomized to 200 mcg of selenized yeast of matching placebo, 598 participants underwent endoscopic screening (flexible sigmoidoscopy or colonoscopy) for CRC sometime during the follow-up period, which ended in February 1, 1996. There was no colorectal screening performed at baseline. Of those screened, 77% were male (with a mean age of 62.8 years), 42% were former and 25% were current smokers. Adenomas were classified as prevalent (identified at the first endoscopic examination post-randomization during the follow-up period) or incident (identified at the second or subsequent examination). Ninety-nine prevalent and 61 incident adenomas were ascertained. Logistic regression odds ratios (OR) and 95% confidence intervals (CI) were calculated, adjusting for age, gender and smoking status. For prevalent adenomas, there was a suggestive but nonsignificant decrease in risk associated with selenium treatment (OR = 0.67, 95% CI = 0.43-1.05). Subjects in the lowest tertile of baseline selenium (OR = 0.27, 95% CI = 0.09-0.77) and current smokers (OR = 0.27, 95% CI = 0.11-0.66) had significant reductions in risk. The OR for incident adenomas was 0.98 (95% CI = 0.57-1.68). In addition to being associated with a reduced risk of incident CRC, selenium supplementation was associated with a significantly reduced risk of prevalent adenomas, but only among subjects with either a low baseline selenium level or among current smokers.

Design and baseline characteristics of participants in a phase III randomized trial of celecoxib and selenium for colorectal adenoma prevention.

PubMed

Thompson, Patricia; Roe, Denise J; Fales, Liane; Buckmeier, Julie; Wang, Fang; Hamilton, Stanley R; Bhattacharyya, Achyut; Green, Sylvan; Hsu, Chiu-Hsieh; Chow, H-H Sherry; Ahnen, Dennis J; Boland, C Richard; Heigh, Russell I; Fay, David E; Martinez, Maria Elena; Jacobs, Elizabeth; Ashbeck, Erin L; Alberts, David S; Lance, Peter

2012-12-01

COX inhibitors reduce colorectal adenoma recurrence by up to 45% and selenium supplementation may prevent colorectal cancer. Following colonoscopic adenoma resection, 1,600 men and women, ages 40 to 80 years, were randomized to celecoxib (400 mg daily), a selective COX-2 inhibitor, and/or selenium (200 μg daily as selenized yeast), or double placebo. The trial was initiated in November 2001. The primary trial endpoint is adenoma recurrence in each intervention group compared with placebo, as determined by surveillance colonoscopy conducted three to five years after baseline. Randomization was stratified by use of low-dose aspirin (81 mg) and clinic site. Following reports of cardiovascular toxicity associated with COX-2 inhibitors, the celecoxib arm was discontinued in December 2004 when 824 participants had been randomized. Accrual continued with randomization to selenium alone or placebo. Randomization of the originally planned cohort (n = 1,621) was completed in November 2008. A further 200 patients with one or more advanced adenomas (denoting increased risk for colorectal cancer) were accrued to enhance statistical power for determining intervention efficacy in this higher-risk subgroup. Accrual of the total cohort (n = 1,824) was completed in January 2011. Baseline cohort characteristics include: mean age 62.9 years; 65% male; body mass index (BMI) 29.1 ± 5.1; 47% taking low-dose aspirin while on trial; 20% with three or more adenomas; and 38% with advanced adenomas. Intervention effects on adenoma recurrence will be determined, and their modification by genetic background and baseline selenium level. The effect of selenium supplementation on risk for type II diabetes will also be reported. ©2012 AACR

Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

PubMed

Ghorbanoghli, Z; Nieuwenhuis, M H; Houwing-Duistermaat, J J; Jagmohan-Changur, S; Hes, F J; Tops, C M; Wagner, A; Aalfs, C M; Verhoef, S; Gómez García, E B; Sijmons, R H; Menko, F H; Letteboer, T G; Hoogerbrugge, N; van Wezel, T; Vasen, H F A; Wijnen, J T

2016-10-01

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

Physical activity reduces risk for colon polyps in a multiethnic colorectal cancer screening population

PubMed Central

2012-01-01

Background Identifying modifiable factors that influence the epidemiology of colorectal cancer incidence among multiethnic groups might be informative for the development of public health strategies targeting the disease. Minimal data exists describing the impact of physical activity on colorectal polyp risk in United States minority populations. The aim of this study is to evaluate the relationship of exercise on the prevalence of polyps in a multiethnic colorectal cancer screening population. Results We enrolled 982 patients: 558 Hispanic, 202 Asian,149 Black, and 69 White. Patients who reported exercising one or more hours weekly had a lower prevalence of any polyps (25.3% vs 33.2%, P = 0.008) as well as adenomas (13.8 vs. 18.9%, P = 0.03) compared to those who did not exercise. Black and Hispanic patients and those who were overweight or obese also had lower prevalence of polyps if they led an active lifestyle. Multivariate analysis revealed that age >55, male sex, and Black race/ethnicity were positively associated with the presence of adenomas, while a history of exercising one hour or more weekly was an independent negative predictor for the presence of adenomas anywhere in the colon (OR 0.67; 95% CI 0.4 - 0.9, P = 0.03). Conclusions Exercising one hour per week was associated with a lower prevalence of polyps and adenomas when compared to those who exercised less or not at all. An active lifestyle provides benefits to groups who are at risk for colorectal cancer, such as Blacks. It also provides significant protection to overweight and obese individuals. Public health initiatives should promote physical activity as a cancer prevention tool in multiethnic populations. Trial registration none PMID:22715975

A healthy lifestyle index is associated with reduced risk of colorectal adenomatous polyps among non-users of non-steroidal anti-inflammatory drugs.

PubMed

Tabung, Fred K; Steck, Susan E; Burch, James B; Chen, Chin-Fu; Zhang, Hongmei; Hurley, Thomas G; Cavicchia, Philip; Alexander, Melannie; Shivappa, Nitin; Creek, Kim E; Lloyd, Stephen C; Hebert, James R

2015-02-01

In a Columbia, South Carolina-based case-control study, we developed a healthy lifestyle index from five modifiable lifestyle factors (smoking, alcohol intake, physical activity, diet, and body mass index), and examined the association between this lifestyle index and the risk of colorectal adenomatous polyps (adenoma). Participants were recruited from a local endoscopy center and completed questionnaires related to lifestyle behaviors prior to colonoscopy. We scored responses on each of five lifestyle factors as unhealthy (0 point) or healthy (1 point) based on current evidence and recommendations. We added the five scores to produce a combined lifestyle index for each participant ranging from 0 (least healthy) to 5 (healthiest), which was dichotomized into unhealthy (0-2) and healthy (3-5) lifestyle scores. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for adenoma with adjustment for multiple covariates. We identified 47 adenoma cases and 91 controls. In the main analyses, there was a statistically nonsignificant inverse association between the dichotomous (OR 0.54; 95% CI 0.22, 1.29) and continuous (OR 0.75; 95% CI 0.51, 1.10) lifestyle index and adenoma. Odds of adenoma were significantly modified by the use of non-steroidal anti-inflammatory drugs (NSAIDs) (p(interaction) = 0.04). For participants who reported no use of NSAIDs, those in the healthy lifestyle category had a 72% lower odds of adenoma as compared to those in the unhealthy category (OR 0.28; 95% CI 0.08, 0.98), whereas a one-unit increase in the index significantly reduced odds of adenoma by 53% (OR 0.47; 95% CI 0.26, 0.88). Although these findings should be interpreted cautiously given our small sample size, our results suggest that higher scores from this index are associated with reduced odds of adenomas, especially in non-users of NSAIDs. Lifestyle interventions are required to test this approach as a strategy to prevent colorectal adenomatous polyps.

Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome.

PubMed

Burn, John; Bishop, D Timothy; Mecklin, Jukka-Pekka; Macrae, Finlay; Möslein, Gabriela; Olschwang, Sylviane; Bisgaard, Marie-Luise; Ramesar, Raj; Eccles, Diana; Maher, Eamonn R; Bertario, Lucio; Jarvinen, Heikki J; Lindblom, Annika; Evans, D Gareth; Lubinski, Jan; Morrison, Patrick J; Ho, Judy W C; Vasen, Hans F A; Side, Lucy; Thomas, Huw J W; Scott, Rodney J; Dunlop, Malcolm; Barker, Gail; Elliott, Faye; Jass, Jeremy R; Fodde, Ricardo; Lynch, Henry T; Mathers, John C

2008-12-11

Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.) 2008 Massachusetts Medical Society

Genetic Biomarkers for Neoplastic Colorectal Cancer in Peripheral Lymphocytes

PubMed Central

Ionescu, Mirela; Ciocirlan, Mihai; Ionescu, Cristina; Becheanu, Gabriel; Gologan, Serban; Teiusanu, Adriana; Arbanas, Tudor; Mircea, Diculescu

2011-01-01

ABSTRACT Background: Loss of genomic stability appears as a key step in colorectal carcinogenesis. Micronucleus (MN) designates a chromosome fragment or an entire chromosme which lags behind mitosis. MN may be noticed as an additional nucleus within the cytoplasm cell during the intermediate mitosis phases. We tested the hypothesis that MN and its related anomalies may be associated with the presence of neoplastic colorectal lesions. Method: Peripheral blood lymphocytes were cultured and microscopically examined. The frequency of micronuclei (FMN) and the presence of nucleoplasmic bridges (NPB) in binucleated cells were compared in patients with of without colorectal neoplastic lesions. Results: We included 45 patients undergoing colonoscopy, 23 males and 22 females, with a median age of 59. 17 patients had polyps, 11 colorectal cancer (CRC) and 17 had a normal colonoscopy. The FMN was significantly higher in women than in men (8.14 vs 4.17, p=0.008); NPB were significantly less frequent in patients with advanced adenomas (>10mm or vilous) or CRC (p=0.044) when compared with patients with normal colonoscopy, hiperplastic polyps or non-advanced adenomas. Conclusion: Micronuclei are more frequent in women, but its frequency was not significantly different in patients with advanced adenomas or CRC. Null or low frequency values for nucleoplasmic bridges presence in peripheral lymphocyte may be predictive for advanced adenomas and colorectal cancer. PMID:22205889

Endoscopic detection of murine colonic dysplasia using a novel fluorescence-labeled peptide

NASA Astrophysics Data System (ADS)

Miller, Sharon J.; Joshi, Bishnu P.; Gaustad, Adam; Fearon, Eric R.; Wang, Thomas D.

2011-03-01

Current endoscopic screening does not detect all pre-malignant (dysplastic) colorectal mucosa, thus requiring the development of more sensitive, targeted techniques to improve detection. The presented work utilizes phage display to identify a novel peptide binder to colorectal dysplasia in a CPC;Apc mouse model. A wide-field, small animal endoscope capable of fluorescence excitation (450-475 nm) identified polyps via white light and also collected fluorescence images (510 nm barrier filter) of peptide binding. The peptide bound ~2-fold greater to the colonic adenomas when compared to the control peptide. We have imaged fluorescence-labeled peptide binding in vivo that is specific towards distal colonic adenomas.

[677T mutation of the MTHFR gene in adenomas and colorectal cancer in a population sample from the Northeastern Mexico. Preliminary results].

PubMed

Delgado-Enciso, I; Martínez-Garza, S G; Rojas-Martínez, A; Ortiz-López, R; Bosques-Padilla, F; Calderón-Garcidueñas, A L; Zárate-Gómez, M; Barrera-Saldaña, H A

2001-01-01

Adequate intake of folates has been associated to low prevalence of colon cancer. Methylenetetrahydrofolate reductase enzyme (MTHFR) plays an important role in folate metabolism. The role of the 677 mutation at the MTHFR gene in the risk for colorectal cancer remains controversial. A recent report established that this mutation has a high prevalence in the healthy Mexican population. To analyze the prevalence of 677T MTHFR mutation in patients with colorectal cancer and controls without chronic gastrointestinal disorders. Seventy-four colorectal cancer, 32 adenomas and 110 normal samples were analyzed. Patients and controls were matched for sex and age. For each sample, DNA isolation, PCR, and mutation detection by restriction enzyme digestion were performed to determine the allele at the 677 position in the MTHFR gene. Genotype 677C/677C was found in 18.7, 20.3, and 30.9% in adenomas, cancer lesions and controls, respectively. Frequencies of the 677C/677T genotype were 59.4, 56.7, and 47.3%, in adenomas, cancer lesions, and controls, respectively. Genotype 677T/677T was found in 21.9, 23.0, and 21.8% in adenomas, cancer lesions, and controls, respectively. The odds ratio between genotypes carrying the mutation (T/T and C/T) and normal genotype (CC) was 1.81 (IC 95% 0.97-3.3), chi 2 = 3.5, p = 0.06. Our results showed that persons who carry the 677T mutation at MTHFR locus have a tendency for an increased risk for colorectal cancer. This study supports the basic concept that low levels of folic acid contribute with the colorectal cancer pathogenesis. Our lack of statistic significance may be due to reduced sample size.

Prevention by daily soluble aspirin of colorectal adenoma recurrence: 4-year results of the APACC randomised trial.

PubMed

Benamouzig, Robert; Uzzan, Bernard; Deyra, Jacques; Martin, Antoine; Girard, Bernard; Little, Julian; Chaussade, Stanislas

2012-02-01

Aspirin inhibits colorectal carcinogenesis. In a randomised double-blind placebo-controlled trial, daily soluble aspirin significantly reduced recurrence of colorectal adenomas at 1-year follow-up. In this study the results of daily intake of low-dose aspirin on polyp recurrence at 4-year follow-up are presented. 272 patients (naive for chronic aspirin use) with colorectal adenomas were randomly assigned to treatment with lysine acetylsalicylate 160 mg/day (n=73) or 300 mg/day (n=67) or placebo (n=132) for 4 years. The primary endpoints were adenoma recurrence and adenomatous polyp burden at year 4, comparing aspirin at either dose with placebo. The same endpoints were also assessed at year 1 or 4 (last colonoscopy performed for each patient). At the final year 4 colonoscopy the analysis included 185 patients (55 receiving aspirin 160 mg/day, 47 aspirin 300 mg/day and 83 placebo). There was no difference in the proportion of patients with at least one recurrent adenoma between patients receiving aspirin at either dose and those treated with placebo (42/102 (41%) vs 33/83 (40%); NS) or in the adenomatous polyp burden (3.1 ± 5.8 mm vs 3.4 ± 6.2 mm; NS). Also, the proportion of patients with at least one advanced recurrent adenoma did not differ (10/102 [corrected] (10%) in the aspirin group vs 7/83 (8.4%) [corrected] in the placebo group; NS). Daily low-dose aspirin decreased adenoma recurrence significantly at 1 year but not at year 4. This discrepancy might be explained by a differential effect of aspirin according to the natural history of the polyp. NCT 00224679.

High Dry Bean Intake and Reduced Risk of Advanced Colorectal Adenoma Recurrence among Participants in the Polyp Prevention Trial

PubMed Central

Lanza, Elaine; Hartman, Terryl J.; Albert, Paul S.; Shields, Rusty; Slattery, Martha; Caan, Bette; Paskett, Electra; Iber, Frank; Kikendall, James Walter; Lance, Peter; Daston, Cassandra; Schatzkin, Arthur

2006-01-01

Adequate fruit and vegetable intake was suggested to protect against colorectal cancer and colorectal adenomas; however, several recent prospective studies reported no association. We examined the association between fruits and vegetables and adenomatous polyp recurrence in the Polyp Prevention Trial (PPT). The PPT was a low-fat, high-fiber, high-fruit, and vegetable dietary intervention trial of adenoma recurrence, in which there were no differences in the rate of adenoma recurrence in participants in the intervention and control arms of the trial. In this analysis of the entire PPT trial–based cohort, multiple logistic regression analysis was used to estimate the odds ratio (OR) of advanced and nonadvanced adenoma recurrence within quartiles of baseline and change (baseline minus the mean over 3 y) in fruit and vegetable intake, after adjustment for age, total energyy intake, use of nonsteroidal anti-inflammatory drugs, BMI, and gender. There were no significant associations between nonadvanced adenoma recurrence and overall change in fruit and vegetable consumption; however, those in the highest quartile of change in dry bean intake (greatest increase) compared with those in the lowest had a significantly reduced OR for advanced adenoma recurrence (OR = 0.35; 95% CI, 0.18–0.69; P for trend = 0.001). The median in the highest quartile of change in dry bean intake was 370% higher than the baseline intake. The PPT trial–based cohort provides evidence that dry beans may be inversely associated with advanced adenoma recurrence. PMID:16772456

Dynamic Tumor Growth Patterns in a Novel Murine Model of Colorectal Cancer

PubMed Central

Olson, Terrah J. Paul; Hadac, Jamie N.; Sievers, Chelsie K.; Leystra, Alyssa A.; Deming, Dustin A.; Zahm, Christopher D.; Albrecht, Dawn M.; Nomura, Alice; Nettekoven, Laura A.; Plesh, Lauren K.; Clipson, Linda; Sullivan, Ruth; Newton, Michael A.; Schelman, William R.; Halberg, Richard B.

2014-01-01

Colorectal cancer (CRC) often arises from adenomatous colonic polyps. Polyps can grow and progress to cancer, but may also remain static in size, regress, or resolve. Predicting which progress and which remain benign is difficult. We developed a novel long-lived murine model of CRC with tumors that can be followed by colonoscopy. Our aim was to assess whether these tumors have similar growth patterns and histologic fates to human colorectal polyps to identify features to aid in risk-stratification of colonic tumors. Long-lived ApcMin/+ mice were treated with dextran sodium sulfate to promote colonic tumorigenesis. Tumor growth patterns were characterized by serial colonoscopy with biopsies obtained for immunohistochemistry and gene expression profiling. Tumors grew, remained static, regressed, or resolved over time with different relative frequencies. Newly developed tumors demonstrated higher rates of growth and resolution than more established tumors that tended to remain static in size. Colonic tumors were hyperplastic lesions (3%), adenomas (73%), intramucosal carcinomas (20%), or adenocarcinomas (3%). Interestingly, the level of β-catenin was higher in adenomas that became intratumoral carcinomas as compared to those that failed to progress. In addition, differentially expressed genes between adenomas and intramucosal carcinomas were identified. This novel murine model of intestinal tumorigenesis develops colonic tumors that can be monitored by serial colonoscopy, mirror growth patterns seen in human colorectal polyps, and progress to CRC. Further characterization of cellular and molecular features are needed to determine which features can be used to risk-stratify polyps for progression to CRC and potentially guide prevention strategies. PMID:24196829

The destruction complex of beta-catenin in colorectal carcinoma and colonic adenoma.

PubMed

Bourroul, Guilherme Muniz; Fragoso, Hélio José; Gomes, José Walter Feitosa; Bourroul, Vivian Sati Oba; Oshima, Celina Tizuko Fujiyama; Gomes, Thiago Simão; Saba, Gabriela Tognini; Palma, Rogério Tadeu; Waisberg, Jaques

2016-01-01

To evaluate the destruction complex of beta-catenin by the expression of the proteins beta-catetenin, adenomatous polyposis coli, GSK3β, axin and ubiquitin in colorectal carcinoma and colonic adenoma. Tissue samples from 64 patients with colorectal carcinoma and 53 patients with colonic adenoma were analyzed. Tissue microarray blocks and slides were prepared and subjected to immunohistochemistry with polyclonal antibodies in carcinoma, adjacent non-neoplastic mucosa, and adenoma tissues. The immunoreactivity was evaluated by the percentage of positive stained cells and by the intensity assessed through of the stained grade of proteins in the cytoplasm and nucleus of cells. In the statistical analysis, the Spearman correlation coefficient, Student's t, χ2, Mann-Whitney, and McNemar tests, and univariate logistic regression analysis were used. In colorectal carcinoma, the expressions of beta-catenin and adenomatous polyposis coli proteins were significantly higher than in colonic adenomas (p<0.001 and p<0.0001, respectively). The immunoreactivity of GSK3β, axin 1 and ubiquitin proteins was significantly higher (p=0.03, p=0.039 and p=0.03, respectively) in colorectal carcinoma than in the colonic adenoma and adjacent non-neoplastic mucosa. The immunohistochemistry staining of these proteins did not show significant differences with the clinical and pathological characteristics of colorectal cancer and colonic adenoma. These results suggest that, in adenomas, the lower expression of the beta-catenin, axin 1 and GSK3β proteins indicated that the destruction complex of beta-catenin was maintained, while in colorectal carcinoma, the increased expression of beta-catenin, GSK3β, axin 1, and ubiquitin proteins indicated that the destruction complex of beta-catenin was disrupted. Avaliar o complexo de destruição da betacatenina no carcinoma colorretal e no adenoma do colo pela expressão das proteínas betacatenina, adenomatous polyposis coli, GSK3β, axina e ubiquitina. Amostras de tecidos de 64 doentes com carcinoma colorretal e de 53 pacientes com adenoma do colo foram analisadas. Blocos de tecidos foram submetidos ao estudo imuno-histoquímico com anticorpos policlonais nos tecidos do carcinoma, mucosa não neoplásica adjacente e adenoma. A imunorreatividade foi avaliada pela porcentagem de positividade de células coradas e pela intensidade do grau de coloração das proteínas no citoplasma e no núcleo das células. Na análise estatística, foram utilizados o coeficiente de correlação de Spearman, os testes t de Student, χ2, Mann-Whitney e de McNemar, e a análise de regressão logística univariada. No carcinoma colorretal, as expressões da betacatenina e da adenomatous polyposis coli foram significativamente maiores do que em adenomas do colo (p<0,001 e p<0,0001, respectivamente). A imunorreatividade das proteínas GSK3β, axina 1 e ubiquitina foi significativamente maior (p=0,03, p=0,039 e p=0,03, respectivamente) no carcinoma colorretal do que no adenoma e na mucosa não neoplásica adjacente. A coloração imuno-histoquímica dessas proteínas não apresentou diferenças significantes em relação às características clinicopatológicas do câncer colorretal e do adenoma. Em adenomas, as menores expressões de betacatenina, axina 1 e GSK3β indicaram que o complexo de destruição da betacatenina estava conservado, enquanto que, no carcinoma colorretal, o aumento das expressões da betacatenina, GSK3β, 1 axina, e ubiquitina indicaram que o complexo de destruição de betacatenina estava alterado.

Circulating levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α and risk of colorectal adenomas: a meta-analysis.

PubMed

Zhang, Xiaoqian; Liu, Shanglong; Zhou, Yanbing

2016-09-27

Results from publications on inflammatory markers of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and risk of colorectal adenomas are not consistent. A meta-analysis was conducted to explore the above-mentioned associations. Relevant studies were identified by a search of Embase, Medline and PubMed through February 2016. A random effect model was adopted to combine study-specific odds ratio (OR) and 95% confidence interval (95% CI). Between-study heterogeneity and publications bias were assessed. Dose-response relationships were assessed by restricted cubic splines. Nineteen observational studies were included. For highest vs. lowest levels, results from this meta-analysis did not support an association between circulating levels of CRP [OR (95% CI): 1.15 (0.94-1.40)], IL-6 [1.17 (0.94-1.46)] and TNF-α [0.99 (0.75-1.31)] and risk of colorectal adenomas, respectively. The findings were supported by sensitivity analysis and subgroup analysis. In dose-response analysis, the risk of colorectal adenomas increased by 2% [1.02 (0.97-1.08)] for each 1 mg/L increment in circulation CRP levels, 9% [1.09 (0.91-1.31)] for each 1 ng/L increment in circulation IL-6 levels, and 6% [1.06 (0.93-1.21)] for each 1 pg/mL increment in circulation TNF-α levels. Moderate between-study heterogeneity was found. No evidence of publication bias was found. Circulation levels of CRP, IL-6 and TNF-α might be not useful biomarkers for identifying colorectal adenomas, respectively.

Current and future molecular diagnostics in colorectal cancer and colorectal adenoma.

PubMed

Tsang, Andy Hin-Fung; Cheng, Ka-Ho; Wong, Apple Siu-Ping; Ng, Simon Siu-Man; Ma, Brigette Buig-Yue; Chan, Charles Ming-Lok; Tsui, Nancy Bo-Yin; Chan, Lawrence Wing-Chi; Yung, Benjamin Yat-Ming; Wong, Sze-Chuen Cesar

2014-04-14

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.

Current and future molecular diagnostics in colorectal cancer and colorectal adenoma

PubMed Central

Tsang, Andy Hin-Fung; Cheng, Ka-Ho; Wong, Apple Siu-Ping; Ng, Simon Siu-Man; Ma, Brigette Buig-Yue; Chan, Charles Ming-Lok; Tsui, Nancy Bo-Yin; Chan, Lawrence Wing-Chi; Yung, Benjamin Yat-Ming; Wong, Sze-Chuen Cesar

2014-01-01

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. PMID:24744577

Relationship between Expression of Onco-Related miRNAs and the Endoscopic Appearance of Colorectal Tumors

PubMed Central

Nakagawa, Yoshihito; Akao, Yukihiro; Taniguchi, Kohei; Kamatani, Akemi; Tahara, Tomomitsu; Kamano, Toshiaki; Nakano, Naoko; Komura, Naruomi; Ikuno, Hirokazu; Ohmori, Takafumi; Jodai, Yasutaka; Miyata, Masahiro; Nagasaka, Mistuo; Shibata, Tomoyuki; Ohmiya, Naoki; Hirata, Ichiro

2015-01-01

Accumulating data indicates that certain microRNAs (miRNAs or miRs) are differently expressed in samples of tumors and paired non-tumorous samples taken from the same patients with colorectal tumors. We examined the expression of onco-related miRNAs in 131 sporadic exophytic adenomas or early cancers and in 52 sporadic flat elevated adenomas or early cancers to clarify the relationship between the expression of the miRNAs and the endoscopic morphological appearance of the colorectal tumors. The expression levels of miR-143, -145, and -34a were significantly reduced in most of the exophytic tumors compared with those in the flat elevated ones. In type 2 cancers, the miRNA expression profile was very similar to that of the exophytic tumors. The expression levels of miR-7 and -21 were significantly up-regulated in some flat elevated adenomas compared with those in exophytic adenomas. In contrast, in most of the miR-143 and -145 down-regulated cases of the adenoma-carcinoma sequence and in some of the de novo types of carcinoma, the up-regulation of oncogenic miR-7 and/or -21 contributed to the triggering mechanism leading to the carcinogenetic process. These findings indicated that the expression of onco-related miRNA was associated with the morphological appearance of colorectal tumors. PMID:25584614

Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.

PubMed

Herkert, Johanna C; Niessen, Renée C; Olderode-Berends, Maria J W; Veenstra-Knol, Hermine E; Vos, Yvonne J; van der Klift, Heleen M; Scheenstra, Rene; Tops, Carli M J; Karrenbeld, Arend; Peters, Frans T M; Hofstra, Robert M W; Kleibeuker, Jan H; Sijmons, Rolf H

2011-05-01

Bi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2, cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening. The first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation. Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression. Our findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8. Copyright © 2011 Elsevier Ltd. All rights reserved.

Carbohydrate, glycemic index, and glycemic load and colorectal adenomas in the Prostate, Lung, Colorectal, and Ovarian Screening Study.

PubMed

Flood, Andrew; Peters, Ulrike; Jenkins, David J A; Chatterjee, Nilanjan; Subar, Amy F; Church, Timothy R; Bresalier, Robert; Weissfeld, Joel L; Hayes, Richard B; Schatzkin, Arthur

2006-11-01

It is possible that high-glycemic-load diets, through their hyperinsulinemic effects, can increase the risk of colorectal cancer. We analyzed data from a cancer screening study to determine whether persons with high-glycemic-load diets would be at an increased risk of distal adenomas. We included subjects with no prior adenoma or cancer from the Prostate, Lung, Colorectal, and Ovarian screening trial and whose results from flexible sigmoidoscopy exams indicated either no lesions (n = 34 817) or >/=1 distal adenoma (n = 3696). We used a 137-item food-frequency questionnaire to assess usual dietary intake over the preceding 12 mo. Using logistic regression analysis, we calculated, separately for men and women, prevalence odds ratios (ORs) and 95% CIs of sigmoidoscopy-detected, distal adenomas for quintiles of energy-adjusted dietary carbohydrate, glycemic index, and glycemic load. ORs decreased with increasing intakes of carbohydrate for both the men and the women in unadjusted models, but these associations were attenuated in multivariate-adjusted models. Among the men, the association remained significant after adjustment (OR: 0.71; 95% CI 0.60, 0.84; P for trend < 0.0001), but in the women it did not (OR: 0.89; 95% CI: 0.73, 1.10; P for trend = 0.30). The results for glycemic index showed no associations in either men or women. Results for glycemic load closely mirrored those for carbohydrate. Despite expectations that increasing glycemic load and glycemic index would increase the risk of adenoma, we observed no association in women and even an inverse association in men.

Hyperplastic polyps of the colon and rectum - reclassification, BRAF and KRAS status in index polyps and subsequent colorectal carcinoma.

PubMed

Janjua, Huma Gul Rehana; Høgdall, Estrid; Linnemann, Dorte

2015-04-01

Hyperplastic polyps (HP) of the colon and rectum were previously considered benign. Newer studies have suggested that colorectal HP are different entities. The aim of this study was to reclassify lesions from a 5-year period previously classified as colorectal HP into traditional hyperplastic polyp (THP), sessile serrated lesions (SSL), and other lesions. All patients were confirmed in the Danish National Pathology Database for the occurrence of metachronous polyps/adenomas, colorectal cancer (CRC), and other gastrointestinal malignancies. Molecular pathology of the CRC were characterized and correlated with the index lesion. In total, 591 HP biopsy specimens were obtained from 480 patients. The lesions were reclassified as: 358 THP, 109 SSL, 35 TA, 81 unspecified non-neoplastic lesions, four traditional serrated adenoma, and 4 SSL with cytological dysplasia. Seven patients developed CRC in the follow-up period (1 patient had SSL, 4 had THP, and 2 had unspecified non-neoplastic lesions). Ten patients developed other gastrointestinal malignancies. The patient with SSL as index lesions who developed CRC harbored V600E BRAF mutation in both index lesion and the carcinoma. Sixteen percent of patients with SSL subsequently developed a neoplastic lesion. Further studies are needed to clarify the cancer risk of SSL. © 2015 APMIS. Published by John Wiley & Sons Ltd.

Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas

PubMed Central

Barry, Elizabeth L.; Peacock, Janet L.; Rees, Judy R.; Bostick, Roberd M.; Robertson, Douglas J.; Bresalier, Robert S.; Baron, John A.

2017-01-01

IMPORTANCE Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial. OBJECTIVE To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin D3 or calcium supplementation on colorectal adenoma recurrence. DESIGN, SETTING, AND PARTICIPANTS We examined 41 candidate single-nucleotide polymorphisms (SNPs) in 2259 participants in a randomized, double-blind, placebo-controlled trial conducted at 11 clinical centers in the United States. Eligibility criteria included a recently diagnosed adenoma and no remaining colorectal polyps after complete colonoscopy. The study’s treatment phase ended on August 31, 2013, and the analysis for the present study took place from July 28, 2014, to October 19, 2016. INTERVENTIONS Daily oral supplementation with vitamin D3 (1000 IU) or calcium carbonate (1200 mg elemental calcium) or both or neither. MAIN OUTCOMES AND MEASURES The outcomes assessed were the occurrence of 1 or more adenomas or advanced adenomas (estimated diameter, ≥ 1 cm; or with villous histologic findings, high-grade dysplasia, or cancer) during follow-up. Treatment effects and genotype associations and interactions were estimated as adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The effective number of independent SNPs was calculated to correct for multiple testing. RESULTS Among the 2259 participants randomized, 1702 were non-Hispanic whites who completed the trial and had genotype data for analysis (1101 men; mean [SD] age 58.1 [6.8] years). The effect of vitamin D3 supplementation on advanced adenomas, but not on adenoma risk overall, significantly varied according to genotype at 2 VDR SNPs (rs7968585 and rs731236) in linkage disequilibrium (D′ = 0.98; r2 = 0.6). For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementation reduced risk by 64% (RR, 0.36; 95% CI, 0.19–0.69; P = .002; absolute risk decreased from 14.4% to 5.1%). Among individuals with 1 or 2 G alleles (74%), vitamin D3 supplementation increased risk by 41% (RR, 1.41; 95%CI, 0.99–2.00; P = .05; absolute risk increased from 7.7% to 11.1%; P < .001 for interaction). There were no significant interactions of genotypes with calcium supplementation. CONCLUSIONS AND RELEVANCE Our findings suggest that benefits from vitamin D3 supplementation for the prevention of advanced colorectal adenomas may vary according to vitamin D receptor genotype. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00153816 PMID:27978548

Volatiles in Breath and Headspace Analysis - Diagnostic Markers

ClinicalTrials.gov

2017-07-24

Tuberculosis; Gastric Cancer; Peptic Ulcer; Atrophic Gastritis; Intestinal Metaplasia; Gastric Dysplasia; Colorectal Cancer; Colorectal Polyp; Colorectal Adenoma; Pancreatic Cancer; Pancreatitis, Chronic; Liver Cancer; Liver Cirrhosis; Flu, Human; Other Infectious Diseases; Inflammatory Bowel Diseases

MicroRNA-320 family is downregulated in colorectal adenoma and affects tumor proliferation by targeting CDK6.

PubMed

Tadano, Toshihiro; Kakuta, Yoichi; Hamada, Shin; Shimodaira, Yosuke; Kuroha, Masatake; Kawakami, Yoko; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Masamune, Atsushi; Takahashi, Seiichi; Kinouchi, Yoshitaka; Shimosegawa, Tooru

2016-07-15

To investigate the microRNA (miRNA) expression during histological progression from colorectal normal mucosa through adenoma to carcinoma within a lesion. Using microarray, the sequential changes in miRNA expression profiles were compared in colonic lesions from matched samples; histologically, non-neoplastic mucosa, adenoma, and submucosal invasive carcinoma were microdissected from a tissue sample. Cell proliferation assay was performed to observe the effect of miRNA, and its target genes were predicted using bioinformatics approaches and the expression profile of SW480 transfected with the miRNA mimics. mRNA and protein levels of the target gene in colon cancer cell lines with a mimic control or miRNA mimics were measured using qRT-PCR and Western blotting. The expression levels of miRNA and target gene in colorectal tissue samples were also measured. Microarray analysis identified that the miR-320 family, including miR-320a, miR-320b, miR-320c, miR-320d and miR-320e, were differentially expressed in adenoma and submucosal invasive carcinoma. The miR-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 mRNA 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. 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.

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

PubMed Central

Tadano, Toshihiro; Kakuta, Yoichi; Hamada, Shin; Shimodaira, Yosuke; Kuroha, Masatake; Kawakami, Yoko; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Masamune, Atsushi; Takahashi, Seiichi; Kinouchi, Yoshitaka; Shimosegawa, Tooru

2016-01-01

AIM: To investigate the microRNA (miRNA) expression during histological progression from colorectal normal mucosa through adenoma to carcinoma within a lesion. METHODS: Using microarray, the sequential changes in miRNA expression profiles were compared in colonic lesions from matched samples; histologically, non-neoplastic mucosa, adenoma, and submucosal invasive carcinoma were microdissected from a tissue sample. Cell proliferation assay was performed to observe the effect of miRNA, and its target genes were predicted using bioinformatics approaches and the expression profile of SW480 transfected with the miRNA mimics. mRNA and protein levels of the target gene in colon cancer cell lines with a mimic control or miRNA mimics were measured using qRT-PCR and Western blotting. The expression levels of miRNA and target gene in colorectal tissue samples were also measured. RESULTS: Microarray analysis identified that the miR-320 family, including miR-320a, miR-320b, miR-320c, miR-320d and miR-320e, were differentially expressed in adenoma and submucosal invasive carcinoma. The miR-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 mRNA 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. PMID:27559432

Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma.

PubMed

Sekine, Shigeki; Yamashita, Satoshi; Tanabe, Taro; Hashimoto, Taiki; Yoshida, Hiroshi; Taniguchi, Hirokazu; Kojima, Motohiro; Shinmura, Kazuya; Saito, Yutaka; Hiraoka, Nobuyoshi; Ushijima, Toshikazu; Ochiai, Atsushi

2016-06-01

The molecular mechanisms underlying the serrated pathway of colorectal tumourigenesis, particularly those related to traditional serrated adenomas (TSAs), are still poorly understood. In this study, we analysed genetic alterations in 188 colorectal polyps, including hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), TSAs, tubular adenomas, and tubulovillous adenomas by using targeted next-generation sequencing and reverse transcription-PCR. Our analyses showed that most TSAs (71%) contained genetic alterations in WNT pathway components. In particular, PTPRK-RSPO3 fusions (31%) and RNF43 mutations (24%) were frequently and almost exclusively observed in TSAs. Consistent with the WNT pathway activation, immunohistochemical analysis showed diffuse and focal nuclear accumulation of β-catenin in 53% and 30% of TSAs, respectively. APC mutations were observed in tubular and tubulovillous adenomas and in a subset of TSAs. BRAF mutations were exclusively and frequently encountered in serrated lesions. KRAS mutations were observed in all types of polyps, but were most commonly encountered in tubulovillous adenomas and TSAs. This study has demonstrated that TSAs frequently harbour genetic alterations that lead to WNT pathway activation, in addition to BRAF and KRAS mutations. In particular, PTPRK-RSPO3 fusions and RNF43 mutations were found to be characteristic genetic features of TSAs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The relationship between cyclooxygenase-2 expression and characteristics of malignant transformation in human colorectal adenomas.

PubMed

Sheehan, Katherine M; O'Connell, Fionnuala; O'Grady, Anthony; Conroy, Ronan M; Leader, Mary B; Byrne, Michael F; Murray, Frank E; Kay, Elaine W

2004-06-01

Cyclooxygenase 2 (COX-2) is a target of aspirin and other non-steroidal anti-inflammatory drugs and is implicated in the pathogenesis of colorectal cancer. The objective of this study was to evaluate the extent of COX-2 in pre-malignant colorectal polyps and to assess the relationship between COX-2 and the level of dysplasia in these lesions. Whole polypectomy specimens were retrieved from 123 patients by endoscopic or surgical resection. Following formalin fixation and paraffin embedding, the polyps were evaluated histologically for size, type and grade of dysplasia. The extent of COX-2 expression was measured by the avidin-biotin immunohistochemical technique using a monoclonal COX-2 antibody. The extent of COX-2 expression was graded according to percentage epithelial COX-2 expression. The polyps were of the following histological types: 10 hyperplastic, 35 tubular adenomas, 61 tubulovillous adenomas and 17 villous adenomas. Twenty showed mild dysplasia, 65 moderate dysplasia, and 28 focal or severe dysplasia (including eight with focal invasion). The average polyp size was 1.7 cm. Nine hyperplastic polyps were COX-2-negative and one was COX-2-positive. COX-2 expression was more extensive in larger polyps and in polyps with a higher villous component. There was a significant increase in the extent of COX-2 protein with increasing severity of dysplasia. Within a polyp, there was a focal corresponding increase in COX-2 expression within epithelium showing a higher grade of dysplasia. COX-2 expression is related directly to colorectal adenomatous polyp size, type and grade of dysplasia. This suggests that the role of COX-2 in colorectal cancer may be at an early stage in the adenoma-to-carcinoma sequence and supports the suggestion that inhibition of COX-2 may be useful chemoprevention for this disease.

Advanced endoscopic imaging to improve adenoma detection

PubMed Central

Neumann, Helmut; Nägel, Andreas; Buda, Andrea

2015-01-01

Advanced endoscopic imaging is revolutionizing our way on how to diagnose and treat colorectal lesions. Within recent years a variety of modern endoscopic imaging techniques was introduced to improve adenoma detection rates. Those include high-definition imaging, dye-less chromoendoscopy techniques and novel, highly flexible endoscopes, some of them equipped with balloons or multiple lenses in order to improve adenoma detection rates. In this review we will focus on the newest developments in the field of colonoscopic imaging to improve adenoma detection rates. Described techniques include high-definition imaging, optical chromoendoscopy techniques, virtual chromoendoscopy techniques, the Third Eye Retroscope and other retroviewing devices, the G-EYE endoscope and the Full Spectrum Endoscopy-system. PMID:25789092

Genetic ancestry is associated with colorectal adenomas and adenocarcinomas in Latino populations.

PubMed

Hernandez-Suarez, Gustavo; Sanabria, Maria Carolina; Serrano, Marta; Herran, Oscar F; Perez, Jesus; Plata, Jose L; Zabaleta, Jovanny; Tenesa, Albert

2014-10-01

Colorectal cancer rates in Latin American countries are less than half of those observed in the United States. Latin Americans are the resultant of generations of an admixture of Native American, European, and African individuals. The potential role of genetic admixture in colorectal carcinogenesis has not been examined. We evaluate the association of genetic ancestry with colorectal neoplasms in 190 adenocarcinomas, 113 sporadic adenomas and 243 age- and sex-matched controls enrolled in a multicentric case-control study in Colombia. Individual ancestral genetic fractions were estimated using the STRUCTURE software, based on allele frequencies and assuming three distinct population origins. We used the Illumina Cancer Panel to genotype 1,421 sparse single-nucleotide polymorphisms (SNPs), and Northern and Western European ancestry, LWJ and Han Chinese in Beijing, China populations from the HapMap project as references. A total of 678 autosomal SNPs overlapped with the HapMap data set SNPs and were used for ancestry estimations. African mean ancestry fraction was higher in adenomas (0.13, 95% confidence interval (95% CI)=0.11-0.15) and cancer cases (0.14, 95% CI=0.12-0.16) compared with controls (0.11, 95% CI=0.10-0.12). Conditional logistic regression analysis, controlling for known risk factors, showed a positive association of African ancestry per 10% increase with both colorectal adenoma (odds ratio (OR)=1.12, 95% CI=0.97-1.30) and adenocarcinoma (OR=1.19, 95% CI=1.05-1.35). In conclusion, increased African ancestry (or variants linked to it) contributes to the increased susceptibility of colorectal cancer in admixed Latin American population.

Novel Stool-Based Protein Biomarkers for Improved Colorectal Cancer Screening: A Case-Control Study.

PubMed

Bosch, Linda J W; de Wit, Meike; Pham, Thang V; Coupé, Veerle M H; Hiemstra, Annemieke C; Piersma, Sander R; Oudgenoeg, Gideon; Scheffer, George L; Mongera, Sandra; Sive Droste, Jochim Terhaar; Oort, Frank A; van Turenhout, Sietze T; Larbi, Ilhame Ben; Louwagie, Joost; van Criekinge, Wim; van der Hulst, Rene W M; Mulder, Chris J J; Carvalho, Beatriz; Fijneman, Remond J A; Jimenez, Connie R; Meijer, Gerrit A

2017-12-19

The fecal immunochemical test (FIT) for detecting hemoglobin is used widely for noninvasive colorectal cancer (CRC) screening, but its sensitivity leaves room for improvement. To identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRC and advanced adenomas. Case-control study. Colonoscopy-controlled referral population from several centers. 315 stool samples from one series of 12 patients with CRC and 10 persons without colorectal neoplasia (control samples) and a second series of 81 patients with CRC, 40 with advanced adenomas, and 43 with nonadvanced adenomas, as well as 129 persons without colorectal neoplasia (control samples); 72 FIT samples from a third independent series of 14 patients with CRC, 16 with advanced adenomas, and 18 with nonadvanced adenomas, as well as 24 persons without colorectal neoplasia (control samples). Stool samples were analyzed by mass spectrometry. Classification and regression tree (CART) analysis and logistic regression analyses were performed to identify protein combinations that differentiated CRC or advanced adenoma from control samples. Antibody-based assays for 4 selected proteins were done on FIT samples. In total, 834 human proteins were identified, 29 of which were statistically significantly enriched in CRC versus control stool samples in both series. Combinations of 4 proteins reached sensitivities of 80% and 45% for detecting CRC and advanced adenomas, respectively, at 95% specificity, which was higher than that of hemoglobin alone (P < 0.001 and P = 0.003, respectively). Selected proteins could be measured in small sample volumes used in FIT-based screening programs and discriminated between CRC and control samples (P < 0.001). Lack of availability of antibodies prohibited validation of the top protein combinations in FIT samples. Mass spectrometry of stool samples identified novel candidate protein biomarkers for CRC screening. Several protein combinations outperformed hemoglobin in discriminating CRC or advanced adenoma from control samples. Proof of concept that such proteins can be detected with antibody-based assays in small sample volumes indicates the potential of these biomarkers to be applied in population screening. Center for Translational Molecular Medicine, International Translational Cancer Research Dream Team, Stand Up to Cancer (American Association for Cancer Research and the Dutch Cancer Society), Dutch Digestive Foundation, and VU University Medical Center.

Nonampullary duodenal adenoma: Current understanding of its diagnosis, pathogenesis, and clinical management

PubMed Central

Lim, Chul-Hyun; Cho, Young-Seok

2016-01-01

Nonampullary duodenal adenomas are relatively common in familial adenomatous polyposis (FAP), but nonampullary sporadic duodenal adenomas (SDAs) are rare. Emerging evidence shows that duodenal adenomas, regardless of their anatomic location and whether they are sporadic or FAP-related, share morphologic and molecular features with colorectal adenomas. The available data suggest that duodenal adenomas develop to duodenal adenocarcinomas via similar mechanisms. The optimal approach for management of duodenal adenomas remains to be determined. The techniques for endoscopic resection of duodenal adenoma include snare polypectomy, endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and argon plasma coagulation ablation. EMR may facilitate removal of large duodenal polyps. Although several studies have reported cases of successful ESD for duodenal adenomas, the procedure is technically difficult to perform safely because of the anatomical properties of the duodenum. Although current clinical practice recommends endoscopic resection of all large duodenal adenomas in patients with FAP, endoscopic treatment is usually insufficient to guarantee a polyp-free duodenum. Surgery is indicated for FAP patients with severe polyposis or nonampullary SDAs or FAP-related polyps not amenable to endoscopic resection. Further studies are needed to develop newer endoscopic techniques to guide diagnostic and therapeutic decisions for future management of nonampullary duodenal adenomas. PMID:26811631

Estimation of Recurrence of Colorectal Adenomas with Dependent Censoring Using Weighted Logistic Regression

PubMed Central

Hsu, Chiu-Hsieh; Li, Yisheng; Long, Qi; Zhao, Qiuhong; Lance, Peter

2011-01-01

In colorectal polyp prevention trials, estimation of the rate of recurrence of adenomas at the end of the trial may be complicated by dependent censoring, that is, time to follow-up colonoscopy and dropout may be dependent on time to recurrence. Assuming that the auxiliary variables capture the dependence between recurrence and censoring times, we propose to fit two working models with the auxiliary variables as covariates to define risk groups and then extend an existing weighted logistic regression method for independent censoring to each risk group to accommodate potential dependent censoring. In a simulation study, we show that the proposed method results in both a gain in efficiency and reduction in bias for estimating the recurrence rate. We illustrate the methodology by analyzing a recurrent adenoma dataset from a colorectal polyp prevention trial. PMID:22065985

Interleukin-6 as a Potential Indicator for Prevention of High Risk Adenoma Recurrence by Dietary Flavonols in the Polyp Prevention Trial

PubMed Central

Bobe, Gerd; Albert, Paul S.; Sansbury, Leah B.; Lanza, Elaine; Schatzkin, Arthur; Colburn, Nancy H.; Cross, Amanda J.

2010-01-01

Serum interleukin (IL)-6, a pro-inflammatory cytokine, is considered an indicator of inflammation and may be an indicator of colorectal carcinogenesis given that inflammation can promote carcinogenesis. Flavonols, which can be found in fruits and vegetables, may inhibit colorectal carcinogenesis partly by inhibiting inflammation. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) to determine whether serum IL-6 was associated with colorectal adenoma recurrence and flavonol intake and, thus may serve as a risk indicator and as a response indicator to dietary flavonols. Serum IL-6 concentrations at baseline, year 1 and 3 were measured in 872 participants from the intervention arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence. Intake of flavonols, especially of isorhamnetin, kaempferol, and quercetin, was inversely associated with serum IL-6 concentrations (highest vs. lowest flavonol intake quartile, 1.80 vs. 2.20 pg/mL) and high risk (OR = 0.51, 95% CI: 0.26–0.98) and advanced adenoma recurrence (OR = 0.17, 95% CI: 0.06–0.50). A decrease in IL-6 concentration during the trial was inversely associated with high risk (OR = 0.44, 95% CI: 0.23–0.84) and advanced adenoma recurrence (OR = 0.47, 95% CI: 0.19–1.18). Individuals with above median flavonol intake and equal or below median IL-6 change after baseline had the lowest risk of recurrence of high risk and advanced adenoma. Our results suggest that serum IL-6 may serve as a risk indicator and as a response indicator to dietary flavonols for colorectal cancer prevention. PMID:20484173

Race and colorectal cancer disparities: health-care utilization vs different cancer susceptibilities.

PubMed

Laiyemo, Adeyinka O; Doubeni, Chyke; Pinsky, Paul F; Doria-Rose, V Paul; Bresalier, Robert; Lamerato, Lois E; Crawford, E David; Kvale, Paul; Fouad, Mona; Hickey, Thomas; Riley, Thomas; Weissfeld, Joel; Schoen, Robert E; Marcus, Pamela M; Prorok, Philip C; Berg, Christine D

2010-04-21

It is unclear whether the disproportionately higher incidence and mortality from colorectal cancer among blacks compared with whites reflect differences in health-care utilization or colorectal cancer susceptibility. A total of 60, 572 non-Hispanic white and black participants in the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial underwent trial-sponsored screening flexible sigmoidoscopy (FSG) without biopsy at baseline in 10 geographically dispersed centers from November 1993 to July 2001. Subjects with polyps or mass lesions detected by FSG were referred to their physicians for diagnostic workup, the cost of which was not covered by PLCO. The records of follow-up evaluations were collected and reviewed. We used log binomial modeling with adjustment for age, education, sex, body mass index, smoking, family history of colorectal cancer, colon examination within previous 3 years, personal history of polyps, and screening center to examine whether utilization of diagnostic colonoscopy and yield of neoplasia differed by race. Among 57 561 whites and 3011 blacks who underwent FSG, 13,743 (23.9%) and 767 (25.5%) had abnormal examinations, respectively. A total of 9944 (72.4%) whites and 480 (62.6%) blacks had diagnostic colonoscopy within 1 year following the abnormal FSG screening. When compared with whites, blacks were less likely to undergo diagnostic evaluation (adjusted risk ratio = 0.88, 95% confidence interval = 0.83 to 0.93). Overall, among subjects with diagnostic colonoscopy (n = 10 424), there was no statistically significant difference by race in the prevalence of adenoma, advanced adenoma, advanced pathology in small adenomas (high-grade dysplasia or villous histology in adenomas <10 mm), or colorectal cancer. We observed a lower follow-up for screen-detected abnormalities among blacks when compared with whites but little difference in the yield of colorectal neoplasia. Health-care utilization may be playing more of a role in colorectal cancer racial disparity than biology.

Case-Control Study of Candidate Gene Methylation and Adenomatous Polyp Formation

PubMed Central

M, Alexander; JB, Burch; SE, Steck; C-F, Chen; TG, Hurley; P, Cavicchia; N, Shivappa; J, Guess; H, Zhang; SD, Youngstedt; KE, Creek; S, Lloyd; K, Jones; JR, Hébert

2016-01-01

Purpose Colorectal cancer (CRC) is one of the most common and preventable forms of cancer, but remains the second leading cause of cancer-related death. Colorectal adenomas are precursor lesions that develop in 70–90% of CRC cases. Identification of peripheral biomarkers for adenomas would help to enhance screening efforts. This exploratory study examined the methylation status of 20 candidate markers in peripheral blood leukocytes and their association with adenoma formation. Methods Patients recruited from a local endoscopy clinic provided informed consent, and completed an interview to ascertain demographic, lifestyle, and adenoma risk factors. Cases were individuals with a histopathologically confirmed adenoma, and controls included patients with a normal colonoscopy, or those with histopathological findings not requiring heightened surveillance (normal biopsy, hyperplastic polyp). Methylation-specific polymerase chain reaction was used to characterize candidate gene promoter methylation. Odds ratios and 95% confidence intervals (OR, 95% CI) were calculated using unconditional multivariable logistic regression to test the hypothesis that candidate gene methylation differed between cases and controls, after adjustment for confounders. Results Complete data were available for 107 participants; 36% had adenomas (men: 40%, women: 31%). Hypomethylation of the MINT1 locus (OR: 5.3, 95% CI: 1.0–28.2), and the PER1 (OR: 2.9, 95% CI: 1.1–7.7) and PER3 (OR: 11.6, 95% CI: 1.6–78.5) clock gene promoters was more common among adenoma cases. While specificity was moderate to high for the three markers (71–97%), sensitivity was relatively low (18–45%). Conclusion Follow-up of these epigenetic markers is suggested to further evaluate their utility for adenoma screening or surveillance. PMID:27771773

Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth

PubMed Central

Grivennikov, Sergei I.; Wang, Kepeng; Mucida, Daniel; Stewart, C. Andrew; Schnabl, Bernd; Jauch, Dominik; Taniguchi, Koji; Yu, Guann-Yi; Osterreicher, Christoph H.; Hung, Kenneth E.; Datz, Christian; Feng, Ying; Fearon, Eric R.; Oukka, Mohamed; Tessarollo, Lino; Coppola, Vincenzo; Yarovinsky, Felix; Cheroutre, Hilde; Eckmann, Lars; Trinchieri, Giorgio; Karin, Michael

2013-01-01

Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses1,2. Curiously, however, ‘inflammatory signature’ genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer3,4. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates5, referred to as ‘tumour elicited inflammation’6. Although infiltrating CD4+ TH1 cells and CD8+ cytotoxic T cells constitute a positive prognostic sign in colorectal cancer7,8, myeloid cells and T-helper interleukin (IL)-17-producing (TH17) cells promote tumorigenesis5,6, and a ‘TH17 expression signature’ in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival9. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier10. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth. PMID:23034650

A Highly Predictive Model for Diagnosis of Colorectal Neoplasms Using Plasma MicroRNA: Improving Specificity and Sensitivity

PubMed Central

Carter, Jane V.; Roberts, Henry L.; Pan, Jianmin; Rice, Jonathan D.; Burton, James F.; Galbraith, Norman J.; Eichenberger, M. Robert; Jorden, Jeffery; Deveaux, Peter; Farmer, Russell; Williford, Anna; Kanaan, Ziad; Rai, Shesh N.; Galandiuk, Susan

2016-01-01

OBJECTIVE(S) Develop a plasma-based microRNA (miRNA) diagnostic assay specific for colorectal neoplasms, building upon our prior work. BACKGROUND Colorectal neoplasms (colorectal cancer [CRC] and colorectal advanced adenoma [CAA]) frequently develop in individuals at ages when other common cancers also occur. Current screening methods lack sensitivity, specificity, and have poor patient compliance. METHODS Plasma was screened for 380 miRNAs using microfluidic array technology from a “Training” cohort of 60 patients, (10 each) control, CRC, CAA, breast (BC), pancreatic (PC) and lung (LC) cancer. We identified uniquely dysregulated miRNAs specific for colorectal neoplasia (p<0.05, false discovery rate: 5%, adjusted α=0.0038). These miRNAs were evaluated using single assays in a “Test” cohort of 120 patients. A mathematical model was developed to predict blinded sample identity in a 150 patient “Validation” cohort using repeat-sub-sampling validation of the testing dataset with 1000 iterations each to assess model detection accuracy. RESULTS Seven miRNAs (miR-21, miR-29c, miR-122, miR-192, miR-346, miR-372, miR-374a) were selected based upon p-value, area-under-the-curve (AUC), fold-change, and biological plausibility. AUC (±95% CI) for “Test” cohort comparisons were 0.91 (0.85-0.96), 0.79 (0.70-0.88) and 0.98 (0.96-1.0), respectively. Our mathematical model predicted blinded sample identity with 69-77% accuracy between all neoplasia and controls, 67-76% accuracy between colorectal neoplasia and other cancers, and 86-90% accuracy between colorectal cancer and colorectal adenoma. CONCLUSIONS Our plasma miRNA assay and prediction model differentiates colorectal neoplasia from patients with other neoplasms and from controls with higher sensitivity and specificity compared to current clinical standards. PMID:27471839

Latest generation, wide-angle, high-definition colonoscopes increase adenoma detection rate.

PubMed

Adler, Andreas; Aminalai, Alireza; Aschenbeck, Jens; Drossel, Rolf; Mayr, Michael; Scheel, Mathias; Schröder, Andreas; Yenerim, Timur; Wiedenmann, Bertram; Gauger, Ulrich; Roll, Stephanie; Rösch, Thomas

2012-02-01

Improvements to endoscopy imaging technologies might improve detection rates of colorectal cancer and patient outcomes. We compared the accuracy of the latest generation of endoscopes with older generation models in detection of colorectal adenomas. We compared data from 2 prospective screening colonoscopy studies (the Berlin Colonoscopy Project 6); each study lasted approximately 6 months and included the same 6 colonoscopists, who worked in private practice. Participants in group 1 (n = 1256) were all examined by using the latest generation of wide-angle, high-definition colonoscopes that were manufactured by the same company. Individuals in group 2 (n = 1400) were examined by endoscopists who used routine equipment (a mixture of endoscopes from different companies; none of those used to examine group 1). The adenoma detection rate was calculated on the basis of the number of all adenomas/number of all patients. There were no differences in patient parameters or withdrawal time between groups (8.0 vs 8.2 minutes). The adenoma detection rate was significantly higher in group 1 (0.33) than in group 2 (0.27; P = .01); a greater number of patients with least 1 adenoma were identified in group 1 (22.1%) than in group 2 (18.2%; P = .01). A higher percentage of high-grade dysplastic adenomas were detected in group 1 (1.19%) than in group 2 (0.57%), but this difference was not statistically significant (P = .06). The latest generation of wide-angle, high-definition colonoscopes improves rates of adenoma detection by 22%, compared with mixed, older technology endoscopes used in routine private practice. These findings might affect definitions of quality control parameters for colonoscopy screening for colorectal cancer. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Association between Diverticular Disease and Pre-Neoplastic Colorectal Lesions in an Urban African-American Population.

PubMed

Ashktorab, Hassan; Panchal, Heena; Shokrani, Babak; Paydar, Mansour; Sanderson, Andrew; Lee, Edward L; Begum, Rehana; Haidary, Tahmineh; Laiyemo, Adeyinka O; McDonald-Pinkett, Shelly; Brim, Hassan; Nouraie, Mehdi

2015-01-01

It is unclear whether there is a shared pathway in the development of diverticular disease (DD) and potentially neoplastic colorectal lesions since both diseases are found in similar age groups and populations. To determine the association between DD and colorectal pre-neoplastic lesions in an African-American urban population. Data from 1986 patients who underwent colonoscopy at the Howard University Hospital from January 2012 through December 2012 were analyzed for this study. The presence of diverticula and polyps was recorded using colonoscopy reports. Polyps were further classified into adenoma or hyperplastic polyp based on histopathology reports. Multiple logistic regression was done to analyze the association between DD and colonic lesions. Of the 1986 study subjects, 1,119 (56%) were females, 35% had DD and 56% had at least one polyp. There was a higher prevalence of polyps (70 vs. 49%; OR = 2.3; 95% CI: 1.9-2.8) and adenoma (43 vs. 25%; OR = 2.0; 95% CI: 1.7-2.5) in the diverticular vs. non-diverticula patients. Among patients who underwent screening colonoscopy, the presence of diverticulosis was associated with increased odds of associated polyps (OR = 9.9; 95% CI: 5.4-16.8) and adenoma (OR = 5.1; 95% CI: 3.4-7.8). Patients with DD are more likely to harbor colorectal lesions. These findings call for more vigilance on the part of endoscopists during colonoscopy in patients known to harbor colonic diverticula. © 2015 S. Karger AG, Basel.

Genetic ancestry is associated with colorectal adenomas and adenocarcinomas in Latino populations

PubMed Central

Hernandez-Suarez, Gustavo; Sanabria, Maria Carolina; Serrano, Marta; Herran, Oscar F; Perez, Jesus; Plata, Jose L; Zabaleta, Jovanny; Tenesa, Albert

2014-01-01

Colorectal cancer rates in Latin American countries are less than half of those observed in the United States. Latin Americans are the resultant of generations of an admixture of Native American, European, and African individuals. The potential role of genetic admixture in colorectal carcinogenesis has not been examined. We evaluate the association of genetic ancestry with colorectal neoplasms in 190 adenocarcinomas, 113 sporadic adenomas and 243 age- and sex-matched controls enrolled in a multicentric case–control study in Colombia. Individual ancestral genetic fractions were estimated using the STRUCTURE software, based on allele frequencies and assuming three distinct population origins. We used the Illumina Cancer Panel to genotype 1,421 sparse single-nucleotide polymorphisms (SNPs), and Northern and Western European ancestry, LWJ and Han Chinese in Beijing, China populations from the HapMap project as references. A total of 678 autosomal SNPs overlapped with the HapMap data set SNPs and were used for ancestry estimations. African mean ancestry fraction was higher in adenomas (0.13, 95% confidence interval (95% CI)=0.11–0.15) and cancer cases (0.14, 95% CI=0.12–0.16) compared with controls (0.11, 95% CI=0.10–0.12). Conditional logistic regression analysis, controlling for known risk factors, showed a positive association of African ancestry per 10% increase with both colorectal adenoma (odds ratio (OR)=1.12, 95% CI=0.97–1.30) and adenocarcinoma (OR=1.19, 95% CI=1.05–1.35). In conclusion, increased African ancestry (or variants linked to it) contributes to the increased susceptibility of colorectal cancer in admixed Latin American population. PMID:24518838

Novel methylation panel for the early detection of colorectal tumors in stool DNA.

PubMed

Azuara, Daniel; Rodriguez-Moranta, Francisco; de Oca, Javier; Soriano-Izquierdo, Antonio; Mora, Josefina; Guardiola, Jordi; Biondo, Sebastiano; Blanco, Ignacio; Peinado, Miguel Angel; Moreno, Victor; Esteller, Manel; Capellá, Gabriel

2010-07-01

Previous studies showed that the assessment of promoter hypermethylation of a limited number of genes in tumor biopsies may identify the majority of colorectal tumors. This study aimed to assess the clinical usefulness of a panel of methylation biomarkers in stool DNA in the identification of colorectal tumors, using methylation-specific melting curve analysis (MS-MCA), a technique that simultaneously analyzes all cytosine-phosphate-guanine (CpG) residues within a promoter. The promoter methylation status of 4 tumor-related genes (RARB2, p16INK4a, MGMT, and APC) was analyzed in DNA stool samples and corresponding tissues in an initial set of 12 patients with newly diagnosed primary colorectal carcinomas and 20 patients with newly diagnosed colorectal adenomas, using methylation-specific polymerase chain reaction. Results were replicated in a set of 82 patients (20 healthy subjects, 16 patients with inflammatory bowel disease (IBD), 20 patients with adenomas, and 26 patients with carcinomas), using MS-MCA analyses. In the initial set, >or= 1 positive methylation marker was detected in the stools of 9 of 12 patients (75%) with carcinomas and 12 of 20 patients (60%) with adenomas, with no false-positive results. Stool analyses missed 7 methylated lesions (25%). In the replication set, stool DNA testing detected 16 of 26 carcinomas (62%) and 8 of 20 adenomas (40%). The MS-MCAs missed 14 methylated tumors (37%). No aberrant methylation was evident in healthy subjects, but the RARB2 marker was positive in 2 of 15 stool samples (13%) of patients with IBD. Analysis via MS-MCA of a panel of methylation markers in stool DNA may offer a good alternative in the early, noninvasive detection of colorectal tumors.

Microsatellite Status of Primary Colorectal Cancer Predicts the Incidence of Postoperative Colorectal Neoplasms.

PubMed

Takiyama, Aki; Tanaka, Toshiaki; Yamamoto, Yoko; Hata, Keisuke; Ishihara, Soichiro; Nozawa, Hiroaki; Kawai, Kazushige; Kiyomatsu, Tomomichi; Nishikawa, Takeshi; Otani, Kensuke; Sasaki, Kazuhito; Watanabe, Toshiaki

2017-10-01

Few studies have evaluated the risk of postoperative colorectal neoplasms stratified by the nature of primary colorectal cancer (CRC). In this study, we revealed it on the basis of the microsatellite (MS) status of primary CRC. We retrospectively reviewed 338 patients with CRC and calculated the risk of neoplasms during postoperative surveillance colonoscopy in association with the MS status of primary CRC. A propensity score method was applied. We identified a higher incidence of metachronous rectal neoplasms after the resection of MS stable CRC than MS instable CRC (adjusted HR 5.74, p=0.04). We also observed a higher incidence of colorectal tubular adenoma in patients with MSS CRC (adjusted hazard ratio 7.09, p<0.01) and a higher incidence of postoperative tubulovillous/villous adenoma in patients with MS instable CRC (adjusted HR=8.50, p=0.03). The MS status of primary colorectal cancer influenced the risk of postoperative colorectal neoplasms. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Enhancing adherence in trials promoting change in diet and physical activity in individuals with a diagnosis of colorectal adenoma; a systematic review of behavioural intervention approaches.

PubMed

McCahon, Deborah; Daley, Amanda J; Jones, Janet; Haslop, Richard; Shajpal, Arjun; Taylor, Aliki; Wilson, Sue; Dowswell, George

2015-07-07

Little is known about colorectal adenoma patients' ability to adhere to behavioural interventions promoting a change in diet and physical activity. This review aimed to examine health behaviour intervention programmes promoting change in diet and/or physical activity in adenoma patients and characterise interventions to which this patient group are most likely to adhere. Searches of eight databases were restricted to English language publications 2000-2014. Reference lists of relevant articles were also reviewed. All randomised controlled trials (RCTs) of diet and physical activity interventions in colorectal adenoma patients were included. Eligibility and quality were assessed and data were extracted by two reviewers. Data extraction comprised type, intensity, provider, mode and location of delivery of the intervention and data to enable calculation of four adherence outcomes. Data were subject to narrative analysis. Five RCTs with a total of 1932 participants met the inclusion criteria. Adherence to the goals of the intervention ranged from 18 to 86 % for diet and 13 to 47 % for physical activity. Diet interventions achieving ≥ 50 % adherence to the goals of the intervention were clinic based, grounded in cognitive theory, delivered one to one and encouraged social support. The findings of this review indicate that behavioural interventions can encourage colorectal adenoma patients to improve their diet. This review was not however able to clearly characterise effective interventions promoting increased physical activity in this patient group. Further research is required to establish effective interventions to promote adherence to physical activity in this population.

A Microbiomic Analysis in African Americans with Colonic Lesions Reveals Streptococcus sp.VT162 as a Marker of Neoplastic Transformation

PubMed Central

Brim, Hassan; Yooseph, Shibu; Lee, Edward; Sherif, Zaki A.; Abbas, Muneer; Laiyemo, Adeyinka O.; Varma, Sudhir; Torralba, Manolito; Dowd, Scot E.; Nelson, Karen E.; Pathmasiri, Wimal; Sumner, Susan; de Vos, Willem; Liang, Qiaoyi; Yu, Jun; Zoetendal, Erwin; Ashktorab, Hassan

2017-01-01

Increasing evidence suggests a role of the gut microbiota in colorectal carcinogenesis (CRC). To detect bacterial markers of colorectal cancer in African Americans a metabolomic analysis was performed on fecal water extracts. DNA from stool samples of adenoma and healthy subjects and from colon cancer and matched normal tissues was analyzed to determine the microbiota composition (using 16S rDNA) and genomic content (metagenomics). Metagenomic functions with discriminative power between healthy and neoplastic specimens were established. Quantitative Polymerase Chain Reaction (q-PCR) using primers and probes specific to Streptococcus sp. VT_162 were used to validate this bacterium association with neoplastic transformation in stool samples from two independent cohorts of African Americans and Chinese patients with colorectal lesions. The metabolomic analysis of adenomas revealed low amino acids content. The microbiota in both cancer vs. normal tissues and adenoma vs. normal stool samples were different at the 16S rRNA gene level. Cross-mapping of metagenomic data led to 9 markers with significant discriminative power between normal and diseased specimens. These markers identified with Streptococcus sp. VT_162. Q-PCR data showed a statistically significant presence of this bacterium in advanced adenoma and cancer samples in an independent cohort of CRC patients. We defined metagenomic functions from Streptococcus sp. VT_162 with discriminative power among cancers vs. matched normal and adenomas vs. healthy subjects’ stools. Streptococcus sp. VT_162 specific 16S rDNA was validated in an independent cohort. These findings might facilitate non-invasive screening for colorectal cancer. PMID:29120399

p16 protein is upregulated in a stepwise fashion in colorectal adenoma and colorectal carcinoma.

PubMed

Al-Ahwal, Mahmoud; Gomaa, Wafaey; Emam, Eman; Qari, Yousif; Buhmeida, Abdelbaset; Radwi, Salman; Al-Maghrabi, Basim; Al-Qahtani, Mohammad; Al-Maghrabi, Jaudah

2016-11-01

p16 is tumor suppressor gene acting as a cell cycle regulator. The present study was conducted to compare p16 expression in normal, dysplastic, and malignant colonic mucosae, and to explore its relation to clinicopathological variables and follow-up data in colorectal carcinoma (CRC). Tissue microarrays were performed from 25 normal colonic mucosae, 41 colonic adenomas, and 191 CRC, with corresponding 50 nodal metastases. Immunohistochemistry was performed using anti-p16 antibody, sections were scored, and statistical analysis was performed. K-ras mutation detection was also performed. Immunoexpression of p16 was significantly higher in CRC than in adenomas (P = 0.033) and normal colonic mucosa (P = 0.005). There was no statistically significant difference between p16 expression in CRC and nodal metastasis. There was no significant association between p16 immunoexpression in CRC and all clinicopathological data and survival probability. K-ras mutations were detected in 34% of CRC. However, there was no correlation between K-ras status and p16 expression (P = 0.325). Absence of p16 expression is correlated to a benign course of CRC adenomas. p16 has a key role in CRC progression and can be used as a marker for colorectal adenoma. On the other hand, it has no role as a predictive and/or prognostic factor in CRC. Further extended studies are required to explore the role of p16 as indicator of premalignant lesions in the colon and to test its relation with CRC histological grade, as well as to test its value as a new therapeutic target.

Genomic Landscape of Colorectal Mucosa and Adenomas in Familial Adenomatous Polyposis

PubMed Central

Borras, Ester; San Lucas, F. Anthony; Chang, Kyle; Zhou, Ruoji; Masand, Gita; Fowler, Jerry; Mork, Maureen E.; You, Y. Nancy; Taggart, Melissa W.; McAllister, Florencia; Jones, David A.; Davies, Gareth E.; Edelmann, Winfried; Ehli, Erik A.; Lynch, Patrick M.; Hawk, Ernest T.; Capella, Gabriel; Scheet, Paul; Vilar, Eduardo

2016-01-01

Purpose The molecular basis of the adenoma to carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. Experimental Design We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances in 37 adenomas using SNP arrays. We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach. Results Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer-driver genes (APC, KRAS, FBXW7, TCF7L2) and allelic imbalances in chromosomes 5, 7 and 13. Moreover, 80% of adenomas had somatic alterations in WNT pathway genes. Adenomas displayed evidence of multiclonality similar to stage I carcinomas. Strong correlations between mutational rate and patient age were observed in at-risk mucosa and adenomas. Our data indicate that at least 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation. Conclusions The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions. Furthermore, substantial genomic variation exists in at-risk mucosa before adenoma formation, and deregulation of the WNT pathway is required to foster carcinogenesis. PMID:27221540

Improving detection of colorectal cancer.

PubMed

Orbell, James; West, Nicholas J

2010-10-01

Colorectal cancer is the third most common cancer in the U.K., with an annual incidence of 36,100 in England and Wales. It is also the second leading cause of death from cancer in the U.K. However, there has been a significant increase in five-year survival over the past decade, from 22% to 50% despite more than 55% of patients presenting with lymph node or distant metastases. Around 80% of colorectal cancer is sporadic, i.e., caused by the interaction of genetic and environmental factors via the adenoma-carcinoma sequence and cancer may take up to ten years to develop in this way. Adenomas are more common with age and one in four of the population aged over 50 will develop one or more polyps, with 10% of these polyps progressing to cancer over time. Risk factors for colorectal cancer include: age over 60; K-ras and p53 mutations; a diet high in saturated animal fat and low in fibre and vegetables; lack of exercise, obesity and excessive alcohol intake. Inflammatory bowel disease is a risk factor for development of colorectal cancer through the association of chronic inflammation and development of malignancy. Around 20% of colorectal cancer cases are familial and in a primary care setting taking a family history may determine those with a higher than average risk who may need onward referral. A large proportion of patients with rectal or sigmoid cancers present with a combination of rectal bleeding and a change in bowel habit (usually an increased frequency of defecation and/or looser stools). Rectal bleeding in the absence of anal symptoms occurs in over 60% of those with cancer, and a palpable rectal mass with or without tenesmus is present in 40-80% of those with rectal cancer.

Estrogen signaling in colorectal carcinoma microenvironment: expression of ERbeta1, AIB-1, and TIF-2 is upregulated in cancer-associated myofibroblasts and correlates with disease progression.

PubMed

Tzelepi, Vassiliki; Grivas, Petros; Kefalopoulou, Zinovia; Kalofonos, Haralabos; Varakis, John N; Melachrinou, Maria; Sotiropoulou-Bonikou, Georgia

2009-04-01

Epidemiological and molecular data suggest the involvement of estrogen signaling in colorectal tissue, mediated mainly through estrogen receptor beta (ERbeta). Estrogens may mediate their effects in epithelial cells indirectly by acting on stromal cells. Expression of ERalpha, ERbeta1, and the ER coregulators, amplified in breast cancer-1 (AIB-1) and transcriptional intermediary factor 2 (TIF-2), was evaluated in myofibroblasts of 107 colorectal carcinomas, 77 paired samples of normal mucosa, and 29 adenomas by immunohistochemistry. Double immunostaining with a-SMA was used to identify the myofibroblasts of normal tissue, adenomas, and cancer microenvironment. ERalpha was not expressed in stromal cells. Nuclear expression of ERbeta1, AIB-1, and TIF-2 in myofibroblasts gradually increased from normal mucosa, through adenomas, to carcinomas. Cytoplasmic ERbeta1 and TIF-2 expression was enhanced in carcinomas compared to normal mucosa and adenomas. Enhanced nuclear and cytoplasmic ERbeta1 expression and elevated nuclear AIB-1 expression were more frequently noted in myofibroblasts of carcinomas of advanced stage. ERbeta1 expression in cancer-associated myofibroblasts correlated to AIB-1 and TIF-2 expression. None of the markers correlated with patients' prognosis. Our findings imply that ERbeta1-dependent (genomic and non-genomic) and ER-coregulator-dependent (AIB-1, TIF-2) signal transductions in myofibroblasts may be involved in the initiation and progression of colorectal carcinomas.

APC gene mutations in individuals with possible attenuated familial adenomatous polyposis coli

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frayling, J.M.; Talbot, J.; Harocopos, C.A.

Spirio et al. have described an attenuated form of familial adenomatous polyposis (FAP) termed AAPC, where affected individuals have been found to have mutations in exons 3 & 4 of the APC gene. AAPC expression within a family appears to be extremely variable and can overlap clinically with FAP, giving rise to between zero and a few hundred adenomas. The phenotypic range associated with AAPC mutations is undefined and the frequency in the population of such alleles of the APC gene is unknown. In addition, it is as yet unclear how many cases of sporadic colorectal adenomas might have AAPC.more » In order to address this we have identified 110 individuals having a phenotype compatible with a diagnosis of AAPC, in three groups: (1) 30 individuals (15m, 15f; median age = 55y, range 8-71y) with some or all of the following: colonic adenomas (28 cases); colorectal cancer (12 cases); extra-colonic features of FAP, either desmoid tumours (4 cases, including 2 without colonic adenomas) or sebaceous cysts (2 cases). Sixteen cases had a family history of adenomas/colorectal cancer/extra-colonic features of FAP. (2) 16 individuals (10m, 6f) from the St. Mark`s Polyposis Registry, diagnosed with FAP (including a family history), who had unusually few adenomas (median = 200) at colectomy (median age = 43y, range 17-62y). (3) 64 individuals (43m, 21f) from the St. Mark`s Hospital Adenoma Follow-up Study who either had >4 adenomas at presentation (median total adenomas = 9), or >4 adenomas detected during follow-up (median total adenomas = 9). Genomic DNA was obtained from these individuals and exons 1-4 of the APC gene were amplified by PCR. Chemical cleavage of mismatch was used to screen for mutations, followed by sequencing if variant bands were found. Germ-line mutations have been identified in exons 3 and 4 in a proportion of these individuals, thus extending the clinical spectrum of phenotypes associated with mutations in this region of the APC gene.« less

RET is a potential tumor suppressor gene in colorectal cancer

PubMed Central

Luo, Yanxin; Tsuchiya, Karen D.; Park, Dong Il; Fausel, Rebecca; Kanngurn, Samornmas; Welcsh, Piri; Dzieciatkowski, Slavomir; Wang, Jianping; Grady, William M.

2012-01-01

Cancer arises as the consequence of mutations and epigenetic alterations that activate oncogenes and inactivate tumor suppressor genes. Through a genome-wide screen for methylated genes in colon neoplasms, we identified aberrantly methylated RET in colorectal cancer. RET, a transmembrane receptor tyrosine kinase and a receptor for the GDNF-family ligands, was one of the first oncogenes to be identified and has been shown to be an oncogene in thyroid cancer and pheochromocytoma. However, unexpectedly, we found RET is methylated in 27% of colon adenomas and in 63% of colorectal cancers, and now provide evidence that RET has tumor suppressor activity in colon cancer. The aberrant methylation of RET correlates with decreased RET expression, whereas the restoration of RET in colorectal cancer cell lines results in apoptosis. Furthermore, in support of a tumor suppressor function of RET, mutant RET has also been found in primary colorectal cancer. We now show that these mutations inactivate RET, which is consistent with RET being a tumor suppressor gene in the colon. These findings suggest that the aberrant methylation of RET and the mutational inactivation of RET promote colorectal cancer formation and that RET can serve as a tumor suppressor gene in the colon. Moreover, the increased frequency of methylated RET in colon cancers compared to adenomas suggests RET inactivation is involved in the progression of colon adenomas to cancer. PMID:22751117

MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms

PubMed Central

Amankwatia, E B; Chakravarty, P; Carey, F A; Weidlich, S; Steele, R J C; Munro, A J; Wolf, C R; Smith, G

2015-01-01

Background: Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients. Methods: We used TaqMan low-density array (TLDA) qRT–PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion. Results: MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial–mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells. Conclusions: We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers. PMID:25919696

Clinicopathological observations of colorectal serrated lesions associated with invasive carcinoma and high-grade intraepithelial neoplasm

PubMed Central

XU, SHENG; WANG, LUPING; YANG, GUANGZHI; LI, LIN; WANG, JIN; XU, CHUNWEI; GE, CHANG

2013-01-01

The aim of this study was to investigate the clinicopathological characteristics of colorectal serrated lesions associated with invasive carcinoma and high-grade intraepithelial neoplasm (HIN), as well as to determine the immunohistochemical expression of MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), K-ras and O6-methylguanine-DNA methyltransferase (MGMT). A total of 5,347 cases diagnosed with colorectal polyp or adenoma were included in this study from October 2002 to September 2009. A total of 16 cases of colorectal serrated lesions associated with invasive carcinoma/HIN were screened. These comprised seven cases of traditional serrated adenoma (TSA) associated with invasive carcinoma and HIN, six cases of sessile serrated adenoma (SSA) associated with invasive carcinoma/HIN and three cases of hyperplastic polyp (HP) associated with invasive carcinoma/HIN. TSA associated with invasive carcinoma/HIN predominantly occurred in the rectum with a clearly serrated structure and ectopic crypts. High-grade dysplasia was observed in filiform TSA, which was more prone to carcinogenesis. SSA associated with invasive carcinoma/HIN mainly occurred in the ileocecal junction, with the SSA serrated glands closely located adjacent to the muscularis mucosa and the basal crypt expanded with inverted T- or L-shaped branches. HPs were observed in three cases in the cancer-adjacent tissues with invasive carcinoma, while a HP-SSA/TSA-carcinoma sequence was found in two cases. Immunohistochemistry showed that MGMT expression was significantly different in the serrated lesion tissues compared with that in cancer tissues (P=0.022), control cancer tissues (P=0.002) and normal colorectal epithelial tissues (P=0.003). TSA and SSA may progress to cancer or directly develop into invasive adenocarcinoma. Filiform TSA easily develops into HIN, followed by infiltration. HP may arise from the cancer-adjacent tissues of the invasive carcinoma, which are closely adjacent to the cancer tissues. Further research is needed to investigate the potential direct involvement of HP in carcinogenesis. PMID:24223631

Up-regulated EMMPRIN/CD147 protein expression might play a role in colorectal carcinogenesis and its subsequent progression without an alteration of its glycosylation and mRNA level.

PubMed

Zheng, Hua-chuan; Wang, Wei; Xu, Xiao-yan; Xia, Pu; Yu, Miao; Sugiyama, Toshiro; Takano, Yasuo

2011-04-01

Extracellular matrix metalloproteinase inducer (EMMPRIN) was reported to involve in the invasion and metastasis of malignancies by regulating the expression of vascular endothelial growth factor (VEGF) in stromal and cancer cells. The study aimed to clarify the role of EMMPRIN expression in tumorigenesis and progression of colorectal carcinomas (CRC). EMMPRIN expression was examined on tissue microarray containing colorectal carcinomas, adenoma and non-neoplastic mucosa (NNM) by immunohistochemistry and in situ hybridization (ISH). Colorectal carcinoma cell lines (DLD-1, HCT-15, SW480 and WiDr) and tissues were studied for EMMPRIN expression by Western blot or RT-PCR, followed by sequencing. All carcinoma cell lines showed EMMPRIN expression at both mRNA and protein levels. Two synonymous mutations were found in carcinoma cell lines at codon109 (GCT → GCC: Ala) or 179 (GAT → GAC: Asp). Frozen CRC tissues displayed higher EMMPRIN expression than paired NNM (P < 0.05). EMMPRIN expression was immunohistochemically stronger in colorectal high-grade adenoma, adenocarcinoma and metastatic carcinoma than non-neoplastic superficial epithelium and low-grade adenoma (P < 0.05). In contrast, its mRNA level was similar from colorectal NNM, adenoma to adenocarcinoma by ISH, in line with the findings of RT-PCR (P > 0.05). Immunohistochemically, EMMPRIN expression was positively correlated with tumor size, depth of invasion, vascular or lymphatic invasion, grade of infiltration (INF), ki-67 and VEGF expression of CRCs (P < 0.05). Among them, depth of invasion was an independent associated factor for EMMPRIN expression in CRCs (P < 0.05). Up-regulated EMMPRIN protein expression might contribute to colorectal carcinogenesis without the alteration of its glycosylation and mRNA level. Aberrant EMMPRIN protein expression might promote growth or invasion of CRCs possibly through increased ki-67 expression and inducible angiogenesis via up-regulating VEGF expression.

A comparison of blood vessel features and local binary patterns for colorectal polyp classification

NASA Astrophysics Data System (ADS)

Gross, Sebastian; Stehle, Thomas; Behrens, Alexander; Auer, Roland; Aach, Til; Winograd, Ron; Trautwein, Christian; Tischendorf, Jens

2009-02-01

Colorectal cancer is the third leading cause of cancer deaths in the United States of America for both women and men. By means of early detection, the five year survival rate can be up to 90%. Polyps can to be grouped into three different classes: hyperplastic, adenomatous, and carcinomatous polyps. Hyperplastic polyps are benign and are not likely to develop into cancer. Adenomas, on the other hand, are known to grow into cancer (adenoma-carcinoma sequence). Carcinomas are fully developed cancers and can be easily distinguished from adenomas and hyperplastic polyps. A recent narrow band imaging (NBI) study by Tischendorf et al. has shown that hyperplastic polyps and adenomas can be discriminated by their blood vessel structure. We designed a computer-aided system for the differentiation between hyperplastic and adenomatous polyps. Our development aim is to provide the medical practitioner with an additional objective interpretation of the available image data as well as a confidence measure for the classification. We propose classification features calculated on the basis of the extracted blood vessel structure. We use the combined length of the detected blood vessels, the average perimeter of the vessels and their average gray level value. We achieve a successful classification rate of more than 90% on 102 polyps from our polyp data base. The classification results based on these features are compared to the results of Local Binary Patterns (LBP). The results indicate that the implemented features are superior to LBP.

Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway

PubMed Central

Cho, Nam-Yun; Kang, Gyeong Hoon

2016-01-01

The presence or absence of MLH1 methylation may critically affect the heterogeneity of colorectal carcinoma (CRC) with the CpG island methylator phenotype (CIMP). Here, we investigated the differential characteristics of CIMP-high (CIMP-H) CRCs according to MLH1 methylation status. To further confirm the MLH1-dependent features in CIMP-H CRC, an independent analysis was performed using data from The Cancer Genome Atlas (TCGA). In our CIMP-H CRC samples, MLH1-methylated tumors were characterized by older patient age, proximal colonic location, mucinous histology, intense lymphoid reactions, RUNX3/SOCS1 promoter methylation, BRAF mutations, and microsatellite instability-high (MSI-H) status. By contrast, MLH1-unmethylated tumors were associated with earlier age of onset, increased distal colorectal localization, adverse pathologic features, and KRAS mutations. In the TCGA dataset, the MLH1-silenced CIMP-H CRC demonstrated proximal location, MSI-H status, hypermutated phenotype, and frequent BRAF mutations, but the MLH1-non-silenced CIMP-H CRC was significantly associated with high frequencies of KRAS and APC mutations. In conclusion, the differential nature of CIMP-H CRCs depends primarily on the MLH1 methylation status. Based on the current knowledge, the sessile serrated adenoma/polyp may be the major precursor of MLH1-methylated CIMP-H CRCs, whereas MLH1-unmethylated CIMP-H CRCs may develop predominantly from KRAS-mutated traditional serrated adenomas and less commonly from BRAF-mutated traditional serrated adenomas and/or sessile serrated adenomas/polyps. PMID:26883113

Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway.

PubMed

Kim, Jung Ho; Bae, Jeong Mo; Cho, Nam-Yun; Kang, Gyeong Hoon

2016-03-22

The presence or absence of MLH1 methylation may critically affect the heterogeneity of colorectal carcinoma (CRC) with the CpG island methylator phenotype (CIMP). Here, we investigated the differential characteristics of CIMP-high (CIMP-H) CRCs according to MLH1 methylation status. To further confirm the MLH1-dependent features in CIMP-H CRC, an independent analysis was performed using data from The Cancer Genome Atlas (TCGA). In our CIMP-H CRC samples, MLH1-methylated tumors were characterized by older patient age, proximal colonic location, mucinous histology, intense lymphoid reactions, RUNX3/SOCS1 promoter methylation, BRAF mutations, and microsatellite instability-high (MSI-H) status. By contrast, MLH1-unmethylated tumors were associated with earlier age of onset, increased distal colorectal localization, adverse pathologic features, and KRAS mutations. In the TCGA dataset, the MLH1-silenced CIMP-H CRC demonstrated proximal location, MSI-H status, hypermutated phenotype, and frequent BRAF mutations, but the MLH1-non-silenced CIMP-H CRC was significantly associated with high frequencies of KRAS and APC mutations. In conclusion, the differential nature of CIMP-H CRCs depends primarily on the MLH1 methylation status. Based on the current knowledge, the sessile serrated adenoma/polyp may be the major precursor of MLH1-methylated CIMP-H CRCs, whereas MLH1-unmethylated CIMP-H CRCs may develop predominantly from KRAS-mutated traditional serrated adenomas and less commonly from BRAF-mutated traditional serrated adenomas and/or sessile serrated adenomas/polyps.

Colorectal polyps

MedlinePlus

... polyp, which protrudes out in the lumen (open space) of the colon Villous adenoma, which is sometimes ... DA, Levin TR; United States Multi-Society Task Force on Colorectal Cancer. Guidelines for colonoscopy surveillance after ...

Evaluation of promoter methylation status of MLH1 gene in Iranian patients with colorectal tumors and adenoma polyps.

PubMed

Zarandi, Ashkan; Irani, Shiva; Savabkar, Sanaz; Chaleshi, Vahid; Ghavideldarestani, Maryam; Mirfakhraie, Reza; Khodadoostan, Mahsa; Nazemalhosseini-Mojarad, Ehsan; Asadzadeh Aghdaei, Hamid

2017-01-01

The aim of this study was to evaluate the methylation status of the promoter region of MLH1 gene in colorectal cancer (CRC) and its precursor lesions as well as elucidate its association with various clinicopathological characteristics among Iranian population. Epigenetic silencing of mismatch repair genes, such as MLH1 , by methylation of CpG islands of their promoter region has been proved to be an important mechanism in colorectal carcinogenesis. Fifty colorectal cancer and polyp tissue samples including 13 Primary colorectal tumor and 37 Adenoma polyp samples were enrolled in this study. Methylation-specific polymerase chain reaction (MSP) was performed to find the frequency of MLH1 Promoter Methylation. Promoter methylation of MLH1 gene was detected in 5 out of 13 tumor tissues and 4 out of 37 adenoma polyp. The frequency of MLH1 methylation in tumor samples was significantly higher compared to that in polyp tissues (P= 0.026). No significant association was observed between MLH1 promoter methylation and clinicopathological characteristics of the patients. The frequency of  MLH1  promoter methylation in CRC and colon polyp was 18%. Our findings indicated that methylation of MLH1 promoter region alone cannot be considered as a biomarker for early detection of CRC.

Variation in Adenoma Detection Rate and the Lifetime Benefits and Cost of Colorectal Cancer Screening: A Microsimulation Model

PubMed Central

Meester, Reinier G.S.; Doubeni, Chyke A.; Lansdorp-Vogelaar, Iris; Jensen, Christopher D.; van der Meulen, Miriam P.; Levin, Theodore R.; Quinn, Virginia P.; Schottinger, Joanne E.; Zauber, Ann G.; Corley, Douglas A.; van Ballegooijen, Marjolein

2015-01-01

IMPORTANCE Colonoscopy is the most commonly used colorectal cancer screening test in the United States. Its quality, as measured by adenoma detection rates, varies widely between physicians with unknown consequences for the cost and benefits of screening programs. OBJECTIVE To estimate the lifetime benefits, complications and costs of a colonoscopy screening program at different levels of adenoma detection. DESIGN, SETTING and PARTICIPANTS This study used microsimulation modeling with data from a community-based healthcare system on adenoma detection rate variation and cancer risk among 136 physicians and 57,588 patients for 1998–2010. EXPOSURE Using modeling, no screening was compared to screening initiation with colonoscopy according to adenoma detection rate quintiles (averages 15.3, 21.3, 25.6, 30.9, and 38.7%) at ages 50, 60 and 70 with appropriate surveillance of adenoma patients. MAIN OUTCOMES Estimated lifetime colorectal cancer incidence, mortality, number of colonoscopies, complications and costs per 1,000 patients, all discounted at 3% per year and including 95% confidence intervals from multiway probabilistic sensitivity analysis (95%CI). RESULTS In simulation modeling, among unscreened patients, the lifetime risks of colorectal cancer incidence and mortality were 34.2 (95%CI:25.9–43.6) and 13.4 (95%CI:10.0–17.6) per 1,000, respectively. Among screened patients, simulated lifetime incidence decreased with lower to higher adenoma detection rates (quintile 1 versus 5: 26.6, 95%CI:20.0–34.3 versus 12.5, 95%CI:9.3–16.5) as did mortality (5.7, 95%CI:4.2–7.7 versus 2.3, 95%CI:1.7–3.1). Compared to quintile 1, simulated lifetime incidence and mortality were on average 11.4% (95%CI:10.3–11.9) and 12.8% (95%CI:11.1–13.7) lower, respectively, for every 5 percentage-point higher adenoma detection rate. Total colonoscopies and associated complications were higher from quintile 1 (2,777, 95%CI:2,626–2,943 and 6.0, 95%CI:4.0–8.5) to subsequent quintiles (quintile 5: 3,376, 95%CI:3,081–3,681 and 8.9, 95%CI:6.1–12.0). Estimated net screening costs were, however, lower from quintile 1 (US $2.1 million, 95%CI:1.8–2.4) to quintile 5 (US$1.8 million, 95%CI:1.3–2.3) due to averted cancer treatment costs. Results were stable across sensitivity analyses. CONCLUSIONS-RELEVANCE Using microsimulation modeling, we found that higher adenoma detection was associated with lower lifetime colorectal cancer incidence and mortality without higher overall costs. Future research is needed to assess if increasing adenoma detection would be associated with improved patient outcomes. PMID:26080339

The association of Streptococcus bovis/gallolyticus with colorectal tumors: The nature and the underlying mechanisms of its etiological role

PubMed Central

2011-01-01

Streptococcus bovis (S. bovis) bacteria are associated with colorectal cancer and adenoma. S. bovis is currently named S. gallolyticus. 25 to 80% of patients with S. bovis/gallolyticus bacteremia have concomitant colorectal tumors. Colonic neoplasia may arise years after the presentation of bacteremia or infectious endocarditis of S. bovis/gallolyticus. The presence of S. bovis/gallolyticus bacteremia and/or endocarditis is also related to the presence of villous or tubular-villous adenomas in the large intestine. In addition, serological relationship of S. gallolyticus with colorectal tumors and direct colonization of S. gallolyticus in tissues of colorectal tumors were found. However, this association is still under controversy and has long been underestimated. Moreover, the etiological versus non-etiological nature of this associationis not settled yet. Therefore, by covering the most of up to date studies, this review attempts to clarify the nature and the core of S. bovis/gallolyicus association with colorectal tumors and analyze the possible underlying mechanisms. PMID:21247505

A new approach to epigenome-wide discovery of non-invasive methylation biomarkers for colorectal cancer screening in circulating cell-free DNA using pooled samples.

PubMed

Gallardo-Gómez, María; Moran, Sebastian; Páez de la Cadena, María; Martínez-Zorzano, Vicenta Soledad; Rodríguez-Berrocal, Francisco Javier; Rodríguez-Girondo, Mar; Esteller, Manel; Cubiella, Joaquín; Bujanda, Luis; Castells, Antoni; Balaguer, Francesc; Jover, Rodrigo; De Chiara, Loretta

2018-01-01

Colorectal cancer is the fourth cause of cancer-related deaths worldwide, though detection at early stages associates with good prognosis. Thus, there is a clear demand for novel non-invasive tests for the early detection of colorectal cancer and premalignant advanced adenomas, to be used in population-wide screening programs. Aberrant DNA methylation detected in liquid biopsies, such as serum circulating cell-free DNA (cfDNA), is a promising source of non-invasive biomarkers. This study aimed to assess the feasibility of using cfDNA pooled samples to identify potential serum methylation biomarkers for the detection of advanced colorectal neoplasia (colorectal cancer or advanced adenomas) using microarray-based technology. cfDNA was extracted from serum samples from 20 individuals with no colorectal findings, 20 patients with advanced adenomas, and 20 patients with colorectal cancer (stages I and II). Two pooled samples were prepared for each pathological group using equal amounts of cfDNA from 10 individuals, sex-, age-, and recruitment hospital-matched. We measured the methylation levels of 866,836 CpG positions across the genome using the MethylationEPIC array. Pooled serum cfDNA methylation data meets the quality requirements. The proportion of detected CpG in all pools (> 99% with detection p value < 0.01) exceeded Illumina Infinium methylation data quality metrics of the number of sites detected. The differential methylation analysis revealed 1384 CpG sites (5% false discovery rate) with at least 10% difference in the methylation level between no colorectal findings controls and advanced neoplasia, the majority of which were hypomethylated. Unsupervised clustering showed that cfDNA methylation patterns can distinguish advanced neoplasia from healthy controls, as well as separate tumor tissue from healthy mucosa in an independent dataset. We also observed that advanced adenomas and stage I/II colorectal cancer methylation profiles, grouped as advanced neoplasia, are largely homogenous and clustered close together. This preliminary study shows the viability of microarray-based methylation biomarker discovery using pooled serum cfDNA samples as an alternative approach to tissue specimens. Our strategy sets an open door for deciphering new non-invasive biomarkers not only for colorectal cancer detection, but also for other types of cancers.

Effectiveness of computer-aided diagnosis of colorectal lesions using novel software for magnifying narrow-band imaging: a pilot study.

PubMed

Tamai, Naoto; Saito, Yutaka; Sakamoto, Taku; Nakajima, Takeshi; Matsuda, Takahisa; Sumiyama, Kazuki; Tajiri, Hisao; Koyama, Ryosuke; Kido, Shoji

2017-08-01

 Magnifying narrow-band imaging (M-NBI) enables detailed observation of microvascular architecture and can be used in endoscopic diagnosis of colorectal lesion. However, in clinical practice, differential diagnosis and estimation of invasion depth of colorectal lesions based on M-NBI findings require experience. Therefore, developing computer-aided diagnosis (CAD) for M-NBI would be beneficial for clinical practice. The aim of this study was to evaluate the effectiveness of software for CAD of colorectal lesions. In collaboration with Yamaguchi University, we developed novel software that enables CAD of colorectal lesions using M-NBI images. This software for CAD further specifically divides original Sano's colorectal M-NBI classification into 3 groups (group A, capillary pattern [CP] type I; group B, CP type II + CP type IIIA; group C, CP type IIIB), which describe hyperplastic polyps (HPs), adenoma/adenocarcinoma (intramucosal [IM] to submucosal [SM]-superficial) lesions, and SM-deep lesions, respectively. We retrospectively reviewed 121 lesions evaluated using M-NBI. The 121 reviewed lesions included 21 HP, 80 adenoma/adenocarcinoma (IM to SM-superficial), and 20 SM-deep lesions. The concordance rate between the CAD and the diagnosis of the experienced endoscopists was 90.9 %. The sensitivity, specificity, positive and negative predictive values, and accuracy of the CAD for neoplastic lesions were 83.9 %, 82.6 %, 53.1 %, 95.6 %, and 82.8 %, respectively. The values for SM-deep lesions were 83.9 %, 82.6 %, 53.1 %, 95.6 %, and 82.8 %, respectively.  Relatively high diagnostic values were obtained using CAD. This software for CAD could possibly lead to a wider use of M-NBI in the endoscopic diagnosis of colorectal lesions.

Analysis of Fecal DNA Methylation to Detect Gastrointestinal Neoplasia

PubMed Central

Tanaka, Noriaki; Cullings, Harry M.; Sun, Dong-Sheng; Sasamoto, Hiromi; Uchida, Takuyuki; Koi, Minoru; Nishida, Naoshi; Naomoto, Yoshio; Boland, C. Richard; Matsubara, Nagahide; Goel, Ajay

2009-01-01

Background The development of noninvasive screening tests is important to reduce mortality from gastrointestinal neoplasia. We sought to develop such a test by analysis of DNA methylation from exfoliated cancer cells in feces. Methods We first analyzed methylation of the RASSF2 and SFRP2 gene promoters from 788 primary gastric and colorectal tissue specimens to determine whether methylation patterns could act as stage-dependent biomarkers of gastrointestinal tumorigenesis. Next, we developed a novel strategy that uses single-step modification of DNA with sodium bisulfite and fluorescence polymerase chain reaction methodology to measure aberrant methylation in fecal DNA. Methylation of the RASSF2 and SFRP2 promoters was analyzed in 296 fecal samples obtained from a variety of patients, including 21 with gastric tumors, 152 with colorectal tumors, and 10 with non-neoplastic or inflammatory lesions in the gastrointestinal lumen. Results Analysis of DNA from tissues showed presence of extensive methylation in both gene promoters exclusively in advanced gastric and colorectal tumors. The assay successfully identified one or more methylated markers in fecal DNA from 57.1% of patients with gastric cancer, 75.0% of patients with colorectal cancer, and 44.4% of patients with advanced colorectal adenomas, but only 10.6% of subjects without neoplastic or active diseases (difference, gastric cancer vs undiseased  =  46.5%, 95% confidence interval (CI)  =  24.6% to 68.4%, P < .001; difference, colorectal cancer vs undiseased = 64.4%, 95% CI = 53.5% to 75.2%, P < .001; difference, colorectal adenoma vs undiseased = 33.8%, 95% CI = 14.2% to 53.4%, P < .001). Conclusions Methylation of the RASSF2 and SFRP2 promoters in fecal DNA is associated with the presence of gastrointestinal tumors relative to non-neoplastic conditions. Our novel fecal DNA methylation assay provides a possible means to noninvasively screen not only for colorectal tumors but also for gastric tumors. PMID:19700653

Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

PubMed Central

Palles, Claire; Cazier, Jean-Baptiste; Howarth, Kimberley M; Domingo, Enric; Jones, Angela M.; Broderick, Peter; Kemp, Zoe; Spain, Sarah L; Almeida, Estrella Guarino; Salguero, Israel; Sherborne, Amy; Chubb, Daniel; Carvajal-Carmona, Luis G; Ma, Yusanne; Kaur, Kulvinder; Dobbins, Sara; Barclay, Ella; Gorman, Maggie; Martin, Lynn; Kovac, Michal B; Humphray, Sean; Lucassen, Anneke; Holmes, Christopher; Bentley, David; Donnelly, Peter; Taylor, Jenny; Petridis, Christos; Roylance, Rebecca; Sawyer, Elinor J; Kerr, David J.; Clark, Susan; Grimes, Jonathan; Kearsey, Stephen E; Thomas, Huw JW; McVean, Gilean; Houlston, Richard S; Tomlinson, Ian

2013-01-01

Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations. PMID:23263490

Prevalence of any size adenomas and advanced adenomas in 40- to 49-year-old individuals undergoing screening colonoscopy because of a family history of colorectal carcinoma in a first-degree relative.

PubMed

Gupta, Akshay K; Samadder, Jewel; Elliott, Eric; Sethi, Saurabh; Schoenfeld, Philip

2011-07-01

Per current guidelines, patients with a first-degree relative (FDR) with colorectal cancer (CRC) should get screened at least at age 40. Data about the prevalence of adenomas and advanced adenomas (AAs) in these patients are lacking. To examine the prevalence of adenomas and AAs in 40- to 49-year-old individuals undergoing screening colonoscopy for family history of CRC. Retrospective chart review. Asymptomatic patients 40 to 49 years of age undergoing their first screening colonoscopy at the University of Michigan during the period 1999 to 2009 because of an FDR with CRC. Prevalence of adenomas (any size), AAs, and risk factors associated with adenomas. Among 640 study patients, the prevalence of adenomas (any size) was 15.4% and 3.3% for AAs. Adenoma prevalence was lower if the FDR with CRC was younger than 60 years of age versus an FDR with CRC older than 60 years of age (12.4% vs 19%, P = .034). Male sex (odds ratio 2.6; 95% CI, 1.06-4.4) and advancing age (odds ratio 1.16; 95% CI, 1.03-1.31) were associated with adenomas. Limited data on risk factor exposure and insufficient sample size to assess risk factors for AAs. Among 40- to 49-year-old patients undergoing screening colonoscopy because of an FDR with CRC, the prevalence of adenomas and AAs is low. Further research should determine whether these individuals have a higher prevalence of adenomas compared with average-risk individuals. Copyright © 2011 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

Evaluation of a 5-Marker Blood Test for Colorectal Cancer Early Detection in a Colorectal Cancer Screening Setting.

PubMed

Werner, Simone; Krause, Friedemann; Rolny, Vinzent; Strobl, Matthias; Morgenstern, David; Datz, Christian; Chen, Hongda; Brenner, Hermann

2016-04-01

In initial studies that included colorectal cancer patients undergoing diagnostic colonoscopy, we had identified a serum marker combination able to detect colorectal cancer with similar diagnostic performance as fecal immunochemical test (FIT). In this study, we aimed to validate the results in participants of a large colorectal cancer screening study conducted in the average-risk, asymptomatic screening population. We tested serum samples from 1,200 controls, 420 advanced adenoma patients, 4 carcinoma in situ patients, and 36 colorectal cancer patients with a 5-marker blood test [carcinoembryonic antigen (CEA)+anti-p53+osteopontin+seprase+ferritin]. The diagnostic performance of individual markers and marker combinations was assessed and compared with stool test results. AUCs for the detection of colorectal cancer and advanced adenomas with the 5-marker blood test were 0.78 [95% confidence interval (CI), 0.68-0.87] and 0.56 (95% CI, 0.53-0.59), respectively, which now is comparable with guaiac-based fecal occult blood test (gFOBT) but inferior to FIT. With cutoffs yielding specificities of 80%, 90%, and 95%, the sensitivities for the detection of colorectal cancer were 64%, 50%, and 42%, and early-stage cancers were detected as well as late-stage cancers. For osteopontin, seprase, and ferritin, the diagnostic performance in the screening setting was reduced compared with previous studies in diagnostic settings while CEA and anti-p53 showed similar diagnostic performance in both settings. Performance of the 5-marker blood test under screening conditions is inferior to FIT even though it is still comparable with the performance of gFOBT. CEA and anti-p53 could contribute to the development of a multiple marker blood-based test for early detection of colorectal cancer. ©2015 American Association for Cancer Research.

Paleolithic and Mediterranean Diet Pattern Scores and Risk of Incident, Sporadic Colorectal Adenomas

PubMed Central

Whalen, Kristine A.; McCullough, Marji; Flanders, W. Dana; Hartman, Terryl J.; Judd, Suzanne; Bostick, Roberd M.

2014-01-01

The Western dietary pattern is associated with higher risk of colorectal neoplasms. Evolutionary discordance could explain this association. We investigated associations of scores for 2 proposed diet patterns, the “Paleolithic” and the Mediterranean, with incident, sporadic colorectal adenomas in a case-control study of colorectal polyps conducted in Minnesota (1991–1994). Persons with no prior history of colorectal neoplasms completed comprehensive questionnaires prior to elective, outpatient endoscopy; of these individuals, 564 were identified as cases and 1,202 as endoscopy-negative controls. An additional group of community controls frequency-matched on age and sex (n = 535) was also recruited. Both diet scores were calculated for each participant and categorized into quintiles, and associations were estimated using unconditional logistic regression. The multivariable-adjusted odds ratios comparing persons in the highest quintiles of the Paleolithic and Mediterranean diet scores relative to the lowest quintiles were, respectively, 0.71 (95% confidence interval (CI): 0.50, 1.02; Ptrend = 0.02) and 0.74 (95% CI: 0.54, 1.03; Ptrend = 0.05) when comparing cases with endoscopy-negative controls and 0.84 (95% CI: 0.56, 1.26; Ptrend = 0.14) and 0.77 (95% CI: 0.53, 1.11; Ptrend = 0.13) when comparing cases with community controls. These findings suggest that greater adherence to the Paleolithic diet pattern and greater adherence to the Mediterranean diet pattern may be similarly associated with lower risk of incident, sporadic colorectal adenomas. PMID:25326623

K-ras mutations and HLA-DR expression in large bowel adenomas.

PubMed Central

Norheim Andersen, S.; Breivik, J.; Løvig, T.; Meling, G. I.; Gaudernack, G.; Clausen, O. P.; Schjölberg, A.; Fausa, O.; Langmark, F.; Lund, E.; Rognum, T. O.

1996-01-01

A total of 72 sporadic colorectal adenomas in 56 patients were studied for the presence of point mutations in codons 12 and 13 of the K-ras gene and for HLA-DR antigen expression related to clinicopathological variables. Forty K-ras mutations in 39 adenomas were found (54%): 31 (77%) in codon 12 and nine (23%) in codon 13. There was a strong relationship between the incidence of K-ras mutations and adenoma type, degree of dysplasia and sex. The highest frequency of K-ras mutations was seen in large adenomas of the villous type with high-grade dysplasia. Fourteen out of 15 adenomas obtained from 14 women above 65 years of age carried mutations. HLA-DR positivity was found in 38% of the adenomas, large tumours and those with high-grade dysplasia having the strongest staining. Coexpression of K-ras mutations and HLA-DR was found significantly more frequently in large and highly dysplastic adenomas, although two-way analysis of variance showing size and grade of dysplasia to be the most important variable. None of the adenomas with low-grade dysplasia showed both K-ras mutation and HLA-DR positivity (P = 0.004). K-ras mutation is recognised as an early event in colorectal carcinogenesis. The mutation might give rise to peptides that may be presented on the tumour cell surface by class II molecules, and thereby induce immune responses against neoplastic cells. Images Figure 3 Figure 4 Figure 5 Figure 6 PMID:8679466

Endoscopic spectral domain optical coherence tomography of murine colonic morphology to determine effectiveness of chemopreventive and chemotherapeutic agents in colorectal cancer

NASA Astrophysics Data System (ADS)

LeGendre-McGhee, Susan; Rice, Photini F. S.; Wall, R. Andrew; Klein, Justin; Luttman, Amber; Sprute, Kyle; Gerner, Eugene; Barton, Jennifer K.

2012-02-01

Optical coherence tomography (OCT) is a minimally-invasive imaging modality capable of tracking the development of individual colonic adenomas. As such, OCT can be used to evaluate the mechanisms and effectiveness of chemopreventive and chemotherapeutic agents in colorectal cancer models. The data presented here represent part of a larger study evaluating α-difluoromethylornithine (DFMO) and Sulindac as chemopreventive and chemotherapeutic agents using mice treated with the carcinogen azoxymethane (AOM). 27 A/J mice were included in the chemoprevention study, subdivided into four treatment groups (No Drug, DFMO, Sulindac, DFMO/Sulindac). 30 mm lateral images of each colon at eight different rotations were obtained at five different time points using a 2 mm diameter spectral domain OCT endoscopy system centered at 890 nm with 3.5 μm axial resolution in air and 5 μm lateral resolution. Images were visually analyzed to determine number and size of adenomas. Gross photos of the excised colons and histology provided gold standard confirmation of the final imaging time point. Preliminary results show that 100% of mice in the No Drug group developed adenomas over the course of the chemoprevention study. Incidence was reduced to 71.43% in mice given DFMO, 85.71% for Sulindac and 0% for DFMO/Sulindac. Discrete adenoma size did not vary significantly between experimental groups. Additional experiments are currently under way to verify these results and evaluate DFMO and Sulindac for chemotherapeutic applications.

Effect of cyanidin-3-glucoside and an anthocyanin mixture from bilberry on adenoma development in the ApcMin mouse model of intestinal carcinogenesis--relationship with tissue anthocyanin levels.

PubMed

Cooke, Darren; Schwarz, Michael; Boocock, David; Winterhalter, Peter; Steward, William P; Gescher, Andreas J; Marczylo, Timothy H

2006-11-01

Anthocyanins are dietary flavonoids, which can prevent carcinogen-induced colorectal cancer in rats. Here, the hypotheses were tested that Mirtoselect, an anthocyanin mixture from bilberry, or isolated cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, interfere with intestinal adenoma formation in the Apc(Min) mouse, a genetic model of human familial adenomatous polyposis, and that consumption of C3G or Mirtoselect generates measurable levels of anthocyanins in the murine biophase. Apc(Min) mice ingested C3G or Mirtoselect at 0.03, 0.1 or 0.3% in the diet for 12 weeks, and intestinal adenomas were counted. Plasma, urine and intestinal mucosa were analyzed for presence of anthocyanins by high-pressure liquid chromatography with detection by UV spectrophotometry (520 nm) or tandem mass spectrometry (multiple reaction monitoring). Ingestion of either C3G or Mirtoselect reduced adenoma load dose-dependently. At the highest doses of C3G and Mirtoselect adenoma numbers were decreased by 45% (p < 0.001) or 30% (p < 0.05), respectively, compared to controls. Anthocyanins were found at the analytical detection limit in the plasma and at quantifiable levels in the intestinal mucosa and urine. Anthocyanin glucuronide and methyl metabolites were identified in intestine and urine. Total anthocyanin levels in mice on C3G or Mirtoselect were 43 ng and 8.1 microg/g tissue, respectively, in the intestinal mucosa, and 7.2 and 12.3 microg/ml in the urine. The efficacy of C3G and Mirtoselect in the Apc(Min) mouse renders the further development of anthocyanins as potential human colorectal cancer chemopreventive agents worthwhile.

The comparative cost-effectiveness of colorectal cancer screening using faecal immunochemical test vs. colonoscopy.

PubMed

Wong, Martin C S; Ching, Jessica Y L; Chan, Victor C W; Sung, Joseph J Y

2015-09-04

Faecal immunochemical tests (FITs) and colonoscopy are two common screening tools for colorectal cancer(CRC). Most cost-effectiveness studies focused on survival as the outcome, and were based on modeling techniques instead of real world observational data. This study evaluated the cost-effectiveness of these two tests to detect colorectal neoplastic lesions based on data from a 5-year community screening service. The incremental cost-effectiveness ratio (ICER) was assessed based on the detection rates of neoplastic lesions, and costs including screening compliance, polypectomy, colonoscopy complications, and staging of CRC detected. A total of 5,863 patients received yearly FIT and 4,869 received colonoscopy. Compared with FIT, colonoscopy detected notably more adenomas (23.6% vs. 1.6%) and advanced lesions or cancer (4.2% vs. 1.2%). Using FIT as control, the ICER of screening colonoscopy in detecting adenoma, advanced adenoma, CRC and a composite endpoint of either advanced adenoma or stage I CRC was US$3,489, US$27,962, US$922,762 and US$23,981 respectively. The respective ICER was US$3,597, US$439,513, -US$2,765,876 and US$32,297 among lower-risk subjects; whilst the corresponding figure was US$3,153, US$14,852, US$184,162 and US$13,919 among higher-risk subjects. When compared to FIT, colonoscopy is considered cost-effective for screening adenoma, advanced neoplasia, and a composite endpoint of advanced neoplasia or stage I CRC.

The comparative cost-effectiveness of colorectal cancer screening using faecal immunochemical test vs. colonoscopy

PubMed Central

Wong, Martin CS; Ching, Jessica YL; Chan, Victor CW; Sung, Joseph JY

2015-01-01

Faecal immunochemical tests (FITs) and colonoscopy are two common screening tools for colorectal cancer(CRC). Most cost-effectiveness studies focused on survival as the outcome, and were based on modeling techniques instead of real world observational data. This study evaluated the cost-effectiveness of these two tests to detect colorectal neoplastic lesions based on data from a 5-year community screening service. The incremental cost-effectiveness ratio (ICER) was assessed based on the detection rates of neoplastic lesions, and costs including screening compliance, polypectomy, colonoscopy complications, and staging of CRC detected. A total of 5,863 patients received yearly FIT and 4,869 received colonoscopy. Compared with FIT, colonoscopy detected notably more adenomas (23.6% vs. 1.6%) and advanced lesions or cancer (4.2% vs. 1.2%). Using FIT as control, the ICER of screening colonoscopy in detecting adenoma, advanced adenoma, CRC and a composite endpoint of either advanced adenoma or stage I CRC was US$3,489, US$27,962, US$922,762 and US$23,981 respectively. The respective ICER was US$3,597, US$439,513, -US$2,765,876 and US$32,297 among lower-risk subjects; whilst the corresponding figure was US$3,153, US$14,852, US$184,162 and US$13,919 among higher-risk subjects. When compared to FIT, colonoscopy is considered cost-effective for screening adenoma, advanced neoplasia, and a composite endpoint of advanced neoplasia or stage I CRC. PMID:26338314

Pathology of serrated colorectal lesions.

PubMed

Bateman, Adrian C

2014-10-01

The concept of serrated colorectal neoplasia has become recognised as a key process in the development of colorectal cancer (CRC) and an important alternative pathway to malignancy compared with the long established ‘adenoma-carcinoma’ sequence. Increasing recognition of the morphological spectrum of serrated lesions has occurred in parallel with elucidation of the distinct molecular genetic characteristics of progression from normal mucosa, via the ‘serrated pathway’, to CRC. Some of these lesions can be difficult to identify at colonoscopy. Challenges for pathologists include the requirement for accurate recognition of the forms of serrated lesions that are associated with a significant risk of malignant progression and therefore the need for widely disseminated reproducible criteria for their diagnosis. Alongside this process, pathologists and endoscopists need to formulate clear guidelines for the management of patients with these lesions, particularly with respect to the optimal follow-up intervals. This review provides practical guidance for the recognition of these lesions by pathologists, a discussion of ‘serrated adenocarcinoma’ and an insight into the distinct molecular genetic alterations that are seen in this spectrum of lesions in comparison to those that characterise the classic ‘adenoma-carcinoma’ sequence.

Chemoprevention of polyp recurrence with curcumin followed by silibinin in a case of multiple colorectal adenomas.

PubMed

Alfonso-Moreno, Vicente; López-Serrano, Antonio; Moreno-Osset, Eduardo

2017-12-01

Chemoprevention is a practical approach to reduce the risk of various cancers including colorectal cancer (CRC). The goal is to reduce the incidence of pre-neoplastic adenomatous polyps and prevent its progression to CRC. Curcumin and silibinin prevent intestinal polyp formation in mice. Curcumin sensitizes silymarin to exert synergistic anticancer activity in colon cancer cells. Patients presenting with multiple colorectal adenomatous polyps (MCRA) have a high lifetime risk for CRC. We present a 57-year-old man with MCRA, without deleterious germline APC or MYH mutations. Our patient had 54 polyps in the first colonoscopy, most of 3 to 8 mm and one of 20 mm with high grade dysplasia / adenocarcinoma. Four subsequent colonoscopies showed continuous development of adenomatous polyps treated by polypectomy for the most part and some with heat. After the treatment with curcumin for 3 months and a half followed by silibinin for 9 months, we find many less polyps than in the previous colonoscopies, going from the finding of 40 adenomas of 3-6 mm in the pre-treatment colonoscopy to 3 polyps after treatment.

[Clinical and endoscopic features of a selected population with serrated colorectal adenomas in a private clinic in Lima - Peru].

PubMed

Castillo, Ofelia; Barreda, Carlos; Recavarren, Sixto; Barriga, José A; Salazar M, Fernando; Yriberry, Simón; Barriga, Eduardo; Salazar C, Fernando

2013-01-01

To describe the clinical and endoscopic caracteristics of a population that has only serrated polyps of colon (mainly sessile serrated adenomas) in a private clinic in Lima, Perú, from 2009-2011. Retrospective study conducted at the endoscopy center of Clinic Ricardo Palma, Lima, Peru. Olympus colonoscope was used with high definition, including NBI (narrow band imaging) and electronic magnification. Patients had pathologic diagnosis of “polyps and / or colorectal serrated adenomas” and excluded those with synchronous tubular or villous adenomas. Images were evaluated by two endoscopists and then by a third gastroenterologist. We found 201 serrated polyps in 108 patients. Women were 60.2% and overweight predominated. Eighty (74.1%) had only one serrated adenoma and 23 (21.3%) with at least one synchronous hyperplastic polyp. The average size of sessile serrated adenomas was 5.12 mm (± 3.87 DS) and the flat type was 91 (58.7%). There were significant differences in the diameter of sessile serrated adenomas between the distal and proximal colon (4.47 mm ± 2.23 vs. 6.90 mm ± 6.25; p<0.000). The common features of sessile serrated adenomas were: White (31/36, 86.1%), smooth (28/36, 77.8%) and regular margins (26/36, 72.2%). There was a relationship between vascular pattern according NBI and serrated polyp histology (p=0.024). The endoscopic features of sessile serrated adenomas can evade detection to white light. NBI is a useful tool to define some features of these lesions.

Sessile Serrated Adenomas: How to Detect, Characterize and Resect

PubMed Central

Ma, Michael X.; Bourke, Michael J.

2017-01-01

Serrated polyps are important contributors to the burden of colorectal cancers (CRC). These lesions were once considered to have no malignant potential, but currently up to 30% of all CRC are recognized to arise from the serrated neoplasia pathway. The primary premalignant lesions are sessile serrated adenomas/polyps (SSA/Ps), although traditional serrated adenomas are relatively uncommon. Compared to conventional adenomas, SSA/Ps are morphologically subtle with indistinct borders, may be difficult to detect endoscopically, are more prevalent than previously thought, are associated with synchronous and metachronous advanced neoplasia, and have a higher risk of incomplete resection. Although many lesions remain “dormant,” progressive disease is associated with the development of dysplasia and more rapid progression to CRC. As a result, SSA/Ps are strongly implicated in the development of interval cancers. These factors represent unique challenges that require a meticulous approach to their management. In this review, we summarize the contemporary literature on the characterization, detection and resection of SSA/Ps. PMID:28494577

Food intake and colorectal adenomas: a case-control study in Malaysia.

PubMed

Ramadas, Amutha; Kandiah, Mirnalini

2009-01-01

It is well established that almost all colorectal cancers arise from benign, neoplastic adenomatous polyps. In previous studies, intake of fruits, vegetables and legumes were found to decrease the risk for colorectal adenomas (CRA) and colorectal cancer. This case-control study aimed to evaluate the roles of a variety of foods in contributing to the risk of CRA in Malaysian subjects. One hundred and eighteen subjects were recruited into case (n=59) and control (n=59) groups at Hospital Kuala Lumpur (HKL). A pre-tested quantitative food frequency questionnaire (FFQ) was used to record the types of food items and frequency consumed. Logistic regression was used to determine the crude and adjusted odds ratios of the independent variables. Soy bean and soy products were associated with a reduced risk for CRA (OR = 0.38, 95% CI = 0.15-0.98), while tubers were associated with increase in risk four-fold (OR = 4.14, 95% CI = 1.60-10.70) and red meat intake was found to increase the risk two and a half-fold (OR = 2.51, 95% CI = 1.02-6.28). Higher servings of fruits and vegetables were found to significantly decrease the risk (OR fruits = 0.47, 95% CI = 0.30-0.74; OR vegetables = 0.49, 95% = 0.29-0.80). In conclusion, our data support protective roles for soy, fruits and vegetables in the aetiology of colorectal adenomas and increase in risk in those with high intakes of red meat and tubers. Food intake of an individual may have an influence on one's risk for developing CRA. This finding warrants further investigation before the protective effect of these food items is to be accepted. New studies should explore the possibility of these associations among individuals in the general population especially with regard to different ethnic or other groups in Malaysia with low fruit and vegetable consumption.

Trimodal endoscopic imaging for the detection and differentiation of colorectal adenomas: a prospective single-centre clinical evaluation.

PubMed

Rotondano, Gianluca; Bianco, Maria Antonia; Sansone, Stefano; Prisco, Antonio; Meucci, Costantino; Garofano, Maria Lucia; Cipolletta, Livio

2012-03-01

The purpose of this study is to evaluate an endoscopic trimodal imaging (ETMI) system (high resolution, autofluorescence, and NBI) in the detection and differentiation of colorectal adenomas. A prospective randomised trial of tandem colonoscopies was carried out using the Olympus XCF-FH260AZI system. Each colonic segment was examined twice for lesions, once with HRE and once with AFI, in random order per patient. All detected lesions were assessed with NBI for pit pattern and with AFI for colour. All lesions were removed and sent for histology. Any lesion identified on the second examination was considered as missed by the first examination. Outcome measures are adenoma miss rates of AFI and HRE, and diagnostic accuracy of NBI and AFI for differentiating neoplastic from non-neoplastic lesions. Ninety-four patients underwent colonoscopy with ETMI (47 in each group). Among 47 patients examined with AFI first, 31 adenomas in 15 patients were detected initially [detection rate 0.66 (0.52-0.75)]. Subsequent HRE inspection identified six additional adenomas. Among 47 patients examined with HRE first, 29 adenomas in 14 patients were detected initially [detection rate 0.62 (0.53-0.79)]. Successive AFI yielded seven additional adenomas. Adenoma miss rates of AFI and HRE were 14% and 16.2%, respectively (p = 0.29). Accuracy of AFI alone for differentiation was lower than NBI (63% vs. 80%, p < 0.001). Combined use of AFI and NBI achieved improved accuracy for differentiation (84%), showing a trend for superiority compared with NBI alone (p = 0.064). AFI did not significantly reduce the adenoma miss rate compared with HRE. AFI alone had a disappointing accuracy for adenoma differentiation, which could be improved by combination of AFI and NBI.

Colonoscopy Reduces Risk of Death from Colorectal Cancer in High-Risk Patients

Cancer.gov

Long-term results from the National Polyp Study confirm that removing precancerous adenomas not only reduces the risk of colorectal cancer but also reduces the number of deaths from the disease by more than half.

Disparities in prevalence, location, and shape characteristics of colorectal neoplasia between South Korean and U.S. patients.

PubMed

Cha, Jae Myung; Kozarek, Richard A; La Selva, Danielle; Gluck, Michael; Ross, Andrew; Chiorean, Michael; Koch, Johannes; Lin, Otto S

2015-12-01

Colon cancer screening is being introduced in many countries, but standard Western screening approaches may not be appropriate for Asian societies if differences in colon cancer epidemiology exist. Comparative analysis of colorectal neoplasia patterns in South Korean and Western subjects has implications for appropriate screening approaches in non-Western societies. The results of concurrent screening colonoscopies performed in average-risk patients 50 to 69 years old in 2 teaching hospitals, Kyung Hee University Hospital (Seoul, South Korea) and Virginia Mason Medical Center (Seattle, Wash), were compared with respect to prevalence, histologic features, anatomic distribution, and shape characteristics of colorectal neoplasia. The U.S. (n = 3460) and South Korean (n = 2193) cohorts were similar with regard to the prevalence of adenomas (28.5% vs 29.8%, respectively, P = .312) and advanced neoplasia (6.4% vs 5.4%, respectively, P = .102), but the proportion of proximal adenomas was greater in the U.S. cohort (62.8% vs 45.9%, P < .001). The prevalence of adenomas and advanced neoplasia was similar in male patients, but there was a greater prevalence of neoplasia (23.5% vs 18.8%, P = .006) and advanced neoplasia (5.1% vs 2.7%, P < .001) in U.S. women than South Korean women. When large (≥10 mm) adenomas were considered, proximal location and nonpolypoid (flat) shape were more common in the U.S. cohort (79.4% vs 37.1%, P = .003 and 43.5% vs 12.3%, P < .001, respectively). The overall prevalence of large flat adenomas in the U.S. cohort was 5 times that of the South Korean cohort (2.6% vs 0.5%, P < .001). Adjustment for sex ratio discrepancies (48.3% men in the U.S. cohort vs 60.8% in the South Korean cohort, P < .001) did not result in any significant changes in the conclusions. Compared with Westerners, South Koreans have a more distal distribution of adenomas and advanced neoplasia and lower prevalence of large flat adenomas. South Korean women have a lower prevalence of colorectal neoplasia than Western women. Such disparities suggest that Western screening strategies cannot be directly adopted by other countries, but need to be customized by society. Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Adiponectin, Leptin, IGF-1, and Tumor Necrosis Factor Alpha As Potential Serum Biomarkers for Non-Invasive Diagnosis of Colorectal Adenoma in African Americans.

PubMed

Ashktorab, Hassan; Soleimani, Akbar; Nichols, Alexandra; Sodhi, Komal; Laiyemo, Adeyinka O; Nunlee-Bland, Gail; Nouraie, Seyed Mehdi; Brim, Hassan

2018-01-01

The potential role of adiponectin, leptin, IGF-1, and tumor necrosis factor alpha (TNF-α) as biomarkers in colorectal adenoma is not clear. Therefore, we aimed to investigate the blood serum levels of these biomarkers in colorectal adenoma. The case-control study consisted of serum from 180 African American patients with colon adenoma (cases) and 198 healthy African Americans (controls) at Howard University Hospital. We used ELISA for adiponectin, leptin, IGF-1, and TNF-α detection and quantification. Statistical analysis was performed by t -test and multivariate logistic regression. The respective differences in median leptin, adiponectin, IGF-1, and TNF-α levels between control and case groups (13.9 vs. 16.4), (11.3 vs. 46.0), (4.5 vs. 12.9), and (71.4 vs. 130.8) were statistically significant ( P  < 0.05). In a multivariate model, the odds ratio for adiponectin, TNF-α, and IGF-1 were 2.0 (95% CI = 1.6-2.5; P  < 0.001), 1.5 (95% CI = 1.5(1.1-2.0); P  = 0.004), and 1.6 (95% CI = 1.3-2.0; P  < 0.001), respectively. There was a positive correlation between serum adiponectin and IGF-1 concentrations with age ( r  = 0.17, P  < 0.001 and r  = 0.13, P  = 0.009), TNF-α, IGF-1, and leptin concentration with body mass index (BMI) ( r  = 0.44, P  < 0.001; r  = 0.11, P  = 0.03; and r  = 0.48, P  < 0.001), respectively. Also, there was a negative correlation between adiponectin and leptin concentrations with BMI ( r  = -0.40, P  < 0.001), respectively. These data support the hypothesis that adiponectin, IGF-1, and TNF-α high levels correlate with higher risk of colon adenoma and can thus be used for colorectal adenomas risk assessment.

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.

PubMed

Palles, Claire; Cazier, Jean-Baptiste; Howarth, Kimberley M; Domingo, Enric; Jones, Angela M; Broderick, Peter; Kemp, Zoe; Spain, Sarah L; Guarino, Estrella; Guarino Almeida, Estrella; Salguero, Israel; Sherborne, Amy; Chubb, Daniel; Carvajal-Carmona, Luis G; Ma, Yusanne; Kaur, Kulvinder; Dobbins, Sara; Barclay, Ella; Gorman, Maggie; Martin, Lynn; Kovac, Michal B; Humphray, Sean; Lucassen, Anneke; Holmes, Christopher C; Bentley, David; Donnelly, Peter; Taylor, Jenny; Petridis, Christos; Roylance, Rebecca; Sawyer, Elinor J; Kerr, David J; Clark, Susan; Grimes, Jonathan; Kearsey, Stephen E; Thomas, Huw J W; McVean, Gilean; Houlston, Richard S; Tomlinson, Ian

2013-02-01

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.

The Intestinal Microbiota in Colorectal Cancer.

PubMed

Tilg, Herbert; Adolph, Timon E; Gerner, Romana R; Moschen, Alexander R

2018-06-11

Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis. Further studies are needed to decipher the mechanisms of tumor promotion and microbial co-evolution in CRC, which may be exploited therapeutically in the future. Copyright © 2018 Elsevier Inc. All rights reserved.

Developments in Colorectal Cancer Screening | NIH MedlinePlus the Magazine

MedlinePlus

... cancer screening test for them? Colonoscopy is considered the gold standard. It is effective for screening and detection, and it is therapeutic as well since adenomas (a type of precancerous polyp) ... be removed. That’s the biggest advantage of colonoscopy as opposed to all ...

Racial differences in the association of insulin-like growth factor pathway and colorectal adenoma risk

PubMed Central

Vaughn, Caila B.; Nie, Jing; Chen, Zhengyi; Thompson, Cheryl L.; Parekh, Niyati; Tracy, Russell

2013-01-01

Purpose Insulin resistance is believed to play an important role in the link between energy imbalance and colon carcinogenesis. Emerging evidence suggests that there are substantial racial differences in genetic and anthropometric influences on insulin-like growth factors (IGFs); however, few studies have examined racial differences in the associations of IGFs and colorectal adenoma, precursor lesions of colon cancer. Methods We examined the association of circulating levels of IGF-1, IGFBP-3 and IGFBP-1, and SNPs in the IGF-1 receptor (IGF1R), IGF-2 receptor (IGF2R), and insulin receptor genes with risk of adenomas in a sample of 410 incident adenoma cases and 1,070 controls from the Case Transdisciplinary Research on Energetics and Cancer (TREC) Colon Adenomas Study. Results Caucasians have higher IGF-1 levels compared to African Americans; mean IGF-1 levels are 119.0 ng/ml (SD = 40.7) and 109.8 ng/ml (SD = 40.8), respectively, among cases (p = 0.02). Mean IGF-1 levels are also higher in Caucasian controls (122.9 ng/ml, SD = 41.2) versus African American controls (106.9, SD = 41.2), p = 0.001. We observed similar differences in IGFBP3 levels by race. Logistic regression models revealed a statistically signifi-cant association of IGF-1 with colorectal adenoma in African Americans only, with adjusted odds ratios (ORs) of 1.68 (95 % CI 1.06–2.68) and 1.68 (95 % CI 1.05–2.71), respectively, for the second and third tertiles as compared to the first tertile. One SNP (rs496601) in IGF1R was associated with adenomas in Caucasians only; the per allele adjusted OR is 0.73 (95 % CI 0.57–0.93). Similarly, one IGF2R SNP (rs3777404) was statistically significant in Caucasians; adjusted per allele OR is 1.53 (95 % CI 1.10–2.14). Conclusion Our results suggest racial differences in the associations of IGF pathway biomarkers and inherited genetic variance in the IGF pathway with risk of adenomas that warrant further study. PMID:24194259

Synchronous occurrence of appendiceal mucinous cystadenoma, with colon adenocarcinoma and tubulovillous rectal adenoma: Management and review of the literature.

PubMed

Salemis, Nikolaos S; Nakos, Georgios; Katikaridis, Ilias; Zografidis, Andreas

2016-01-01

Appendiceal mucocele (AM) is a rare clinical entity comprising 8% of all appendiceal tumors, and it is seen in 0.2-0.3% of all appendectomy specimens. Apart from sporadic cases, there are no enough published data about the incidence of synchronous appendiceal tumors in patients with colorectal cancer. We describe a very rare case of synchronous occurrence of AM, colon adenocarcinoma, and tubulovillous adenoma of the rectum and review the relevant literature. We conclude that thorough preoperative and perioperative evaluations are mandatory in patients undergoing surgery for colorectal cancer to exclude a synchronous colon or an appendiceal primary tumor. Larger prospective studies are necessary to accurately determine the incidence of synchronous appendiceal tumors and colorectal cancer.

Synchronous occurrence of appendiceal mucinous cystadenoma, with colon adenocarcinoma and tubulovillous rectal adenoma: Management and review of the literature

PubMed Central

Salemis, Nikolaos S.; Nakos, Georgios; Katikaridis, Ilias; Zografidis, Andreas

2016-01-01

Appendiceal mucocele (AM) is a rare clinical entity comprising 8% of all appendiceal tumors, and it is seen in 0.2-0.3% of all appendectomy specimens. Apart from sporadic cases, there are no enough published data about the incidence of synchronous appendiceal tumors in patients with colorectal cancer. We describe a very rare case of synchronous occurrence of AM, colon adenocarcinoma, and tubulovillous adenoma of the rectum and review the relevant literature. We conclude that thorough preoperative and perioperative evaluations are mandatory in patients undergoing surgery for colorectal cancer to exclude a synchronous colon or an appendiceal primary tumor. Larger prospective studies are necessary to accurately determine the incidence of synchronous appendiceal tumors and colorectal cancer. PMID:27433069

Colorectal Cancer: Chemopreventive Role of Curcumin and Resveratrol

PubMed Central

Patel, Vaishali B.; Misra, Sabeena; Patel, Bhaumik B.; Majumdar, Adhip P. N.

2013-01-01

Colorectal cancer (CRC) is a second leading cause of cancer deaths in the Western world. Currently there is no effective treatment except resection at a very early stage with or with-out chemotherapy. Of various epithelial cancers, CRC in particular has a potential for prevention, since most cancers follow the adenoma-carcinoma sequence, and the interval between detection of an adenoma and its progression to carcinoma is usually about a decade. However no effective chemopreventive agent except COX-2 inhibitors, limited in their scope due to cardiovascular side effects, have shown promise in reducing adenoma recurrence. To this end, natural agents that can target important carcinogenic pathways without demonstrating discernible adverse effects would serve as ideal chemoprevention agents. In this review, we discuss merits of two such naturally occurring dietary agents—curcumin and resveratrol—for chemoprevention of CRC. PMID:20924971

Association between markers of glucose metabolism and risk of colorectal adenoma.

PubMed

Rampal, Sanjay; Yang, Moon Hee; Sung, Jidong; Son, Hee Jung; Choi, Yoon-Ho; Lee, Jun Haeng; Kim, Young-Ho; Chang, Dong Kyung; Rhee, Poong-Lyul; Rhee, Jong Chul; Guallar, Eliseo; Cho, Juhee

2014-07-01

Diabetes is a risk factor for colorectal cancer. We studied the association between markers of glucose metabolism and metabolic syndrome and the presence of colorectal adenomas in a large number of asymptomatic men and women attending a health screening program in South Korea. We also investigated whether these associations depend on adenoma location. In a cross-sectional study, we measured fasting levels of glucose, insulin, hemoglobin A1c, and C-peptide and calculated homeostatic model assessment (HOMA) values (used to quantify insulin resistance) for 19,361 asymptomatic South Korean subjects who underwent colonoscopy examinations from January 2006 to June 2009. Participants completed a standardized self-administered health questionnaire and a validated semiquantitative food frequency questionnaire. Blood samples were collected on the day of the colonoscopy; fasting blood samples were also collected. Robust Poisson regression was used to model the associations of glucose markers with the prevalence of any adenoma. Using detailed multivariable-adjusted dose-response models, the prevalence ratios (aPR, 95% confidence interval [CI]) for any adenoma, comparing the 90th with the 10th percentile, were 1.08 (1.00-1.16; P = .04) for fasting glucose, 1.07 (0.99-1.15; P = .10) for insulin, 1.09 (1.02-1.18, P = .02) for HOMA, 1.09 (1.01-1.17; P = .02) for hemoglobin A1c, and 1.14 (1.05-1.24; P = .002) for C-peptide. The corresponding ratios for nonadvanced adenomas were 1.11 (0.99-1.25; P = .08), 1.10 (0.98-1.24; P = .12), 1.15 (1.02-1.29; P = .02), 1.14 (1.01-1.28; P = .03), and 1.20 (1.05-1.37; P = .007), respectively. The corresponding ratios for advanced adenomas were 1.32 (0.94-1.84; P = .11), 1.23 (0.87-1.75; P = .24), 1.30 (0.92-1.85; P = .14), 1.13 (0.79-1.61; P = .50), and 1.67 (1.15-2.42; P = .007), respectively. Metabolic syndrome was associated with the prevalence of any adenoma (aPR, 1.18; 95% CI, 1.13-1.24; P < .001), nonadvanced adenoma (aPR, 1.30; 95% CI, 1.20-1.40; P < .001), and advanced adenoma (aPR, 1.42; 95% CI, 1.14-1.78; P = .002). Associations were similar for adenomas located in the distal versus proximal colon. Increasing levels of glucose, HOMA values, levels of hemoglobin A1c and C-peptide, and metabolic syndrome are significantly associated with the prevalence of adenomas. Adenomas should be added to the list of consequences of altered glucose metabolism. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients.

PubMed

Ahearn, Thomas U; Shaukat, Aasma; Flanders, W Dana; Rutherford, Robin E; Bostick, Roberd M

2012-10-01

APC/β-catenin pathway perturbation is a common early event in colorectal carcinogenesis and is affected by calcium and vitamin D in basic science studies. To assess the effects of calcium and vitamin D on adenomatous polyposis coli (APC), β-catenin, and E-cadherin expression in the normal appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Pathology-confirmed colorectal adenoma cases were treated with 2 g/day elemental calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months (N = 92; 23/group). Overall APC, β-catenin, and E-cadherin expression and distributions in colon crypts in normal-appearing rectal mucosa biopsies were detected by standardized automated immunohistochemistry and quantified by image analysis. In the vitamin D(3)-supplemented group relative to placebo, the proportion of APC in the upper 40% of crypts (Φh APC) increased 21% (P = 0.01), β-catenin decreased 12% (P = 0.18), E-cadherin increased 72% (P = 0.03), and the Φh APC/β-catenin ratio (APC/β-catenin score) increased 31% (P = 0.02). In the calcium-supplemented group Φh APC increased 10% (P = 0.12), β-catenin decreased 15% (P = 0.08), and the APC/β-catenin score increased 41% (P = 0.01). In the calcium/vitamin D(3)-supplemented group, β-catenin decreased 11% (P = 0.20), E-cadherin increased 51% (P = 0.08), and the APC/β-catenin score increased 16% (P = 0.26). These results support (i) that calcium and vitamin D modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms, (ii) calcium and vitamin D as potential chemopreventive agents against colorectal neoplasms, and (iii) the potential of APC, β-catenin, and E-cadherin expression as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.

Colorectal tumors within an urban minority population in New York City.

PubMed

Kanna, Balavenkatesh; Schori, Melissa; Azeez, Sulaiman; Kumar, Suresh; Soni, Anita

2007-06-01

Data on gender- and age-specific predisposition to colorectal tumors and colorectal tumor location and stage among the urban minority population in Northeastern United States is limited. To study the age and gender distribution of colorectal tumor type, location, and stage of colorectal tumors among urban minorities. Retrospective analysis of a database of 4,043 consecutive colonoscopies performed over a 2-year period. PARTICIPANTS/MEASUREMENTS: Of study participants, 99% were Hispanic or African American and two-thirds were women. Age, gender, colonoscopy findings, and biopsy results were analyzed in all study subjects. Outcome measures are expressed as odds ratios (OR) with 95% confidence intervals (CI). Colonoscopies, 2,394 (63.4%), were performed for cancer screening. Women had higher visit volume adjusted odds to undergo colonoscopy (OR 1.35; CI 1.26-1.44, P < .001). Individuals, 960 (23.7%), had adenomas, and 82 (2.0%) had colorectal cancer. Although cancers were outnumbered by adenomas in the colon proximal to splenic flexure (OR 0.48; CI 0.29-0.80 P = .002), 51% of all abnormalities and 35.4% of cancers were found in this region. Of cancers, 75% belonged to AJCC stage 0 to 2. Men had higher odds for both adenomas and cancers (OR 2.38, CI 2.0-2.82, P < .001). More polyps occurred at a younger age. Of the cancers, 38% were noted among the 50- to 59-year-old subjects. However, the odds of colorectal cancers were higher at age greater than 70 years (OR 1.91; CI 1.09-3.27, P < .05), specifically among men (OR 2.27, 95% CI 1.07-4.65, P < .05). Our study of colonoscopies demonstrates lower odds of colonoscopy after adjusting for visit volume and greater predilection for colorectal cancer among urban minority men. Although older individuals were more likely to have colorectal cancer, a high percentage of colorectal tumors were noted at a younger age. These findings emphasize the vital need for preventive health education and improving early access to colorectal screening among urban minority men. A large proportion of colorectal tumors were found proximal to splenic flexure, which supports colonoscopy as the preferred method for colorectal cancer screening in the urban minority population in New York City.

Developing screening services for colorectal cancer on Android smartphones.

PubMed

Wu, Hui-Ching; Chang, Chiao-Jung; Lin, Chun-Che; Tsai, Ming-Chang; Chang, Che-Chia; Tseng, Ming-Hseng

2014-08-01

Colorectal cancer (CRC) is an important health problem in Western countries and also in Asia. It is the third leading cause of cancer deaths in both men and women in Taiwan. According to the well-known adenoma-to-carcinoma sequence, the majority of CRC develops from colorectal adenomatous polyps. This concept provides the rationale for screening and prevention of CRC. Removal of colorectal adenoma could reduce the mortality and incidence of CRC. Mobile phones are now playing an ever more crucial role in people's daily lives. The latest generation of smartphones is increasingly viewed as hand-held computers rather than as phones, because of their powerful on-board computing capability, capacious memories, large screens, and open operating systems that encourage development of applications (apps). If we can detect the potential CRC patients early and offer them appropriate treatments and services, this would not only promote the quality of life, but also reduce the possible serious complications and medical costs. In this study, an intelligent CRC screening app on Android™ (Google™, Mountain View, CA) smartphones has been developed based on a data mining approach using decision tree algorithms. For comparison, the stepwise backward multivariate logistic regression model and the fecal occult blood test were also used. Compared with the stepwise backward multivariate logistic regression model and the fecal occult blood test, the proposed app system not only provides an easy and efficient way to quickly detect high-risk groups of potential CRC patients, but also brings more information about CRC to customer-oriented services. We developed and implemented an app system on Android platforms for ubiquitous healthcare services for CRC screening. It can assist people in achieving early screening, diagnosis, and treatment purposes, prevent the occurrence of complications, and thus reach the goal of preventive medicine.

Time Lapse to Colorectal Cancer: Telomere Dynamics Define the Malignant Potential of Polyps.

PubMed

Druliner, Brooke R; Ruan, Xiaoyang; Johnson, Ruth; Grill, Diane; O'Brien, Daniel; Lai, Tsung-Po; Rashtak, Shahrooz; Felmlee-Devine, Donna; Washechek-Aletto, Jill; Malykh, Andrei; Smyrk, Thomas; Oberg, Ann; Liu, Hongfang; Shay, Jerry W; Ahlquist, David A; Boardman, Lisa A

2016-09-01

Whereas few adenomas become cancer, most colorectal cancers arise from adenomas. Telomere length is a recognized biomarker in multiple cancers, and telomere maintenance mechanisms (TMM) are exploited by malignant cells. We sought to determine whether telomere length and TMM distinguish cancer-associated adenomas from those that are cancer-free. Tissues were identified as cancer-adjacent polyp (CAP)-residual adenoma contiguous with cancer-and cancer-free polyp (CFP)-adenomas without malignancy. Telomere length, TMM, and expression were measured in 102 tissues including peripheral blood leukocytes (PBLs), normal colon epithelium, adenoma, and cancer (in CAP cases) from 31 patients. Telomere length was measured in a separate cohort of 342 PBL from CAP and CFP patients. The mean differences in telomere length between normal and adenoma were greater in CAP than in CFP cases, P=0.001; telomere length in PBL was 91.7 bp greater in CAP than in CFP, P=0.007. Each 100 bp telomere increase was associated with a 1.14 (1.04-1.26) increased odds of being a CAP, P=0.0063. The polyp tissue from CAP patients had shorter telomeres and higher Telomerase reverse transcriptase (hTERT) expression compared with polyps from CFP patients, P=0.05. There was a greater degree of alternative lengthening of telomere (ALT) level difference in CFP polyps than in CAP polyps. The polyp telomere lengths of aggressive CAPs were significantly different from the polyps of non-aggressive CAPs, P=0.01. Adenomas that progress to cancer exhibit distinct telomere length and TMM profiles. We report for the first time that PBL telomeres differ in patients with polyps that become malignant, and therefore may have clinical value in adenoma risk assessment and management.

Paleolithic and Mediterranean diet pattern scores and risk of incident, sporadic colorectal adenomas.

PubMed

Whalen, Kristine A; McCullough, Marji; Flanders, W Dana; Hartman, Terryl J; Judd, Suzanne; Bostick, Roberd M

2014-12-01

The Western dietary pattern is associated with higher risk of colorectal neoplasms. Evolutionary discordance could explain this association. We investigated associations of scores for 2 proposed diet patterns, the "Paleolithic" and the Mediterranean, with incident, sporadic colorectal adenomas in a case-control study of colorectal polyps conducted in Minnesota (1991-1994). Persons with no prior history of colorectal neoplasms completed comprehensive questionnaires prior to elective, outpatient endoscopy; of these individuals, 564 were identified as cases and 1,202 as endoscopy-negative controls. An additional group of community controls frequency-matched on age and sex (n = 535) was also recruited. Both diet scores were calculated for each participant and categorized into quintiles, and associations were estimated using unconditional logistic regression. The multivariable-adjusted odds ratios comparing persons in the highest quintiles of the Paleolithic and Mediterranean diet scores relative to the lowest quintiles were, respectively, 0.71 (95% confidence interval (CI): 0.50, 1.02; Ptrend = 0.02) and 0.74 (95% CI: 0.54, 1.03; Ptrend = 0.05) when comparing cases with endoscopy-negative controls and 0.84 (95% CI: 0.56, 1.26; Ptrend = 0.14) and 0.77 (95% CI: 0.53, 1.11; Ptrend = 0.13) when comparing cases with community controls. These findings suggest that greater adherence to the Paleolithic diet pattern and greater adherence to the Mediterranean diet pattern may be similarly associated with lower risk of incident, sporadic colorectal adenomas. © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Do factors related to endogenous and exogenous estrogens modify the relationship between obesity and risk of colorectal adenomas in women?

PubMed

Wolf, Lesley A; Terry, Paul D; Potter, John D; Bostick, Roberd M

2007-04-01

Obesity has consistently been associated with increased colorectal cancer risk in men, but not in women. In the absence of postmenopausal hormone use (PMH), adipose-derived estrogen is the primary determinant of circulating estrogen levels in postmenopausal women, perhaps ameliorating the mitogenic effects of obesity in this group. Using data from a case-control study in the United States, we examined associations among obesity, potential modifying effects of factors related to endogenous and exogenous estrogen levels, and risk of colorectal adenoma. Cases (n = 219) were women of ages 30 to 74 years with colonoscopy proven, incident, sporadic, pathology-confirmed, adenomatous polyps of the colon and rectum. Two control groups were recruited: colonoscopy-confirmed polyp-free women (n = 438) and age- and zip code frequency-matched women randomly selected from the community (n = 247). Multivariate odds ratios and 95% confidence intervals (95% CI) for obese [body mass index (BMI) >or=30.0; compared with nonobese, BMI <25.0] premenopausal women were 2.09 (95% CI, 0.81-5.41) versus colonoscopy controls, and 5.18 (95% CI, 1.40-19.32) versus population controls. For PMH users, the corresponding odds ratios were 0.29 (95% CI, 0.12-0.70) versus colonoscopy controls and 0.64 (95% CI, 0.23-1.83) versus population controls. There was no significant association of BMI with adenoma risk for PMH nonusers. Findings for waist-to-hip ratio were similar to those for BMI. These data support the hypothesis that risk for colorectal adenoma may be increased with obesity among premenopausal women but decreased among postmenopausal women, especially if they also take PMH.

Results of faecal immunochemical test for colorectal cancer screening, in average risk population, in a cohort of 1389 subjects.

PubMed

Miuţescu, Bogdan; Sporea, Ioan; Popescu, Alina; Bota, Simona; Iovănescu, Dana; Burlea, Amelia; Mos, Liana; Miuţescu, Eftimie

2013-01-01

The aim of this study is to evaluate the usefulness of the fecal immunochemical test (FIT) in colorectal cancer screening, detection of precancerous lesions and early colorectal cancer. The study evaluated asymptomatic patients with average risk (no personal or family antecedents of polyps or colorectal cancer), aged between 50 and 74 years. The presence of the occult haemorrhage was tested with the immunochemical faecal test Hem Check 1 (Veda Lab, France). The subjects were not requested to have any dietary or drug restrictions. Colonoscopy was recommended in all subjects that tested positive. In our study, we had a total of 1389 participants who met the inclusion criteria, with a mean age of 61.2 ± 12.8 years, 565 (40.7%) men and 824 (59.3%) women. FIT was positive in 87 individuals (6.3%). In 57/87 subjects (65.5%) with positive FIT, colonoscopy was performed, while the rest of the subjects refused or delayed the investigation. A number of 5 (8.8%) patients were not able to have a complete colonoscopy, due to neoplastic stenosis. The colonoscopies revealed in 10 cases (0.7%) cancer, in 29 cases (2.1%) advanced adenomas and in 15 cases (1.1%) non advanced adenomas from the total participants in the study. The colonoscopies performed revealed a greater percentage of advanced adenomas in the left colon compared to the right colon, 74.1% vs. 28.6% (p<0.001). In our study, FIT had a positivity rate of 6.3%. The detection rate for advanced neoplasia was 2.8% (0.7% for cancer, 2.1% for advanced adenomas) in our study group. Adherence to colonoscopy for FIT-positive subjects was 65.5%.

Greater adherence to a Mediterranean diet is associated with lower prevalence of colorectal adenomas in men of all races.

PubMed

Haslam, Alyson; Robb, Sara Wagner; Hébert, James R; Huang, Hanwen; Ebell, Mark H

2017-12-01

To examine potential racial differences in Mediterranean diet scores and whether these differences are associated with the prevalence of colorectal adenoma (CRA), a cross-sectional analysis of data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was performed. The authors hypothesize that people consuming a more Mediterranean-like diet have lower odds of CRA. Flexible sigmoidoscopy was used to determine the presence of colorectal adenoma. Mediterranean diet scores were calculated from food frequency questionnaire responses. Logistic regression was used to determine the association between Mediterranean diet scores and the odds of prevalent CRA, as well as the joint effects of race and diet. Asians, followed by blacks, had higher Mediterranean diet scores than whites. Generally, men with better Mediterranean diet scores (altMED) had lower odds of CRA, but black and Asian men had even lower odds of prevalent CRA with better altMED diet scores than did white men with higher altMED diet scores. In this study population, all men had lower odds of prevalent CRA, but black and Asian men, who had higher (more favorable) altMED diet scores than whites, had even lower odds of prevalent CRA compared with white men. An altMED diet prescription may be especially beneficial for certain subpopulations who may be at higher risk of CRA. Copyright © 2017 Elsevier Inc. All rights reserved.

Can gallbladder polyps predict colorectal adenoma or even neoplasia? A systematic review.

PubMed

Stergios, Konstantinos; Damaskos, Christos; Frountzas, Maximos; Nikiteas, Nikolaos; Lalude, Olutunde

2016-09-01

The purpose of the present systematic review is to identify whether an association between gallbladder polyps and colorectal adenoma or neoplasia exists. We conducted a systematic review searching the Medline (1966-2016), Scopus (2004-2016), ClinicalTrials.gov (2008-2016) and Cochrane Central Register of Controlled Trials CENTRAL (1999-2016) databases together with reference lists from included studies. All prospective and retrospective observational cohort studies were included. Four studies were finally included which included 17,437 patients. The association between gallbladder polyps and colorectal adenoma or even neoplasia is not unanimously supported. However, a possible association is clearly depicted. According to one study it seems that this correlation seems to become significant only when the gallbladder polyps exceed the size of 5 mm. However, the impact of size of gallbladder polyps was not investigated in the remaining studies. According to the results of our systematic review there is some evidence to support the hypothesis that gallbladder polyps might adequately predict future risk of colorectal neoplasia. At present, however, current knowledge is very limited and the available data scarce. In this context further studies are necessary to be carried out, before the presence of gallbladder polyps on ultrasound can be recommended as an indication to perform a screening colonoscopy on the same patient. Copyright © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Nationwide bowel cancer screening programme in England: cohort study of lifestyle factors affecting participation and outcomes in women

PubMed Central

Blanks, R G; Benson, V S; Alison, R; Brown, A; Reeves, G K; Beral, V; Patnick, J; Green, J

2015-01-01

Background: In 2006, the National Health Service Bowel Cancer Screening Programme in England (NHSBCSP) began offering routine population-based biennial faecal occult blood testing (FOBt) at ages 60–69. There is, however, limited information on how characteristics of individuals affect participation and outcomes of screening, and we studied this association by linking NHSBCSP data to a large prospective cohort of women. Methods: Electronic linkage of the NHSBCSP and Million Women Study records identified 899 166 women in the study cohort with at least one invitation for screening. NHSBCSP provided information on screening acceptance, FOBt results, screen-detected colorectal cancer and other outcomes. The Million Women Study provided prospectively collected information on personal and lifestyle factors. Multiple regression was used to estimate relative risks (RRs) of factors associated with acceptance and outcomes of screening. Results: Overall, 70% of women (628 976/899 166) accepted their first invitation for bowel cancer screening, of whom 9133 (1.5%) were FOBt-positive, 743 (0.1%) had screen-detected colorectal cancer and 3056 (0.5%) had screen-detected colorectal adenoma. Acceptance was lower in women from the most than the least deprived tertile, in South Asians and in Blacks than in Whites, in current than in never smokers and in obese than in normal weight women: adjusted RRs (95% confidence interval) for acceptance vs not, 0.90 (0.90–0.90); 0.77 (0.75–79); 0.94 (0.92–0.96); 0.78 (0.77–0.78); and 0.88 (0.88–0.89), respectively: P<0.001 for each. These factors were also associated with an increased risk of being FOBt-positive and of having screen-detected adenoma, but were not strongly associated with the risk of screen-detected colorectal cancer. Relative risks for screen-detected adenoma were 1.22 (1.12–1.34), 2.46 (1.75–3.45), 1.61 (1.05–2.48), 1.53 (1.38–1.68) and 1.77 (1.60–1.95), respectively (P<0.001 for all, except for Blacks vs Whites P=0.03). Use of hormone therapy for menopause was associated with reduced risk of screen-detected adenoma, RR ever vs never use, 0.87 (0.81–0.93), P<0.001 and colorectal cancer, 0.78 (0.68–0.91), P=0.001. Interpretation: Among women in England, socioeconomic and lifestyle factors strongly affect participation in routine bowel cancer screening, risk of being FOBt-positive and risk of having screen-detected colorectal adenoma. However, screen-detected colorectal cancer risk is not strongly related to these factors. PMID:25742470

A study of prostaglandin pathway genes and interactions with current nonsteroidal anti-inflammatory drug use in colorectal adenoma.

PubMed

Edwards, Todd L; Shrubsole, Martha J; Cai, Qiuyin; Li, Guoliang; Dai, Qi; Rex, Douglas K; Ulbright, Thomas M; Fu, Zhenming; Murff, Harvey J; Smalley, Walter; Ness, Reid; Zheng, Wei

2012-06-01

Colorectal cancer (CRC) is the second leading cause of cancer-related death and usually arises from colorectal polyps. Screening and removal of polyps reduce mortality from CRC. Colorectal polyps are known to aggregate in families; however the genetic determinants for risk of polyps are unknown. In addition, it has been shown that nonsteroidal anti-inflammatory drug (NSAID) use decreases the risk of CRC and the incidence and size of polyps. In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to evaluate selected genes from the prostaglandin (PG) metabolism and signaling pathways for association with risk of polyps and for interactions with NSAIDs. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian polyp cases and 3,285 Caucasian controls. We carried out multivariable logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. We detected association signals in the genes PGE receptor 3 (PTGER3) and 15-hydroxyprostaglandin dehydrogenase (HPGD), both strong biologic candidates for influence on polyp risk. We did not observe the previously reported effects and effect modification in PG-endoperoxide synthase 2 (PTGS2), PGE receptor 2 (PTGER2), or PGE receptor 4 (PTGER4), although we did observe a single nucleotide polymorphism in PTGER2 associated with risk of multiple adenomas. We also observed effect modification of the HPGD signal by NSAID exposure. ©2012 AACR.

Hyoscine butylbromide for colorectal polyp detection: prospective, randomized, placebo-controlled trial

PubMed Central

dos Santos, Carlos Eduardo Oliveira; Moreira, Hamilton; Pereira-Lima, Julio Carlos; Ribas, Carmen Australia Paredes Marcondes; de Quadros Onófrio, Fernanda; Czecko, Alexandre Eduardo Augusti; Ramos, Rafael Koerich; de Carvalho, Caroline Aragão

2017-01-01

OBJECTIVES: The removal of pre-malignant colorectal lesions prevents cancer. Hyoscine has been proposed as a means of improving diagnosis by reducing colonic movements. The aim of this study was to analyze whether this anti-spasmodic enhances the detection of pre-malignant colorectal lesions. METHODS: In a randomized, double-blinded fashion patients received hyoscine or a saline solution in all consecutive colonoscopies in which the cecum was reached. Lesions were analysed with respect to number, size, location, histology and capillary pattern. RESULTS: A total of 440 colonoscopies were randomized. The overall polyp detection rate (PDR) and the adenoma detection rate (ADR) were 65.2% and 49.3%, respectively. In the hyoscine group, non-polypoid lesions were detected significantly more often (p=0.01). In the placebo group 281 lesions were diagnosed (202 adenomas) and in the hyoscine group 282 lesions were detected (189 adenomas) (p=0.23). The PDR and ADR were similar between the placebo and hyoscine groups (64% vs 66% and 50% vs 47%, respectively). No differences were observed between the two groups in the advanced-ADR or advanced neoplasia detection rate, as well the mean numbers of polyps, adenomas, advanced adenomas and advanced neoplasias detected per patient. The administration of hyoscine also did not improve the diagnostic accuracy of digital chromoendoscopy. The presence of adenomatous polyps in the right colon was detected significantly more frequently in the hyoscine group (OR 5.41 95% CI 2.7 - 11; p<0.01 vs OR 2.3 95% CI 1.1 - 4.6; p=0.02). CONCLUSION: The use of hyoscine before beginning the withdrawal of the colonoscope does not seem to enhance the PDR and the ADR. PMID:28792997

Hyoscine butylbromide for colorectal polyp detection: prospective, randomized, placebo-controlled trial.

PubMed

Dos Santos, Carlos Eduardo Oliveira; Moreira, Hamilton; Pereira-Lima, Julio Carlos; Ribas, Carmen Australia Paredes Marcondes; de Quadros Onófrio, Fernanda; Czecko, Alexandre Eduardo Augusti; Ramos, Rafael Koerich; de Carvalho, Caroline Aragão

2017-07-01

The removal of pre-malignant colorectal lesions prevents cancer. Hyoscine has been proposed as a means of improving diagnosis by reducing colonic movements. The aim of this study was to analyze whether this anti-spasmodic enhances the detection of pre-malignant colorectal lesions. In a randomized, double-blinded fashion patients received hyoscine or a saline solution in all consecutive colonoscopies in which the cecum was reached. Lesions were analysed with respect to number, size, location, histology and capillary pattern. A total of 440 colonoscopies were randomized. The overall polyp detection rate (PDR) and the adenoma detection rate (ADR) were 65.2% and 49.3%, respectively. In the hyoscine group, non-polypoid lesions were detected significantly more often (p=0.01). In the placebo group 281 lesions were diagnosed (202 adenomas) and in the hyoscine group 282 lesions were detected (189 adenomas) (p=0.23). The PDR and ADR were similar between the placebo and hyoscine groups (64% vs 66% and 50% vs 47%, respectively). No differences were observed between the two groups in the advanced-ADR or advanced neoplasia detection rate, as well the mean numbers of polyps, adenomas, advanced adenomas and advanced neoplasias detected per patient. The administration of hyoscine also did not improve the diagnostic accuracy of digital chromoendoscopy. The presence of adenomatous polyps in the right colon was detected significantly more frequently in the hyoscine group (OR 5.41 95% CI 2.7 - 11; p<0.01 vs OR 2.3 95% CI 1.1 - 4.6; p=0.02). The use of hyoscine before beginning the withdrawal of the colonoscope does not seem to enhance the PDR and the ADR.

DNA methylation of phosphatase and actin regulator 3 detects colorectal cancer in stool and complements FIT.

PubMed

Bosch, Linda J W; Oort, Frank A; Neerincx, Maarten; Khalid-de Bakker, Carolina A J; Terhaar sive Droste, Jochim S; Melotte, Veerle; Jonkers, Daisy M A E; Masclee, Ad A M; Mongera, Sandra; Grooteclaes, Madeleine; Louwagie, Joost; van Criekinge, Wim; Coupé, Veerle M H; Mulder, Chris J; van Engeland, Manon; Carvalho, Beatriz; Meijer, Gerrit A

2012-03-01

Using a bioinformatics-based strategy, we set out to identify hypermethylated genes that could serve as biomarkers for early detection of colorectal cancer (CRC) in stool. In addition, the complementary value to a Fecal Immunochemical Test (FIT) was evaluated. Candidate genes were selected by applying cluster alignment and computational analysis of promoter regions to microarray-expression data of colorectal adenomas and carcinomas. DNA methylation was measured by quantitative methylation-specific PCR on 34 normal colon mucosa, 71 advanced adenoma, and 64 CRC tissues. The performance as biomarker was tested in whole stool samples from in total 193 subjects, including 19 with advanced adenoma and 66 with CRC. For a large proportion of these series, methylation data for GATA4 and OSMR were available for comparison. The complementary value to FIT was measured in stool subsamples from 92 subjects including 44 with advanced adenoma or CRC. Phosphatase and Actin Regulator 3 (PHACTR3) was identified as a novel hypermethylated gene showing more than 70-fold increased DNA methylation levels in advanced neoplasia compared with normal colon mucosa. In a stool training set, PHACTR3 methylation showed a sensitivity of 55% (95% CI: 33-75) for CRC and a specificity of 95% (95% CI: 87-98). In a stool validation set, sensitivity reached 66% (95% CI: 50-79) for CRC and 32% (95% CI: 14-57) for advanced adenomas at a specificity of 100% (95% CI: 86-100). Adding PHACTR3 methylation to FIT increased sensitivity for CRC up to 15%. PHACTR3 is a new hypermethylated gene in CRC with a good performance in stool DNA testing and has complementary value to FIT.

Right-sided rhabdoid colorectal tumors might be related to the Serrated Pathway

PubMed Central

2013-01-01

Background Rhabdoid colorectal tumor (RCT) is a rare, highly aggressive neoplasm recurrent in elderly patients, commonly at the caecum. The molecular mechanisms underlying RCT pathogenesis remain poorly elucidated. The differential diagnosis is with the malignant rhabdoid tumors of infancy characterized by genetic inactivation of SMARCB1 (INI1) or deletions of chromosome 22q12 locus. Materials and methods To shed light on RCT pathogenesis, we investigated genetic and epigenetic alterations in two cases of pure and composite RCT and compared them with the profiles of matched adenomas and normal mucosa. Immunohistochemical analysis, FISH, methylation specific PCR and DNA sequencing analysis were performed on paraffin-embedded tissues. Results Loss of epithelial markers, (CK20, CDX2 and E-cadherin) and intense vimentin expression was observed in RCTs but neither in the normal mucosa or adenomas. INI1 expression was detected in normal mucosa, adenomas and retained in pure RCT, while it was undetected in composite RCT. Rearrangement of the 22q12 locus was found only in pure RCT. The APC/β-catenin pathway was not altered, while MLH1 immunostaining was negative in RCTs and positive in adenomas and normal mucosa. These expression profiles were associated with V600E BRAF mutation, a progressive accumulation of promoter methylation at specific CIMP loci and additional genes from the normal mucosa to tubular adenoma and RCT. Conclusions Right-sided RCT could be characterized by epigenetic events and molecular features likely similar to those occurring in the serrated pathway and associated with epithelial-mesenchymal transition. These extremely rare tumors may benefit from the use of new biological molecules specific for colorectal carcinoma. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1641385210804556 PMID:23425390

Nuclear Division Index may Predict Neoplastic Colorectal Lesions.

PubMed

Ionescu, Mirela E; Ciocirlan, Mihai; Becheanu, Gabriel; Nicolaie, Tudor; Ditescu, Cristina; Teiusanu, Adriana G; Gologan, Serban I; Arbanas, Tudor; Diculescu, Mircea M

2011-07-01

Colorectal cancer (CRC) develops by accumulation of multiple genetic damages leading to genetic instability that can be evaluated by cytogenetic methods. In the current study we used Cytokinesis-Blocked Micronucleus Assay (CBMN) technique to assess the behavior of Nuclear Division Index(NDI) in peripheral lymphocytes of patients with CRC and polyps versus patients with normal colonoscopy. Blood samples were collected from patients after informed consent. By CBMN technique we assessed the proportion of mono-nucleated, bi-nucleated, tri-nucleated and tetra-nucleated cells/500 cells, to calculate NDI. Data were statistically analyzed using the SPSS 11.0 package. 45 patients were available for analysis, 23 men and 22 women, with a mean age of 58.7±13.5. 17 had normal colonoscopy, 17 colonic polyps and 11 CRC. The mean NDI values were significantly smaller for patients with CRC or polyps than in patients with normal colonoscopy (1.57 vs 1.73, p=0.013). The difference persisted for patients with neoplastic lesions (adenomas and carcinomas) when compared with patients with normal colonoscopy or non neoplastic (hyperplastic) polyps (1.56 vs.1.71, p=0.018). The NDI cut-off value to predict the presence of adenomas or carcinomas was equal to 1.55 with a 54.2% sensitivity and 81% specificity of lower values (p=0.019). The NDI cut off value to predict the presence of advanced adenomas or cancer was 1.525 for a sensitivity of 56.3% and a specificity of 82.8% (p=0.048). NDI may be useful in screening strategies for colorectal cancer as simple, noninvasive, inexpensive cytogenetic biomarker.

Diagnostic value of stool DNA testing for multiple markers of colorectal cancer and advanced adenoma: a meta-analysis.

PubMed

Yang, Hua; Xia, Bing-Qing; Jiang, Bo; Wang, Guozhen; Yang, Yi-Peng; Chen, Hao; Li, Bing-Sheng; Xu, An-Gao; Huang, Yun-Bo; Wang, Xin-Ying

2013-08-01

The diagnostic value of stool DNA (sDNA) testing for colorectal neoplasms remains controversial. To compensate for the lack of large-scale unbiased population studies, a meta-analysis was performed to evaluate the diagnostic value of sDNA testing for multiple markers of colorectal cancer (CRC) and advanced adenoma. The PubMed, Science Direct, Biosis Review, Cochrane Library and Embase databases were systematically searched in January 2012 without time restriction. Meta-analysis was performed using a random-effects model using sensitivity, specificity, diagnostic OR (DOR), summary ROC curves, area under the curve (AUC), and 95% CIs as effect measures. Heterogeneity was measured using the χ(2) test and Q statistic; subgroup analysis was also conducted. A total of 20 studies comprising 5876 individuals were eligible. There was no heterogeneity for CRC, but adenoma and advanced adenoma harboured considerable heterogeneity influenced by risk classification and various detection markers. Stratification analysis according to risk classification showed that multiple markers had a high DOR for the high-risk subgroups of both CRC (sensitivity 0.759 [95% CI 0.711 to 0.804]; specificity 0.883 [95% CI 0.846 to 0.913]; AUC 0.906) and advanced adenoma (sensitivity 0.683 [95% CI 0.584 to 0.771]; specificity 0.918 [95% CI 0.866 to 0.954]; AUC 0.946) but not for the average-risk subgroups of either. In the methylation subgroup, sDNA testing had significantly higher DOR for CRC (sensitivity 0.753 [95% CI 0.685 to 0.812]; specificity 0.913 [95% CI 0.860 to 0.950]; AUC 0.918) and advanced adenoma (sensitivity 0.623 [95% CI 0.527 to 0.712]; specificity 0.926 [95% CI 0.882 to 0.958]; AUC 0.910) compared with the mutation subgroup. There was no significant heterogeneity among studies for subgroup analysis. sDNA testing for multiple markers had strong diagnostic significance for CRC and advanced adenoma in high-risk subjects. Methylation makers had more diagnostic value than mutation markers.

Helicobacter Pylori Associated Gastritis Increases Risk of Colorectal Polyps: a Hospital Based-Cross-Sectional Study in Nakhon Ratchasima Province, Northeastern Thailand.

PubMed

Tongtawee, Taweesak; Kaewpitoon, Soraya; Kaewpitoon, Natthawut; Dechsukhum, Chavaboon; Leeanansaksiri, Wilairat; Loyd, Ryan A; Matrakool, Likit; Panpimanmas, Sukij

2016-01-01

Colorectal polyps are common in Thailand, particularly in the northeastern region. The present study aimed to determine any correlation between Helicobacter pylori-associated gastritis and colorectal polyps in the Thai population. A total of 303 patients undergoing esophagogastroduodenoscopy with colonoscopy for investigation of chronic abdominal pain participated in this study from November 2014 to October 2015. A diagnosis of Helicobacter pylori associated gastritis was made if the bacteria were seen on histopathological examination and a rapid urease test was positive. Colorectal polyps were confirmed by histological examination of colorectal biopsies. Patient demographic data were analyzed for correlations. The prevalence of colorectal polyps was 77 (25.4%), lesions being found more frequently in Helicobacter pylori infected patients than non-infected subjects [38.4% vs. 12.5%; Odds Ratio (OR) (95% CI): 2.26 (1.32 - 3.86), p < 0.01]. Patients with Helicobacter pylori - associated gastritis were at high risk of having adenomas featuring dysplasia [OR (95% CI): 1.15 (1.16 - 7.99); P = 0.02]. There was no varaition in location of polyps, age group, sex and gastric lesions with respect to Helicobacter pylori status. This study showed that Helicobacter pylori associated gastritis is associated with an increased risk of colorectal polyps, especially adenomas with dysplasia in the Thai population. Patients with Helicobacter pylori-associated gastritis may benefit from concurrent colonoscopy for diagnosis of colorectal polyps as a preventive and early treatment for colorectal cancer.

The gut microbiota in conventional and serrated precursors of colorectal cancer.

PubMed

Peters, Brandilyn A; Dominianni, Christine; Shapiro, Jean A; Church, Timothy R; Wu, Jing; Miller, George; Yuen, Elizabeth; Freiman, Hal; Lustbader, Ian; Salik, James; Friedlander, Charles; Hayes, Richard B; Ahn, Jiyoung

2016-12-30

Colorectal cancer is a heterogeneous disease arising from at least two precursors-the conventional adenoma (CA) and the serrated polyp. We and others have previously shown a relationship between the human gut microbiota and colorectal cancer; however, its relationship to the different early precursors of colorectal cancer is understudied. We tested, for the first time, the relationship of the gut microbiota to specific colorectal polyp types. Gut microbiota were assessed in 540 colonoscopy-screened adults by 16S rRNA gene sequencing of stool samples. Participants were categorized as CA cases (n = 144), serrated polyp cases (n = 73), or polyp-free controls (n = 323). CA cases were further classified as proximal (n = 87) or distal (n = 55) and as non-advanced (n = 121) or advanced (n = 22). Serrated polyp cases were further classified as hyperplastic polyp (HP; n = 40) or sessile serrated adenoma (SSA; n = 33). We compared gut microbiota diversity, overall composition, and normalized taxon abundance among these groups. CA cases had lower species richness in stool than controls (p = 0.03); in particular, this association was strongest for advanced CA cases (p = 0.004). In relation to overall microbiota composition, only distal or advanced CA cases differed significantly from controls (p = 0.02 and p = 0.002). In taxon-based analysis, stool of CA cases was depleted in a network of Clostridia operational taxonomic units from families Ruminococcaceae, Clostridiaceae, and Lachnospiraceae, and enriched in the classes Bacilli and Gammaproteobacteria, order Enterobacteriales, and genera Actinomyces and Streptococcus (all q < 0.10). SSA and HP cases did not differ in diversity or composition from controls, though sample size for these groups was small. Few taxa were differentially abundant between HP cases or SSA cases and controls; among them, class Erysipelotrichi was depleted in SSA cases. Our results indicate that gut microbes may play a role in the early stages of colorectal carcinogenesis through the development of CAs. Findings may have implications for developing colorectal cancer prevention therapies targeting early microbial drivers of colorectal carcinogenesis.

The influence of methylated septin 9 gene on RNA and protein level in colorectal cancer.

PubMed

Tóth, Kinga; Galamb, Orsolya; Spisák, Sándor; Wichmann, Barnabás; Sipos, Ferenc; Valcz, Gábor; Leiszter, Katalin; Molnár, Béla; Tulassay, Zsolt

2011-09-01

Colorectal cancer is one of the leading death causes in the world. Specificity and sensitivity of the present screening methods are unsuitable and their compliance is too low. Nowadays the most effective method is the colonoscopy, because it gives not only macroscopic diagnosis but therapeutic possibility as well, however the compliance of the patients is very low. Hence development of new diagnostic methods is needed. Altered expression of septin 9 was found in several tumor types including colorectal cancer. The aim of this study was to detect the methylation related mRNA and protein expression changes of septin 9 in colorectal adenoma-dysplasia-carcinoma sequence and to analyze its reversibility by demethylation treatment. Septin 9 protein expression showed significant difference between normal and colorectal cancer (CRC) samples (p < 0,001). According to biopsy microarray results, septin 9 mRNA expression decreased in the progression of colon neoplastic disease (p < 0,001). In laser microdissected epithelial cells, septin 9 significantly underexpressed in CRC compared to healthy controls (p < 0,001). The expression of septin9_v1 region was higher in the healthy samples, while septin9_v2, v4, v4*, v5 overexpression were detected in cancer epithelial cells compared to normal. The septin 9 mRNA and protein levels of HT29 cells increased after demethylation treatment. The increasing methylation of septin 9 gene during colorectal adenoma-dysplasia-carcinoma sequence progression is reflected in the decreasing mRNA and protein expression, especially in the epithelium. These changes can be reversed by demethylation agents converting this screening marker gene into therapeutic target.

Higher Order Chromatin Modulator Cohesin SA1 Is an Early Biomarker for Colon Carcinogenesis: Race-Specific Implications.

PubMed

Wali, Ramesh K; Momi, Navneet; Dela Cruz, Mart; Calderwood, Audrey H; Stypula-Cyrus, Yolanda; Almassalha, Luay; Chhaparia, Anuj; Weber, Christopher R; Radosevich, Andrew; Tiwari, Ashish K; Latif, Bilal; Backman, Vadim; Roy, Hemant K

2016-11-01

Alterations in high order chromatin, with concomitant modulation in gene expression, are one of the earliest events in the development of colorectal cancer. Cohesins are a family of proteins that modulate high-order chromatin, although the role in colorectal cancer remains incompletely understood. We, therefore, assessed the role of cohesin SA1 in colorectal cancer biology and as a biomarker focusing in particular on the increased incidence/mortality of colorectal cancer among African-Americans. Immunohistochemistry on tissue arrays revealed dramatically decreased SA1 expression in both adenomas (62%; P = 0.001) and adenocarcinomas (75%; P = 0.0001). RT-PCR performed in endoscopically normal rectal biopsies (n = 78) revealed a profound decrease in SA1 expression in adenoma-harboring patients (field carcinogenesis) compared with those who were neoplasia-free (47%; P = 0.03). From a racial perspective, colorectal cancer tissues from Caucasians had 56% higher SA1 expression than in African-Americans. This was mirrored in field carcinogenesis where healthy Caucasians expressed more SA1 at baseline compared with matched African-American subjects (73%; P = 0.003). However, as a biomarker for colorectal cancer risk, the diagnostic performance as assessed by area under ROC curve was greater in African-Americans (AUROC = 0.724) than in Caucasians (AUROC = 0.585). From a biologic perspective, SA1 modulation of high-order chromatin was demonstrated with both biophotonic (nanocytology) and chromatin accessibility [micrococcal nuclease (MNase)] assays in SA1-knockdown HT29 colorectal cancer cells. The functional consequences were underscored by increased proliferation (WST-1; P = 0.0002, colony formation; P = 0.001) in the SA1-knockdown HT29 cells. These results provide the first evidence indicating a tumor suppressor role of SA1 in early colon carcinogenesis and as a risk stratification biomarker giving potential insights into biologic basis of racial disparities in colorectal cancer. Cancer Prev Res; 9(11); 844-54. ©2016 AACR. ©2016 American Association for Cancer Research.

Study protocol for BeWEL: The impact of a BodyWEight and physicaL activity intervention on adults at risk of developing colorectal adenomas

PubMed Central

2011-01-01

Background Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second highest cause of cancer death in the UK. Most cases occur in people over 50 years and CRC often co-exists with other lifestyle related disorders including obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). These diseases share risk factors related to the metabolic syndrome including large body size, abnormal lipids and markers of insulin resistance indicating common aetiological pathways. Methods/Design This 3 year study will be a two-arm, multicentre, randomised controlled trial comparing the BeWEL lifestyle (diet, physical activity and behaviour change) programme against usual care. The pre-trial development will take 6 months and participants will be recruited over a 12 month period and undertake the intervention and follow up for 12 months (total 24 months recruitment and intervention implementation) with a further 6 months for data collection, analysis and interpretation. Four hundred and fifty two participants who have had a colorectal adenoma detected and removed (through the national colorectal screening programme) will provide 80% power to detect a weight loss of 7% over 12 months. Primary outcomes are changes in body weight and waist circumference. Secondary outcomes will include cardiovascular risk factors, psycho-social measures and intervention costs. Discussion The results from this study will enhance the evidence base for lifestyle change in patients at higher risk of chronic disease including obesity related cancers. International Standard Randomised Controlled Trials No: ISRCTN53033856 PMID:21439044

A New Scoring System to Predict the Risk for High-risk Adenoma and Comparison of Existing Risk Calculators.

PubMed

Murchie, Brent; Tandon, Kanwarpreet; Hakim, Seifeldin; Shah, Kinchit; O'Rourke, Colin; Castro, Fernando J

2017-04-01

Colorectal cancer (CRC) screening guidelines likely over-generalizes CRC risk, 35% of Americans are not up to date with screening, and there is growing incidence of CRC in younger patients. We developed a practical prediction model for high-risk colon adenomas in an average-risk population, including an expanded definition of high-risk polyps (≥3 nonadvanced adenomas), exposing higher than average-risk patients. We also compared results with previously created calculators. Patients aged 40 to 59 years, undergoing first-time average-risk screening or diagnostic colonoscopies were evaluated. Risk calculators for advanced adenomas and high-risk adenomas were created based on age, body mass index, sex, race, and smoking history. Previously established calculators with similar risk factors were selected for comparison of concordance statistic (c-statistic) and external validation. A total of 5063 patients were included. Advanced adenomas, and high-risk adenomas were seen in 5.7% and 7.4% of the patient population, respectively. The c-statistic for our calculator was 0.639 for the prediction of advanced adenomas, and 0.650 for high-risk adenomas. When applied to our population, all previous models had lower c-statistic results although one performed similarly. Our model compares favorably to previously established prediction models. Age and body mass index were used as continuous variables, likely improving the c-statistic. It also reports absolute predictive probabilities of advanced and high-risk polyps, allowing for more individualized risk assessment of CRC.

Effects of supplemental vitamin D and calcium on biomarkers of inflammation in colorectal adenoma patients: a randomized, controlled clinical trial.

PubMed

Hopkins, Myfanwy H; Owen, Joy; Ahearn, Thomas; Fedirko, Veronika; Flanders, W Dana; Jones, Dean P; Bostick, Roberd M

2011-10-01

Vitamin D and calcium affect several pathways involved in inflammation, tumor growth, and immune surveillance relevant to carcinogenesis. Also, epidemiologic evidence indicates that calcium and vitamin D may reduce risk for developing colorectal adenomas and cancer. To investigate the effects of calcium and vitamin D on biomarkers of inflammation in colorectal adenoma patients, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n = 92) of 2 g/d calcium and/or 800 IU/d vitamin D(3) supplementation versus placebo over 6 months. Plasma concentrations of proinflammatory markers [C-reactive protein (CRP), TNF-α, interleukin (IL)-6, IL-1β, and IL-8] and an anti-inflammatory marker (IL-10) were measured using ELISAs. After 6 months of treatment, in the vitamin D(3) supplementation group, CRP decreased 32% overall (P = 0.11), 37% in men (P = 0.05), and 41% among non-nonsteroidal anti-inflammatory drug (NSAID) users (P = 0.05) relative to placebo. In the vitamin D(3) supplementation group, TNF-α decreased 13%, IL-6 32%, IL-1β 50%, and IL-8 15%; in the calcium supplementation group, IL-6 decreased 37%, IL-8 11%, and IL-1β 27%. Although these changes were not statistically significant, a combined inflammatory markers z-score decreased 77% (P = 0.003) in the vitamin D(3) treatment group overall, 83% (P = 0.01) among men, and 48% among non-NSAID users (P = 0.01). There was no evidence of synergy between vitamin D(3) and calcium or effects on IL-10. These preliminary results are consistent with a pattern of reduction in tumor-promoting inflammation biomarkers with vitamin D(3) or calcium supplementation alone and support further investigation of vitamin D(3) as a chemopreventive agent against inflammation and colorectal neoplasms.

Virtual chromoendoscopy for the real-time assessment of colorectal polyps in vivo: a systematic review and economic evaluation.

PubMed

Picot, Joanna; Rose, Micah; Cooper, Keith; Pickett, Karen; Lord, Joanne; Harris, Petra; Whyte, Sophie; Böhning, Dankmar; Shepherd, Jonathan

2017-12-01

Current clinical practice is to remove a colorectal polyp detected during colonoscopy and determine whether it is an adenoma or hyperplastic by histopathology. Identifying adenomas is important because they may eventually become cancerous if untreated, whereas hyperplastic polyps do not usually develop into cancer, and a surveillance interval is set based on the number and size of adenomas found. Virtual chromoendoscopy (VCE) (an electronic endoscopic imaging technique) could be used by the endoscopist under strictly controlled conditions for real-time optical diagnosis of diminutive (≤ 5 mm) colorectal polyps to replace histopathological diagnosis. To assess the clinical effectiveness and cost-effectiveness of the VCE technologies narrow-band imaging (NBI), flexible spectral imaging colour enhancement (FICE) and i-scan for the characterisation and management of diminutive (≤ 5 mm) colorectal polyps using high-definition (HD) systems without magnification. Systematic review and economic analysis. People undergoing colonoscopy for screening or surveillance or to investigate symptoms suggestive of colorectal cancer. NBI, FICE and i-scan. Diagnostic accuracy, recommended surveillance intervals, health-related quality of life (HRQoL), adverse effects, incidence of colorectal cancer, mortality and cost-effectiveness of VCE compared with histopathology. Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and Database of Abstracts of Reviews of Effects were searched for published English-language studies from inception to June 2016. Bibliographies of related papers, systematic reviews and company information were screened and experts were contacted to identify additional evidence. Systematic reviews of test accuracy and economic evaluations were undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Meta-analyses were conducted, where possible, to inform the independent economic model. A cost-utility decision-analytic model was developed to estimate the cost-effectiveness of VCE compared with histopathology. The model used a decision tree for patients undergoing endoscopy, combined with estimates of long-term outcomes (e.g. incidence of colorectal cancer and subsequent morbidity and mortality) derived from University of Sheffield School of Health and Related Research's bowel cancer screening model. The model took a NHS perspective, with costs and benefits discounted at 3.5% over a lifetime horizon. There were limitations in the data on the distribution of adenomas across risk categories and recurrence rates post polypectomy. Thirty test accuracy studies were included: 24 for NBI, five for i-scan and three for FICE (two studies assessed two interventions). Polyp assessments made with high confidence were associated with higher sensitivity and endoscopists experienced in VCE achieved better results than those without experience. Two economic evaluations were included. NBI, i-scan and FICE are cost-saving strategies compared with histopathology and the number of quality-adjusted life-years gained was similar for histopathology and VCE. The correct surveillance interval would be given to 95% of patients with NBI, 94% of patients with FICE and 97% of patients with i-scan. Limited evidence was available for i-scan and FICE and there was heterogeneity among the NBI studies. There is a lack of data on longer-term health outcomes of patients undergoing VCE for assessment of diminutive colorectal polyps. VCE technologies, using HD systems without magnification, could potentially be used for the real-time assessment of diminutive colorectal polyps, if endoscopists have adequate experience and training. Future research priorities include head-to-head randomised controlled trials of all three VCE technologies; more research on the diagnostic accuracy of FICE and i-scan (when used without magnification); further studies evaluating the impact of endoscopist experience and training on outcomes; studies measuring adverse effects, HRQoL and anxiety; and longitudinal data on colorectal cancer incidence, HRQoL and mortality. This study is registered as PROSPERO CRD42016037767. The National Institute for Health Research Health Technology Assessment programme.

Cancer testis antigen OY-TES-1 expression and serum immunogenicity in colorectal cancer: its relationship to clinicopathological parameters.

PubMed

Luo, Bin; Yun, Xiang; Fan, Rong; Lin, Yong-Da; He, Shu-Jia; Zhang, Qing-Mei; Mo, Fa-Rong; Chen, Fang; Xiao, Shao-Wen; Xie, Xiao-Xun

2013-01-01

Cancer testis (CT) antigens are attractive targets for cancer immunotherapy because their expression is restricted in normal germ line tissues but frequently detected in variety of tumors. OY-TES-1 is identified as a member of CT antigens. Current knowledge about OY-TES-1 expression in colorectal cancer (CRC) is solely based on mRNA analysis. None of previous researches has studied OY-TES-1 at protein level. In this study, OY-TES-1 polyclonal antibody was generated. The expression of OY-TES-1 mRNA and protein was detected by RT-PCR and immunohistochemistry in 60 CRC and paired adjacent non-tumor tissues, 24 colorectal adenoma and 3 normal colon tissues, respectively. Sera from 73 CRC patients were also tested for OY-TES-1 antibody by ELISA. Our results showed that the frequency of OY-TES-1 mRNA expression was statistically higher in CRC (73.3%, 44/60) than that in adjacent non-tumor tissue (55.0%, 33/60) and colorectal adenoma (45.8%, 11/24). For the first time, OY-TES-1 protein expression was found in (43.3%, 26/60) of CRC tissues, but absent in any of adjacent non-tumor and colorectal adenoma tissues. No OY-TES-1 expression was found in normal colon by either RT-PCR or immunohistochemistry. Furthermore, OY-TES-1 protein expression was correlated with tumor invasion stage (P=0.004) and histological grade (P=0.040). Anti-OY-TES-1 antibody was detected in (9.6%, 7/73) of CRC patients' sera but not in 76 healthy donors. This finding demonstrates that OY-TES-1 is frequently expressed in CRC and is able to induce humoral immune response spontaneously in CRC patients, suggesting that it might be a promising immunotherapy target for CRC.

MicroRNA-31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions.

PubMed

Ito, Miki; Mitsuhashi, Kei; Igarashi, Hisayoshi; Nosho, Katsuhiko; Naito, Takafumi; Yoshii, Shinji; Takahashi, Hiroaki; Fujita, Masahiro; Sukawa, Yasutaka; Yamamoto, Eiichiro; Takahashi, Taiga; Adachi, Yasushi; Nojima, Masanori; Sasaki, Yasushi; Tokino, Takashi; Baba, Yoshifumi; Maruyama, Reo; Suzuki, Hiromu; Imai, Kohzoh; Yamamoto, Hiroyuki; Shinomura, Yasuhisa

2014-12-01

The CpG island methylator phenotype (CIMP) is a distinct form of epigenomic instability. Many CIMP-high colorectal cancers (CRCs) with BRAF mutation are considered to arise from serrated pathway. We recently reported that microRNA-31 (miR-31) is associated with BRAF mutation in colorectal tumors. Emerging new approaches have revealed gradual changes in BRAF mutation and CIMP-high throughout the colorectum in CRCs. Here, we attempted to identify a possible association between miR-31 and epigenetic features in serrated pathway, and hypothesized that miR-31 supports the "colorectal continuum" concept. We evaluated miR-31 expression, BRAF mutation and epigenetic features including CIMP status in 381 serrated lesions and 222 non-serrated adenomas and examined associations between them and tumor location (rectum; sigmoid, descending, transverse and ascending colon and cecum). A significant association was observed between high miR-31 expression and CIMP-high status in serrated lesions with BRAF mutation (p = 0.0001). In contrast, miR-31 was slightly but insignificantly associated with CIMP status in the cases with wild-type BRAF. miR-31 expression in sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that in SSAs, whereas, no significant difference was observed between traditional serrated adenomas (TSAs) and TSAs with high-grade dysplasia. The frequency of miR-31, BRAF mutation CIMP-high and MLH1 methylation increased gradually from the rectum to cecum in serrated lesions. In conclusion, miR-31 expression was associated with CIMP-high status in serrated lesions with BRAF mutation. Our data also suggested that miR-31 plays an important role in SSA evolution and may be a molecule supporting the colorectal continuum. © 2014 UICC.

Colorectal Cancer Epidemiology in the Nurses’ Health Study

PubMed Central

Lee, Dong Hoon; Giovannucci, Edward L.

2016-01-01

Objectives. To review the contribution of the Nurses’ Health Study (NHS) to identifying risk and protective factors for colorectal adenomas and colorectal cancer (CRC). Methods. We performed a narrative review of the publications using the NHS between 1976 and 2016. Results. Existing epidemiological studies using the NHS have reported that red and processed meat, alcohol, smoking, and obesity were associated with an increased risk of CRC, whereas folate, calcium, vitamin D, aspirin, and physical activity were associated with decreased risk of CRC. Moreover, modifiable factors, such as physical activity, vitamin D, folate, insulin and insulin-like growth factor binding protein-1, and diet quality, were identified to be associated with survival among CRC patients. In recent years, molecular pathological epidemiological studies have been actively conducted and have shown refined results by molecular subtypes of CRC. Conclusions. The NHS has provided new insights into colorectal adenomas, CRC etiology, and pathogenic mechanisms. With its unique strengths, the NHS should continue to contribute to the field of CRC epidemiology and play a major role in public health. PMID:27459444

Glycoprotein expression by adenomatous polyps of the colon

NASA Astrophysics Data System (ADS)

Roney, Celeste A.; Xie, Jianwu; Xu, Biying; Jabour, Paul; Griffiths, Gary; Summers, Ronald M.

2008-03-01

Colon cancer is the second leading cause of cancer related deaths in the United States. Specificity in diagnostic imaging for detecting colorectal adenomas, which have a propensity towards malignancy, is desired. Adenomatous polyp specimens of the colon were obtained from the mouse model of colorectal cancer called adenomatous polyposis coli-multiple intestinal neoplasia (APC Min). Histological evaluation, by the legume protein Ulex europaeus agglutinin I (UEA-1), determined expression of the glycoprotein α-L-fucose. FITC-labelled UEA-1 confirmed overexpression of the glycoprotein by the polyps on fluorescence microscopy in 17/17 cases, of which 13/17 included paraffin-fixed mouse polyp specimens. In addition, FITC-UEA-1 ex vivo multispectral optical imaging of 4/17 colonic specimens displayed over-expression of the glycoprotein by the polyps, as compared to non-neoplastic mucosa. Here, we report the surface expression of α-L-fucosyl terminal residues by neoplastic mucosal cells of APC specimens of the mouse. Glycoprotein expression was validated by the carbohydrate binding protein UEA-1. Future applications of this method are the development of agents used to diagnose cancers by biomedical imaging modalities, including computed tomographic colonography (CTC). UEA-1 targeting to colonic adenomas may provide a new avenue for the diagnosis of colorectal carcinoma by CT imaging.

Colorectal Cancer Screening: Stool DNA and Other Noninvasive Modalities.

PubMed

Bailey, James R; Aggarwal, Ashish; Imperiale, Thomas F

2016-03-01

Colorectal cancer screening dates to the discovery of precancerous adenomatous tissue. Screening modalities and guidelines directed at prevention and early detection have evolved and resulted in a significant decrease in the prevalence and mortality of colorectal cancer via direct visualization or using specific markers. Despite continued efforts and an overall reduction in deaths attributed to colorectal cancer over the last 25 years, colorectal cancer remains one of the most common causes of malignancy-associated deaths. In attempt to further reduce the prevalence of colorectal cancer and associated deaths, continued improvement in screening quality and adherence remains key. Noninvasive screening modalities are actively being explored. Identification of specific genetic alterations in the adenoma-cancer sequence allow for the study and development of noninvasive screening modalities beyond guaiac-based fecal occult blood testing which target specific alterations or a panel of alterations. The stool DNA test is the first noninvasive screening tool that targets both human hemoglobin and specific genetic alterations. In this review we discuss stool DNA and other commercially available noninvasive colorectal cancer screening modalities in addition to other targets which previously have been or are currently under study.

Differential expression proteomics of human colorectal cancer based on a syngeneic cellular model for the progression of adenoma to carcinoma.

PubMed

Roth, Udo; Razawi, Hanieh; Hommer, Julia; Engelmann, Katja; Schwientek, Tilo; Müller, Stefan; Baldus, Stephan E; Patsos, Georgios; Corfield, Anthony P; Paraskeva, Christos; Hanisch, Franz-Georg

2010-01-01

This is the first differential expression proteomics study on a human syngeneic cellular in vitro progression model of the colorectal adenoma-to-carcinoma sequence, the anchorage-dependent non-tumorigenic adenoma derived cell line AA/C1 and the derived anchorage-independent and tumorigenic carcinoma cell line AA/C1/SB10C. The study is based on quantitative 2-DE and is complemented by Western blot validation. Excluding redundancies due to proteolysis and post-translational modified isoforms of over 2000 protein spots, 13 proteins were revealed as regulated with statistical variance being within the 95th confidence level and were identified by peptide mass fingerprinting in MALDI MS. Progression-associated proteins belong to the functional complexes of anaerobic glycolysis/gluconeogenesis, steroid biosynthesis, prostaglandin biosynthesis, the regulation and maintenance of the cytoskeleton, protein biosynthesis and degradation, the regulation of apoptosis or other functions. Partial but significant overlap was revealed with previous proteomics and transcriptomics studies in colorectal carcinoma. Among upregulated proteins we identified 3-HMG-CoA synthase, protein phosphatase 1, prostaglandin E synthase 2, villin 1, annexin A1, triosephosphate isomerase, phosphoserine aminotransferase 1, fumarylacetoacetate hydrolase and pyrroline-5-carboxylate reductase 1 (PYCR1), while glucose-regulated protein 78, cathepsin D, lamin A/C and quinolate phosphoribosyltransferase were downregulated.

High resolution microendoscopy for classification of colorectal polyps.

PubMed

Chang, S S; Shukla, R; Polydorides, A D; Vila, P M; Lee, M; Han, H; Kedia, P; Lewis, J; Gonzalez, S; Kim, M K; Harpaz, N; Godbold, J; Richards-Kortum, R; Anandasabapathy, S

2013-07-01

It can be difficult to distinguish adenomas from benign polyps during routine colonoscopy. High resolution microendoscopy (HRME) is a novel method for imaging colorectal mucosa with subcellular detail. HRME criteria for the classification of colorectal neoplasia have not been previously described. Study goals were to develop criteria to characterize HRME images of colorectal mucosa (normal, hyperplastic polyps, adenomas, cancer) and to determine the accuracy and interobserver variability for the discrimination of neoplastic from non-neoplastic polyps when these criteria were applied by novice and expert microendoscopists. Two expert pathologists created consensus HRME image criteria using images from 68 patients with polyps who had undergone colonoscopy plus HRME. Using these criteria, HRME expert and novice microendoscopists were shown a set of training images and then tested to determine accuracy and interobserver variability. Expert microendoscopists identified neoplasia with sensitivity, specificity, and accuracy of 67 % (95 % confidence interval [CI] 58 % - 75 %), 97 % (94 % - 100 %), and 87 %, respectively. Nonexperts achieved sensitivity, specificity, and accuracy of 73 % (66 % - 80 %), 91 % (80 % - 100 %), and 85 %, respectively. Overall, neoplasia were identified with sensitivity 70 % (65 % - 76 %), specificity 94 % (87 % - 100 %), and accuracy 85 %. Kappa values were: experts 0.86; nonexperts 0.72; and overall 0.78. Using the new criteria, observers achieved high specificity and substantial interobserver agreement for distinguishing benign polyps from neoplasia. Increased expertise in HRME imaging improves accuracy. This low-cost microendoscopic platform may be an alternative to confocal microendoscopy in lower-resource or community-based settings.

Evaluation of the Effectiveness and Cost-Effectiveness of Personalized Surveillance After Colorectal Adenomatous Polypectomy.

PubMed

McFerran, Ethna; O'Mahony, James F; Fallis, Richard; McVicar, Duncan; Zauber, Ann G; Kee, Frank

2017-01-01

Lifetime risk of developing colorectal cancer is 5%, and 5-year survival at early stage is 92%. Individuals with precancerous lesions removed at primary screening are typically recommended surveillance colonoscopy. Because greater benefits are anticipated for those with higher risk of colorectal cancer, scope for risk-specific surveillance recommendations exists. This review assesses published cost-effectiveness estimates of postpolypectomy surveillance to consider the potential for personalized recommendations by risk group. Meta-analyses of incidence of advanced neoplasia postpolypectomy for low-risk cases were comparable to those without adenoma, with both rates under the lifetime risk of 5%. This group may not benefit from intensive surveillance, which risks unnecessary harm and inefficient use of often scarce colonoscopy capacity. Therefore, greater personalization through deintensified strategies for low-risk individuals could be beneficial. The potential for noninvasive testing, such as fecal immunochemical tests, combined with primary prevention or chemoprevention may reserve colonoscopy for targeted use in personalized risk-stratified surveillance. This review appraised evidence supporting a program of personalized surveillance in patients with colorectal adenoma according to risk group and compared the effectiveness of surveillance colonoscopy with alternative prevention strategies. It assessed trade-offs among costs, benefits, and adverse effects that must be considered in a decision to adopt or reject personalized surveillance. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Longitudinal molecular characterization of endoscopic specimens from colorectal lesions

PubMed Central

Minarikova, Petra; Benesova, Lucie; Halkova, Tereza; Belsanova, Barbora; Suchanek, Stepan; Cyrany, Jiri; Tuckova, Inna; Bures, Jan; Zavoral, Miroslav; Minarik, Marek

2016-01-01

AIM: To compare molecular profiles of proximal colon, distal colon and rectum in large adenomas, early and late carcinomas. To assess feasibility of testing directed at molecular markers from this study in routine clinical practice. METHODS: A prospective 3-year study has resulted in the acquisition of samples from 159 large adenomas and 138 carcinomas along with associated clinical parameters including localization, grade and histological type for adenomas and localization and stage for carcinomas. A complex molecular phenotyping has been performed using multiplex ligation-dependent probe amplification technique for the evaluation of CpG-island methylator phenotype (CIMP), PCR fragment analysis for detection of microsatellite instability and denaturing capillary electrophoresis for sensitive detection of somatic mutations in KRAS, BRAF, TP53 and APC genes. RESULTS: Molecular types according to previously introduced Jass classification have been evaluated for large adenomas and early and late carcinomas. An increase in CIMP+ type, eventually accompanied with KRAS mutations, was notable between large adenomas and early carcinomas. As expected, the longitudinal observations revealed a correlation of the CIMP+/BRAF+ type with proximal location. CONCLUSION: Prospective molecular classification of tissue specimens is feasible in routine endoscopy practice. Increased frequency of some molecular types corresponds to the developmental stages of colorectal tumors. As expected, a clear distinction is notable for tumors located in proximal colon supposedly arising from the serrated (methylation) pathway. PMID:27239120

The Effect of Strict Adherence to a High-Fiber, High-Fruit and -Vegetable, and Low-Fat Eating Pattern on Adenoma Recurrence

PubMed Central

Wanke, Kay; Albert, Paul S.; Kahle, Lisa; Schatzkin, Arthur; Lanza, Elaine

2009-01-01

Individual differences in dietary intake are thought to account for substantial variation in cancer incidence. However, there has been a consistent lack of effect for low-fat, high-fiber dietary interventions and risk of colorectal cancer. These inconsistencies may reflect the multistage process of cancer as well as the range and timing of dietary change. Another potential reason for the lack of effect is poor dietary adherence among participants in these trials. The authors examined the effect of strict adherence to a low-fat, high-fiber, high-fruit and -vegetable intervention over 4 years among participants (n = 1,905) in the US Polyp Prevention Trial (1991–1998) on colorectal adenoma recurrence. There was a wide range of individual variation in the level of compliance among intervention participants. The most adherent participants, defined as “super compliers” (n = 210), consistently reported that they met or exceeded each of the 3 dietary goals at all 4 annual visits. Multivariate logistic regression models were used to estimate the association between dietary adherence and adenoma recurrence. The authors observed a 35% reduced odds of adenoma recurrence among super compliers compared with controls (odds ratio = 0.65, 95% confidence interval: 0.47, 0.92). Findings suggest that high compliance with a low-fat, high-fiber diet is associated with reduced risk of adenoma recurrence. PMID:19643809

Real-time differentiation of adenomatous and hyperplastic diminutive colorectal polyps during analysis of unaltered videos of standard colonoscopy using a deep learning model.

PubMed

Byrne, Michael F; Chapados, Nicolas; Soudan, Florian; Oertel, Clemens; Linares Pérez, Milagros; Kelly, Raymond; Iqbal, Nadeem; Chandelier, Florent; Rex, Douglas K

2017-10-24

In general, academic but not community endoscopists have demonstrated adequate endoscopic differentiation accuracy to make the 'resect and discard' paradigm for diminutive colorectal polyps workable. Computer analysis of video could potentially eliminate the obstacle of interobserver variability in endoscopic polyp interpretation and enable widespread acceptance of 'resect and discard'. We developed an artificial intelligence (AI) model for real-time assessment of endoscopic video images of colorectal polyps. A deep convolutional neural network model was used. Only narrow band imaging video frames were used, split equally between relevant multiclasses. Unaltered videos from routine exams not specifically designed or adapted for AI classification were used to train and validate the model. The model was tested on a separate series of 125 videos of consecutively encountered diminutive polyps that were proven to be adenomas or hyperplastic polyps. The AI model works with a confidence mechanism and did not generate sufficient confidence to predict the histology of 19 polyps in the test set, representing 15% of the polyps. For the remaining 106 diminutive polyps, the accuracy of the model was 94% (95% CI 86% to 97%), the sensitivity for identification of adenomas was 98% (95% CI 92% to 100%), specificity was 83% (95% CI 67% to 93%), negative predictive value 97% and positive predictive value 90%. An AI model trained on endoscopic video can differentiate diminutive adenomas from hyperplastic polyps with high accuracy. Additional study of this programme in a live patient clinical trial setting to address resect and discard is planned. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Nuclear Division Index may Predict Neoplastic Colorectal Lesions

PubMed Central

IONESCU, Mirela E.; CIOCIRLAN, Mihai; BECHEANU, Gabriel; NICOLAIE, Tudor; DITESCU, Cristina; TEIUSANU, Adriana G.; GOLOGAN, Serban I.; ARBANAS, Tudor; DICULESCU, Mircea M.

2011-01-01

ABSTRACT Background: Colorectal cancer (CRC) develops by accumulation of multiple genetic damages leading to genetic instability that can be evaluated by cytogenetic methods. In the current study we used Cytokinesis-Blocked Micronucleus Assay (CBMN) technique to assess the behavior of Nuclear Division Index(NDI) in peripheral lymphocytes of patients with CRC and polyps versus patients with normal colonoscopy. Methods: Blood samples were collected from patients after informed consent. By CBMN technique we assessed the proportion of mono-nucleated, bi-nucleated, tri-nucleated and tetra-nucleated cells/500 cells, to calculate NDI. Data were statistically analyzed using the SPSS 11.0 package. Results: 45 patients were available for analysis, 23 men and 22 women, with a mean age of 58.7±13.5. 17 had normal colonoscopy, 17 colonic polyps and 11 CRC. The mean NDI values were significantly smaller for patients with CRC or polyps than in patients with normal colonoscopy (1.57 vs 1.73, p=0.013). The difference persisted for patients with neoplastic lesions (adenomas and carcinomas) when compared with patients with normal colonoscopy or non neoplastic (hyperplastic) polyps (1.56 vs.1.71, p=0.018). The NDI cut-off value to predict the presence of adenomas or carcinomas was equal to 1.55 with a 54.2% sensitivity and 81% specificity of lower values (p=0.019). The NDI cut off value to predict the presence of advanced adenomas or cancer was 1.525 for a sensitivity of 56.3% and a specificity of 82.8% (p=0.048). Conclusion: NDI may be useful in screening strategies for colorectal cancer as simple, noninvasive, inexpensive cytogenetic biomarker. PMID:22368693

Systematic review with meta-analysis: the incidence of advanced neoplasia after polypectomy in patients with and without low-risk adenomas.

PubMed

Hassan, C; Gimeno-García, A; Kalager, M; Spada, C; Zullo, A; Costamagna, G; Senore, C; Rex, D K; Quintero, E

2014-05-01

Patients with one to two tubular adenomas <1 cm in size without high-grade dysplasia (low-risk group) are considered at low risk for colorectal cancer. However, it is uncertain whether they have the same risk of subsequent advanced neoplasia as those with no neoplasia at baseline colonoscopy. To compare incidence of metachronous advanced neoplasia between patients in the low-risk adenoma group and those without neoplasia at index colonoscopy. Relevant publications were identified by MEDLINE/EMBASE and other databases for the period 1992-2013. Studies comparing the incidence of post-polypectomy advanced neoplasia (adenomas ≥10 mm/high-grade dysplasia/villous or cancer) between the low-risk group and patients without colorectal neoplasia at the first colonoscopy were included. Detection rates for advanced neoplasia at endoscopic surveillance were extracted. Study quality was ascertained according to Newcastle-Ottawa Scale. Forest plot was produced based on random-effect models. Inter-study heterogeneity was assessed using the I(2) statistic. Seven studies provided data on 11 387 patients. Mean surveillance periods ranged between 2 and 5 years. Altogether, 267 patients with post-polypectomy advanced neoplasia were detected in the two groups. The incidence of advanced neoplasia was 1.6% (119/7308) in those without neoplasia and 3.6% (148/4079) in those with low-risk adenoma, respectively, corresponding to a relative risk of 1.8 (95% CI: 1.3-2.6). Inter-study heterogeneity was only moderate (I(2) : 37%). No publication bias was present. Patients with low-risk adenomas at baseline had a higher risk of metachronous advanced neoplasia than the group with no adenomas at baseline, though the absolute risk was low in both groups. © 2014 John Wiley & Sons Ltd.

Unmetabolized Folic Acid, Tetrahydrofolate, and Colorectal Adenoma Risk.

PubMed

Rees, Judy R; Morris, Carolyn B; Peacock, Janet L; Ueland, Per M; Barry, Elizabeth L; McKeown-Eyssen, Gail E; Figueiredo, Jane C; Snover, Dale C; Baron, John A

2017-08-01

In a randomized trial of folic acid supplementation for the prevention of colorectal adenomas, we previously found indications of increased risk during later treatment and follow-up. This could have been due to the unmetabolized folic acid (UFA) or natural reduced and methylated folates (mF) to which it is metabolized. In post hoc analyses, we measured mF (the sum of 5-methyl-tetrahydrofolate and 4-alfa-hydroxy-5-methyl-THF) and UFA concentrations in the serum of 924 participants. Using binomial regression models with a log link, we assessed the associations between plasma mF or UFA and adenoma occurrence. We found no association between plasma mF or UFA and overall adenoma risk. However, during later follow-up, the prespecified, composite endpoint of high-risk findings (advanced or multiple adenomas) was positively associated with plasma mF ( P linear trend = 0.009), with a 58% increased risk for participants in the upper versus lowest quartile. An irregular association was seen with plasma UFA, with suggestions of an inverse trend ( P linear trend =0.049). A modest, significant inverse association was also seen between mF and risk of serrated lesions, with a 39% lower risk for upper versus lower quartile participants ( P linear trend = 0.03). In conclusion, during the later follow-up period in which folic acid supplementation was previously seen to increase the risk of advanced and multiple adenomas, higher serum mF was associated with a higher risk of multiple and/or advanced adenomas, but no clear indication that UFA played a direct role. There were indications that higher mF was associated with reduced risk of serrated polyps. Cancer Prev Res; 10(8); 451-8. ©2017 AACR . ©2017 American Association for Cancer Research.

Do Interleukin Polymorphisms Play a Role in the Prevention of Colorectal Adenoma Recurrence by Dietary Flavonols?

PubMed Central

Bobe, Gerd; Murphy, Gwen; Albert, Paul S.; Sansbury, Leah B.; Young, Matthew R.; Lanza, Elaine; Schatzkin, Arthur; Colburn, Nancy H.; Cross, Amanda J.

2010-01-01

Chemopreventive dietary compounds, such as flavonols, may inhibit colorectal carcinogenesis partly by altering cytokine expression and attenuating inflammation. Single nucleotide polymorphisms (SNPs) in the promoter regions of genes encoding cytokines may influence flavonol-induced changes in cytokine expression and consequently cancer risk. Using logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between SNPs of interleukin (IL)-1β, 6, 8, and 10, alone or combined with flavonol intake or serum IL concentration changes, and adenoma recurrence in 808 participants from the intervention arm of the Polyp Prevention Trial, a 4-year intervention study evaluating the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence.. Overall, SNPs in genes encoding IL-1β, 6, 8, and 10 were not associated with their corresponding serum concentrations or adenoma recurrence. However, individuals homozygous for IL-10 -592 C (OR = 2.23, 95% CI: 1.07–4.66, P interaction = 0.03) or IL-10 -819 C (OR = 2.18, 95% CI: 1.05–4.51, P interaction = 0.05) had an elevated risk of high risk adenoma recurrence when their serum IL-10 concentrations increased during the trial. In addition, IL-6 -174 GG in combination with above median flavonol intake (OR = 0.14, 95% CI: 0.03–0.66) or with decreased IL 6 concentrations (OR = 0.14, 95% CI: 0.03–0.65) reduced the risk of advanced adenoma recurrence, although the interaction term was not statistically significant. In conclusion, our results suggest that IL SNPs, in combination with a flavonol-rich diet or decreased serum IL, may lower the risk of adenoma recurrence. PMID:21160427

New endoscopy advances to refine adenoma detection rate for colorectal cancer screening: None is the winner.

PubMed

Maida, Marcello; Camilleri, Salvatore; Manganaro, Michele; Garufi, Serena; Scarpulla, Giuseppe

2017-10-15

Colorectal cancer (CRC) is the third most common cancer in males and second in females, and globally the fourth cause for cancer death worldwide. Oncological screening of CRC has a major role in the management of the disease and it is mostly performed by colonoscopy. Anyway, effectiveness of endoscopic screening for CRC strictly depends on adequate detection and removal of potentially precancerous lesions, and accuracy of colonoscopy in detection of adenomas is still suboptimal. For this reason, several technological advances have been implemented in order to improve the diagnostic sensitivity of colonoscopy in adenoma detection. Among these: (1) Visual technologies such as chromoendoscopy and narrow band imaging; (2) optical innovation as high definition endoscopy, full-spectrum endoscopy or Third Eye Retroscope; and (3) mechanical advances as Cap assisted colonoscopy, Endocuff, Endoring and G-Eye endoscope. All these technologies advances have been tested over time by clinical studies with mixed results. Which of them is more likely to be successful in the next future?

Comparison of the diagnostic ability of blue laser imaging magnification versus pit pattern analysis for colorectal polyps.

PubMed

Nakano, Arihiro; Hirooka, Yoshiki; Yamamura, Takeshi; Watanabe, Osamu; Nakamura, Masanao; Funasaka, Kohei; Ohno, Eizaburo; Kawashima, Hiroki; Miyahara, Ryoji; Goto, Hidemi

2017-04-01

Background and study aims  There have been few evaluations of the diagnostic ability of new narrow band light observation blue laser imaging (BLI). The present prospective study compared the diagnostic ability of BLI magnification and pit pattern analysis for colorectal polyps. Patients and methods  We collected lesions prospectively, and the analysis of images was made by two endoscopists, retrospectively. A total of 799 colorectal polyps were examined by BLI magnification and pit pattern analysis at Nagoya University Hospital. The Hiroshima narrow-band imaging classification was used for BLI. Differentiation of neoplastic from non-neoplastic lesions and diagnosis of deeply invasive submucosal cancer (dSM) were compared between BLI magnification and pit pattern analysis. Type C2 in the Hiroshima classification was evaluated separately, because application of this category as an index of the depth of cancer invasion was considered difficult. Results  We analyzed 748 colorectal polyps, excluding 51 polyps that were inflammatory polyps, sessile serrated adenoma/polyps, serrated adenomas, advanced colorectal cancers, or other lesions. The accuracy of differential diagnosis between neoplastic and non-neoplastic lesions was 98.4 % using BLI magnification and 98.7 % with pit pattern analysis. In addition, the diagnostic accuracy of BLI magnification and pit pattern analysis for dSM for cancer was 89.5 % and 92.1 %, respectively. When type C2 lesions were excluded, the diagnostic accuracy of BLI for dSM was 95.9 %. The 18 type C2 lesions comprised 1 adenoma, 9 intramucosal or slightly invasive submucosal cancers, and 8 dSM. Pit pattern analysis allowed accurate diagnosis of the depth of invasion in 13 lesions (72.2 %). Conclusions  Most colorectal polyps could be diagnosed accurately by BLI magnification without pit pattern analysis, but we should add pit pattern analysis for type C2 lesions in the Hiroshima classification.

Prevalence and management of colorectal neoplasia in surgically treated esophageal cancer patients.

PubMed

Takeuchi, Daisuke; Koide, Naohiko; Komatsu, Daisuke; Suzuki, Akira; Miyagawa, Shinichi

2015-05-01

The existence of other primary tumors during the treatment of esophageal cancer patients has been an important issue. Our aim is to investigate the prevalence and management of colorectal neoplasia (CRN) in surgically treated esophageal cancer patients. Between 2002 and 2008, 93 patients with esophageal cancer were surgically treated. Seventy-three patients underwent subtotal esophagectomy and 20 underwent lower esophagectomy for esophageal cancer. Colonoscopy was available for detecting CRN before and after surgery. Eighty-nine (95.7%) of the 93 patients were screened by colonoscopy preoperatively or within a year from the operation. Thirty-nine patients (43.8%) with CRN were synchronously identified: adenoma in 34 (38.2%) and adenocarcinoma in 5 patients (5.6%). Eleven adenomas with high grade-dysplasia and 8 adenomas with low grade-dysplasia were removed endoscopically. Three superficial adenocarcinomas were endoscopically removed before surgery, and 2 adenocarcinomas were surgically removed. Seventy-four patients (83.1%) were followed using colonoscopy, and 11 subsequent CRN, including 2 superficial adenocarcinomas, were endoscopically detected in 8 patients (10.8%). The size of esophageal cancer was larger in the patients with than without CRN (p = 0.036). The body mass index in esophageal cancer patients with CRN tended to be higher than in those without CRN (p = 0.065). We noted that esophageal cancer is frequently associated with synchronous and/or metachronous colorectal cancer and adenomas. Colonoscopy is useful to detect and manage CRN before and after esophagectomy, although a few limitations exist. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

Aspirin in the Chemoprevention of Colorectal Neoplasia: An Overview

PubMed Central

Chan, Andrew T.; Arber, Nadir; Burn, John; Chia, John Whay-Kuang; Elwood, Peter; Hull, Mark A.; Logan, Richard F.; Rothwell, Peter M.; Schrör, Karsten; Baron, John A.

2011-01-01

Considerable evidence supports the effectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-established benefits in the prevention of vascular disease. Epidemiologic studies have consistently observed an inverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term post-trial follow-up of nearly 14,000 patients from 4 randomized, cardiovascular disease prevention trials showed that daily aspirin treatment for about 5 years was associated with a 34% reduction in 20-year CRC mortality. A separate meta-analysis of nearly 3,000 patients with a history of colorectal adenoma or cancer in 4 randomized adenoma prevention trials demonstrated that aspirin reduced the occurrence of advanced adenomas by 28% and any adenoma by 17%. Aspirin has also been shown to be beneficial in a clinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirin for at least 2 years, there was a ≥ 50% reduction in the risk of CRC commencing 5 years after randomization and after aspirin had been discontinued. A few observational studies have shown an increase in survival among patients with CRC who use aspirin. Taken together, these findings strengthen the case for consideration of long-term aspirin use in CRC prevention. Despite these compelling data, there is a lack of consensus about the balance of risks and benefits associated with long-term aspirin use, particularly in low-risk populations. The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin’s anticancer effect require further investigation. PMID:22084361

Computed Tomography Colonography vs Colonoscopy for Colorectal Cancer Surveillance After Surgery.

PubMed

Weinberg, David S; Pickhardt, Perry J; Bruining, David H; Edwards, Kristin; Fletcher, Joel G; Gollub, Marc J; Keenan, Eileen M; Kupfer, Sonia S; Li, Tianyu; Lubner, Sam J; Markowitz, Arnold J; Ross, Eric A

2018-03-01

Recommendations for surveillance after curative surgery for colorectal cancer (CRC) include a 1-year post-resection abdominal-pelvic computed tomography (CT) scan and optical colonoscopy (OC). CT colonography (CTC), when used in CRC screening, effectively identifies colorectal polyps ≥10 mm and cancers. We performed a prospective study to determine whether CTC, concurrent with CT, could substitute for OC in CRC surveillance. Our study enrolled 231 patients with resected stage 0-III CRC, identified at 5 tertiary care academic centers. Approximately 1 year after surgery, participants underwent outpatient CTC plus CT, followed by same-day OC. CTC results were revealed after endoscopic visualization of sequential colonic segments, which were re-examined for discordant findings. The primary outcome was performance of CTC in the detection of colorectal adenomas and cancers using endoscopy as the reference standard. Of the 231 participants, 116 (50.2%) had polyps of any size or histology identified by OC, and 15.6% had conventional adenomas and/or serrated polyps ≥6 mm. No intra-luminal cancers were detected. CTC detected patients with polyps of ≥6 mm with 44.0% sensitivity (95% CI, 30.2-57.8) and 93.4% specificity (95% CI, 89.7-97.0). CTC detected polyps ≥10 mm with 76.9% sensitivity (95% CI, 54.0-99.8) and 89.0% specificity (95% CI, 84.8-93.1). Similar values were found when only adenomatous polyps were considered. The negative predictive value of CTC for adenomas ≥6 mm was 90.7% (95% CI, 86.7-94.5) and for adenomas ≥10 mm the negative predictive value was 98.6% (95% CI, 97.0-100). In a CRC surveillance population 1 year following resection, CTC was inferior to OC for detecting patients with polyps ≥6 mm. Clinical Trials.gov Registration Number: NCT02143115. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Screening, management and surveillance for the sessile serrated adenomas/polyps.

PubMed

Fu, Xiangsheng; Qiu, Ye; Zhang, Yali

2014-01-01

The incidence and mortality rates from right-sided colorectal cancers (CRCs) have not decreased, compared with the significant reduction of CRCs in the left colon in recent years. It is likely that a significant proportion of right-sided CRCs evolve from undetected sessile serrated adenomas/polyps (SSA/Ps) in the primary colonoscopy. Increasing evidences suggest that SSA/Ps are high-risk lesions, with 15% of the SSA/P patients developing subsequent CRCs or adenomas with high-grade dysplasia. However, there are many issues in the screening, management and surveillance of SSA/Ps. Based on new evidences, this review addresses major issues in the diagnostic criteria for the serrated polyps of the colorectum, new endoscopic techniques (high-resolution magnifying endoscopy, narrow-band imaging, autofluorescence imaging, confocal laser endoscopy, and endocytoscopy) for the realtime identification of SSA/Ps, and the management of SSA/Ps by endoscopic mucosal resection, endoscopic sub-mucosal dissection or surgical resection in practice.

Developing Screening Services for Colorectal Cancer on Android Smartphones

PubMed Central

Wu, Hui-Ching; Chang, Chiao-Jung; Lin, Chun-Che; Tsai, Ming-Chang; Chang, Che-Chia

2014-01-01

Abstract Introduction: Colorectal cancer (CRC) is an important health problem in Western countries and also in Asia. It is the third leading cause of cancer deaths in both men and women in Taiwan. According to the well-known adenoma-to-carcinoma sequence, the majority of CRC develops from colorectal adenomatous polyps. This concept provides the rationale for screening and prevention of CRC. Removal of colorectal adenoma could reduce the mortality and incidence of CRC. Mobile phones are now playing an ever more crucial role in people's daily lives. The latest generation of smartphones is increasingly viewed as hand-held computers rather than as phones, because of their powerful on-board computing capability, capacious memories, large screens, and open operating systems that encourage development of applications (apps). Subjects and Methods: If we can detect the potential CRC patients early and offer them appropriate treatments and services, this would not only promote the quality of life, but also reduce the possible serious complications and medical costs. In this study, an intelligent CRC screening app on Android™ (Google™, Mountain View, CA) smartphones has been developed based on a data mining approach using decision tree algorithms. For comparison, the stepwise backward multivariate logistic regression model and the fecal occult blood test were also used. Results: Compared with the stepwise backward multivariate logistic regression model and the fecal occult blood test, the proposed app system not only provides an easy and efficient way to quickly detect high-risk groups of potential CRC patients, but also brings more information about CRC to customer-oriented services. Conclusions: We developed and implemented an app system on Android platforms for ubiquitous healthcare services for CRC screening. It can assist people in achieving early screening, diagnosis, and treatment purposes, prevent the occurrence of complications, and thus reach the goal of preventive medicine. PMID:24848873

Nutrition Frontiers - Spring 2017 | Division of Cancer Prevention

Cancer.gov

Volume 8, Issue 2 Dear Colleague, The spring issue of Nutrition Frontiers showcases the calcium/magnesium intake ratio in colorectal adenoma, the role of PPARγ in metabolism and reproduction, and the effects of time-restricted feeding on metabolic parameters. Meet our spotlight investigator, Dr. Maria Cruz-Correa, and her research on gut bacterial genes, diet, and colorectal

Potential of soluble CD26 as a serum marker for colorectal cancer detection

PubMed Central

Cordero, Oscar J; Imbernon, Monica; Chiara, Loretta De; Martinez-Zorzano, Vicenta S; Ayude, Daniel; de la Cadena, Maria Paez; Rodriguez-Berrocal, F Javier

2011-01-01

Colorectal cancer is characterized by a low survival rate even though the basis for colon cancer development, which involves the evolution of adenomas to carcinoma, is known. Moreover, the mortality rates continue to rise in economically transitioning countries although there is the opportunity to intervene in the natural history of the adenoma–cancer sequence through risk factors, screening, and treatment. Screening in particular accounted for most of the decline in colorectal cancer mortality achieved in the USA during the period 1975-2000. Patients show a better prognosis when the neoplasm is diagnosed early. Among the variety of screening strategies, the methods range from invasive and costly procedures such as colonoscopy to more low-cost and non-invasive tests such as the fecal occult blood test (guaiac and immunochemical). As a non-invasive biological serum marker would be of great benefit because of the performance of the test, several biomarkers, including cytologic assays, DNA and mRNA, and soluble proteins, have been studied. We found that the soluble CD26 (sCD26) concentration is diminished in serum of colorectal cancer patients compared to healthy donors, suggesting the potential utility of a sCD26 immunochemical detection test for early diagnosis. sCD26 originates from plasma membrane CD26 lacking its transmembrane and cytoplasmic domains. Some 90%–95% of sCD26 has been associated with serum dipeptidyl peptidase IV (DPP-IV) activity. DPP-IV, assigned to the CD26 cluster, is a pleiotropic enzyme expressed mainly on epithelial cells and lymphocytes. Our studies intended to validate this test for population screening to detect colorectal cancer and advanced adenomas are reviewed here. PMID:21773075

A randomized, placebo-controlled, preoperative trial of allopurinol in subjects with colorectal adenoma.

PubMed

Puntoni, Matteo; Branchi, Daniela; Argusti, Alessandra; Zanardi, Silvia; Crosta, Cristiano; Meroni, Emanuele; Munizzi, Francesco; Michetti, Paolo; Coccia, Gianni; De Roberto, Giuseppe; Bandelloni, Roberto; Turbino, Laura; Minetti, Egle; Mori, Marco; Salvi, Sandra; Boccardo, Simona; Gatteschi, Beatrice; Benelli, Roberto; Sonzogni, Angelica; DeCensi, Andrea

2013-02-01

Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis. After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, β-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue. Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas β-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of -10.6%, 95% confidence interval (CI), -20.5 to -0.7, and -8.1%, 95% CI, -22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (-16.4%; 95% CI, -29.0 to -3.8). No dose-response relationship was noted, except for NF-κB expression in normal tissue. Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity.

Diffuse reflectance spectroscopy as a tool for real-time tissue assessment during colorectal cancer surgery

NASA Astrophysics Data System (ADS)

Baltussen, Elisabeth J. M.; Snaebjornsson, Petur; de Koning, Susan G. Brouwer; Sterenborg, Henricus J. C. M.; Aalbers, Arend G. J.; Kok, Niels; Beets, Geerard L.; Hendriks, Benno H. W.; Kuhlmann, Koert F. D.; Ruers, Theo J. M.

2017-10-01

Colorectal surgery is the standard treatment for patients with colorectal cancer. To overcome two of the main challenges, the circumferential resection margin and postoperative complications, real-time tissue assessment could be of great benefit during surgery. In this ex vivo study, diffuse reflectance spectroscopy (DRS) was used to differentiate tumor tissue from healthy surrounding tissues in patients with colorectal neoplasia. DRS spectra were obtained from tumor tissue, healthy colon, or rectal wall and fat tissue, for every patient. Data were randomly divided into training (80%) and test (20%) sets. After spectral band selection, the spectra were classified using a quadratic classifier and a linear support vector machine. Of the 38 included patients, 36 had colorectal cancer and 2 had an adenoma. When the classifiers were applied to the test set, colorectal cancer could be discriminated from healthy tissue with an overall accuracy of 0.95 (±0.03). This study demonstrates the possibility to separate colorectal cancer from healthy surrounding tissue by applying DRS. High classification accuracies were obtained both in homogeneous and inhomogeneous tissues. This is a fundamental step toward the development of a tool for real-time in vivo tissue assessment during colorectal surgery.

Risk factors cannot explain the higher prevalence rates of precancerous colorectal lesions in men

PubMed Central

Waldmann, Elisabeth; Heinze, Georg; Ferlitsch, Arnulf; GessI, Irina; Sallinger, Daniela; Jeschek, Philip; Britto-Arias, Martha; Salzl, Petra; Fasching, Elisabeth; Jilma, Bernd; Kundi, Michael; Trauner, Michael; Ferlitsch, Monika

2016-01-01

Background: Prevalence of (pre)cancerous colorectal lesions are higher in men than in women, although transition rates from advanced lesions to cancer is similar in both sexes. Our aim was to investigate whether the sex-specific difference in incidence of premalignant colorectal lesions might be explained by the impact of risk factors. Methods: A cross-sectional study analysing health check-up examinations and screening colonoscopies performed within a national quality assurance program. Results: A total of 25 409 patients were included in this study, 50.8% were women. Median age for both sexes was 60 years (interquartile range (IQR) 54–67). A multivariable model showed that risk factors mediated only 0.6 of the 10.4% gender gap in adenoma and 0.47 of the 3.2% gender gap in advanced adenoma detection rate. Smoking was the only independent risk factor with a varying sex-specific effect (men OR 1.46, CI 1.29, 1.64, women OR 1.76, CI 1.53, 2.06) and advanced adenomas (men OR 1.06, CI 0.80–1.42; women OR 2.08, CI 1.52–2.83). Independent risk factors for adenomas were BMI (OR 1.35 per IQR, CI 1.25–1.47) and triglyceride level (OR 1.03 per IQR, CI 1.00–1.06); for advanced adenomas physical activity (none vs regular: OR 1.54, CI 1.18–2.00, occasional vs regular: OR 1.17, CI 1.00–1.38), cholesterol level (OR 1.13 per IQR, CI 1.02–1.25), blood glucose level (OR 1.05 per IQR, CI 1.01–1.09) and alcohol score (OR 1.09 per IQR, CI 1.01–1.18). Conclusions: Risk factors cannot explain higher prevalence rates in men. Results of this study strongly underline the need for sex-specific screening recommendations. PMID:27764840

The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential.

PubMed

Renaud, Florence; Mariette, Christophe; Vincent, Audrey; Wacrenier, Agnès; Maunoury, Vincent; Leclerc, Julie; Coppin, Lucie; Crépin, Michel; Van Seuningen, Isabelle; Leteurtre, Emmanuelle; Buisine, Marie-Pierre

2016-03-15

The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention. © 2015 UICC.

Test performance of immunologic fecal occult blood testing and sigmoidoscopy compared with primary colonoscopy screening for colorectal advanced adenomas.

PubMed

Khalid-de Bakker, Carolina A J; Jonkers, Daisy M A E; Sanduleanu, Silvia; de Bruïne, Adriaan P; Meijer, Gerrit A; Janssen, Jan B M J; van Engeland, Manon; Stockbrügger, Reinhold W; Masclee, Ad A M

2011-10-01

Given the current increase in colorectal cancer screening, information on performance of screening tests is needed, especially in groups with a presumed lower test performance. We compared test performance of immunologic fecal occult blood testing (FIT) and pseudosigmoidoscopy with colonoscopy for detection of advanced adenomas in an average risk screening population. In addition, we explored the influence of gender, age, and location on test performance. FIT was collected prior to colonoscopy with a 50 ng/mL cutoff point. FIT results and complete colonoscopy findings were available from 329 subjects (mean age: 54.6 ± 3.7 years, 58.4% women). Advanced adenomas were detected in 38 (11.6%) of 329 subjects. Sensitivity for advanced adenomas of FIT and sigmoidoscopy were 15.8% (95% CI: 6.0-31.3) and 73.7% (95% CI: 56.9-86.6), respectively. No sensitivity improvement was obtained using the combination of sigmoidoscopy and FIT. Mean fecal hemoglobin in FIT positives was significantly lower for participants with only proximal adenomas versus those with distal ones (P = 0.008), for women versus men (P = 0.023), and for younger (<55 years) versus older (≥55 years) subjects (P = 0.029). Sensitivities of FIT were 0.0% (95% CI: 0.0-30.9) in subjects with only proximal versus 21.4% (95% CI: 8.3-41.0) in those with distal nonadvanced adenomas; 5.3% (95% CI: 0.0-26.0) in women versus 26.3% (95% CI: 9.2-51.2) in men; 9.5% (95% CI: 1.2-30.4) in younger versus 23.5% (95% CI: 6.8-49.9) in older subjects. Sigmoidoscopy had a significantly higher sensitivity for advanced adenomas than FIT. A single FIT showed very low sensitivity, especially in subjects with only proximal nonadvanced adenomas, in women, and in younger subjects. This points to the existence of "low" FIT performance in subgroups and the need for more tailored screening strategies.

Variation of adenoma prevalence by age, sex, race, and colon location in a large population: implications for screening and quality programs.

PubMed

Corley, Douglas A; Jensen, Christopher D; Marks, Amy R; Zhao, Wei K; de Boer, Jolanda; Levin, Theodore R; Doubeni, Chyke; Fireman, Bruce H; Quesenberry, Charles P

2013-02-01

Reliable community-based colorectal adenoma prevalence estimates are needed to inform colonoscopy quality standards and to estimate patient colorectal cancer risks; however, minimal data exist from populations with large numbers of diverse patients and examiners. We evaluated the prevalence of adenomas detected by sex, age, race/ethnicity, and colon location among 20,792 Kaiser Permanente Northern California members ≥50 years of age who received a screening colonoscopy examination (102 gastroenterologists, 2006-2008). Prevalence of detected adenomas increased more rapidly with age in the proximal colon (adjusted odds ratio [OR], 2.39; 95% confidence interval [CI], 2.05-2.80; 70-74 vs 50-54 years) than in the distal colon (OR, 1.89; 95% CI, 1.63-2.19). Prevalence was higher among men vs women at all ages (OR, 1.77; 95% CI, 1.66-1.89), increasing in men from 25% to 39% at ≥70 years and in women from 15% at 50-54 years to 26% (P < .001). Proximal adenoma prevalence was higher among blacks than whites (OR, 1.26; 95% CI, 1.04-1.54), although total prevalence was similar, including persons <60 years old (OR, 1.17; 95% CI, 0.91-1.50). Prevalence of detected adenomas increases substantially with age and is much higher in men; proximal adenomas are more common among blacks than whites, although the total prevalence and the prevalence for ages <60 years were similar by race. These demographic differences are such that current adenoma detection guidelines may not be valid, without adjustment, for comparing providers serving different populations. The variation in prevalence and location may also have implications for the effectiveness of screening methods in different demographic groups. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

The relationship of quantitative nuclear morphology to molecular genetic alterations in the adenoma-carcinoma sequence of the large bowel.

PubMed Central

Mulder, J. W.; Offerhaus, G. J.; de Feyter, E. P.; Floyd, J. J.; Kern, S. E.; Vogelstein, B.; Hamilton, S. R.

1992-01-01

The relationship of abnormal nuclear morphology to molecular genetic alterations that are important in colorectal tumorigenesis is unknown. Therefore, Feulgen-stained isolated nuclei from 22 adenomas and 42 carcinomas that had been analyzed for ras gene mutations and allelic deletions on chromosomes 5q, 18q, and 17p were characterized by computerized image analysis. Both nuclear area and the nuclear shape factor representing irregularity correlated with adenoma-carcinoma progression (r = 0.57 and r = 0.52, P < 0.0001), whereas standard nuclear texture, a parameter of chromatin homogeneity, was inversely correlated with progression (r = -0.80, P < 0.0001). The nuclear parameters were strongly interrelated (P < 0.0005). In multivariate analysis, the nuclear parameters were predominantly associated with adenoma-carcinoma progression (P < or = 0.0001) and were not influenced significantly by the individual molecular genetic alterations. Nuclear texture, however, was inversely correlated with fractional allelic loss, a global measure of genetic changes, in carcinomas (r = -0.39, P = 0.011). The findings indicate that nuclear morphology in colorectal neoplasms is strongly related to tumor progression. Nuclear morphology and biologic behavior appear to be influenced by accumulated alterations in cancer-associated genes. Images Figure 1 PMID:1357973

Immunohistochemical expression of metallothionein in normal human colorectal mucosa, in adenomas and in adenocarcinomas and their associated metastases.

PubMed

Giuffrè, G; Barresi, G; Sturniolo, G C; Sarnelli, R; D'Incà, R; Tuccari, G

1996-10-01

The immunohistochemical distribution pattern of metallothionein, a low molecular weight protein with strong affinity for divalent heavy metal ions, has been investigated in normal and neoplastic conditions of the large bowel. Utilizing a monoclonal mouse antibody the following formalin-fixed paraffin-embedded surgical or biopsy samples were studied: tubulo-villous adenomas (8 cases); adenocarcinomas with various degree of differentiation (85), nine of which were mucinous-type; synchronous tubular or tubulo-villous adenomas separate from carcinomas (30); transitional mucosa (45); metastases in lymph nodes (43); and distant metastases (45). Twenty biopsies from the right and left colon of 10 patients affected by irritable bowel syndrome were also analyzed. Normal colonic mucosa as well as transitional mucosa showed metallothionein immunopositivity in enterocytes at the luminal surface and crypts. Evident nuclear and cytoplasmic staining was encountered in tubulo-villous adenomas; the same reactivity was noted in the basal glandular component of colorectal carcinomas-synchronous adenomas, while less intense staining was noted in the apical villous portions. A variable metallothionein immunostaining was observed in adenocarcinomas (62.3%), in lymph node (55.8%) and distant hepatic (17.2%) and omental (43.8%) metastases, although it was not always concordant with that reported in the corresponding primary tumour. Whether the metallothionein positivity observed in normal and neoplastic cells is the result of expression of a stable form of the protein or an accumulation in the nucleus and cytoplasm remains to be clarified.

Cost-effectiveness and budget impact analyses of a colorectal cancer screening programme in a high adenoma prevalence scenario using MISCAN-Colon microsimulation model.

PubMed

Arrospide, Arantzazu; Idigoras, Isabel; Mar, Javier; de Koning, Harry; van der Meulen, Miriam; Soto-Gordoa, Myriam; Martinez-Llorente, Jose Miguel; Portillo, Isabel; Arana-Arri, Eunate; Ibarrondo, Oliver; Lansdorp-Vogelaar, Iris

2018-04-25

The Basque Colorectal Cancer Screening Programme began in 2009 and the implementation has been complete since 2013. Faecal immunological testing was used for screening in individuals between 50 and 69 years old. Colorectal Cancer in Basque country is characterized by unusual epidemiological features given that Colorectal Cancer incidence is similar to other European countries while adenoma prevalence is higher. The object of our study was to economically evaluate the programme via cost-effectiveness and budget impact analyses with microsimulation models. We applied the Microsimulation Screening Analysis (MISCAN)-Colon model to predict trends in Colorectal Cancer incidence and mortality and to quantify the short- and long-term effects and costs of the Basque Colorectal Cancer Screening Programme. The model was calibrated to the Basque demographics in 2008 and age-specific Colorectal Cancer incidence data in the Basque Cancer Registry from 2005 to 2008 before the screening begun. The model was also calibrated to the high adenoma prevalence observed for the Basque population in a previously published study. The multi-cohort approach used in the model included all the cohorts in the programme during 30 years of implementation, with lifetime follow-up. Unit costs were obtained from the Basque Health Service and both cost-effectiveness analysis and budget impact analysis were carried out. The goodness-of-fit of the model adaptation to observed programme data was evidence of validation. In the cost-effectiveness analysis, the savings from treatment were larger than the added costs due to screening. Thus, the Basque programme was dominant compared to no screening, as life expectancy increased by 29.3 days per person. The savings in the budget analysis appeared 10 years after the complete implementation of the programme. The average annual budget was €73.4 million from year 2023 onwards. This economic evaluation showed a screening intervention with a major health gain that also produced net savings when a long follow-up was used to capture the late economic benefit. The number of colonoscopies required was high but remain within the capacity of the Basque Health Service. So far in Europe, no other population Colorectal Cancer screening programme has been evaluated by budget impact analysis.

New-Generation High-Definition Colonoscopes Increase Adenoma Detection when Screening a Moderate-Risk Population for Colorectal Cancer.

PubMed

Bond, Ashley; O'Toole, Paul; Fisher, Gareth; Subramanian, Sreedhar; Haslam, Neil; Probert, Chris; Cox, Trevor; Sarkar, Sanchoy

2017-03-01

Adenoma detection rate (ADR) is the most important quality indicator for screening colonoscopy, due to its association with colorectal cancer outcomes. As a result, a number of techniques and technologies have been proposed that have the potential to improve ADR. The aim of this study was to assess the potential impact of new-generation high-definition (HD) colonoscopy on ADR within the Bowel Cancer Screening Programme (BCSP). This was a retrospective single-center observational study in patients undergoing an index screening colonoscopy. The examination was performed with either standard-definition colonoscopes (Olympus Q240/Q260 series) or HD colonoscopes (Olympus HQ290 EVIS LUCERA ELITE system) with the primary outcome measures of ADR and mean adenoma per procedure (MAP) between the 2 groups. A total of 395 patients (60.5% male, mean age 66.8 years) underwent screening colonoscopy with 45% performed with HD colonoscopes. The cecal intubation rate was 97.5% on an intention-to-treat basis and ADR was 68.6%. ADR with standard-definition was 63.13%, compared with 75.71% with HD (P = .007). The MAP in the HD group was 2.1 (± 2.0), whereas in the standard-definition group it was 1.6 (± 1.8) (P = .01). There was no significant difference in withdrawal time between the 2 groups. In the multivariate regression model, only HD scopes (P = .03) and male sex (P = .04) independently influenced ADR. Olympus H290 LUCERA ELITE HD colonoscopes improved adenoma detection within the moderate-risk population. A 12% improvement in ADR might be expected to increase significantly the protection afforded by colonoscopy against subsequent colorectal cancer mortality. Copyright © 2016 Elsevier Inc. All rights reserved.

Colorectal Chemoprevention with Calcium and Vitamin D | Division of Cancer Prevention

Cancer.gov

In this application we propose to complete CA098286, a double-blind, randomized, controlled trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas. The study builds on extensive epidemiological and experimental data indicating that both vitamin D and calcium have anti-neoplastic effects in the large bowel and that these agents

Natural dietary compound naringin prevents azoxymethane/dextran sodium sulfate-induced chronic colorectal inflammation and carcinogenesis in mice.

PubMed

Zhang, Yu-Sheng; Wang, Feng; Cui, Shu-Xiang; Qu, Xian-Jun

2018-03-26

Naringin, a natural occurring flavonoid compound, enriches in citrus fruits. We aimed to evaluate the inhibitory effect of naringin on colitis and chronic inflammation-driven carcinogenesis. Male C57BL/6 mice were exposed to AOM/DSS to induce colorectal inflammation and carcinogenesis. Naringin by oral administration prevented AOM/DSS-induced ulcerative colitis and carcinogenesis without significant side effects. Naringin attenuated the severity of colitis and colorectal adenomas through inhibiting myeloid-derived suppressor cells (MDSCs), pro-inflammatory mediators GM-CSF/M-CSF, IL-6 and TNF-α and the NF-κB/IL-6/STAT3 cascades in colorectal tissues. Naringin-treated mice exhibited normalized structures of colorectal tissues. Electron microscopy analysis showed the suppression of robust endoplasmic reticulum (ER) stress-induced autophagy. Naringin inhibited the secretion of the ER-spanning transmembrane proteins, such as GRP78 ATF6, IRE1α and activated PERK phosphorylated eIF-2α and complex of autophagosomes ATG3, ATG5, ATG7, ATG12, ATG16 and ATG16L1 in the colorectal mucosal cells. Naringin prevented colitis and colorectal carcinogenesis through suppressing robust ER stress-induced autophagy in colorectal mucosal cells. Naringin could develop a promising therapeutic agent for the prevention of ulcerative colitis and colorectal tumor.

Effects of calcium on the incidence of recurrent colorectal adenomas

PubMed Central

Veettil, Sajesh K.; Ching, Siew Mooi; Lim, Kean Ghee; Saokaew, Surasak; Phisalprapa, Pochamana; Chaiyakunapruk, Nathorn

2017-01-01

Abstract Background: Protective effects of calcium supplementation against colorectal adenomas have been documented in systematic reviews; however, the results have not been conclusive. Our objective was to update and systematically evaluate the evidence for calcium supplementation taking into consideration the risks of systematic and random error and to GRADE the evidence. Methods: The study comprised a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials (RCTs). We searched for RCTs published up until September 2016. Retrieved trials were evaluated using risk of bias. Primary outcome measures were the incidences of any recurrent adenomas and of advanced adenomas. Meta-analytic estimates were calculated with the random-effects model and random errors were evaluated with trial sequential analyses (TSAs). Results: Five randomized trials (2234 patients with a history of adenomas) were included. Two of the 5 trials showed either unclear or high risks of bias in most criteria. Meta-analysis of good quality RCTs suggest a moderate protective effect of calcium supplementation on recurrence of adenomas (relative risk [RR], 0.88 [95% CI 0.79–0.99]); however, its effects on advanced adenomas did not show statistical significance (RR, 1.02 [95% CI 0.67–1.55]). Subgroup analyses demonstrated a greater protective effect on recurrence of adenomas with elemental calcium dose ≥1600 mg/day (RR, 0.74 [95% CI 0.56–0.97]) compared to ≤1200 mg/day (RR, 0.84 [95% CI 0.73–0.97]). No major serious adverse events were associated with the use of calcium, but there was an increase in the incidence of hypercalcemia (P = .0095). TSA indicated a lack of firm evidence for a beneficial effect. Concerns with directness and imprecision rated down the quality of the evidence to “low.” Conclusion: The available good quality RCTs suggests a possible beneficial effect of calcium supplementation on the recurrence of adenomas; however, TSA indicated that the accumulated evidence is still inconclusive. Using GRADE-methodology, we conclude that the quality of evidence is low. Large well-designed randomized trials with low risk of bias are needed. PMID:28796047

Dietary Flavonoids and Colorectal Adenoma Recurrence in the Polyp Prevention Trial

PubMed Central

Bobe, Gerd; Sansbury, Leah B.; Albert, Paul S.; Cross, Amanda J.; Kahle, Lisa; Ashby, Jason; Slattery, Martha L.; Caan, Bette; Paskett, Electra; Iber, Frank; Kikendall, James Walter; Lance, Peter; Daston, Cassandra; Marshall, James R.; Schatzkin, Arthur; Lanza, Elaine

2008-01-01

Two recent case-control studies suggested that some flavonoid subgroups may play a role in preventing colorectal cancer. Previous prospective cohort studies generally reported no association; however, only a small subset of flavonoids was evaluated and partial flavonoid databases were used. We used the newly constructed U.S. Department of Agriculture flavonoid database to examine the association between consumption of total flavonoids, 6 flavonoid subgroups, and 29 individual flavonoids with adenomatous polyp recurrence in the Polyp Prevention Trial. The Polyp Prevention Trial was a randomized dietary intervention trial, which examined the effectiveness of a low-fat, high-fiber, high-fruit, and high-vegetable diet on adenoma recurrence. Intakes of flavonoids were estimated from a food frequency questionnaire. Multivariate logistic regression models (adjusted for age, body mass index, sex, regular non–steroidal anti-inflammatory use, and dietary fiber intake) were used to estimate odds ratios and 95% confidence intervals for both any and advanced adenoma recurrence within quartiles of energy-adjusted flavonoid intake (baseline, during the trial, and change during the trial). Total flavonoid intake was not associated with any or advanced adenoma recurrence. However, high intake of flavonols, which are at greater concentrations in beans, onions, apples, and tea, was associated with decreased risk of advanced adenoma recurrence (4th versus 1st quartile during the trial; odds ratio, 0.24; 95% confidence interval, 0.11, 0.53; Ptrend = 0.0006). Similar inverse associations were observed to a smaller extent for isoflavonoids, the flavonol kaempferol, and the isoflavonoids genistein and formononetin. Our data suggest that a flavonol-rich diet may decrease the risk of advanced adenoma recurrence. PMID:18559549

Prevalence of colorectal cancer in acute uncomplicated diverticulitis and the role of the interval colonoscopy.

PubMed

Soh, Nicholas Yock Teck; Chia, Daryl Kai Ann; Teo, Nan Zun; Ong, Calvin Jian Ming; Wijaya, Ramesh

2018-04-16

Although computed tomography (CT) is the imaging modality of choice for diagnosing colonic diverticulitis today, there remains a risk of colorectal cancer mimicking diverticulitis due to overlapping imaging features. Current practice guidelines recommend interval colonoscopy after diverticulitis to exclude occult malignancy. Some authors have suggested that this may be unnecessary in patients with uncomplicated diverticulitis. The aim of our study was to examine the prevalence of occult colorectal cancer in patients with CT-proven acute uncomplicated diverticulitis in an Asian population. This was a retrospective study of all patients admitted for CT-proven acute uncomplicated diverticulitis between 2007 and 2011 in a single institution. Colonoscopy and histopathology reports were reviewed for patients who underwent interval colonic evaluation. For patients who defaulted follow-up, national health records were reviewed for any subsequent diagnoses of colorectal cancer. The primary outcome was prevalence of colorectal cancer in the cohort. Secondary outcome was prevalence of advanced adenomas. A total of 227 patients with acute uncomplicated diverticulitis were included in our study. One hundred and thirty-five patients (59.5%) underwent follow-up colonic evaluation. The overall prevalence of colorectal cancer was 1.8%, with half these patients presenting with acute colonic obstruction after defaulting follow-up evaluation. Of the patients, 1.5% who underwent colonoscopy had advanced adenomas. Prevalence of colorectal cancer in patients with CT-proven acute uncomplicated diverticulitis may not be as low as previously suggested. We recommend that patients with acute uncomplicated diverticulitis continue to be offered interval colonoscopy until larger studies demonstrate the safety of omission.

CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway.

PubMed

Rhee, Ye-Young; Kim, Kyung-Ju; Kang, Gyeong Hoon

2017-01-15

The concept of a CpG island methylator phenotype (CIMP) was first introduced by Toyota and Issa to describe a subset of colorectal cancers (CRCs) with concurrent hypermethylation of multiple CpG island loci. The concept of CIMP as a molecular carcinogenesis mechanism was consolidated by the identification of the serrated neoplasia pathway, in which CIMP participates in the initiation and progression of serrated adenomas. Distinct clinicopathological and molecular features of CIMP-high (CIMP-H) CRCs have been characterized, including proximal colon location, older age of onset, female preponderance, and frequent associations of high-level microsatellite instability and BRAF mutations. CIMP-H CRCs arise in sessile or traditional serrated adenomas and thus tend to display the morphological characteristics of serrated adenomas, including epithelial serration, vesicular nuclei, and abundant cytoplasm. Both the frequent association of CIMP and poor prognosis and different responses of CRCs to adjuvant therapy depending on CIMP status indicate clinical implications. In this review, we present an overview of the literature documenting the relevant findings of CIMP-H CRCs and their relationships with the serrated neoplasia pathway.

Factors Associated With Shorter Colonoscopy Surveillance Intervals for Patients With Low-Risk Colorectal Adenomas and Effects on Outcome.

PubMed

Anderson, Joseph C; Baron, John A; Ahnen, Dennis J; Barry, Elizabeth L; Bostick, Roberd M; Burke, Carol A; Bresalier, Robert S; Church, Timothy R; Cole, Bernard F; Cruz-Correa, Marcia; Kim, Adam S; Mott, Leila A; Sandler, Robert S; Robertson, Douglas J

2017-06-01

Endoscopists do not routinely follow guidelines to survey individuals with low-risk adenomas (LRAs; 1-2 small tubular adenomas, < 1 cm) every 5-10 years for colorectal cancer; many recommend shorter surveillance intervals for these individuals. We aimed to identify the reasons that endoscopists recommend shorter surveillance intervals for some individuals with LRAs and determine whether timing affects outcomes at follow-up examinations. We collected data from 1560 individuals (45-75 years old) who participated in a prospective chemoprevention trial (of vitamin D and calcium) from 2004 through 2008. Participants in the trial had at least 1 adenoma, detected at their index colonoscopy, and were recommended to receive follow-up colonoscopy examinations at 3 or 5 years after adenoma identification, as recommended by the endoscopist. For this analysis we collected data from only participants with LRAs. These data included characteristics of participants and endoscopists and findings from index and follow-up colonoscopies. Primary endpoints were frequency of recommending shorter (3-year) vs longer (5-year) surveillance intervals, factors associated with these recommendations, and effect on outcome, determined at the follow-up colonoscopy. A 3-year surveillance interval was recommended for 594 of the subjects (38.1%). Factors most significantly associated with recommendation of 3-year vs a 5-year surveillance interval included African American race (relative risk [RR] to white, 1.41; 95% confidence interval [CI], 1.14-1.75), Asian/Pacific Islander ethnicity (RR to white, 1.7; 95% CI, 1.22-2.43), detection of 2 adenomas at the index examination (RR vs 1 adenoma, 1.47; 95% CI, 1.27-1.71), more than 3 serrated polyps at the index examination (RR=2.16, 95% CI, 1.59-2.93), or index examination with fair or poor quality bowel preparation (RR vs excellent quality, 2.16; 95% CI, 1.66-2.83). Other factors that had a significant association with recommendation for a 3-year surveillance interval included family history of colorectal cancer and detection of 1-2 serrated polyps at the index examination. In comparisons of outcomes, we found no significant differences between the 3-year vs 5-year recommendation groups in proportions of subjects found to have 1 or more adenomas (38.8% vs 41.7% respectively; P = .27), advanced adenomas (7.7% vs 8.2%; P = .73) or clinically significant serrated polyps (10.0% vs 10.3%; P = .82) at the follow-up colonoscopy. Possibly influenced by patients' family history, race, quality of bowel preparation, or number or size of polyps, endoscopists frequently recommend 3-year surveillance intervals instead of guideline-recommended intervals of 5 years or longer for individuals with LRAs. However, at the follow-up colonoscopy, similar proportions of participants have 1 or more adenomas, advanced adenomas, or serrated polyps. These findings support the current guideline recommendations of performing follow-up examinations of individuals with LRAs at least 5 years after the index colonoscopy. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Cancer testis antigen OY-TES-1 expression and serum immunogenicity in colorectal cancer: its relationship to clinicopathological parameters

PubMed Central

Luo, Bin; Yun, Xiang; Fan, Rong; Lin, Yong-Da; He, Shu-Jia; Zhang, Qing-Mei; Mo, Fa-Rong; Chen, Fang; Xiao, Shao-Wen; Xie, Xiao-Xun

2013-01-01

Cancer testis (CT) antigens are attractive targets for cancer immunotherapy because their expression is restricted in normal germ line tissues but frequently detected in variety of tumors. OY-TES-1 is identified as a member of CT antigens. Current knowledge about OY-TES-1 expression in colorectal cancer (CRC) is solely based on mRNA analysis. None of previous researches has studied OY-TES-1 at protein level. In this study, OY-TES-1 polyclonal antibody was generated. The expression of OY-TES-1 mRNA and protein was detected by RT-PCR and immunohistochemistry in 60 CRC and paired adjacent non-tumor tissues, 24 colorectal adenoma and 3 normal colon tissues, respectively. Sera from 73 CRC patients were also tested for OY-TES-1 antibody by ELISA. Our results showed that the frequency of OY-TES-1 mRNA expression was statistically higher in CRC (73.3%, 44/60) than that in adjacent non-tumor tissue (55.0%, 33/60) and colorectal adenoma (45.8%, 11/24). For the first time, OY-TES-1 protein expression was found in (43.3%, 26/60) of CRC tissues, but absent in any of adjacent non-tumor and colorectal adenoma tissues. No OY-TES-1 expression was found in normal colon by either RT-PCR or immunohistochemistry. Furthermore, OY-TES-1 protein expression was correlated with tumor invasion stage (P=0.004) and histological grade (P=0.040). Anti-OY-TES-1 antibody was detected in (9.6%, 7/73) of CRC patients’ sera but not in 76 healthy donors. This finding demonstrates that OY-TES-1 is frequently expressed in CRC and is able to induce humoral immune response spontaneously in CRC patients, suggesting that it might be a promising immunotherapy target for CRC. PMID:24294369

Tumor-associated down-regulation of 15-lipoxygenase-1 is reversed by celecoxib in colorectal cancer.

PubMed

Heslin, Martin J; Hawkins, Ashley; Boedefeld, William; Arnoletti, J Pablo; Frolov, Andrey; Soong, Richie; Urist, Marshall M; Bland, Kirby I

2005-06-01

To evaluate the role of celecoxib on 15-lipoxygenase-1 (15-LOX-1) expression, protein levels, and rates of apoptosis in colorectal cancer cell lines. Also, to evaluate the expression of 15-LOX-1 in human normal mucosa, adenoma, and carcinoma with correlation to overall survival. The function of 15-LOX-1 is to maintain normal rates of apoptosis (programmed cell death). Decreased apoptosis is one mechanism of cancer growth and dissemination. It is our hypothesis that expression of 15-LOX-1 is reduced in human colorectal cancer (CRC) and the administration of celecoxib can reverse this process and induce apoptosis. Effect of celecoxib in cell culture: The effect of 40 micromol/L celecoxib was compared with untreated controls in tissue culture utilizing HT-29 and DLD-1 CRC cell lines. Expression of 15-LOX-1 protein was measured by immunoblot. Induction of apoptosis was evaluated by annexin V staining. All data are presented as mean +/- SEM, with significance defined as P < 0.05. 15-LOX-1 in human CRC: From February 1998 to January 2002, 126 patients underwent surgical resection of either colorectal adenomas (n = 24) or carcinomas (n = 102), or both (n = 25). Tissue was macrodissected, snap frozen, and stored at -80 degrees C. After tissue processing, RNA was extracted and gene expression of 15-LOX-1 was quantified utilizing ABI prism real-time quantitative RT-PCR. Significance evaluated by the Wilcoxon signed rank test. Effect of celecoxib in cell culture: After 72 hours of treatment with celecoxib, immunoblot demonstrated a 1.5- to 2-fold increase in 15-LOX-1 protein expression in HT-29 and DLD-1 cells, respectively. Celecoxib produced greater than a 2-fold increase in the rate of apoptosis compared with control cells in both cell lines (P < 0.05). 15-LOX-1 in human CRC: The mean age of the patients was 62 +/- 1 years; 78% were white and 48% were female. The mean size of the polyps and cancers were 3.0 +/- 0.4 and 5.0 +/- 0.1 cm, respectively. Expression of 15-LOX-1 relative to S9 was 30 in normal mucosa and significantly down-regulated to 11 in adenomas and 16 in carcinomas (P < 0.05). 15-LOX-1 gene expression is significantly reduced in both human colorectal adenomas and carcinomas and associated with decreased survival. Administration of celecoxib restores 15-LOX-1 protein expression and induces apoptosis. Down-regulation of 15-LOX-1 is an early event in the adenoma to carcinoma sequence, and reversal with celecoxib may represent one mechanism for chemoprevention of polyps or treatment of carcinomas.

Risk of Advanced Neoplasia in First-Degree Relatives with Colorectal Cancer: A Large Multicenter Cross-Sectional Study

PubMed Central

Quintero, Enrique; Gargallo, Carla; Lanas, Angel; Bujanda, Luis; Gimeno-García, Antonio Z.; Hernández-Guerra, Manuel; Nicolás-Pérez, David; Alonso-Abreu, Inmaculada; Morillas, Juan Diego; Balaguer, Francesc; Muriel, Alfonso

2016-01-01

Background First-degree relatives (FDR) of patients with colorectal cancer have a higher risk of developing colorectal cancer than the general population. For this reason, screening guidelines recommend colonoscopy every 5 or 10 y, starting at the age of 40, depending on whether colorectal cancer in the index-case is diagnosed at <60 or ≥60 y, respectively. However, studies on the risk of neoplastic lesions are inconclusive. The aim of this study was to determine the risk of advanced neoplasia (three or more non-advanced adenomas, advanced adenoma, or invasive cancer) in FDR of patients with colorectal cancer compared to average-risk individuals (i.e., asymptomatic adults 50 to 69 y of age with no family history of colorectal cancer). Methods and Findings This cross-sectional analysis includes data from 8,498 individuals undergoing their first lifetime screening colonoscopy between 2006 and 2012 at six Spanish tertiary hospitals. Of these individuals, 3,015 were defined as asymptomatic FDR of patients with colorectal cancer (“familial-risk group”) and 3,038 as asymptomatic with average-risk for colorectal cancer (“average-risk group”). The familial-risk group was stratified as one FDR, with one family member diagnosed with colorectal cancer at ≥60 y (n = 1,884) or at <60 y (n = 831), and as two FDR, with two family members diagnosed with colorectal cancer at any age (n = 300). Multiple logistic regression analysis was used for between-group comparisons after adjusting for potential confounders (age, gender, and center). Compared with the average-risk group, advanced neoplasia was significantly more prevalent in individuals having two FDR with colorectal cancer (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.36–2.66, p < 0.001), but not in those having one FDR with colorectal cancer diagnosed at ≥60 y (OR 1.03; 95% CI 0.83–1.27, p = 0.77) and <60 y (OR 1.19; 95% CI 0.90–1.58, p = 0.20). After the age of 50 y, men developed advanced neoplasia over two times more frequently than women and advanced neoplasia appeared at least ten y earlier. Fewer colonoscopies by 2-fold were required to detect one advanced neoplasia in men than in women. Major limitations of this study were first that although average-risk individuals were consecutively included in a randomized control trial, this was not the case for all individuals in the familial-risk cohort; and second, the difference in age between the average-risk and familial-risk cohorts. Conclusions Individuals having two FDR with colorectal cancer showed an increased risk of advanced neoplasia compared to those with average-risk for colorectal cancer. Men had over 2-fold higher risk of advanced neoplasia than women, independent of family history. These data suggest that screening colonoscopy guidelines should be revised in the familial-risk population. PMID:27138769

Genomic Aberrations Occurring in Subsets of Serrated Colorectal Lesions but not Conventional Adenomas

PubMed Central

Burnett-Hartman, Andrea N.; Newcomb, Polly A.; Potter, John D.; Passarelli, Michael N.; Phipps, Amanda I.; Wurscher, Michelle A.; Grady, William M.; Zhu, Lee-Ching; Upton, Melissa P.; Makar, Karen W.

2013-01-01

A subset of aggressive colorectal cancers exhibit BRAF mutation, MLH1 methylation, and a CpG island methylator phenotype (CIMP), but precursors are poorly established. In this study, we determined the status of these markers in colorectal polyps and evaluated associated risk factors. The study included 771 polyp cases and 1,027 controls who were ages 24-80, part of a group health program, received a colonoscopy from 1998-2007, and completed a structured questionnaire assessing risk factors. Following standard pathology review, polyps were assayed for BRAF mutation (V600E) and tested for MLH1 and CIMP methylation, the latter including the genes: CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Polytomous logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between molecularly-defined subsets of polyps and potential risk factors. There were 580 conventional adenomas and 419 serrated lesions successfully assayed. For adenomas, the prevalence of each marker was ≤1%. In contrast, 55% of serrated lesions harbored mutant BRAF, 26% were CIMP-high, and 5% had methylated MLH1. In these lesions, the highest prevalence of markers was in sessile serrated polyps (SSPs) of ≥10 mm that were in the right-side/cecal regions of the colon. Risk factors for CIMP-high serrated lesions included Caucasian race, current smoking status, and a history of polyps, whereas for serrated lesions with mutant BRAF the significant risk factors were male sex, current smoking status, obesity, and a history of polyps. Our results suggest that SSPs and other large, right-sided serrated lesions have a unique molecular profile that is similar to CIMP-high, BRAF-mutated colorectal cancers. PMID:23539450

Underwater colorectal EMR: remodeling endoscopic mucosal resection.

PubMed

Curcio, Gabriele; Granata, Antonino; Ligresti, Dario; Tarantino, Ilaria; Barresi, Luca; Liotta, Rosa; Traina, Mario

2015-05-01

Underwater EMR (UEMR) has been reported as a new technique for the removal of large sessile colorectal polyps without need for submucosal injection. To evaluate (1) outcomes of UEMR, (2) whether UEMR can be easily performed by an endoscopist skilled in traditional EMR without specific dedicated training in UEMR, and (3) whether EUS is required before UEMR. Prospective, observational study. Single, tertiary-care referral center. Underwater EMR. Complete resection and adverse events. A total of 72 consecutive patients underwent UEMR of 81 sessile colorectal polyps. EUS was performed before UEMR in 9 cases (11.1%) with a suspicious mucosal/vascular pattern. The mean polyp size was 18.7 mm (range 10-50 mm); the mean UEMR time was 11.8 minutes. Fifty-five polyps (68%) were removed en bloc, and 26 (32%) were removed with a piecemeal technique. Histopathology consisted of tubular adenomas (25.9%), tubulovillous adenomas (5%), adenomas with high-grade dysplasia (42%), serrated polyps (4.9%), carcinoma in situ (13.6%), and hyperplastic polyps (8.6%). Surveillance colonoscopy was scheduled at 3 months. Complete resection was successful in all patients. No adverse events or recurrence was recorded in any of the patients. Limited follow-up; single-center, uncontrolled study. Interventional endoscopists skilled in conventional EMR performed UEMR without specific dedicated training. EUS may not be required for lesions with no invasive features on high-definition narrow-band imaging. UEMR appears to be an effective and safe alternative to traditional EMR and could eventually improve the way in which we can effectively and safely treat colorectal lesions. Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

The effects of selected drugs and dietary compounds on proliferation and apoptosis in colorectal carcinoma.

PubMed

Kiedrowski, Miroslaw; Mroz, Andrzej

2014-01-01

Like many malignancies, the development of colorectal carcinoma (CRC) can be considered as an imbalance between the compromised process of programmed cell death (apoptosis) and excessive, uncontrolled proliferation. Several mutations and epigenetic alterations are acquired during colorectal carcinogenesis. These are responsible for the cell cycle regulation, cellular sensitivity to pro- and antiapoptotic factors, cell proliferation, angiogenesis, invasiveness, as well as metastatic potential. The molecular alterations, along with their morphological expressions, have been recognised in detail, and most of the CRC cases can be attributed to either adenoma-carcinoma or serrated neoplasia pathways: in the first, the antiapoptotic features prevail; while in the second, the proliferative activity is of the utmost importance. The aim of the work is to discuss the influence of selected drugs and dietary compounds on the proliferation and apoptosis in CRC.

Phosphorylated Protein Kinase C (Zeta/Lambda) Expression in Colorectal Adenocarcinoma and Its Correlation with Clinicopathologic Characteristics and Prognosis.

PubMed

Yeo, Min-Kyung; Kim, Ji Yeon; Seong, In-Ock; Kim, Jin-Man; Kim, Kyung-Hee

2017-01-01

Background: Protein kinase C zeta/lambda (PKCζ/λ) is a family of protein kinase enzymes that contributes to cell proliferation and regulation, which are important for cancer development. PKCζ/λ has been shown to be an important regulator of tumorigenesis in intestinal cancer. The phosphorylated form of PKCζ/λ, p-PKCζ/λ, is suggested as an active form of PKCζ/λ. However, p-PKCζ/λ expression and its clinicopathologic implication in colorectal adenocarcinoma (CRAC) are unclear. Methods: Seven whole-tissue sections of malignant polyps containing both non-neoplastic and neoplastic mucosa, 11 adenomas with low-grade dysplasia, and 173 CRACs were examined by immunohistochemistry and western blot assay for p-PKCζ/λ protein expression. The association of p-PKCζ/λ expression with clinicopathologic factors including patient survival was studied. Results: In non-neoplastic epithelia, p-PKCζ/λ showed a weak cytoplasmic immunostaining. Adenomas and CRACs demonstrated up-regulated p-PKCζ/λ detection. Cytoplasmic p-PKCζ/λ expression was higher in CRAC than in adenoma. In CRACs, p-PKCζ/λ expression was inversely correlated with pathologic TNM stage (I-II versus III-IV) and poor differentiation. Statistical correlations between low expression of p-PKCζ/λ with shortened overall survival and disease-free survival were seen (p=0.004 and p=0.034, respectively). Conclusions: P-PKCζ/λ overexpression is implicated in tumorigenesis but down-regulation was a poor prognostic factor in CRAC.

A CpG island methylator phenotype of colorectal cancer that is contiguous with conventional adenomas, but not serrated polyps

PubMed Central

HOKAZONO, KOJI; UEKI, TAKASHI; NAGAYOSHI, KINUKO; NISHIOKA, YASUNOBU; HATAE, TATSUNOBU; KOGA, YUTAKA; HIRAHASHI, MINAKO; ODA, YOSHINAO; TANAKA, MASAO

2014-01-01

A subset of colorectal cancers (CRCs) harbor the CpG island methylator phenotype (CIMP), with concurrent multiple promoter hypermethylation of tumor-related genes. A serrated pathway in which CIMP is developed from serrated polyps is proposed. The present study characterized CIMP and morphologically examined precursor lesions of CIMP. In total, 104 CRCs treated between January 1996 and December 2004 were examined. Aberrant promoter methylation of 15 cancer-related genes was analyzed. CIMP status was classified according to the number of methylated genes and was correlated with the clinicopathological features, including the concomitant polyps in and around the tumors. The frequency of aberrant methylation in each CRC showed a bimodal pattern, and the CRCs were classified as CIMP-high (CIMP-H), CIMP-low (CIMP-L) and CIMP-negative (CIMP-N). CIMP-H was associated with aberrant methylation of MLH1 (P=0.005) and with an improved recurrence-free survival (RFS) rate following curative resection compared with CIMP-L/N (five-year RFS rate, 93.8 vs. 67.1%; P=0.044), while CIMP-N tumors were associated with frequent distant metastases at diagnosis (P=0.023). No concomitant serrated lesions were present in the tumors, whereas conventional adenoma was contiguous with 11 (10.6%) of 104 CRCs, including four CIMP-H CRCs. CIMP-H was classified in CRCs by a novel CIMP marker panel and the presence of concomitant tumors revealed that certain CIMP-H CRCs may have arisen from conventional adenomas. PMID:25289081

A CpG island methylator phenotype of colorectal cancer that is contiguous with conventional adenomas, but not serrated polyps.

PubMed

Hokazono, Koji; Ueki, Takashi; Nagayoshi, Kinuko; Nishioka, Yasunobu; Hatae, Tatsunobu; Koga, Yutaka; Hirahashi, Minako; Oda, Yoshinao; Tanaka, Masao

2014-11-01

A subset of colorectal cancers (CRCs) harbor the CpG island methylator phenotype (CIMP), with concurrent multiple promoter hypermethylation of tumor-related genes. A serrated pathway in which CIMP is developed from serrated polyps is proposed. The present study characterized CIMP and morphologically examined precursor lesions of CIMP. In total, 104 CRCs treated between January 1996 and December 2004 were examined. Aberrant promoter methylation of 15 cancer-related genes was analyzed. CIMP status was classified according to the number of methylated genes and was correlated with the clinicopathological features, including the concomitant polyps in and around the tumors. The frequency of aberrant methylation in each CRC showed a bimodal pattern, and the CRCs were classified as CIMP-high (CIMP-H), CIMP-low (CIMP-L) and CIMP-negative (CIMP-N). CIMP-H was associated with aberrant methylation of MLH1 (P=0.005) and with an improved recurrence-free survival (RFS) rate following curative resection compared with CIMP-L/N (five-year RFS rate, 93.8 vs. 67.1%; P=0.044), while CIMP-N tumors were associated with frequent distant metastases at diagnosis (P=0.023). No concomitant serrated lesions were present in the tumors, whereas conventional adenoma was contiguous with 11 (10.6%) of 104 CRCs, including four CIMP-H CRCs. CIMP-H was classified in CRCs by a novel CIMP marker panel and the presence of concomitant tumors revealed that certain CIMP-H CRCs may have arisen from conventional adenomas.

Outcome of 24 years national surveillance in different hereditary colorectal cancer subgroups leading to more individualised surveillance.

PubMed

Lindberg, Lars Joachim; Ladelund, Steen; Frederiksen, Birgitte Lidegaard; Smith-Hansen, Lars; Bernstein, Inge

2017-05-01

Individuals with hereditary non-polyposis colorectal cancer (HNPCC) have a high risk of colorectal cancer (CRC). The benefits of colonic surveillance in Lynch syndrome and Amsterdam-positive (familial CRC type X familial colorectal cancer type X (FCCTX)) families are clear; only the interval between colonoscopies is debated. The potential benefits for families not fulfilling the Amsterdam criteria are uncertain. The aim of this study was to compare the outcome of colonic surveillance in different hereditary subgroups and to evaluate the surveillance programmes. A prospective, observational study on the outcome of colonic surveillance in different hereditary subgroups based on 24 years of surveillance data from the national Danish HNPCC register. We analysed 13 444 surveillance sessions, including 8768 incidence sessions and 20 450 years of follow-up. CRC was more incident in the Lynch subgroup (2.0%) than in any other subgroup (0.0-0.4%, p<0.0001), but the incidence of advanced adenoma did not differ between the Lynch (3.6%) and non-Lynch (2.3-3.9%, p=0.28) subgroups. Non-Lynch Amsterdam-positive and Amsterdam-negative families were similar in their CRC (0.1-0.4%, p=0.072), advanced adenoma (2.3-3.3%, p=0.32) and simple adenoma (8.4-9.9%, p=0.43) incidence. In moderate-risk families, no CRC and only one advanced adenoma was found. The risk of CRC in Lynch families is considerable, despite biannual surveillance. We suggest less frequent and more individualised surveillance in non-Lynch families. Individuals from families with a strong history of CRC could be offered 5-year surveillance colonoscopies (unless findings at the preceding surveillance session indicate shorter interval) and individuals from moderate-risk families could be handled with the population-based screening programme for CRC after an initial surveillance colonoscopy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Dietary fibre for the prevention of recurrent colorectal adenomas and carcinomas.

PubMed

Yao, Yibo; Suo, Tao; Andersson, Roland; Cao, Yongqing; Wang, Chen; Lu, Jingen; Chui, Evelyne

2017-01-08

This is an update of the Cochrane review published in 2002.Colorectal cancer (CRC) is a major cause of morbidity and mortality in industrialised countries. Experimental evidence has supported the hypothesis that dietary fibre may protect against the development of CRC, although epidemiologic data have been inconclusive. To assess the effect of dietary fibre on the recurrence of colorectal adenomatous polyps in people with a known history of adenomatous polyps and on the incidence of CRC compared to placebo. Further, to identify the reported incidence of adverse effects, such as abdominal pain or diarrhoea, that resulted from the fibre intervention. We identified randomised controlled trials (RCTs) from Cochrane Colorectal Cancer's Specialised Register, CENTRAL, MEDLINE and Embase (search date, 4 April 2016). We also searched ClinicalTrials.gov and WHO International Trials Registry Platform on October 2016. We included RCTs or quasi-RCTs. The population were those having a history of adenomatous polyps, but no previous history of CRC, and repeated visualisation of the colon/rectum after at least two-years' follow-up. Dietary fibre was the intervention. The primary outcomes were the number of participants with: 1. at least one adenoma, 2. more than one adenoma, 3. at least one adenoma greater than or equal to 1 cm, or 4. a new diagnosis of CRC. The secondary outcome was the number of adverse events. Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. We used risk ratios (RR) and risk difference (RD) with 95% confidence intervals (CI) to measure the effect. If statistical significance was reached, we reported the number needed to treat for an additional beneficial outcome (NNTB) or harmful outcome (NNTH). We combined the study data using the fixed-effect model if it was clinically, methodologically, and statistically reasonable. We included seven studies, of which five studies with 4798 participants provided data for analyses in this review. The mean ages of the participants ranged from 56 to 66 years. All participants had a history of adenomas, which had been removed to achieve a polyp-free colon at baseline. The interventions were wheat bran fibre, ispaghula husk, or a comprehensive dietary intervention with high fibre whole food sources alone or in combination. The comparators were low-fibre (2 to 3 g per day), placebo, or a regular diet. The combined data showed no statistically significant difference between the intervention and control groups for the number of participants with at least one adenoma (5 RCTs, n = 3641, RR 1.04, 95% CI 0.95 to 1.13, low-quality evidence), more than one adenoma (2 RCTs, n = 2542, RR 1.06, 95% CI 0.94 to 1.20, low-quality evidence), or at least one adenoma 1 cm or greater (4 RCTs, n = 3224, RR 0.99, 95% CI 0.82 to 1.20, low-quality evidence) at three to four years. The results on the number of participants diagnosed with colorectal cancer favoured the control group over the dietary fibre group (2 RCTS, n = 2794, RR 2.70, 95% CI 1.07 to 6.85, low-quality evidence). After 8 years of comprehensive dietary intervention, no statistically significant difference was found in the number of participants with at least one recurrent adenoma (1 RCT, n = 1905, RR 0.97, 95% CI 0.78 to 1.20), or with more than one adenoma (1 RCT, n = 1905, RR 0.89, 95% CI 0.64 to 1.24). More participants given ispaghula husk group had at least one recurrent adenoma than the control group (1 RCT, n = 376, RR 1.45, 95% CI 1.01 to 2.08). Other analyses by types of fibre intervention were not statistically significant. The overall dropout rate was over 16% in these trials with no reasons given for these losses. Sensitivity analysis incorporating these missing data shows that none of the results can be considered as robust; when the large numbers of participants lost to follow-up were assumed to have had an event or not, the results changed sufficiently to alter the conclusions that we would draw. Therefore, the reliability of the findings may have been compromised by these missing data (attrition bias) and should be interpreted with caution. There is a lack of evidence from existing RCTs to suggest that increased dietary fibre intake will reduce the recurrence of adenomatous polyps in those with a history of adenomatous polyps within a two to eight year period. However, these results may be unreliable and should be interpreted cautiously, not only because of the high rate of loss to follow-up, but also because adenomatous polyp is a surrogate outcome for the unobserved true endpoint CRC. Longer-term trials with higher dietary fibre levels are needed to enable confident conclusion.

Expression of 11β-hydroxysteroid dehydrogenase type 2 is deregulated in colon carcinoma.

PubMed

Moravec, Martin; Svec, Jirí; Ergang, Peter; Mandys, Václav; Reháková, Lenka; Zádorová, Zdena; Hajer, Jan; Kment, Milan; Pácha, Jirí

2014-04-01

Although the effects of glucocorticoids on proliferation, differentiation and apoptosis are well known, and steroid hormones have been identified to play a role in pathogenesis and the development of various cancers, limited data are available regarding the relationship between the local metabolism of glucocorticoids and colorectal adenocarcinoma (CRC) formation. Glucocorticoid metabolism is determined by 11β-hydroxysteroid dehydrogenases type 1 and 2 (11HSD1, 11HSD2), which increase the local concentration of cortisol due to the reduction of cortisone, or decrease this concentration due to the oxidation of cortisol. The objective of this study was to evaluate the extent of 11HSD1 and 11HSD2 mRNA in pre-malignant colorectal polyps and in CRC. The specimens were retrieved from patients by endoscopic or surgical resection and the expression of 11HSD1 and 11HSD2 was measured by real-time PCR. The polyps were of the following histological types: hyperplastic polyps and adenomas with low- or high-grade dysplasia. The neoplastic tissue of CRC obtained during tumor surgery was also studied. It was found that 11HSD2 was not only downregulated in CRC but already in the early stages of neoplastic transformation (adenoma with low-grade dysplasia). In contrast, the level of 11HSD1 was significantly increased in CRC but not in pre-malignant polyps. The results demonstrate that the downregulation of 11HSD2 gene expression is a typical feature of the development of colorectal polypous lesions and their transformation into CRC.

Race and Prevalence of Large Bowel Polyps Among the Low-Income and Uninsured in South Carolina.

PubMed

Wallace, Kristin; Brandt, Heather M; Bearden, James D; Blankenship, Bridgette F; Caldwell, Renay; Dunn, James; Hegedus, Patricia; Hoffman, Brenda J; Marsh, Courtney H; Marsh, William H; Melvin, Cathy L; Seabrook, March E; Sterba, Ronald E; Stinson, Mary Lou; Thibault, Annie; Berger, Franklin G; Alberg, Anthony J

2016-01-01

Compared to whites, blacks have higher colorectal cancer incidence and mortality rates and are at greater risk for early-onset disease. The reasons for this racial disparity are poorly understood, but one contributing factor could be differences in access to high-quality screening and medical care. The present study was carried out to assess whether a racial difference in prevalence of large bowel polyps persists within a poor and uninsured population (n = 233, 124 blacks, 91 whites, 18 other) undergoing screening colonoscopy. Eligible patients were uninsured, asymptomatic, had no personal history of colorectal neoplasia, and were between the ages 45-64 years (blacks) or 50-64 years (whites, other). We examined the prevalence of any adenoma (conventional, serrated) and then difference in adenoma/polyp type by race and age categories. Prevalence for ≥1 adenoma was 37 % (95 % CI 31-43 %) for all races combined and 36 % in blacks <50 years, 38 % in blacks ≥50 years, and 35 % in whites. When stratified by race, blacks had a higher prevalence of large conventional proximal neoplasia (8 %) compared to whites (2 %) (p value = 0.06) but a lower prevalence of any serrated-like (blacks 18 %, whites 32 %; p value = 0.02) and sessile serrated adenomas/polyps (blacks 2 %, whites 8 % Chi-square p value; p = 0.05). Within this uninsured population, the overall prevalence of adenomas was high and nearly equal by race, but the racial differences observed between serrated and conventional polyp types emphasize the importance of taking polyp type into account in future research on this topic.

Association of plasma concentrations of branched-chain amino acids with risk of colorectal adenoma in a large Japanese population.

PubMed

Budhathoki, S; Iwasaki, M; Yamaji, T; Yamamoto, H; Kato, Y; Tsugane, S

2017-04-01

Available evidence from animal studies suggests that branched-chain amino acids (BCAAs) may have a protective effect against colorectal carcinogenesis. However, a possible effect of BCAAs against colorectal neoplasia has not been evaluated in humans. Here, we aimed to evaluate whether plasma concentrations of BCAA are associated with the risk of colorectal adenoma (CRA), a precursor lesion of colorectal cancer. CRA cases and controls were identified from examinees who underwent total colonoscopy as part of a cancer screening program between 2004 and 2005 and responded to self-administered dietary and lifestyle questionnaires. We measured plasma concentrations of leucine, isoleucine and valine in 629 patients with adenoma and 584 controls. Unconditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between BCAA and CRA risk after adjustment for potential confounders. High plasma concentrations of leucine, valine and total BCAA were inversely associated with CRA risk after adjustment of potential confounders. The multivariate-adjusted ORs for the highest versus lowest quartiles were 0.60 (95% CI 0.42-0.87, Ptrend = 0.006) for leucine, 0.68 (95% CI 0.48-0.97, Ptrend = 0.09) for valine and 0.68 (95% CI 0.48-0.98, Ptrend = 0.10) for total BCAA. Further analysis by gender revealed that this inverse association was clearly evident in men, but not in women: the corresponding OR for leucine, valine and total BCAA was 0.50 (95% CI 0.32-0.80, Ptrend = 0.003), 0.60 (95% CI 0.38-0.95, Ptrend = 0.01) and 0.58 (95% CI 0.37-0.93, Ptrend = 0.04), respectively, in men and 0.78 (95% CI 0.42-1.45, Ptrend = 0.44), 0.77 (95% CI 0.41-1.43, Ptrend = 0.85) and 0.84 (95% CI 0.45-1.57, Ptrend = 0.81), respectively, in women. Our finding suggests that BCAAs may have a beneficial influence against the process of colorectal carcinogenesis, at least in the early stage. The mechanisms underlying this potential association between BCAA and colorectal carcinogenesis warrant further investigation. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Altered saturated and monounsaturated plasma phospholipid fatty acid profiles in adult males with colon adenomas

PubMed Central

Pickens, C. Austin; Lane-Elliot, Ami; Comstock, Sarah S.; Fenton, Jenifer I.

2016-01-01

Background Altered lipid metabolism and plasma fatty acid (FA) levels are associated with colorectal cancer (CRC). Obesity and elevated waist circumference (WC) increase the likelihood of developing precancerous colon adenomas. Methods Venous blood was collected from 126 males, ages 48 to 65 years, who received routine colonoscopies. Plasma phospholipid (PPL) FAs were isolated, derivatized, and then analyzed using gas chromatography. Odds ratios (ORs) and 95% confidence intervals were determined using polytomous logistic regression after adjusting for confounding factors (i.e. age, smoking, WC, and BMI). Results PPL palmitic acid (PA) was inversely correlated with the presence of colon adenomas (p = 0.01). For each unit increase in palmitoleic acid (OR: 3.75, p = 0.04) or elaidic acid (OR: 2.92, p = 0.04) an individual was more likely to have adenomas relative to no colon polyps. Higher enzyme activity estimates (EAEs) of stearoyl-CoA desaturase-1 (SCD-1, p = 0.02) and elongation of very long chain-6 (Elovl-6, p = 0.03) were associated with an individual being approximately 1.5 times more likely to have an adenoma compared to no polyps. Conclusions PPL FAs and EAEs, which have previously been associated with CRC, are significantly different in those with adenomas when compared to those without polyps. PPL PA, elaidic acid, and SCD-1 and Elovl-6 EAEs are associated with adenomas independent of BMI and WC. Impact PPL PA, elaidic acid, and SCD-1 and Elovl-6 EAEs are associated with adenomas even after adjusting for obesity-related risk factors and may function as novel biomarkers of early CRC risk. PMID:26721667

A comparison of an immunological faecal occult blood test Fecatwin sensitive/FECA EIA with Haemoccult in population screening for colorectal cancer.

PubMed Central

Armitage, N.; Hardcastle, J. D.; Amar, S. S.; Balfour, T. W.; Haynes, J.; James, P. D.

1985-01-01

Two faecal occult blood tests, a simple chemical test Haemoccult and an immunological test, Fecatwin Sensitive/Feca EIA, were offered to 3,225 asymptomatic individuals as screening for colorectal cancer. One thousand three hundred and four (44%) completed and returned the tests and of these 126 (9.7%) were found to be positive - Haemoccult 40 (3%) and Feca EIA 106 (8.1%). Five cancers (4 Dukes' Stage A, 1 Dukes' Stage C) and 23 adenomas greater than 1 cm were detected - rates of 3.8 per 1000 persons screened and 17.7 per 1000 persons screened respectively. Of the five cancers identified 5 were Feca EIA positive and 3 were Haemoccult positive. Of the 23 adenomas greater than 1 cm diameter identified, J1 were Feca EIA positive and 20 were Haemoccult positive. Seventy-eight Feca EIA positive subjects were investigated and no neoplastic disease was identified. Whilst this sensitive immunological test increases the yield of carcinomas, the high false positive rate makes it unsuitable for population screening for colorectal cancer in its present form. PMID:4005139

BowelScope: Accuracy of Detection Using ENdocuff Optimisation of Mucosal Abnormalities

ClinicalTrials.gov

2017-05-05

Colorectal Neoplasms; Colonic Polyp; Adenoma; Neoplasia GI; Digestive System Neoplasms; Intestinal Neoplasms; Neoplasms, Glandular and Epithelial; Digestive Disease; Intestinal Diseases; Colonic Diseases; Rectal Diseases; Intestinal Polyps; Polyps; Pathological Conditions, Anatomical

Endoscopic treatment by snare electrocoagulation prior to Nd:YAG laser photocoagulation in 85 voluminous colorectal villous adenomas.

PubMed

Aubert, A; Meduri, B; Fritsch, J; Aime, F; Baglin, A; Barbagelata, M

1991-05-01

The association of endoscopic resection with Nd:YAG laser photocoagulation was used to treat benign colorectal villous adenomas. Eight-five patients were included: 49 with surgical contraindications, 35 for whom surgical resection appeared to be too hazardous, and 1 who refused surgery. Forty-five tumors had an axial extension between 1 and 3 cm, and 40 tumors had an axial extension of at least 4 cm. Diathermic snare resection was performed to remove large tumoral fragments prior to laser photocoagulation of the residual flat lesions. Treatments were repeated every 15 days until total tumor destruction was achieved. A carcinoma was detected in biopsy specimens obtained during endoscopic treatment of five patients. Two patients were lost to follow-up. Treatment results could be analyzed in 78 patients. Successful treatment was achieved in 67 patients. Tumor destruction was complete in 77 percent of patients who had lesions of at least 4 cm diameter and in 93 percent of patients with smaller lesions. The axial extension of the tumor was the main factor affecting the results of treatment. No major complications occurred. During the average 103-week follow-up period, 21 percent of the patients with total tumor destruction had a recurrence. The risk of recurrence was correlated with the number of initial treatment sessions and previous surgery treatment. It would appear that the treatment with endoscopic resection prior to Nd:YAG laser photocoagulation is a safe and effective method in the destruction of colorectal villous adenomas.

Clinicopathological features colon polyps from African-Americans

PubMed Central

Nouraie, Mehdi; Hosseinkhah, Fatemeh; Zamanifekri, Behrouz; Hamond, Issa W.; Ashktorab, Hassan

2013-01-01

Background & Aims Among the ethnic groups age standardized incidence rate of colorectal cancer (CRC) is highest among African-Americans. The majority of CRC arise from preexisting adenoma. It is shown that 30% of the US adult population has adenomas. The potential risk of malignant transformation in adenomas differs by specific pathologic and clinical characteristics that we aimed to study in AAs. Material and Methods All pathologic reports (150,000) in Howard University Hospital from 1959 to 2006 were reviewed manually. Those pathology reports compatible with the colorectal polyps were carefully reviewed and selected by a GI pathologist. All cases with cancer then excluded from the list. Data then were entered into excel and checked for missing data and duplications. Differences in right side and left side polyps for sex, histology, clinical symptoms were assessed by chi-2 test. Results A total number of 5013 colorectal polyps were diagnosed in this period that include 47% male, with mean age (SD) of 63 (12). Half of cases were diagnosed in 2001–2006. Tubular adenoma was the most frequent pathology (73%). The highest frequency of right sided polyps was observed in 1990’s (56%). Left sided polyps were younger (P<0.000), more hyperplasic (23% vs. 5%; P<0.000) and more frequent in female (56% vs. 52%; P=0.02) compared to right sided. The frequency of right sided adenoma significantly increases from 18% in 60’s to 51% in the period of 2001–2006 (P<0.000). The most frequent symptom in both sides was GI bleeding (21%). Conclusion There was a ratio of 9:1 for neoplastic to hyperplastic polyps in our study which is more than what has been reported in Caucasians (7:1). Our data shows a shift in polyps from the left side to the right side of the colon in recent years. This data is consistent with the lack of a reduction in the incidence of colon cancer in African Americans. Screening is thus very important in AA to reduce the incidence of colon cancer. PMID:20225129

Epigenetic-Mediated Downregulation of μ-Protocadherin in Colorectal Tumours

PubMed Central

Mateusz, Bujko; Paulina, Kober; Małgorzata, Statkiewicz; Michal, Mikula; Marcin, Ligaj; Lech, Zwierzchowski; Jerzy, Ostrowski; Aleksander, Siedlecki Janusz

2015-01-01

Carcinogenesis involves altered cellular interaction and tissue morphology that partly arise from aberrant expression of cadherins. Mucin-like protocadherin is implicated in intercellular adhesion and its expression was found decreased in colorectal cancer (CRC). This study has compared MUPCDH (CDHR5) expression in three key types of colorectal tissue samples, for normal mucosa, adenoma, and carcinoma. A gradual decrease of mRNA levels and protein expression was observed in progressive stages of colorectal carcinogenesis which are consistent with reports of increasing MUPCDH 5′ promoter region DNA methylation. High MUPCDH methylation was also observed in HCT116 and SW480 CRC cell lines that revealed low gene expression levels compared to COLO205 and HT29 cell lines which lack DNA methylation at the MUPCDH locus. Furthermore, HCT116 and SW480 showed lower levels of RNA polymerase II and histone H3 lysine 4 trimethylation (H3K4me3) as well as higher levels of H3K27 trimethylation at the MUPCDH promoter. MUPCDH expression was however restored in HCT116 and SW480 cells in the presence of 5-Aza-2′-deoxycytidine (DNA methyltransferase inhibitor). Results indicate that μ-protocadherin downregulation occurs during early stages of tumourigenesis and progression into the adenoma-carcinoma sequence. Epigenetic mechanisms are involved in this silencing. PMID:25972897

Validation of Models Used to Inform Colorectal Cancer Screening Guidelines: Accuracy and Implications.

PubMed

Rutter, Carolyn M; Knudsen, Amy B; Marsh, Tracey L; Doria-Rose, V Paul; Johnson, Eric; Pabiniak, Chester; Kuntz, Karen M; van Ballegooijen, Marjolein; Zauber, Ann G; Lansdorp-Vogelaar, Iris

2016-07-01

Microsimulation models synthesize evidence about disease processes and interventions, providing a method for predicting long-term benefits and harms of prevention, screening, and treatment strategies. Because models often require assumptions about unobservable processes, assessing a model's predictive accuracy is important. We validated 3 colorectal cancer (CRC) microsimulation models against outcomes from the United Kingdom Flexible Sigmoidoscopy Screening (UKFSS) Trial, a randomized controlled trial that examined the effectiveness of one-time flexible sigmoidoscopy screening to reduce CRC mortality. The models incorporate different assumptions about the time from adenoma initiation to development of preclinical and symptomatic CRC. Analyses compare model predictions to study estimates across a range of outcomes to provide insight into the accuracy of model assumptions. All 3 models accurately predicted the relative reduction in CRC mortality 10 years after screening (predicted hazard ratios, with 95% percentile intervals: 0.56 [0.44, 0.71], 0.63 [0.51, 0.75], 0.68 [0.53, 0.83]; estimated with 95% confidence interval: 0.56 [0.45, 0.69]). Two models with longer average preclinical duration accurately predicted the relative reduction in 10-year CRC incidence. Two models with longer mean sojourn time accurately predicted the number of screen-detected cancers. All 3 models predicted too many proximal adenomas among patients referred to colonoscopy. Model accuracy can only be established through external validation. Analyses such as these are therefore essential for any decision model. Results supported the assumptions that the average time from adenoma initiation to development of preclinical cancer is long (up to 25 years), and mean sojourn time is close to 4 years, suggesting the window for early detection and intervention by screening is relatively long. Variation in dwell time remains uncertain and could have important clinical and policy implications. © The Author(s) 2016.

Type 2 diabetes mellitus and risk of colorectal adenoma: a meta-analysis of observational studies.

PubMed

Yu, Feifei; Guo, Yibin; Wang, Hao; Feng, Jian; Jin, Zhichao; Chen, Qi; Liu, Yu; He, Jia

2016-08-17

To summarize the relationship between type 2 diabetes mellitus (T2DM) and risk of colorectal adenomas (CRA), we performed a meta-analysis of observational studies. To find studies, we searched PubMed, Embase, the Cochrane Library, Web of Science and conference abstracts and related publications for American Society of Clinical Oncology and the European Society of Medical Oncology. Studies that reported relative risks (RRs) or odds ratios (ORs) with 95 % confidence intervals (CIs) for the association between T2DM and risk of CRA were included. The meta-analysis assessed the relationships between T2DM and risk of CRA. Sensitivity analyses were performed in two ways: (1) by omitting each study iteratively and (2) by keeping high-quality studies only. Publication bias was detected by Egger's and Begg's tests and corrected using the trim and fill method. This meta-analysis included 17 studies with 28,999 participants and 6798 CRA cases. We found that T2DM was a risk factor for CRA (RR: 1.52; 95 % CI: 1.29-1.80), and also for the advanced adenoma (RR: 1.41; 95 % CI: 1.06-1.87). Patients with existing T2DM (RR: 1.56; 95 % CI: 1.16-2.08) or newly diagnosed T2DM (RR: 1.51; 95 % CI: 1.16-1.97) have a risk of CRA. Similar significant results were found in retrospective studies (RR: 1.57; 95 % CI: 1.30-1.89) and population based cross-sectional studies (RR: 1.46; 95 % CI: 1.21-1.89), but not in prospective studies (RR: 1.27; 95 % CI: 0.77-2.10). Our results suggested that T2DM plays a risk role in the risk of developing CRA. Consequently, medical workers should increase the rate of CRA screening for T2DM patients so that they can benefit from behavioural interventions that can help prevent the development of colorectal cancer. Additional, large prospective cohort studies are needed to make a more convincing case for these associations.

Genetic and epigenetic markers in colorectal cancer screening: recent advances.

PubMed

Singh, Manish Pratap; Rai, Sandhya; Suyal, Shradha; Singh, Sunil Kumar; Singh, Nand Kumar; Agarwal, Akash; Srivastava, Sameer

2017-07-01

Colorectal cancer (CRC) is a heterogenous disease which develops from benign intraepithelial lesions known as adenomas to malignant carcinomas. Acquired alterations in Wnt signaling, TGFβ, MAPK pathway genes and clonal propagation of altered cells are responsible for this transformation. Detection of adenomas or early stage cancer in asymptomatic patients and better prognostic and predictive markers is important for improving the clinical management of CRC. Area covered: In this review, the authors have evaluated the potential of genetic and epigenetic alterations as markers for early detection, prognosis and therapeutic predictive potential in the context of CRC. We have discussed molecular heterogeneity present in CRC and its correlation to prognosis and response to therapy. Expert commentary: Molecular marker based CRC screening methods still fail to gain trust of clinicians. Invasive screening methods, molecular heterogeneity, chemoresistance and low quality test samples are some key challenges which need to be addressed in the present context. New sequencing technologies and integrated omics data analysis of individual or population cohort results in GWAS. MPE studies following a GWAS could be future line of research to establish accurate correlations between CRC and its risk factors. This strategy would identify most reliable biomarkers for CRC screening and management.

Cancer-preventive Properties of an Anthocyanin-enriched Sweet Potato in the APCMIN Mouse Model

PubMed Central

Asadi, Khalid; Ferguson, Lynnette R.; Philpott, Martin; Karunasinghe, Nishi

2017-01-01

Background Anthocyanin-rich foods and preparations have been reported to reduce the risk of life-style related diseases, including cancer. The SL222 sweet potato, a purple-fleshed cultivar developed in New Zealand, accumulates high levels of anthocyanins in its storage root. Methods We examined the chemopreventative properties of the SL222 sweet potato in the C57BL/6J-APCMIN/+ (APCMIN) mouse, a genetic model of colorectal cancer. APCMIN and C57BL/6J wild-type mice (n=160) were divided into four feeding groups consuming diets containing 10% SL222 sweet potato flesh, 10% SL222 sweet potato skin, or 0.12% ARE (Anthocyanin rich-extract prepared from SL222 sweet potato at a concentration equivalent to the flesh-supplemented diet) or a control diet (AIN-76A) for 18 weeks. At 120 days of age, the mice were anaesthetised, and blood samples were collected before the mice were sacrificed. The intestines were used for adenoma enumeration. Results The SL222 sweet potato-supplemented diets reduced the adenoma number in the APCMIN mice. Conclusions These data have significant implications for the use of this sweet potato variant in protection against colorectal cancer. PMID:29018778

Association of Sulindac and Erlotinib vs Placebo With Colorectal Neoplasia in Familial Adenomatous Polyposis: Secondary Analysis of a Randomized Clinical Trial.

PubMed

Samadder, N Jewel; Kuwada, Scott K; Boucher, Kenneth M; Byrne, Kathryn; Kanth, Priyanka; Samowitz, Wade; Jones, David; Tavtigian, Sean V; Westover, Michelle; Berry, Therese; Jasperson, Kory; Pappas, Lisa; Smith, Laurel; Sample, Danielle; Burt, Randall W; Neklason, Deborah W

2018-02-08

Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for colorectal polyps and cancer. A combination of sulindac and erlotinib led to a 71% reduction in duodenal polyp burden in a phase 2 trial. To evaluate effect of sulindac and erlotinib on colorectal adenoma regression in patients with FAP. Prespecified secondary analysis for colorectal adenoma regression was carried out using data from a double-blind, randomized, placebo-controlled trial, enrolling 92 patients with FAP, conducted from July 2010 to June 2014 in Salt Lake City, Utah. Patients were randomized to sulindac, 150 mg twice daily, and erlotinib, 75 mg daily (n = 46), vs placebo (n = 46) for 6 months. The total number of polyps in the intact colorectum, ileal pouch anal anastomosis, or ileo-rectum were recorded at baseline and 6 months. The primary outcomes were change in total colorectal polyp count and percentage change in colorectal polyps, following 6 months of treatment. Eighty-two randomized patients (mean [SD] age, 40 [13] years; 49 [60%] women) had colorectal polyp count data available for this secondary analysis: 22 with intact colon, 44 with ileal pouch anal anastomosis and 16 with ileo-rectal anastomosis; 41 patients received sulindac/erlotinib and 41 placebo. The total colorectal polyp count was significantly different between the placebo and sulindac-erlotinib group at 6 months in patients with net percentage change of 69.4% in those with an intact colorectum compared with placebo (95% CI, 28.8%-109.2%; P = .009). In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum. clinicaltrials.gov Identifier: NCT01187901.

Methionine Synthase A2756G Polymorphism and Risk of Colorectal Adenoma and Cancer: Evidence Based on 27 Studies

PubMed Central

Jiang, Xun; Lu, Lie-sheng

2013-01-01

Methionine synthase (MTR), which plays a central role in maintaining adequate intracellular folate, methionine and normal homocysteine concentrations, was thought to be involved in the development of colorectal cancer (CRC) and colorectal adenoma (CRA) by affecting DNA methylation. However, studies on the association between MTR A2756G polymorphism and CRC/CRA remain conflicting. We conducted a meta-analysis of 27 studies, including 13465 cases and 20430 controls for CRC, and 4844 cases and 11743 controls for CRA. Potential sources of heterogeneity and publication bias were also systematically explored. Overall, the summary odds ratio of G variant for CRC was 1.03 (95% CI: 0.96–1.09) and 1.05 (95% CI: 0.99–1.12) for CRA. No significant results were observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. In the stratified analyses according to ethnicity, source of controls, sample size, sex, and tumor site, no evidence of any gene-disease association was obtained. Results from the meta-analysis of four studies on MTR stratified according to smoking and alcohol drinking status showed an increased CRC risk in heavy smokers (OR = 2.06, 95% CI: 1.32–3.20) and heavy drinkers (OR = 2.00, 95% CI: 1.28–3.09) for G allele carriers. This meta-analysis suggests that the MTR A2756G polymorphism is not associated with CRC/CRA susceptibility and that gene-environment interaction may exist. PMID:23593229

Clinical features of familial adenomas polyps in Chinese and establishment of its immortal lymphocyte cell lines.

PubMed

Cai, Shan-Rong; Zhang, Su-Zhang; Zheng, Shu

2007-05-28

To reserve the rare Chinese familial adenomas polyp (FAP) family resource and to investigate the clinical features of FAP in Chinese for its diagnosis. Clinical features of patients with FAP were investigated. If there is any question, their medical records were verified. Blood sample was taken and lymphocyte immortal cell lines were established with modified EB-transformation methods. Congenital hypertrophy of retinal pigment epithelium (CHRPE) was checked by an experienced ophthalmologist. Twenty seven families including 21 classical FAP (CFAP) families, 3 attenuated FAP (AFAP) families, and 3 suspected AFAP families were investigated. A total of 116 lymphocyte immortal cell lines were established from 26 families. In all the FAP families, colorectal cancer occurred at the mean age of 42.84 years. Of the 16 families checked, 15 (93.75%) had CHRPE. The mean number of patients suffering from colorectal neoplasm was 3.14 in CFAP families and 2.0 in AFAP families (P<0.01). The mean oldest age at diagnosis of FAP was 41.75 years in CFAP families, and 58.67 years in AFAP families, respectively (P<0.01). Mean age of development of colorectal cancer was 42.23 in CFAP and 57.33 years old in AFAP (P<0.01). Mean of the earliest age at diagnosis of FAP was 29.95 years in the FAP families with a positive family history and 46.80 years in the FAP families with a negative family history (P < 0.01). The ratio of extra-intestinal tumors to colorectal neoplasms was different in the two kinds of families with positive and negative family history (P<0.01). Additional use of ciclosporin will effectively improve to establish lymphocyte immortal cell lines with modified EB- transformation methods. In Chinese FAP, there was a high frequency of CHRPE , and a later age at diagnosis and a later age of development of colorectal cancer in AFAP. And earlier age at diagnosis in FAP with positive family history was also found that will help to diagnose various kinds of FAP in Chinese.

Serrated Colon Polyps as Precursors to Colorectal Cancer

PubMed Central

Sweetser, Seth; Smyrk, Thomas C.; Sinicrope, Frank A.

2013-01-01

Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights have included an increased recognition of the malignant potential of different types of serrated polyps, such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors, such as microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. There is evidence that the serrated pathway contributes to interval or missed cancers. These data have important implications for clinical practice and CRC prevention, since hyperplastic polyps were previously regarded as having no malignant potential. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins, and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps, which would facilitate their detection and removal, to ensure a high-quality colonoscopy examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in post-polypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence. PMID:23267866

CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway

PubMed Central

Rhee, Ye-Young; Kim, Kyung-Ju; Kang, Gyeong Hoon

2017-01-01

The concept of a CpG island methylator phenotype (CIMP) was first introduced by Toyota and Issa to describe a subset of colorectal cancers (CRCs) with concurrent hypermethylation of multiple CpG island loci. The concept of CIMP as a molecular carcinogenesis mechanism was consolidated by the identification of the serrated neoplasia pathway, in which CIMP participates in the initiation and progression of serrated adenomas. Distinct clinicopathological and molecular features of CIMP-high (CIMP-H) CRCs have been characterized, including proximal colon location, older age of onset, female preponderance, and frequent associations of high-level microsatellite instability and BRAF mutations. CIMP-H CRCs arise in sessile or traditional serrated adenomas and thus tend to display the morphological characteristics of serrated adenomas, including epithelial serration, vesicular nuclei, and abundant cytoplasm. Both the frequent association of CIMP and poor prognosis and different responses of CRCs to adjuvant therapy depending on CIMP status indicate clinical implications. In this review, we present an overview of the literature documenting the relevant findings of CIMP-H CRCs and their relationships with the serrated neoplasia pathway. PMID:27885175

β-Catenin—A Linchpin in Colorectal Carcinogenesis?

PubMed Central

Wong, Newton Alexander Chiang Shuek; Pignatelli, Massimo

2002-01-01

An important role for β-catenin pathways in colorectal carcinogenesis was first suggested by the protein’s association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of β-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to β-catenin pathways. Pro-oncogenic factors that also release β-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-βΙΙ, MUC1, and PPAR-γ, whereas anti-oncogenic factors that also inhibit nuclear β-catenin signaling include transforming growth factor (TGF)-β, retinoic acid, and vitamin D. Association of nuclear β-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the β-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that β-catenin represents a key molecule in the development of colorectal carcinoma. PMID:11839557

The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer.

PubMed

Akino, Kimishige; Toyota, Minoru; Suzuki, Hiromu; Mita, Hiroaki; Sasaki, Yasushi; Ohe-Toyota, Mutsumi; Issa, Jean-Pierre J; Hinoda, Yuji; Imai, Kohzoh; Tokino, Takashi

2005-07-01

Activation of Ras signaling is a hallmark of colorectal cancer (CRC), but the roles of negative regulators of Ras are not fully understood. Our aim was to address that question by surveying genetic and epigenetic alterations of Ras-Ras effector genes in CRC cells. The expression and methylation status of 6 RASSF family genes were examined using RT-PCR and bisulfite PCR in CRC cell lines and in primary CRCs and colorectal adenomas. Colony formation assays and flow cytometry were used to assess the tumor suppressor activities of RASSF1 and RASSF2. Immunofluorescence microscopy was used to determine the effect of altered RASSF2 expression on cell morphology. Mutations of K- ras , BRAF, and p53 were identified using single-strand conformation analysis and direct sequencing. Aberrant methylation and histone deacetylation of RASSF2 was associated with the gene's silencing in CRC. The activities of RASSF2, which were distinct from those of RASSF1, included induction of morphologic changes and apoptosis; moreover, its ability to prevent cell transformation suggests that RASSF2 acts as a tumor suppressor in CRC. Primary CRCs that showed K- ras /BRAF mutations also frequently showed RASSF2 methylation, and inactivation of RASSF2 enhanced K- ras -induced oncogenic transformation. RASSF2 methylation was also frequently identified in colorectal adenomas. RASSF2 is a novel tumor suppressor gene that regulates Ras signaling and plays a pivotal role in the early stages of colorectal tumorigenesis.

Colonoscopic screening shows increased early incidence and progression of adenomas in cystic fibrosis

PubMed Central

Niccum, David E.; Billings, Joanne L.; Dunitz, Jordan M.; Khoruts, Alexander

2018-01-01

Background Colorectal cancer is an emerging problem in cystic fibrosis (CF). The goal of this study was to evaluate adenoma detection by systematic colonoscopic screening and surveillance. Methods We analyzed prospectively collected results of colonoscopies initiated at age 40 years from 88 CF patients at a single Cystic Fibrosis Center. We also reviewed results of diagnostic colonoscopies from 27 patients aged 30–39 years performed during the same time period at the Center. Results The incidence of polyp detection increased markedly after age 40 in CF patients. Greater than 50% were found to have adenomatous polyps; approximately 25% had advanced adenomas as defined by size and/or histopathology; 3% were found to have colon cancer. Multivariate analysis demonstrated specific risk factors for adenoma formation and progression. Conclusions Early screening and more frequent surveillance should be considered in patients with CF due to early incidence and progression of adenomas in this patient population. PMID:26851188

Colorectal cancer screening: results of a 5-year program in asymptomatic subjects at increased risk.

PubMed

Pezzoli, A; Matarese, V; Rubini, M; Simoni, M; Caravelli, G C; Stockbrugger, R; Cifalà, V; Boccia, S; Feo, C; Simone, L; Trevisani, L; Liboni, A; Gullini, S

2007-01-01

The province of Ferrara has one of the highest incidences of colorectal cancer (CRC) in Italy. In January 2000, we set up a colonoscopy screening program focussing on first-degree relatives of CRC patients. We now report the results 5 years after the beginning of the project. SCREENEES AND METHODS: In October 1999, we started a campaign stressing the usefulness of colonoscopy for the first-degree relatives of CRC patients. Subjects included in the screening program were aged between 45 and 75 years with at least one first-degree relative affected by CRC. They were invited to an interview where a physician suggested colonoscopy as a screening option. In 5 years, 776 subjects were interviewed and 733 (94.4%) agreed to an endoscopic examination (M/F:375/401; mean age 55 years): 562 colonoscopies were performed. Adenomas and cancers were found in 122 (21.7%) and 12 (2.1%) subjects, respectively. Histological examination in 181 persons with lesions (32.8%) showed (most serious lesion quoted) 47 hyperplastic polyps (26% of all lesions), 2 serrated adenomas (1.1%), 68 tubular adenomas (48%), 24 tubulovillous adenomas (13.3%), 9 adenomas with high grade dysplasia (5%) and 12 adenocarcinomas (6.6%). The majority of the cancers were at an early stage (8 Dukes A and 3 Dukes B). Sedation was used in only 42 colonoscopies (7.5%). A colonoscopy-based screening in this selected high-risk population is feasible. Even without sedation subjects readily agreed to the endoscopic procedure. We identified a significant number of advanced neoplasms and cancers at an early stage suggesting that this could be a useful tool in early identification of CRC.

Antioxidant supplement and long-term reduction of recurrent adenomas of the large bowel. A double-blind randomized trial.

PubMed

Bonelli, Luigina; Puntoni, Matteo; Gatteschi, Beatrice; Massa, Paolo; Missale, Guido; Munizzi, Francesco; Turbino, Laura; Villanacci, Vincenzo; De Censi, Andrea; Bruzzi, Paolo

2013-06-01

Patients who undergo polypectomy are at increased risk of adenoma recurrence. The preventive potential of vitamins (A, C and E) and selenium supplementation represent an interesting opportunity for colorectal cancer prevention. To assess the efficacy of a combination of these micronutrients in reducing the incidence of recurrent adenomas in subjects on post-polypectomy endoscopic follow-up, a double-blind placebo-controlled randomized trial was started in Italy in 1988. A total of 411 patients were randomized to receive either an active compound (200 μg selenium, 30 mg zinc, 2 mg vitamin A, 180 mg vitamin C, 30 mg vitamin E) or a placebo daily for 5 years. Of them, 330 had follow-up colonoscopy (164 in the intervention and 166 in the placebo group). After a median follow-up of 4 years (range 1-15 years), 100 patients had recurrence: 38 in the intervention and 62 in the placebo arm. The 15-year cumulative incidence of recurrence was 48.3% in the intervention and 64.5% in the placebo arm (HR = 0.59; log-rank P = 0.009). A 39% reduction of the risk of recurrence was observed in the intervention compared to the placebo group (adjusted HR = 0.61; 95% CI 0.41-0.92): the risk reduction was similar for small tubular (adjusted HR = 0.61; 95% CI 0.37-0.99) and advanced adenomas (adjusted HR = 0.50; 95% CI 0.24-1.01). Our study showed a statistically significant effect of antioxidant supplementation on adenoma recurrence. Further clinical trials are needed to address the role of antioxidants in subgroups of subjects at increased risk for colorectal cancer.

Screening colonoscopy in 40- to 50-year-old first-degree relatives of patients with colorectal cancer is efficient: a controlled multicentre study.

PubMed

Menges, Markus; Fischinger, Johannes; Gärtner, Barbara; Georg, Thomas; Woerdehoff, Dietrich; Maier, Matthias; Harloff, Matthias; Stegmaier, Christa; Raedle, Jochen; Zeitz, Martin

2006-05-01

Persons with a familial risk of colorectal cancer (CRC) account for about 25% of all CRC cases. The adenoma prevalence in relatives of CRC patients 50-60 years of age is 17-34%; data on younger individuals are scarce. Our aim was to prospectively define the adenoma prevalence in 40- to 50-year-old first-degree relatives of CRC patients compared to controls. CRC patients were identified via the regional cancer registry, and their 40- to 50-year-old first-degree relatives (risk group) were invited for screening colonoscopy. Additional probands and controls of the same age were recruited by newspaper articles and radio or television broadcastings. Using high-resolution video colonoscopy, each detected polyp was removed and histopathologically assessed. Each participant completed demographic and epidemiological questionnaires. Of 228 subjects in the risk group 36.4% had polypoid lesions compared to 20.9% of 220 controls (p<0.001). Forty-three (18.9%) subjects in the risk group had adenomas compared to 18 (8.2%) in the control group (p=0.001). High-risk adenomas (>10 mm and/or of villous type) were found in 12 persons in the risk group compared to 5 controls (not significant). In the risk group most lesions (52%) were located proximal to the sigmoid colon compared to 29% in controls. Subjects between 40-50 years with first-degree relatives with CRC demonstrate a significantly higher prevalence of adenomas than controls, with a tendency towards a more proximal location. These data support a screening colonoscopy in persons with familial risk already between 40 and 50 years.

Surveillance of individuals at intermediate risk of colorectal cancer--the impact of new guidelines.

PubMed

Clark, S K; Carpenter, S; Broughton, C I M; Marks, C G

2003-11-01

Individuals with two first degree relatives, or one diagnosed at age < 45 years, with colorectal cancer are at sufficient risk to merit surveillance. Most undergo colonoscopy four to five yearly, starting 10 years before the youngest case. The aim of this study was to assess the impact of a proposed new surveillance protocol. We identified individuals with these risk criteria seen in our clinic from 1989 to 2001 and reviewed their notes with respect to colonoscopy. Colonoscopy (n = 295) was performed on 186 patients in accordance with current recommendations. Cancer was detected in three and adenoma in 21 individuals. Applying the proposed protocol, 123 (42%) fewer colonoscopies would have been performed. No cancers would have been missed, but in five cases a small adenoma would not have been detected. Proposed new guidelines for surveillance of those at intermediate risk reduce the burden of colonoscopy without compromising identification of significant neoplasia.

Fecal immunochemical tests in combination with blood tests for colorectal cancer and advanced adenoma detection—systematic review

PubMed Central

Niedermaier, Tobias; Weigl, Korbinian; Hoffmeister, Michael; Brenner, Hermann

2017-01-01

Background Colorectal cancer (CRC) is a common but largely preventable cancer. Although fecal immunochemical tests (FITs) detect the majority of CRCs, they miss some of the cancers and most advanced adenomas (AAs). The potential of blood tests in complementing FITs for the detection of CRC or AA has not yet been systematically investigated. Methods We conducted a systematic review of performance of FIT combined with an additional blood test for CRC and AA detection versus FIT alone. PubMed and Web of Science were searched until June 9, 2017. Results Some markers substantially increased sensitivity for CRC when combined with FIT, albeit typically at a major loss of specificity. For AA, no relevant increase in sensitivity could be achieved. Conclusion Combining FIT and blood tests might be a promising approach to enhance sensitivity of CRC screening, but comprehensive evaluation of promising marker combinations in screening populations is needed. PMID:29435309

Testing in semiparametric models with interaction, with applications to gene-environment interactions.

PubMed

Maity, Arnab; Carroll, Raymond J; Mammen, Enno; Chatterjee, Nilanjan

2009-01-01

Motivated from the problem of testing for genetic effects on complex traits in the presence of gene-environment interaction, we develop score tests in general semiparametric regression problems that involves Tukey style 1 degree-of-freedom form of interaction between parametrically and non-parametrically modelled covariates. We find that the score test in this type of model, as recently developed by Chatterjee and co-workers in the fully parametric setting, is biased and requires undersmoothing to be valid in the presence of non-parametric components. Moreover, in the presence of repeated outcomes, the asymptotic distribution of the score test depends on the estimation of functions which are defined as solutions of integral equations, making implementation difficult and computationally taxing. We develop profiled score statistics which are unbiased and asymptotically efficient and can be performed by using standard bandwidth selection methods. In addition, to overcome the difficulty of solving functional equations, we give easy interpretations of the target functions, which in turn allow us to develop estimation procedures that can be easily implemented by using standard computational methods. We present simulation studies to evaluate type I error and power of the method proposed compared with a naive test that does not consider interaction. Finally, we illustrate our methodology by analysing data from a case-control study of colorectal adenoma that was designed to investigate the association between colorectal adenoma and the candidate gene NAT2 in relation to smoking history.

Diet, microbiota, and colorectal cancer.

PubMed

Akin, Hakan; Tözün, Nurdan

2014-01-01

Colorectal cancer (CRC) is the third most common cancer in the world causing nearly 500,000 deaths every year. In addition to genetic background, environmental factors including diet and lifestyle are accepted as major contributors to adenoma and CRC development. Lifestyle factors include high BMI, obesity, and reduced physical activity. Growing interest and accumulating data on human microbiota implicate that host-microbe interplay has an important role in the development of metabolic, neoplastic, and inflammatory diseases. Findings from recent studies suggest that colon cancer risk is determined by the interaction between diet and gut microbiota. Dietary changes affect gut microbiota and conversely microbiota mediates the generation of dietary factors triggering colon cancer. Identification of the microbial communities associated with carcinogenesis is of crucial importance. Nowadays, with the evolvement of culture-independent molecular techniques, it has become possible to identify main bacterial species in healthy individuals, inflammatory conditions, and CRC. Some recent studies have shown the differences in intestinal microbiota between colon cancer patients and healthy individuals. Animal studies have provided a better understanding of interaction between pathobionts and symbionts in the development of colon cancer. There is no single causative organism identified in CRC; however, there is strong evidence that reduction of protective bacteria, increase in some bacteria (ie, fusobacterium members; Bacteroides/Prevotella), and age-related changes in microbiota have an impact on adenoma or cancer development. Future studies will enable us to understand procarcinogenic and anticarcinogenic mechanisms and give insights to rational manipulation of the microbiota with prebiotics, probiotics, or dietary modifications.

Adenoma Prevalence and Distribution Among US Latino Subgroups Undergoing Screening Colonoscopy.

PubMed

Chablani, Sumedha V; Jandorf, Lina; DuHamel, Katherine; Lee, Kristen K; Sriphanlop, Pathu; Villagra, Cristina; Itzkowitz, Steven H

2017-06-01

Colorectal cancer (CRC) is the second leading malignancy diagnosed among US Latinos. Latinos in the USA represent a heterogeneous amalgam of subgroups varying in genetic background, culture, and socioeconomic status. Little is known about the frequency of CRC precursor lesions found at screening colonoscopy among Latino subgroups. The aim was to determine the prevalence and distribution of histologically confirmed adenomas found at screening colonoscopy among average-risk, asymptomatic US Latinos according to their subgroup and socio-demographic background. Cross-sectional analysis of pathological findings resulting from screening colonoscopy among average-risk, asymptomatic US Latinos aged ≥50 in two prospective randomized controlled trials at an academic medical center. Among the 561 Latinos who completed screening colonoscopy, the two largest subgroups were Puerto Ricans and Dominicans. The findings among both subgroups were: adenomas 30.6%, proximal adenomas 23.5%, advanced adenomas 12.0%, and proximal advanced adenomas 8.9%. These rates are at least as high as those found at screening colonoscopy among US whites. While Puerto Ricans were more likely than Dominicans to be born in the USA, speak English, be acculturated, have a smoking history, and be obese, there were no significant differences in adenoma rates between these subgroups. The prevalence of adenomas, advanced adenomas, and proximal neoplasia was high among both subgroups. These findings have implications for CRC screening and surveillance among the increasingly growing Latino population in the USA.

PTT analysis of polyps from FAP patients reveals a great majority of APC truncating mutations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luijt, R.B. van der; Khan, P.M.; Tops, C.M.J.

The adenomatous polyposis coli (APC) gene plays an important role in colorectal carcinogenesis. Germline APC mutations are associated with familial adenomatous polyposis (FAP), an autosomal dominantly inherited predisposition to colorectal cancer, characterized by the development of numerous adenomatous polyps in the large intestine. In order to investigate whether somatic inactivation of the remaining APC allele is necessary for adenoma formation, we collected multiple adenomatous polyps from individual FAP patients and investigated the presence of somatic mutations in the APC gene. The analysis of somatic APC mutations in these tumor samples was performed using a rapid and sensitive assay, called themore » protein truncation test (PTT). Chain-terminating somatic APC mutations were detected in the great majority of the tumor samples investigated. As expected, these mutations were mainly located in the mutation cluster region (MCR) in exon 15. Our results confirm that somatic mutation of the second APC allele is required for adenoma formation in FAP. Interestingly, in the polyps investigated in our study, the second APC allele is somatically inactivated through point mutation leading to a stop codon rather than by loss of heterozygosity. The observation that somatic second hits in APC are required for tumor development in FAP is in apparent accordance with the Knudson hypothesis for classical tumor suppressor genes. However, it is yet unknown whether chain-terminating APC mutations lead to a truncated protein exerting a dominant-negative effect or whether these mutations result in a null allele. Further investigation of this important issue will hopefully provide a better understanding of the mechanism of action of the mutated APC alleles in colorectal carcinogenesis.« less

Lifetime alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- but not BRAF+ colorectal cancer.

PubMed

Jayasekara, Harindra; MacInnis, Robert J; Williamson, Elizabeth J; Hodge, Allison M; Clendenning, Mark; Rosty, Christophe; Walters, Rhiannon; Room, Robin; Southey, Melissa C; Jenkins, Mark A; Milne, Roger L; Hopper, John L; Giles, Graham G; Buchanan, Daniel D; English, Dallas R

2017-04-01

Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose-dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow-up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04-1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer (p homogeneity  = 0.02). Alcohol intake was associated with increased risks of KRAS+ (HR = 1.07, 95% CI: 1.00-1.15) and BRAF-/KRAS- (HR = 1.05, 95% CI: 1.00-1.11) but not BRAF+ tumors (HR = 0.89, 95% CI: 0.78-1.01; p homogeneity  = 0.01). Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma-carcinoma pathway. © 2016 UICC.

Effects of supplemental calcium and vitamin D on the APC/β-catenin pathway in the normal colorectal mucosa of colorectal adenoma patients.

PubMed

Liu, Siyu; Barry, Elizabeth L; Baron, John A; Rutherford, Robin E; Seabrook, March E; Bostick, Roberd M

2017-02-01

APC/β-catenin pathway malfunction is a common and early event in colorectal carcinogenesis. To assess calcium and vitamin D effects on the APC/β-catenin pathway in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, nested within a larger randomized, double-blind, placebo-controlled, partial 2 × 2 factorial chemoprevention clinical trial of supplemental calcium (1200 mg daily) and vitamin D (1000 IU daily), alone and in combination versus placebo, we assessed APC, β-catenin, and E-cadherin expression in colon crypts in normal-appearing rectal mucosa biopsies from 104 participants at baseline and 1-yr follow up using standardized, automated immunohistochemistry and quantitative image analysis. For vitamin D versus no vitamin D, the ratio of APC expression to β-catenin expression in the upper 40% (differentiation zone) of crypts (APC/β-catenin score) increased by 28% (P = 0.02), for calcium versus no calcium it increased by 1% (P = 0.88), and for vitamin D + calcium versus calcium by 35% (P = 0.01). Total E-cadherin expression increased by 7% (P = 0.35) for vitamin D versus no vitamin D, 8% (P = 0.31) for calcium versus no calcium, and 12% (P = 0.21) for vitamin D + calcium versus calcium. These results support (i) that vitamin D, alone or in combination with calcium, may modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms; (ii) vitamin D as a potential chemopreventive agent against colorectal neoplasms; and (iii) the potential of APC, β-catenin, and E-cadherin expression as treatable, pre-neoplastic risk biomarkers for colorectal neoplasms. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Suppression of colorectal tumorigenesis by recombinant Bacteroides fragilis enterotoxin-2 in vivo.

PubMed

Lv, You; Ye, Tao; Wang, Hui-Peng; Zhao, Jia-Ying; Chen, Wen-Jie; Wang, Xin; Shen, Chen-Xia; Wu, Yi-Bin; Cai, Yuan-Kun

2017-01-28

To evaluate the impact of recombinant Bacteroides fragilis enterotoxin-2 (BFT-2, or Fragilysin) on colorectal tumorigenesis in mice induced by azoxymethane/dextran sulfate sodium (AOM/DSS). Recombinant proBFT-2 was expressed in Escherichia coli strain Rosetta (DE3) and BFT-2 was obtained and tested for its biological activity via colorectal adenocarcinoma cell strains SW-480. Seventy C57BL/6J mice were randomly divided into a blank (BC; n = 10), model (AD; n = 20), model + low-dose toxin (ADLT; n = 20, 10 μg), and a model + high-dose toxin (ADHT; n = 20, 20 μg) group. Mice weight, tumor formation and pathology were analyzed. Immunohistochemistry determined Ki-67 and Caspase-3 expression in normal and tumor tissues of colorectal mucosa. Recombinant BFT-2 was successfully obtained, along with its biological activity. The most obvious weight loss occurred in the AD group compared with the ADLT group (21.82 ± 0.68 vs 23.23 ± 0.91, P < 0.05) and the ADHT group (21.82 ± 0.68 vs 23.57 ± 1.06, P < 0.05). More tumors were found in the AD group than in the ADLT and ADHT groups (19.75 ± 3.30 vs 6.50 ± 1.73, P < 0.05; 19.75 ± 3.30 vs 6.00 ± 2.16, P < 0.05). Pathology showed that 12 mice had adenocarcinoma and 6 cases had adenoma in the AD group. Five mice had adenocarcinoma and 15 had adenoma in the ADLT group. Four mice had adenocarcinoma and 16 had adenoma in the ADHT group. The incidence of colorectal adenocarcinoma in both the ADHT group and the ADHT group was reduced compared to that in the AD group ( P < 0.05, P < 0.05). The positive rate of Ki-67 in the ADLT group and the ADHT group was 50% and 40%, respectively, both of which were lower than that found in the AD group (94.44%, P < 0.05, P < 0.05). Caspase-3 expression in the ADLT group and the ADHT group was 45% and 55%, both of which were higher than that found in the BC group (16.67%, P < 0.05, P < 0.05). Oral administration with lower-dose biologically active recombinant BFT-2 inhibited colorectal tumorigenesis in mice.

Suppression of colorectal tumorigenesis by recombinant Bacteroides fragilis enterotoxin-2 in vivo

PubMed Central

Lv, You; Ye, Tao; Wang, Hui-Peng; Zhao, Jia-Ying; Chen, Wen-Jie; Wang, Xin; Shen, Chen-Xia; Wu, Yi-Bin; Cai, Yuan-Kun

2017-01-01

AIM To evaluate the impact of recombinant Bacteroides fragilis enterotoxin-2 (BFT-2, or Fragilysin) on colorectal tumorigenesis in mice induced by azoxymethane/dextran sulfate sodium (AOM/DSS). METHODS Recombinant proBFT-2 was expressed in Escherichia coli strain Rosetta (DE3) and BFT-2 was obtained and tested for its biological activity via colorectal adenocarcinoma cell strains SW-480. Seventy C57BL/6J mice were randomly divided into a blank (BC; n = 10), model (AD; n = 20), model + low-dose toxin (ADLT; n = 20, 10 μg), and a model + high-dose toxin (ADHT; n = 20, 20 μg) group. Mice weight, tumor formation and pathology were analyzed. Immunohistochemistry determined Ki-67 and Caspase-3 expression in normal and tumor tissues of colorectal mucosa. RESULTS Recombinant BFT-2 was successfully obtained, along with its biological activity. The most obvious weight loss occurred in the AD group compared with the ADLT group (21.82 ± 0.68 vs 23.23 ± 0.91, P < 0.05) and the ADHT group (21.82 ± 0.68 vs 23.57 ± 1.06, P < 0.05). More tumors were found in the AD group than in the ADLT and ADHT groups (19.75 ± 3.30 vs 6.50 ± 1.73, P < 0.05; 19.75 ± 3.30 vs 6.00 ± 2.16, P < 0.05). Pathology showed that 12 mice had adenocarcinoma and 6 cases had adenoma in the AD group. Five mice had adenocarcinoma and 15 had adenoma in the ADLT group. Four mice had adenocarcinoma and 16 had adenoma in the ADHT group. The incidence of colorectal adenocarcinoma in both the ADHT group and the ADHT group was reduced compared to that in the AD group (P < 0.05, P < 0.05). The positive rate of Ki-67 in the ADLT group and the ADHT group was 50% and 40%, respectively, both of which were lower than that found in the AD group (94.44%, P < 0.05, P < 0.05). Caspase-3 expression in the ADLT group and the ADHT group was 45% and 55%, both of which were higher than that found in the BC group (16.67%, P < 0.05, P < 0.05). CONCLUSION Oral administration with lower-dose biologically active recombinant BFT-2 inhibited colorectal tumorigenesis in mice. PMID:28216966

Technological advances for improving adenoma detection rates: The changing face of colonoscopy.

PubMed

Ishaq, Sauid; Siau, Keith; Harrison, Elizabeth; Tontini, Gian Eugenio; Hoffman, Arthur; Gross, Seth; Kiesslich, Ralf; Neumann, Helmut

2017-07-01

Worldwide, colorectal cancer is the third commonest cancer. Over 90% follow an adenoma-to-cancer sequence over many years. Colonoscopy is the gold standard method for cancer screening and early adenoma detection. However, considerable variation exists between endoscopists' detection rates. This review considers the effects of different endoscopic techniques on adenoma detection. Two areas of technological interest were considered: (1) optical technologies and (2) mechanical technologies. Optical solutions, including FICE, NBI, i-SCAN and high definition colonoscopy showed mixed results. In contrast, mechanical advances, such as cap-assisted colonoscopy, FUSE, EndoCuff and G-EYE™, showed promise, with reported detections rates of up to 69%. However, before definitive recommendations can be made for their incorporation into daily practice, further studies and comparison trials are required. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Effects of phenotypes in heterocyclic aromatic amine (HCA) metabolism-related genes on the association of HCA intake with the risk of colorectal adenomas.

PubMed

Barbir, Aline; Linseisen, Jakob; Hermann, Silke; Kaaks, Rudolf; Teucher, Birgit; Eichholzer, Monika; Rohrmann, Sabine

2012-09-01

Heterocyclic aromatic amines (HCA), formed by high-temperature cooking of meat, are well-known risk factors for colorectal cancer (CRC). Enzymes metabolizing HCAs may influence the risk of CRC depending on the enzyme activity level. We aimed to assess effect modification by polymorphisms in the HCA-metabolizing genes on the association of HCA intake with colorectal adenoma (CRA) risk, which are precursors of CRC. A case-control study nested in the EPIC-Heidelberg cohort was conducted. Between 1994 and 2005, 413 adenoma cases were identified and 796 controls were matched to cases. Genotypes were determined and used to predict phenotypes (i.e., enzyme activities). Odds ratios (OR) and corresponding 95 % confidence intervals (CI) were calculated by logistic regression analysis. CRA risk was positively associated with PhIP, MeIQx, and DiMeIQx (p trend = 0.006, 0.022, and 0.045, respectively) intake. SULT1A1 phenotypes modified the effect of MeIQx on CRA risk (p (Interaction) > 0.01) such that the association of MeIQx intake with CRA was stronger for slow than for normal phenotypes. Other modifying effects by phenotypes did not reach statistical significance. HCA intake is positively associated with CRA risk, regardless of phenotypes involved in the metabolizing process. Due to the number of comparisons made in the analysis, the modifying effect of SULT1A1 on the association of HCA intake with CRA risk may be due to chance.

Calcium intake and colorectal adenoma risk: dose-response meta-analysis of prospective observational studies.

PubMed

Keum, NaNa; Lee, Dong Hoon; Greenwood, Darren C; Zhang, Xuehong; Giovannucci, Edward L

2015-04-01

Evidence from randomized controlled trials suggests that calcium may protect against recurrence of colorectal adenomas, which could lead to the subsequent prevention of cancer. Yet the trials used only a large single dose and were of small sizes, and thus, knowledge of the dose-response relationship and influence on high-risk adenomas is limited. To address these issues, we conducted linear and nonlinear dose-response meta-analyses primarily based on prospective observational studies published up to July 2014 identified from PubMed and Embase. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated for total and supplemental calcium intake, respectively, using a random-effects model. For total calcium intake, summary RR for each 300 mg/day increase was 0.95 (95% CI = 0.92-0.98; I(2)  = 45%; eight studies with 11,005 cases; range of intake = 333-2,229 mg/day). Evidence of nonlinearity was indicated: approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.92 (95% CI = 0.89-0.94) at 1,000 mg/day and 0.87 (95% CI = 0.84-0.90) at 1,450 mg/day (pnonlinearity  < 0.01). Associations were stronger for high-risk adenomas (≥1 cm in diameter, (tubulo)villous histology, dysplasia, or multiplicity): approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.77 (95% CI = 0.74-0.81) at 1,000 mg/day and reduced to 0.69 (95% CI = 0.66-0.73) at 1,450 mg/da (pnonlinearity  < 0.01). For supplemental calcium intake, summary RR of total adenoma risk for each 300 mg/day increase was 0.96 (95% CI = 0.93-0.99; I(2)  = 0%; three studies with 4,548 cases; range of supplementation = 0-1,366 mg/day). In conclusion, calcium intake may continue to decrease the risk of adenomas, particularly high-risk adenomas, over a wide range of calcium intake. © 2014 UICC.

Passage from normal mucosa to adenoma and colon cancer: alteration of normal sCD30 mechanisms regulating TH1/TH2 cell functions.

PubMed

Contasta, Ida; Berghella, Anna Maria; Pellegrini, Patrizia; Adorno, Domenico

2003-08-01

The pathogenesis of cancer is currently under intensive investigation to identify reliable prognostic indices for the early detection of disease. Adenomas have been identified as precursors of colorectal cancer and tumor establishment, and disease progression has been found to reflect a malfunction of the immune system. On the basis of the role of the CD30 molecule in the regulation of TH1/TH2 functions and our previous results, strongly suggesting the validity of serum TH1/TH2 cytokines in the study of tumor progression, we studied network interaction between the production of soluble (s) CD30/sBCl2 in whole blood culture [in basic conditions and after PHA, LPS, and anti-CD3 monoclonal antibody (mAb) stimulation] and levels of TH1/TH2 cytokines (IL2, IFN gamma, IL12, IL4, IL5, IL10). Peripheral blood from a group of healthy subjects, as well as from patients with adenoma and colorectal cancer was used. Our objective was to gain a better insight into the role of the CD30 molecule in the passage from normal mucosa to adenoma and tumor and identify specific disease markers. Our results suggest that the decrease in CD30 expression and the abnormal increase in Bcl2 expression, observed in the peripheral cells of both adenoma and tumor groups determine an imbalance between TH1/TH2 functions. Consequently, changes in sCD30/sBcl2 culture production and TH1/TH2 cytokine serum levels may be reliable markers for tumor progression. In fact, our overall data show that a decrease of sCD30 levels in basic and PHA conditions and an increase of IFN gamma, IL4, IL5, and IL12 serum levels and sBcl2 in all activation condition are indicative of the passage from normal mucosa to adenoma; whilst a decrease of sBcl2 level in basic, LPS and anti-CD3 conditions and of IL2, IFN gamma serum levels, together with an increase of IL5 are indicative of the passage from adenoma to tumor.

Charity colonoscopy event to commemorate the 185th anniversary of Singapore General Hospital.

PubMed

Ng, Kheng Hong; Lim, Jit Fong; Ho, Kok Sun; Ooi, Boon Swee; Tang, Choong Leong; Eu, Kong Weng

2008-03-01

Colorectal cancer is now the cancer with the highest incidence in Singapore. However, the overall mortality rate is still about 50% because the majority of the patients present at a late stage of disease. A charity event of screening colonoscopy was offered to the public in conjunction with the 185th anniversary of Singapore General Hospital. The aim of this event was to raise awareness about early detection of colorectal cancer and the safety of colonoscopy. We conducted a one-off free screening event for colorectal cancer using colonoscopy. Four hundred and ninety individuals responded to a multimedia advertisement for the event. Of these, 220 individuals were selected for the screening based on National Guidelines for colorectal cancer screening and financial status. One hundred and fifty-two individuals turned up for the colonoscopy. The median age was 55 years (range, 22 to 82), with 84 males. Significant pathology was found in 33% of the individuals (n = 51). Colorectal polyps were detected in 34 individuals (22%). A total of 45 polyps were removed, with 20 hyperplastic polyps and 25 adenomas. Eight out of 25 adenomas were located proximal to the splenic flexure. Rectal cancer was diagnosed in 1 individual (0.6%). One individual had a large dysplastic rectosigmoid ulcer and refused further intervention. There were no significant complications from any of the colonoscopies. Colonoscopy is an invaluable screening modality as it has a high pick-up rate for colorectal polyp and cancer in an asymptomatic population. It is also proven to be safe in our study. It has the added advantage over flexible sigmoidoscopy of detecting a significant number of proximal lesions. Also, therapeutic polypectomy can be performed in the same setting.

Accuracy of early detection of colorectal tumours by stool methylation markers: A meta-analysis

PubMed Central

Zhang, Hu; Qi, Jian; Wu, Ya-Qiong; Zhang, Ping; Jiang, Jun; Wang, Qi-Xian; Zhu, You-Qing

2014-01-01

AIM: To evaluate the accuracy of methylation of genes in stool samples for diagnosing colorectal tumours. METHODS: Electronic databases including PubMed, Web of Science, Chinese Journals Full-Text Database and Wanfang Journals Full-Text Database were searched to find relevant original articles about methylated genes to be used in diagnosing colorectal tumours. A quality assessment of diagnostic accuracy studies tool (QADAS) was used to evaluate the quality of the included articles, and the Meta-disc 1.4 and SPSS 13.0 software programs were used for data analysis. RESULTS: Thirty-seven articles met the inclusion criteria, and 4484 patients were included. The sensitivity and specificity for the detection of colorectal cancer (CRC) were 73% (95%CI: 71%-75%) and 92% (95%CI: 90%-93%), respectively. For adenoma, the sensitivity and specificity were 51% (95%CI: 47%-54%) and 92% (95%CI: 90%-93%), respectively. Pooled diagnostic performance of SFRP2 methylation for CRC provided the following results: the sensitivity was 79% (95%CI: 75%-82%), the specificity was 93% (95%CI: 90%-96%), the diagnostic OR was 47.57 (95%CI: 20.08-112.72), the area under the curve was 0.9565. Additionally, the results of accuracy of SFRP2 methylation for detecting colorectal adenomas were as follows: sensitivity was 43% (95%CI: 38%-49%), specificity was 94% (95%CI: 91%-97%), the diagnostic OR was 11.06 (95%CI: 5.77-21.18), and the area under the curve was 0.9563. CONCLUSION: Stool-based DNA testing may be useful for noninvasively diagnosing colorectal tumours and SFRP2 methylation is a promising marker that has great potential in early CRC diagnosis. PMID:25320544

Predictive cytogenetic biomarkers for colorectal neoplasia in medium risk patients.

PubMed

Ionescu, E M; Nicolaie, T; Ionescu, M A; Becheanu, G; Andrei, F; Diculescu, M; Ciocirlan, M

2015-01-01

DNA damage and chromosomal alterations in peripheral lymphocytes parallels DNA mutations in tumor tissues. The aim of our study was to predict the presence of neoplastic colorectal lesions by specific biomarkers in "medium risk" individuals (age 50 to 75, with no personal or family of any colorectal neoplasia). We designed a prospective cohort observational study including patients undergoing diagnostic or opportunistic screening colonoscopy. Specific biomarkers were analyzed for each patient in peripheral lymphocytes - presence of micronuclei (MN), nucleoplasmic bridges (NPB) and the Nuclear Division Index (NDI) by the cytokinesis-blocked micronucleus assay (CBMN). Of 98 patients included, 57 were "medium risk" individuals. MN frequency and NPB presence were not significantly different in patients with neoplastic lesions compared to controls. In "medium risk" individuals, mean NDI was significantly lower for patients with any neoplastic lesions (adenomas and adenocarcinomas, AUROC 0.668, p 00.5), for patients with advanced neoplasia (advanced adenoma and adenocarcinoma, AUROC 0.636 p 0.029) as well as for patients with adenocarcinoma (AUROC 0.650, p 0.048), for each comparison with the rest of the population. For a cut-off of 1.8, in "medium risk" individuals, an NDI inferior to that value may predict any neoplastic lesion with a sensitivity of 97.7%, an advanced neoplastic lesion with a sensitivity of 97% and adenocarcinoma with a sensitivity of 94.4%. NDI score may have a role as a colorectal cancer-screening test in "medium risk" individuals. DNA = deoxyribonucleic acid; CRC = colorectal cancer; EU = European Union; WHO = World Health Organization; FOBT = fecal occult blood test; CBMN = cytokinesis-blocked micronucleus assay; MN = micronuclei; NPB = nucleoplasmic bridges; NDI = Nuclear Division Index; FAP = familial adenomatous polyposis; HNPCC = hereditary non-polypoid colorectal cancer; IBD = inflammatory bowel diseases; ROC = receiver operating characteristics; AUROC = area under the receiver operating characteristics curve.

Accuracy of early detection of colorectal tumours by stool methylation markers: a meta-analysis.

PubMed

Zhang, Hu; Qi, Jian; Wu, Ya-Qiong; Zhang, Ping; Jiang, Jun; Wang, Qi-Xian; Zhu, You-Qing

2014-10-14

To evaluate the accuracy of methylation of genes in stool samples for diagnosing colorectal tumours. Electronic databases including PubMed, Web of Science, Chinese Journals Full-Text Database and Wanfang Journals Full-Text Database were searched to find relevant original articles about methylated genes to be used in diagnosing colorectal tumours. A quality assessment of diagnostic accuracy studies tool (QADAS) was used to evaluate the quality of the included articles, and the Meta-disc 1.4 and SPSS 13.0 software programs were used for data analysis. Thirty-seven articles met the inclusion criteria, and 4484 patients were included. The sensitivity and specificity for the detection of colorectal cancer (CRC) were 73% (95%CI: 71%-75%) and 92% (95%CI: 90%-93%), respectively. For adenoma, the sensitivity and specificity were 51% (95%CI: 47%-54%) and 92% (95%CI: 90%-93%), respectively. Pooled diagnostic performance of SFRP2 methylation for CRC provided the following results: the sensitivity was 79% (95%CI: 75%-82%), the specificity was 93% (95%CI: 90%-96%), the diagnostic OR was 47.57 (95%CI: 20.08-112.72), the area under the curve was 0.9565. Additionally, the results of accuracy of SFRP2 methylation for detecting colorectal adenomas were as follows: sensitivity was 43% (95%CI: 38%-49%), specificity was 94% (95%CI: 91%-97%), the diagnostic OR was 11.06 (95%CI: 5.77-21.18), and the area under the curve was 0.9563. Stool-based DNA testing may be useful for noninvasively diagnosing colorectal tumours and SFRP2 methylation is a promising marker that has great potential in early CRC diagnosis.

EpiGeNet: A Graph Database of Interdependencies Between Genetic and Epigenetic Events in Colorectal Cancer.

PubMed

Balaur, Irina; Saqi, Mansoor; Barat, Ana; Lysenko, Artem; Mazein, Alexander; Rawlings, Christopher J; Ruskin, Heather J; Auffray, Charles

2017-10-01

The development of colorectal cancer (CRC)-the third most common cancer type-has been associated with deregulations of cellular mechanisms stimulated by both genetic and epigenetic events. StatEpigen is a manually curated and annotated database, containing information on interdependencies between genetic and epigenetic signals, and specialized currently for CRC research. Although StatEpigen provides a well-developed graphical user interface for information retrieval, advanced queries involving associations between multiple concepts can benefit from more detailed graph representation of the integrated data. This can be achieved by using a graph database (NoSQL) approach. Data were extracted from StatEpigen and imported to our newly developed EpiGeNet, a graph database for storage and querying of conditional relationships between molecular (genetic and epigenetic) events observed at different stages of colorectal oncogenesis. We illustrate the enhanced capability of EpiGeNet for exploration of different queries related to colorectal tumor progression; specifically, we demonstrate the query process for (i) stage-specific molecular events, (ii) most frequently observed genetic and epigenetic interdependencies in colon adenoma, and (iii) paths connecting key genes reported in CRC and associated events. The EpiGeNet framework offers improved capability for management and visualization of data on molecular events specific to CRC initiation and progression.

Endoscopic follow-up of 383 patients with colorectal adenoma: an observational study in daily practice.

PubMed

Jonkers, Daisy; Ernst, Justi; Pladdet, Ingrid; Stockbrügger, Reinhold; Hameeteman, Wim

2006-06-01

Endoscopic removal of colorectal adenomas reduces the incidence and mortality of colorectal cancer (CRC), but follow-up surveillance is recommended. Compliance with the Dutch surveillance guidelines and detection of neoplasia during follow-up has been evaluated in daily practice. From 1987 to 1996, 383 consecutive patients with colorectal adenomas (56.4% male, 61.8+/-11.3 years) were included and followed until December 2000. The mean follow-up was 80.5+/-42.5 months with 2.2+/-0.9 follow-up endoscopies. A total of 32.5 and 27.3% of follow-up endoscopies were performed >25% (time between advised and actual endoscopy) too late or too early, respectively. At the end of follow-up, 33.4% of patients had left the follow-up (two-thirds died) and 60.1% were known with co-morbidity. A first, second, third, fourth and fifth follow-up endoscopy had been performed in 327, 238, 132, 64 and 35 patients, respectively. Adenomatous polyps (with high-risk polyps) were detected in 100% (42.6%) of the index endoscopies and in 25.1% (17.4%), 23.9% (10.5%), 28.0% (12.1%), 34.4% (25.0%) and 37.1% (17.1%) of the first to fifth follow-up endoscopy, respectively. CRC was diagnosed in seven patients (46.1+/-22.9 months after index endoscopy), resulting in a standardized incidence ratio of 1.4 (confidence interval 0.6-3.0, P=0.4) compared to the general population. In this daily practice, high numbers of total and high-risk adenomatous polyps were found during follow-up surveillance. The incidence of CRC was not significantly different from the general population, which might be due to the intensive follow-up and removal of polyps. These findings support the importance of follow-up surveillance. However, the high overall morbidity and mortality should be taken into account when selecting patients for an intensive follow-up programme.

Increased risk of advanced neoplasms among asymptomatic siblings of patients with colorectal cancer.

PubMed

Ng, Siew C; Lau, James Y W; Chan, Francis K L; Suen, Bing Yee; Leung, Wai-Keung; Tse, Yee Kit; Ng, Simon S M; Lee, Janet F Y; To, Ka-Fai; Wu, Justin C Y; Sung, Joseph J Y

2013-03-01

Colorectal cancer (CRC) is the second-most common cancer in Hong Kong. Relatives of patients with CRC have an increased risk of colorectal neoplasm. We assessed the prevalence of advanced neoplasms among asymptomatic siblings of patients with CRC. Patients with CRC were identified from the Prince of Wales Hospital CRC Surgery Registry from 2001 to 2011. Colonoscopies were performed for 374 siblings of patients (age, 52.6 ± 7.4 y) and 374 age- and sex-matched siblings of healthy subjects who had normal colonoscopies and did not have a family history of CRC (controls, 52.7 ± 7.4 y). We identified individuals with advanced neoplasms (defined as cancers or adenomas of at least 10 mm in diameter, high-grade dysplasia, with villous or tubulovillous characteristics). The prevalence of advanced neoplasms was 7.5% among siblings of patients and 2.9% among controls (matched odds ratio [mOR], 3.07; 95% confidence interval [CI], 1.5-6.3; P = .002). The prevalence of adenomas larger than 10 mm was higher among siblings of patients than in controls (5.9% vs 2.1%; mOR, 3.34; 95% CI, 1.45-7.66; P = .004), as was the presence of colorectal adenomas (31.0% vs 18.2%; mOR, 2.19; 95% CI, 1.52-3.17; P < .001). Six cancers were detected among siblings of patients; no cancers were detected in controls. The prevalence of advanced neoplasms among siblings of patients was higher when their index case was female (mOR, 4.95; 95% CI, 1.81-13.55) and had distally located CRC (mOR, 3.10; 95% CI, 1.34-7.14). In Hong Kong, siblings of patients with CRC have a higher prevalence of advanced neoplasms, including CRC, than siblings of healthy individuals. Screening is indicated in this high-risk population. ClinicalTrials.gov number: NCT00164944. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Effects of supplemental vitamin D and calcium on biomarkers of inflammation in colorectal adenoma patients: A randomized, controlled clinical trial

PubMed Central

Hopkins, Myfanwy H.; Owen, Joy; Ahearn, Thomas; Fedirko, Veronika; Flanders, W. Dana; Jones, Dean P.; Bostick, Roberd M.

2011-01-01

Vitamin D and calcium affect several pathways involved in inflammation, tumor growth, and immune surveillance relevant to carcinogenesis. Also, epidemiologic evidence indicates that calcium and vitamin D may reduce risk for colorectal adenomas and cancer. To investigate the effects of calcium and vitamin D on biomarkers of inflammation in colorectal adenoma patients, we conducted a pilot, randomized, double-blind, placebo-controlled, 2×2 factorial clinical trial (n=92), of 2 g/day calcium and/or 800 IU/day vitamin D3 supplementation vs. placebo over six months. Plasma concentrations of pro-inflammatory markers (CRP, TNF-α, IL-6, IL-1β, and IL-8) and an anti-inflammatory marker (IL-10) were measured using enzyme-linked immunoassays. After six months of treatment, in the vitamin D3 supplementation group, CRP decreased 32% overall (p=0.11), 37% in men (p=0.05), and 41% among non-NSAID users (p=0.05) relative to placebo. In the vitamin D3 supplementation group, TNF-α decreased 13%, IL-6 32%, IL-1β 50%, and IL-8 15%; in the calcium supplementation group, IL-6 decreased 37%, IL-8 11%, and IL-1β 27%. Although these changes were not statistically significant, a combined inflammatory markers z-score decreased 77% (p=0.003) in the vitamin D3 treatment group overall, 83% (p=0.01) among men, and 48% among non-NSAID users (p=0.01). There was no evidence of synergy between vitamin D3 and calcium or effects on IL-10. These preliminary results are consistent with a pattern of reduction in tumor-promoting inflammation biomarkers with vitamin D3 or calcium supplementation alone, and support further investigation of vitamin D3 as a chemopreventive agent against inflammation and colorectal neoplasms. PMID:21724580

Altered Polyamine Profiles in Colorectal Cancer.

PubMed

Venäläinen, Markus K; Roine, Antti N; Häkkinen, Merja R; Vepsäläinen, Jouko J; Kumpulainen, Pekka S; Kiviniemi, Mikko S; Lehtimäki, Terho; Oksala, Niku K; Rantanen, Tuomo K

2018-06-01

The declining mortality rate of patients with colorectal cancer (CRC) can be explained, at least partially, with early diagnosis. Simple diagnostic methods are needed to achieve a maximal patient participation rate in screening. Liquid chromatography electrospray tandem mass spectrometry (LC-MS/MS) was used to determine urinary polyamine (PA) profiles. In a prospective setting, 116 patients were included in the study: 57 with CRC, 13 with inflammatory bowel disease (IBD), 12 with adenoma, and 34 controls. N1,N12-diacetylspermine (DiAcSPM) level was significantly higher in patients with CRC than controls (sensitivity=78.0%, specificity=70.6%; p=0.00049). The level of diacetylated cadaverine (p=0.0068) was lower and that of diacetylated putrescine (p=0.0078) was higher in patients with CRC than in those with IBD. Cadaverine (p=0.00010) and spermine (p=0.042) levels were lower and that of DiAcSPM (p=0.018) higher in patients with CRC than in those with adenoma. The simultaneous determination of urinary PAs by means of LC-MS/MS can be used to discriminate CRC from controls and patients with benign colorectal diseases. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Prevalence of synchronous colorectal neoplasms in surgically treated gastric cancer patients and significance of screening colonoscopy.

PubMed

Suzuki, Akira; Koide, Naohiko; Takeuchi, Daisuke; Okumura, Motohiro; Ishizone, Satoshi; Suga, Tomoaki; Miyagawa, Shinichi

2014-05-01

The existence of other primary tumors during the treatment and management of gastric cancer (GC) is an important issue. The present study investigated the prevalence and management of synchronous colorectal neoplasms (CRN) in surgically treated GC patients. Of 381 surgically treated GC patients, 332 (87.1%) underwent colonoscopy to detect CRN before surgery or within a year after surgery. CRN were synchronously observed in 140 patients (42.2%). Adenoma was observed in 131 patients (39.4%). Endoscopic resection was done in 18 patients with adenoma. Colorectal cancer (CRC) was observed in 16 patients (4.8%), superficial CRC in 13 and advanced CRC in three patients. Endoscopic resection of superficial CRC was carried out in seven patients, whereas simultaneous surgical resection of CRC was done in nine patients. CRN were more frequently observed in men. CRC was more frequently observed in GC patients with distant metastasis, albeit without significance. The overall survival of GC patients with CRN or CRC was poorer than that of patients without CRN or CRC. Synchronous CRN were commonly associated with GC and screening colonoscopy should be offered to patients with GC. © 2013 The Authors. Digestive Endoscopy © 2013 Japan Gastroenterological Endoscopy Society.

Fresh vs Frozen Samples and Ambient Temperature Have Little Effect on Detection of Colorectal Cancer or Adenomas by a Fecal Immunochemical Test in a Colorectal Cancer Screening Cohort in Germany.

PubMed

Chen, Hongda; Werner, Simone; Brenner, Hermann

2017-10-01

Fecal immunochemical tests (FITs) are used in colorectal cancer (CRC) screening. We compared detection of CRCs and colorectal neoplasms by FITs using fresh samples (collected into buffer-filled tubes) vs frozen samples, and we assessed the effects of seasonal variations in ambient temperature on test performance. We performed a prospective study of 3466 individuals (50% male; mean age, 62 years) undergoing screening colonoscopies at 20 gastroenterology practices in southern Germany from November 2008 through September 2014. Frozen stool samples (collected and frozen by patients through February 2012, n = 1644) and fresh stool samples (collected by patients into buffer-filled tubes after February 2012, n = 1822) were obtained; hemoglobin (Hgb) concentrations were measured by using a commercial, quantitative FIT (cutoff value for positive result, 17 μg Hgb/g feces). Colonoscopy results were used as the gold standard, with results categorized as CRC, advanced adenoma, non-advanced adenoma, or no colorectal neoplasm. Differences in detection of colorectal neoplasms with fresh vs frozen samples were compared by using Wilcoxon rank sum test (continuous variables) and Fisher exact test (categorical variables). We also compared test performance when samples were collected during different seasons (based on outdoor temperature less than 8°, 8°-15°, or more than 15°). Of the samples analyzed by FIT, 12.8% of frozen stool samples (95% confidence interval [CI], 11.3%-14.5%) and 8.7% of fresh stool samples (95% CI, 7.5%-10.1%) had positive results (P value for difference < .001). When adjusting the Hgb cutoff value to produce the same percentage of positive results for fresh and frozen samples (10% and 5%), FIT with frozen vs fresh samples detected colorectal neoplasms with similar levels of sensitivity and specificity. For example, at cutoff values that produced 5% positive results for each sample type, FIT detected advanced neoplasms with 27.8% sensitivity when frozen samples were used (95% CI, 21.4%-35.1%) and 25.6% sensitivity when fresh samples were used (95% CI, 19.8%-32.1%). Specificity values were 97.7% when frozen samples were used (95% CI, 96.8%-98.4%) and 97.6% when fresh samples were used (95% CI, 96.7%-98.3%). We did not observe any differences in detection of neoplasms during different seasons that were based on outdoor temperature. In a prospective study of 3466 individuals who underwent screening colonoscopies and received FITs, we found that use of fresh vs frozen samples slightly affected positivity rates and the proportions of CRCs or adenomas detected at the recommended Hgb cutoff value. However, after we adjusted Hgb cutoff values to produce equal proportions of positive results for fresh vs frozen samples, the performance of the FIT was similar with each sample type. Season of sample collection (based on outdoor temperature) did not affect detection of CRC using either sample type in this study from Middle Europe. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Familial adenomatous polyposis

PubMed Central

Half, Elizabeth; Bercovich, Dani; Rozen, Paul

2009-01-01

Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after the appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present with some extraintestinal manifestations such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner variant of FAP. Classic FAP is inherited in an autosomal dominant manner and results from a germline mutation in the adenomatous polyposis (APC) gene. Most patients (~70%) have a family history of colorectal polyps and cancer. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract. Diagnosis is based on a suggestive family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed. Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing is possible. Referral to a geneticist or genetic counselor is mandatory. Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome). Cancer prevention and maintaining a good quality of life are the main goals of management and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy, they need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery (when possible to perform). Adjunctive therapy with celecoxib has been approved by the US Food and Drug Administration and the European Medicines Agency in patients with FAP. Individuals with FAP carry a 100% risk of CRC; however, this risk is reduced significantly when patients enter a screening-treatment program. PMID:19822006

Type 2 diabetes mellitus and colorectal neoplasia risk in Hispanics: a case-control study.

PubMed

Díaz-Algorri, Yaritza; Lozada, María Eugenia; López, Sofía M; Bertrán-Rodríguez, Carlos E; González-Hernández, Cinthia M; González, Dilka; Pérez-Cardona, Cynthia M; Hernández, Jessica; Pedrosa, Carmen; Toro, Doris H; González-Pons, María; Cruz-Correa, Marcia

2015-01-01

There is inconclusive evidence regarding the potential link between diabetes mellitus (DM) and colorectal cancer (CRC). Associations between type 2 DM and colorectal neoplasia (CRN; colorectal cancer and/or adenomas) have not been well studied in Hispanics, an ethnic minority at high risk for type 2 DM. This study aims to assess the association between type 2 DM and CRN in Hispanics. Hispanics with incident CRN and colonoscopy-negative controls from 2005 to 2009 were evaluated. Diagnosis of type 2 DM was established by previous medical diagnosis and/or use of DM treatments. Unconditional logistic regression was performed to estimate odds ratios for the association between type 2 DM and CRN. A total of 451 participants (mean age 61.1±11.9years, 59.6 % men) were evaluated (218 with incident CRC, 77 with colorectal adenomas, and 156 colonoscopy-negative controls). The prevalence of type 2 DM in this study was 25.1%. After adjusting for potential confounding variables, women with type 2 DM were 2.74 (95% CI: 0.94-7.99) times more likely to have CRN and 4.83 times more likely to present with proximal colonic CRN (95% CI: 1.25-18.58) than women without type 2 DM. No statistically significant associations were found between type 2 DM and CRN among men. An increased odds for CRN and proximal location of CRN was observed among Hispanic women with type 2 DM. Since DM is a highly prevalent disease in this population, adherence to routine CRC screening is of outmost importance. Copyright © 2015 Elsevier Inc. All rights reserved.

Diagnosing lynch syndrome in absence of colorectal cancer.

PubMed

Lynch, Henry T; Knezetic, Joseph; Lanspa, Stephen

2012-11-01

There are many ways in which a diagnosis of Lynch syndrome can be made, most prominent of which is family history, presence of cancer, high microsatellite instability, immunohistochemistry, and a mismatch repair germline mutation. There are at least four molecular pathways for colorectal cancer carcinogenesis: 1) adenoma-carcinoma sequence; 2) hereditary microsatellite instability; 3) serrated pathway; 4) epidermal growth factor receptor. The answer to diagnosing Lynch syndrome in the absence of colorectal cancer may be partially based upon the phenotypic characteristics of the colonic polyps should they be identified at colonoscopy, specifically their phenotypic characteristics of location, size, histology, number, and age of polyp onset.

Many private mutations originate from the first few divisions of a human colorectal adenoma.

PubMed

Kang, Haeyoun; Salomon, Matthew P; Sottoriva, Andrea; Zhao, Junsong; Toy, Morgan; Press, Michael F; Curtis, Christina; Marjoram, Paul; Siegmund, Kimberly; Shibata, Darryl

2015-11-01

Intratumoural mutational heterogeneity (ITH) or the presence of different private mutations in different parts of the same tumour is commonly observed in human tumours. The mechanisms generating such ITH are uncertain. Here we find that ITH can be remarkably well structured by measuring point mutations, chromosome copy numbers, and DNA passenger methylation from opposite sides and individual glands of a 6 cm human colorectal adenoma. ITH was present between tumour sides and individual glands, but the private mutations were side-specific and subdivided the adenoma into two major subclones. Furthermore, ITH disappeared within individual glands because the glands were clonal populations composed of cells with identical mutant genotypes. Despite mutation clonality, the glands were relatively old, diverse populations when their individual cells were compared for passenger methylation and by FISH. These observations can be organized into an expanding star-like ancestral tree with co-clonal expansion, where many private mutations and multiple related clones arise during the first few divisions. As a consequence, most detectable mutational ITH in the final tumour originates from the first few divisions. Much of the early history of a tumour, especially the first few divisions, may be embedded within the detectable ITH of tumour genomes. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mitotic and apoptotic activity in colorectal neoplasia.

PubMed

Kohoutova, Darina; Pejchal, Jaroslav; Bures, Jan

2018-05-18

Colorectal cancer (CRC) is third most commonly diagnosed cancer worldwide. The aim of the prospective study was to evaluate mitosis and apoptosis of epithelial cells at each stage of colorectal neoplasia. A total of 61 persons were enrolled into the study: 18 patients with non-advanced colorectal adenoma (non-a-A), 13 patients with advanced colorectal adenoma (a-A), 13 patients with CRC and 17 controls: individuals with normal findings on colonoscopy. Biopsy samples were taken from pathology (patients) and healthy mucosa (patients and healthy controls). Samples were formalin-fixed paraffin-embedded and stained with haematoxylin-eosin. Mitotic and apoptotic activity were evaluated in lower and upper part of the crypts and in the superficial compartment. Apoptotic activity was also assessed using detection of activated caspase-3. In controls, mitotic activity was present in lower part of crypts, accompanied with low apoptotic activity. Mitotic and apoptotic activity decreased (to almost zero) in upper part of crypts. In superficial compartment, increase in apoptotic activity was observed. Transformation of healthy mucosa into non-a-A was associated with significant increase of mitotic activity in lower and upper part of the crypts and with significant increase of apoptotic activity in all three compartments; p < 0.05. Transformation of non-a-A into a-A did not lead to any further significant increase in apoptotic activity, but was related to significant increase in mitotic activity in upper part of crypts and superficial compartment. A significant decrease in apoptotic activity was detected in all three comparments of CRC samples compared to a-A; p < 0.05. No differences in mitotic and apoptotic activity between biopsies in healthy controls and biopsy samples from healthy mucosa in patients with colorectal neoplasia were observed. Detection of activated caspase-3 confirmed the above findings in apoptotic activity. Significant dysregulation of mitosis and apoptosis during the progression of colorectal neoplasia, corresponding with histology, was confirmed. In patients with sporadic colorectal neoplasia, healthy mucosa does not display different mitotic and apoptotic activity compared to mucosa in healthy controls and therefore adequate endoscopic/surgical removal of colorectal neoplasia is sufficient.

Organized colorectal cancer screening in Serbia - the first round within 2013-2014.

PubMed

Banković Lazarević, Dušica; Krivokapić, Zoran; Barišić, Goran; Jovanović, Verica; Ilić, Dragan; Veljković, Marko

2016-04-01

The National Organized Colorectal Cancer Screening Program was conducted in the Republic of Serbia during 2013-2014 covering the population of both genders, aged 50 to 74 years, in 28 municipalities out of 180, with the target population of 651,445 people. This organized colorectal cancer screening aims to reduce mortality from colorectal cancer in the target population. The aim of this study was to show the results of organized screening for colorectal cancer during the first biannual round in Serbia. General practitioners from the primary health centers, invited target population by letters and by phone to perform immunochemical fecal occult blood test. Persons with a positive test results were referred to the colonoscopy. The database of health insurance and other citizens of the target population was used for invitation for screening in primary health centers. Descriptive statistical analysis of the results in organized colorectal cancer screening in the first round was performed for the key screening indicators. In the first round, a total of 99,592 persons were invited. The participation rate was 62.5%. Colonoscopy was performed in 1,554 persons. Adenomas were found in 586 persons (0.9% of all the tested), e.g. 37.7 % of all colonoscopied. In 129 persons colorectal cancer was diagnosed (0.2% of all the tested), e.g. 8.3% of all the colonoscopied. In the left half of the colon (rectum, sigmoid and descending colon) there were 70.4% diagnosed polyps and 77.3% carcinomas, while 29.6% of polyps and 22.7% carcinomas were found in the proximal parts of the colon. In the first round of the organized colorectal cancer screening in Serbia the participation rate of the targeted population was high and gave encouraging result. It was expected that in the forthcoming rounds even higher coverage of the target population would be accomplished. A positive predictive value of the completed colonoscopies showed that further work on observing the stages of diagnosed adenomas and carcinomas would reach the goals of the expected improvement in early detection of colorectal cancer in Serbia.

Sarcopenia is associated with an increased risk of advanced colorectal neoplasia.

PubMed

Park, Youn Su; Kim, Ji Won; Kim, Byeong Gwan; Lee, Kook Lae; Lee, Jae Kyung; Kim, Joo Sung; Koh, Seong-Joon

2017-04-01

Although sarcopenia is associated with an increased risk for mortality after the curative resection of colorectal cancer, its influence on the development of advanced colonic neoplasia remains unclear. This study included 1270 subjects aged 40 years or older evaluated with first-time screening colonoscopy at Seoul National University Boramae Health Care Center from January 2010 to February 2015. Skeletal muscle mass was measured with a body composition analyzer (direct segmental multifrequency bioelectrical impedance analysis method). Multiple logistic regression analysis was performed to determine whether sarcopenia is associated with advanced colorectal neoplasia. Of 1270 subjects, 139 (10.9%) were categorized into the sarcopenia group and 1131 (89.1%) into the non-sarcopenia group. In the non-sarcopenia group, 55 subjects (4.9%) had advanced colorectal neoplasia. However, in the sarcopenia group, 19 subjects (13.7%) had advanced colorectal neoplasia, including 1 subject with invasive colorectal cancer (0.7%). In addition, subjects with sarcopenia had a higher prevalence of advanced adenoma (P < 0.001) than those without sarcopenia. According to the multiple logistic regression analysis adjusted for variable confounders, age (odds ratio 1.062, 95% confidence interval 1.032-1.093; P < 0.001), male sex (odds ratio 1.749, 95% confidence interval 1.008-3.036; P = 0.047), and sarcopenia (odds ratio 2.347, 95% confidence interval 1.311-4.202; P = 0.004) were associated with an advanced colorectal neoplasia. Sarcopenia is associated with an increased risk of advanced colorectal neoplasia.

Comparing the outcomes of two strategies for colorectal tumor detection: policy-promoted screening program versus health promotion service.

PubMed

Wu, Ping-Hsiu; Lin, Yu-Min; Liao, Chao-Sheng; Chang, Hung-Chuen; Chen, Yu-Hung; Yang, Kuo-Ching; Shih, Chia-Hui

2013-06-01

The Taiwanese government has proposed a population-based colorectal tumor detection program for the average-risk population. This study's objectives were to understand the outcomes of these screening policies and to evaluate the effectiveness of the program. We compared two databases compiled in one medical center. The "policy-promoted cancer screening" (PPS) database was built on the basis of the policy of the Taiwan Bureau of National Health Insurance for cancer screening. The "health promotion service" (HPS) database was built to provide health check-ups for self-paid volunteers. Both the PPS and HPS databases employ the immunochemical fecal occult blood test (iFOBT) and colonoscopy for colorectal tumor screening using different strategies. A comparison of outcomes between the PPS and HPS included: (1) quality indicators-compliance rate, cecum reaching rate, and tumor detection rate; and (2) validity indicators-sensitivity, specificity, positive, and negative predictive values for detecting colorectal neoplasms. A total of 10,563 and 1481 individuals were enrolled in PPS and HPS, respectively. Among quality indicators, there was no statistically significant difference in the cecum reaching rate between PPS and HPS. The compliance rates were 56.1% for PPS and 91.8% for HPS (p < 0.001). The advanced adenoma detection rates of PPS and HPS were 1.0% and 3.6%, respectively (p < 0.01). The carcinoma detection rates were 0.3% and 0.4%, respectively (p = 0.59). For validity indicators, PPS provides only a positive predictive value for colorectal tumor detection. HPS provides additional validity indicators, including sensitivity, specificity, positive predictive value, and negative predictive value, for colorectal tumor screening. In comparison with the outcomes of the HPS database, the screening efficacy of the PPS database is even for detecting colorectal carcinoma but is limited in detecting advanced adenoma. HPS may provide comprehensive validity indicators and will be helpful in adjusting current policies for improving screening performance. Copyright © 2013. Published by Elsevier B.V.

Clinical Significance of Colonoscopy in Patients with Upper Gastrointestinal Polyps and Neoplasms: A Meta-Analysis

PubMed Central

Wu, Zhen-Jie; Lin, Yuan; Xiao, Jun; Wu, Liu-Cheng; Liu, Jun-Gang

2014-01-01

Background Some authors have studied the relationship between the presence of polyps, adenomas and cancers of upper gastrointestinal tract (stomach and duodenum) and risk of colorectal polyps and neoplasms; however, the results are controversial, which may be due to study sample size, populations, design, clinical features, and so on. No meta-analysis, which can be generalized to a larger population and could provide a quantitative pooled risk estimate of the relationship, of this issue existed so far. Methods We performed a meta-analysis to evaluate risk of colorectal polyps or neoplasms in patients with polyps, adenomas or cancers in upper gastrointestinal tract comparing with controls. A search was conducted through PubMed, EMBASE, reference lists of potentially relevant papers, and practice guidelines up to 27 November 2013 without languages restriction. Odd ratios (ORs) were pooled using random-effects models. Results The search yielded 3 prospective and 21 retrospective case-control studies (n = 37152 participants). The principal findings included: (1) OR for colorectal polyps was 1.15 (95% CI, 1.04–1.26) in the gastric polyps group comparing with control groups; (2) Patients with gastric polyps and neoplasms have higher risk (OR, 1.31 [95% CI, 1.06–1.62], and 1.72 [95% CI, 1.42–2.09], respectively) of colorectal neoplasms comparing with their controls; and (3) Positive association was found between the presence of colorectal neoplasms and sporadic duodenal neoplasms (OR, 2.59; 95% CI, 1.64–4.11). Conclusions Findings from present meta-analysis of 24 case-control studies suggest that the prevalence of colorectal polyps was higher in patients with gastric polyps than in those without gastric polyps, and the risk of colorectal neoplasms increases significantly in patients with gastric polyps, neoplasms, and duodenal neoplasms. Therefore, screening colonoscopy should be considered for patients with upper gastrointestinal polyps and neoplasms. PMID:24637723

MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms.

PubMed

Joosten, Sander P J; Zeilstra, Jurrit; van Andel, Harmen; Mijnals, R Clinton; Zaunbrecher, Joost; Duivenvoorden, Annet A M; van de Wetering, Marc; Clevers, Hans; Spaargaren, Marcel; Pals, Steven T

2017-10-01

Resistance of metastatic human colorectal cancer cells to drugs that block epidermal growth factor (EGF) receptor signaling could be caused by aberrant activity of other receptor tyrosine kinases, activating overlapping signaling pathways. One of these receptor tyrosine kinases could be MET, the receptor for hepatocyte growth factor (HGF). We investigated how MET signaling, and its interaction with CD44 (a putative MET coreceptor regulated by Wnt signaling and highly expressed by intestinal stem cells [ISCs] and adenomas) affects intestinal homeostasis, regeneration, and adenoma formation in mini-gut organoids and mice. We established organoid cultures from ISCs stimulated with HGF or EGF and assessed intestinal differentiation by immunohistochemistry. Mice with total epithelial disruption of MET (Ah Cre /Met fl/fl /LacZ) or ISC-specific disruption of MET (Lgr5 Creert2 /Met fl/fl /LacZ) and control mice (Ah Cre /Met +/+ /LacZ, Lgr5 Creert2 /Met +/+ /LacZ) were exposed to 10 Gy total body irradiation; intestinal tissues were collected, and homeostasis and regeneration were assessed by immunohistochemistry. We investigated adenoma organoid expansion stimulated by HGF or EGF using adenomas derived from Lgr5 Creert2 /Met fl/fl /Apc fl/fl and Lgr5 Creert2 /Met +/+ /Apc fl/fl mice. The same mice were evaluated for adenoma prevalence and size. We also quantified adenomas in Ah Cre /Met fl/fl /Apc fl/+ mice compared with Ah Cre /Met +/+ /Apc fl/+ control mice. We studied expansion of organoids generated from crypts and adenomas, stimulated by HGF or EGF, that were derived from mice expressing different CD44 splice variants (Cd44 +/+ , Cd44 -/- , Cd44 s/s , or Cd44 v4-10/v4-10 mice). Crypts incubated with EGF or HGF expanded into self-organizing mini-guts with similar levels of efficacy and contained all differentiated cell lineages. MET-deficient mice did not have defects in intestinal homeostasis. Total body irradiation reduced numbers of proliferating crypts in Ah Cre /Met fl/fl /LacZ mice. Lgr5 Creert2 /Met fl/fl /LacZ mice had impaired regeneration of MET-deficient ISCs. Adenoma organoids stimulated with EGF or HGF expanded to almost twice the size of nonstimulated organoids. MET-deficient adenoma organoids did not respond to HGF stimulation, but did respond to EGF. ISC-specific disruption of Met (Lgr5 Creert2 /Met fl/fl /Apc fl/fl mice) caused a twofold increase in apoptosis in microadenomas, resulting in an approximately 50% reduction of microadenoma numbers and significantly reduced average adenoma size. Total epithelial disruption of Met (Ah Cre /Met fl/fl /Apc fl/+ mice) resulted in an approximate 50% reduction in (micro)adenoma numbers. Intestinal crypts from Cd44 -/- mice did not expand to the same extent as crypts from Cd44 +/+ mice on stimulation with HGF, but had the same response to EGF. The negative effect on HGF-mediated growth was overcome by expression of CD44v4-10, but not by CD44s. Similarly, HGF-mediated expansion of adenoma organoids required CD44v4-10. In studies of intestinal organoid cultures and mice with inducible deletion of MET, we found HGF receptor signaling to regulate intestinal homeostasis and regeneration, as well as adenoma formation. These activities of MET are promoted by the stem cell CD44 isoform CD44v4-10. Our findings provide rationale for targeting signaling via MET and CD44 during anti-EGF receptor therapy of patients with colorectal cancer or in patients resistant to EGF receptor inhibitors. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence.

PubMed

Hadac, Jamie N; Leystra, Alyssa A; Paul Olson, Terrah J; Maher, Molly E; Payne, Susan N; Yueh, Alexander E; Schwartz, Alexander R; Albrecht, Dawn M; Clipson, Linda; Pasch, Cheri A; Matkowskyj, Kristina A; Halberg, Richard B; Deming, Dustin A

2015-10-01

Human colorectal cancers often possess multiple mutations, including three to six driver mutations per tumor. The timing of when these mutations occur during tumor development and progression continues to be debated. More advanced lesions carry a greater number of driver mutations, indicating that colon tumors might progress from adenomas to carcinomas through the stepwise accumulation of mutations following tumor initiation. However, mutations that have been implicated in tumor progression have been identified in normal-appearing epithelial cells of the colon, leaving the possibility that these mutations might be present before the initiation of tumorigenesis. We utilized mouse models of colon cancer to investigate whether tumorigenesis still occurs through the adenoma-to-carcinoma sequence when multiple mutations are present at the time of tumor initiation. To create a model in which tumors could concomitantly possess mutations in Apc, Kras, and Pik3ca, we developed a novel minimally invasive technique to administer an adenovirus expressing Cre recombinase to a focal region of the colon. Here, we demonstrate that the presence of these additional driver mutations at the time of tumor initiation results in increased tumor multiplicity and an increased rate of progression to invasive adenocarcinomas. These cancers can even metastasize to retroperitoneal lymph nodes or the liver. However, despite having as many as three concomitant driver mutations at the time of initiation, these tumors still proceed through the adenoma-to-carcinoma sequence. ©2015 American Association for Cancer Research.

Colon tumors with the simultaneous induction of driver mutations in APC, KRAS, and PIK3CA still progress through the adenoma-to-carcinoma sequence

PubMed Central

Hadac, Jamie N.; Leystra, Alyssa A.; Olson, Terrah J. Paul; Maher, Molly E.; Payne, Susan N; Yueh, Alexander E.; Schwartz, Alexander R.; Albrecht, Dawn M.; Clipson, Linda; Pasch, Cheri A.; Matkowskyj, Kristina A.; Halberg, Richard B.; Deming, Dustin A.

2015-01-01

Human colorectal cancers often possess multiple mutations, including 3–6 driver mutations per tumor. The timing of when these mutations occur during tumor development and progression continues to be debated. More advanced lesions carry a greater number of driver mutations, indicating that colon tumors might progress from adenomas to carcinomas through the stepwise accumulation of mutations following tumor initiation. However, mutations that have been implicated in tumor progression have been identified in normal-appearing epithelial cells of the colon, leaving the possibility that these mutations might be present prior to the initiation of tumorigenesis. We utilized mouse models of colon cancer to investigate whether tumorigenesis still occurs through the adenoma-to-carcinoma sequence when multiple mutations are present at the time of tumor initiation. To create a model in which tumors could concomitantly possess mutations in Apc, Kras, and Pik3ca, we developed a novel minimally invasive technique to administer an adenovirus expressing Cre recombinase to a focal region of the colon. Here we demonstrate that the presence of these additional driver mutations at the time of tumor initiation results in increased tumor multiplicity and an increased rate of progression to invasive adenocarcinomas. These cancers can even metastasize to retroperitoneal lymph nodes or the liver. However, despite having as many as three concomitant driver mutations at the time of initiation, these tumors still proceed through the adenoma-to-carcinoma sequence. PMID:26276752

Importance of histological evaluation in endoscopic resection of early colorectal cancer

PubMed Central

Yoshida, Naohisa; Naito, Yuji; Yagi, Nobuaki; Yanagisawa, Akio

2012-01-01

The diagnostic criteria for colonic intraepithelial tumors vary from country to country. While intramucosal adenocarcinoma is recognized in Japan, in Western countries adenocarcinoma is diagnosed only if the tumor invades to the submucosa and accesses the muscularis mucosae. However, endoscopic therapy, including endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), is used worldwide to treat adenoma and early colorectal cancer. Precise histopathological evaluation is important for the curativeness of these therapies as inappropriate endoscopic therapy causes local recurrence of the tumor that may develop into fatal metastasis. Therefore, colorectal ESD and EMR are not indicated for cancers with massive submucosal invasion. However, diagnosis of cancer with massive submucosal invasion by endoscopy is limited, even when magnifying endoscopy for pit pattern and narrow band imaging and flexible spectral imaging color of enhancement are performed. Therefore, occasional cancers with massive submucosal invasion will be treated by ESD and EMR. Precise histopathological evaluation of these lesions should be performed in order to determine the necessity of additional therapy, including surgical resection. PMID:22532932

Factors Associated with Adenoma Detection Rate and Diagnosis of Polyps and Colorectal Cancer during Colonoscopy in France: Results of a Prospective, Nationwide Survey

PubMed Central

Barret, Maximilien; Boustiere, Christian; Canard, Jean-Marc; Arpurt, Jean-Pierre; Bernardini, David; Bulois, Philippe; Chaussade, Stanislas; Heresbach, Denis; Joly, Isabelle; Lapuelle, Jean; Laugier, René; Lesur, Gilles; Pienkowski, Patrice; Ponchon, Thierry; Pujol, Bertrand; Richard-Molard, Bruno; Robaszkiewicz, Michel; Systchenko, Rémi; Abbas, Fatima; Schott-Pethelaz, Anne-Marie; Cellier, Christophe

2013-01-01

Introduction Colonoscopy can prevent deaths due to colorectal cancer (CRC) through early diagnosis or resection of colonic adenomas. We conducted a prospective, nationwide study on colonoscopy practice in France. Methods An online questionnaire was administered to 2,600 French gastroenterologists. Data from all consecutive colonoscopies performed during one week were collected. A statistical extrapolation of the results to a whole year was performed, and factors potentially associated with the adenoma detection rate (ADR) or the diagnosis of polyps or cancer were assessed. Results A total of 342 gastroenterologists, representative of the overall population of French gastroenterologists, provided data on 3,266 colonoscopies, corresponding to 1,200,529 (95% CI: 1,125,936-1,275,122) procedures for the year 2011. The indication for colonoscopy was CRC screening and digestive symptoms in 49.6% and 38.9% of cases, respectively. Polypectomy was performed in 35.5% of cases. The ADR and prevalence of CRC were 17.7% and 2.9%, respectively. The main factors associated with a high ADR were male gender (p=0.0001), age over 50 (p=0.0001), personal or family history of CRC or colorectal polyps (p<0.0001 and p<0.0001, respectively), and positive fecal occult blood test (p=0.0005). The prevalence of CRC was three times higher in patients with their first colonoscopy (4.2% vs. 1.4%; p<0.0001). Conclusions For the first time in France, we report nationwide prospective data on colonoscopy practice, including histological results. We found an average ADR of 17.7%, and observed reduced CRC incidence in patients with previous colonoscopy. PMID:23874822

Factors associated with adenoma detection rate and diagnosis of polyps and colorectal cancer during colonoscopy in France: results of a prospective, nationwide survey.

PubMed

Barret, Maximilien; Boustiere, Christian; Canard, Jean-Marc; Arpurt, Jean-Pierre; Bernardini, David; Bulois, Philippe; Chaussade, Stanislas; Heresbach, Denis; Joly, Isabelle; Lapuelle, Jean; Laugier, René; Lesur, Gilles; Pienkowski, Patrice; Ponchon, Thierry; Pujol, Bertrand; Richard-Molard, Bruno; Robaszkiewicz, Michel; Systchenko, Rémi; Abbas, Fatima; Schott-Pethelaz, Anne-Marie; Cellier, Christophe

2013-01-01

Colonoscopy can prevent deaths due to colorectal cancer (CRC) through early diagnosis or resection of colonic adenomas. We conducted a prospective, nationwide study on colonoscopy practice in France. An online questionnaire was administered to 2,600 French gastroenterologists. Data from all consecutive colonoscopies performed during one week were collected. A statistical extrapolation of the results to a whole year was performed, and factors potentially associated with the adenoma detection rate (ADR) or the diagnosis of polyps or cancer were assessed. A total of 342 gastroenterologists, representative of the overall population of French gastroenterologists, provided data on 3,266 colonoscopies, corresponding to 1,200,529 (95% CI: 1,125,936-1,275,122) procedures for the year 2011. The indication for colonoscopy was CRC screening and digestive symptoms in 49.6% and 38.9% of cases, respectively. Polypectomy was performed in 35.5% of cases. The ADR and prevalence of CRC were 17.7% and 2.9%, respectively. The main factors associated with a high ADR were male gender (p=0.0001), age over 50 (p=0.0001), personal or family history of CRC or colorectal polyps (p<0.0001 and p<0.0001, respectively), and positive fecal occult blood test (p=0.0005). The prevalence of CRC was three times higher in patients with their first colonoscopy (4.2% vs. 1.4%; p<0.0001). For the first time in France, we report nationwide prospective data on colonoscopy practice, including histological results. We found an average ADR of 17.7%, and observed reduced CRC incidence in patients with previous colonoscopy.

Pi (Spleen)-deficiency syndrome in tumor microenvironment is the pivotal pathogenesis of colorectal cancer immune escape.

PubMed

Sun, Xue-Gang; Lin, Xiao-Chang; Diao, Jian-Xin; Yu, Zhi-Ling; Li, Kun

2016-10-01

Cancer immunoediting consists of three sequential phases: elimination, equilibrium, and escape. For colorectal adenoma-carcinoma sequence, the adenoma dysplastic progression may represent an equilibrium phase and the cancer stage as escape phase. Immune system eliminates transformed enterocytes by destroying them at first, sculpts them at the same time and selects the variants subsequently that are no longer recognized and insensitive to immune effectors, and finally induces immunosuppressive state within the tumor microenvironment that facilitates immune escape and tumor outgrowth. Immunosuppression and inflammation are the two crucial features of Pi (Spleen)-deficiency. Classic quotations, immune evidence and clinical observations suggest that Spleen (but not other organs) deficiency is the key pathogenesis of colorectal cancer (CRC) microenvironment. Weakness of old age, immunosuppressive cytokines from chronic inflammation, tumor-derived immunosuppressive factors and surrendered immune cells-regulatory T cells, myeloid-derived suppressor cells and tumor associated macrophages (TAMs) constitutes CRC microenvironment of Pi-deficiency. Furthermore, excess in superficiality, such as phlegm stagnation, blood stasis and toxin accumulation are induced by chronic inflammation on the basis of asthenia in origin, an immunosuppressive state. Great masters of Chinese medicine emphasize that strengthen Pi is the chief therapeutic principle for CRC which receives good therapeutic effects. So, Pi-deficiency based syndrome is the pivotal pathogenesis of tumor microenvironment. The immunosuppressive microenvironment facilitates immune escape which play an important role in the transition from adenoma to adenocarcinoma. There are some signs that strengthen Pi based treatment has potential capacity to ameliorate tumor environment. It might be a novel starting point to explore the mechanism of strengthen Pi based therapy in the prevention and treatment of CRC through regulation of tumor environment and immunoediting.

Evaluation of a clinical risk index for advanced colorectal neoplasia among a North American population of screening age.

PubMed

Ruco, Arlinda; Stock, David; Hilsden, Robert J; McGregor, S Elizabeth; Paszat, Lawrence F; Saskin, Refik; Rabeneck, Linda

2015-11-19

A clinical risk index employing age, sex, family history of colorectal cancer (CRC), smoking history and body mass index (BMI) may be useful for prioritizing screening with colonoscopy. The aim of this study was to conduct an external evaluation of a previously published risk index for advanced neoplasia (AN) in a large, well-characterized cohort. Five thousand one hundred thirty-seven asymptomatic persons aged 50 to 74 (54.9 % women) with a mean age (SD) of 58.3 (6.2) years were recruited for the study from a teaching hospital and colorectal cancer screening centre between 2003 and 2011. All participants underwent a complete screening colonoscopy and removal of all polyps. AN was defined as cancer or a tubular adenoma, traditional serrated adenoma (TSA), or sessile serrated adenoma (SSA) with villous characteristics (≥25% villous component), and/or high-grade dysplasia and/or diameter ≥10 mm. Risk scores for each participant were summed to derive an overall score (0-8). The c-statistic was used to measure discriminating ability of the risk index. The prevalence of AN in the study cohort was 6.8 %. The likelihood of detecting AN increased from 3.6 to 13.1 % for those with a risk score of 1 to 6 respectively. The c-statistic for the multivariable logistic model in our cohort was 0.64 (95 % CI = 0.61-067) indicating modest overlap between risk scores. The risk index for AN using age, sex, family history, smoking history and BMI was found to be of limited discriminating ability upon external validation. The index requires further refinement to better predict AN in average risk persons of screening age.

The association of physical activity and body mass index with the risk of large bowel polyps.

PubMed

Wallace, Kristin; Baron, John A; Karagas, Margaret R; Cole, Bernard F; Byers, Tim; Beach, Michael A; Pearson, Loretta H; Burke, Carol A; Silverman, William B; Sandler, Robert S

2005-09-01

Several studies have suggested that physical inactivity and obesity increase the risk for colorectal neoplasia. In this study, we investigated the association of physical activity and body mass index (BMI) with the risk of different types of large bowel polyps. We did an observational analysis nested within a randomized double-blind placebo-controlled chemoprevention trial among patients with one or more recently resected histologically confirmed colorectal adenoma. Nine hundred thirty patients were randomized to calcium (1,200 mg/d, as carbonate) or placebo. Follow-up colonoscopies were conducted approximately 1 and 4 years after the qualifying examination. At study entry, we obtained each subject's current body weight and height, which we used to calculate BMI. After the second study colonoscopy, we asked subjects questions about their leisure time physical activity. Seven hundred eighty-seven subjects completed at least part of the physical activity questionnaire. We found no association between measures of physical activity or BMI and tubular adenomas or hyperplastic polyps. However, among men, there were strong inverse associations observed between physical activity and advanced neoplastic polyps. Compared with men whose total daily energy expenditure was in the lowest tertile, those in the highest tertile had a risk ratio of 0.35 (95% confidence interval, 17-0.72); there was no similar reduction observed among women (risk ratio, 1.21; 95% confidence interval, 0.36-4.03; P for interaction = 0.04). We found a significant inverse relationship between several measures of physical activity and risk of advanced colorectal neoplasms, particularly among men. No associations were found between BMI and hyperplastic polyps, tubular adenomas, or advanced neoplastic polyps.

Complex Patterns of Altered MicroRNA Expression during the Adenoma-Adenocarcinoma Sequence for Microsatellite-Stable Colorectal Cancer

PubMed Central

Bartley, Angela N.; Yao, Hui; Barkoh, Bedia A.; Ivan, Cristina; Mishra, Bal M.; Rashid, Asif; Calin, George A.; Luthra, Rajyalakshmi; Hamilton, Stanley R.

2012-01-01

Purpose MicroRNAs are short noncoding RNAs that regulate gene expression and are over- or under-expressed in most tumors, including colorectal adenocarcinoma. MicroRNAs are potential biomarkers and therapeutic targets and agents, but limited information on microRNAome alterations during progression in the well-known adenoma-adenocarcinoma sequence is available to guide their usage. Experimental Design We profiled 866 human microRNAs by microarray analysis in 69 matched specimens of microsatellite-stable adenocarcinomas, adjoining precursor adenomas including areas of high- and low-grade dysplasia, and nonneoplastic mucosa. Results We found 230 microRNAs that were significantly differentially expressed during progression, including 19 not reported previously. Altered microRNAs clustered into two major patterns of early (type I) and late (type II) differential expression. The largest number (n = 108) was altered at the earliest step from mucosa to low-grade dysplasia (subtype IA) prior to major nuclear localization of β-catenin, including 36 microRNAs that had persistent differential expression throughout the entire sequence to adenocarcinoma. Twenty microRNAs were intermittently altered (subtype IB), and six were transiently altered (subtype IC). In contrast, 33 microRNAs were altered late in high-grade dysplasia and adenocarcinoma (subtype IIA), and 63 in adenocarcinoma only (subtype IIB). Predicted targets in 12 molecular pathways were identified for highly altered microRNAs, including the Wnt signaling pathway leading to low-grade dysplasia. β-catenin expression correlated with downregulated microRNAs. Conclusions Our findings suggest that numerous microRNAs play roles in the sequence of molecular events, especially early events, resulting in colorectal adenocarcinoma. The temporal patterns and complexity of microRNAome alterations during progression will influence the efficacy of microRNAs for clinical purposes. PMID:21948089

Regional colorectal cancer screening program using colonoscopy on an island: a prospective Nii-jima study.

PubMed

Hotta, Kinichi; Matsuda, Takahisa; Kakugawa, Yasuo; Ikematsu, Hiroaki; Kobayashi, Nozomu; Kushima, Ryoji; Hozawa, Atsushi; Nakajima, Takeshi; Sakamoto, Taku; Mori, Mika; Fujii, Takahiro; Saito, Yutaka

2017-02-13

Colorectal cancer screening program using fecal immunochemical test had been conducted on an isolated island named Nii-jima. However, the participation rate of the program had been approximately 12%, which was lower than average level of Japan. This study aimed to evaluate the participation rate, safety and efficacy of a colorectal cancer screening program using colonoscopy on the island. Educational campaigns were actively conducted every month using information bulletins and special propaganda pamphlets. The primary recommended modality was colonoscopy, followed by fecal immunochemical test. The participants of this program were 1671 individuals aged 40–79 years (men, 819; women, 852). A total of 789 (47.2%) individuals provided consent for this screening program, and 89.2% (704/789) of participants chose colonoscopy as the primary screening procedure. The completion rate of total colonoscopy was 99.7%, and there was no complication during this program. Detection rates of invasive cancer, intramucosal cancer, advanced neoplasia and any adenoma were 0.9% (n = 6), 2.4% (n = 17), 11.8% (n = 83) and 50.0% (n = 352), respectively. The adenoma detection rate and incidence of advanced neoplasia were significantly higher in men than in women in all age groups. The colorectal cancer screening program using colonoscopy that was conducted on an island achieved considerably higher participation rate than the conventional screening program using fecal immunochemical test. Completion rate and safety of screening colonoscopy were excellent during this program.

β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis

PubMed Central

Cai, Jing; Maitra, Anirban; Anders, Robert A.; Taketo, Makoto M.; Pan, Duojia

2015-01-01

Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the β-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo–YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the β-catenin destruction complex. PMID:26193883

Colorectal laterally spreading tumors show characteristic expression of cell polarity factors, including atypical protein kinase C λ/ι, E-cadherin, β-catenin and basement membrane component.

PubMed

Ichikawa, Yasushi; Nagashima, Yoji; Morioka, Kaori; Akimoto, Kazunori; Kojima, Yasuyuki; Ishikawa, Takashi; Goto, Ayumu; Kobayashi, Noritoshi; Watanabe, Kazuteru; Ota, Mitsuyoshi; Fujii, Shoichi; Kawamata, Mayumi; Takagawa, Ryo; Kunizaki, Chikara; Takahashi, Hirokazu; Nakajima, Atsushi; Maeda, Shin; Shimada, Hiroshi; Inayama, Yoshiaki; Ohno, Shigeo; Endo, Itaru

2014-09-01

Colorectal flat-type tumors include laterally spreading tumors (LSTs) and flat depressed-type tumors. The former of which shows a predominant lateral spreading growth rather than an invasive growth. The present study examined the morphological characteristics of LSTs, in comparison with polypoid- or flat depressed-type tumors, along with the expression of atypical protein kinase C (aPKC) λ/ι, a pivotal cell polarity regulator, and the hallmarks of cell polarity, as well as with type IV collagen, β-catenin and E-cadherin. In total, 37 flat-type (24 LSTs and 13 flat depressed-type tumors) and 20 polypoid-type colorectal tumors were examined. The LSTs were classified as 15 LST adenoma (LST-A) and nine LST cancer in adenoma (LST-CA). An immunohistochemical examination was performed on aPKC λ/ι, type IV collagen, β-catenin and E-cadherin. The LST-A and -CA showed a superficial replacing growth pattern, with expression of β-catenin and E-cadherin in the basolateral membrane and type IV collagen along the basement membrane. In addition, 86.6% of LST-A and 55.6% of LST-CA showed aPKC λ/ι expression of 1+ (weak to normal intensity staining in the cytoplasm compared with the normal epithelium). Furthermore, ~45% of the polypoid-type adenomas showed 2+ (moderate intensity staining in the cytoplasm and/or nucleus) and 66.7% of the polypoid-type cancer in adenoma were 3+ (strong intensity staining in the cytoplasm and nucleus). A statistically significant positive correlation was observed between the expression of aPKC λ/ι and β-catenin (r=0.842; P<0.001), or type IV collagen (r=0.823; P<0.001). The LSTs showed a unique growth pattern, different from the expanding growth pattern presented by a polypoid tumor and invasive cancer. The growth characteristics of LST appear to be caused by adequate coexpression of β-catenin, type IV collagen and aPKC λ/ι.

APC hypermethylation for early diagnosis of colorectal cancer: a meta-analysis and literature review.

PubMed

Liang, Tie-Jun; Wang, Hong-Xu; Zheng, Yan-Yan; Cao, Ying-Qing; Wu, Xiaoyu; Zhou, Xin; Dong, Shu-Xiao

2017-07-11

Adenomatous polyposis coli (APC) promoter hypermethylation has been frequently observed in colorectal cancer (CRC). The association between APC promoter methylation and clinicopathological significance in CRC is under investigation. We performed a meta-analysis to quantitatively evaluate the significance of APC methylation in CRC. The study included a total of 24 articles and 2025 CRC patients. The frequency of APC promoter hypermethylation was significantly higher in colorectal adenoma than in normal colorectal tissue, OR was 5.76, 95% CI, 2.45-13.56; p<0.0001, I2=0%. APC promoter more frequently hypermethylated in CRC stage I compared to normal colorectal tissue, OR was 13.42, 95% CI, 3.66-49.20; p<0.0001, I2=31%. The risk of incidence of CRC was significantly correlated to APC promoter hypermethylation, pooled OR was 9.80, 95%CI, 6.07-15.81; p<0.00001, I2=43%. APC methylation was not associated with grade, stage of CRC as well as tumor location, patients' gender, and smoking behavior. The results indicate that APC promoter hypermethylation is an early event in carcinogenesis of CRC, could be a valuable diagnostic marker for early-stage CRC. APC methylation is not significantly associated with overall survival in patients with CRC. APC is a potential drug target for development of personalized treatment.

Impact of screening colonoscopy on outcomes in colorectal cancer.

PubMed

Matsuda, Takahisa; Ono, Akiko; Kakugawa, Yasuo; Matsumoto, Minori; Saito, Yutaka

2015-10-01

Colorectal cancer is one of the most common cancers in both men and women worldwide and a good candidate for screening programs. There are two modalities of colorectal cancer screening: (i) population-based screening and (ii) opportunistic screening. The first one is based on organized, well-coordinated, monitored and established programs with a systematic invitation covering the entire target population. In contrast, opportunistic screening tests are offered to people who are being examined for other reasons. Recently, a variety of colorectal cancer screening tests have become available; each country should make a choice, based on national demographics and resources, on the screening method to be used. Fecal occult blood test, especially the fecal immunochemical test, would be the best modality for decreasing colorectal cancer mortality through population-based screening. In contrast, if the aim includes the early detection of colorectal cancer and adenomas, endoscopic methods are more appropriate. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas.

PubMed

Sekine, Shigeki; Ogawa, Reiko; Hashimoto, Taiki; Motohiro, Kojima; Yoshida, Hiroshi; Taniguchi, Hirokazu; Saito, Yutaka; Yasuhiro, Ohno; Ochiai, Atsushi; Hiraoka, Nobuyoshi

2017-10-01

Traditional serrated adenoma (TSA) is a rare but distinct type of colorectal polyp. Our previous study showed that PTPRK-RSPO3 fusions are frequent and characteristic genetic alterations in TSAs. This study aimed to characterize comprehensively the prevalence and variability of RSPO fusions in colorectal TSAs. We examined RSPO expression and explored novel RSPO fusions in 129 TSAs, including 66 lesions analysed previously for WNT pathway gene mutations. Quantitative polymerase chain reaction (qPCR) analyses identified three and 43 TSAs overexpressing RSPO2 and RSPO3, respectively, whereas the expression of RSPO1 and RSPO4 was marginal or undetectable in all cases. RSPO overexpression was always mutually exclusive with other WNT pathway gene mutations. Known PTPRK-RSPO3 fusions were detected in 37 TSAs, all but one of which overexpressed RSPO3. In addition, rapid amplification of cDNA ends revealed three novel RSPO fusion transcripts, an NRIP1-RSPO2 fusion and two PTPRK-RSPO3 fusion isoforms, in six TSAs. Overall, 43 TSAs had RSPO fusions (33%), whereas four TSAs (3%) overexpressed RSPO in the absence of RSPO fusions. TSAs with RSPO fusions showed several clinicopathological features, including distal localization (P = 0.0063), larger size (P = 0.0055), prominent ectopic crypt foci (P = 8.4 × 10 -4 ), association of a high-grade component (P = 1.1 × 10 -4 ), and the presence of KRAS mutations (P = 4.5 × 10 -5 ). The present study identified RSPO fusion transcripts, including three novel transcripts, in one-third of colorectal TSAs and showed that PTPRK-RSPO3 fusions were the predominant cause of RSPO overexpression in colorectal TSA. © 2017 John Wiley & Sons Ltd.

Pattern of cell kinetics in colorectal mucosa of patients with different types of adenomatous polyps of the large bowel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roncucci, L.; Scalmati, A.; Ponz de Leon, M.

1991-08-15

It is generally accepted that adenomatous polyps represent the natural precursor of many colorectal malignancies. The sequence, however, which leads from a normally appearing mucosa to cancer is complex and involves many steps, including a hyperproliferative mucosa with an upward expansion of the replicative compartment. The current study evaluates cell replication in normal colorectal mucosa of patients with adenomatous polyps of various types and relates the observed findings to the main clinical and morphologic features of adenomas. Forty-four patients with polyps and 27 controls entered the study. Samples of colorectal mucosa were taken at endoscopy and cell replication was evaluatedmore » with a standard autoradiographic procedure. Cell replication was expressed as labeling index (LI), in the whole crypt and in each of the five longitudinal compartments in which the crypts were divided. Total LI and LI per crypt compartment were significantly higher (P less than 0.02 and P less than 0.01, respectively) than in controls. There was no appreciable difference of LI values between patients with single or multiple, tubular or tubulovillous, small or large adenomas, but in all of these subgroups LI was significantly higher than in controls. In conclusion, in normally appearing colorectal mucosa of patients with adenomatous polyps there was a significant increase of cell replication and a marked upward expansion of the proliferative zone; these changes were more evident in the left colon and in the rectum. Finally, cell replication did not seem to be related to the number of polyps, to the most common histotypes, or to the pattern of recurrence.« less

Effects of calcium and vitamin D supplementation on crypt morphology in normal colon mucosa: A randomized clinical trial.

PubMed

Shen, Huafeng; Ahearn, Thomas U; Bostick, Roberd M

2015-03-01

Calcium and vitamin D modify the molecular phenotypic profiles of colon crypts in the normal colorectal mucosa of colorectal adenoma patients, but their effects on crypt morphology (length, perimeter, and area) are unknown. We analyzed data from a previously conducted pilot, randomized, double-blind, placebo-controlled 2 × 2 factorial chemoprevention clinical trial of supplemental calcium 2000 mg/d and vitamin D3 800 IU/d, alone and in combination, versus placebo over 6 mo. Colorectal crypt length, perimeter, and area in the normal-appearing rectal mucosa were quantified by image analysis. The mean crypt length increased by 1% (P=0.92) in the calcium group, and decreased by 2% (P=0.69) and 4% (P=0.40) in the vitamin D and calcium plus vitamin D groups, respectively, relative to the placebo group. The mean crypt perimeter decreased by 2% (P=0.70) and 4% (P=0.40) in the vitamin D and calcium plus vitamin D groups, respectively, relative to the placebo group, but did not change appreciably in the calcium group. The mean crypt area decreased by 2% (P=0.74), 5% (P=0.41) and 7% (P=0.30) in the calcium, vitamin D and calcium plus vitamin D groups, respectively, relative to the placebo group. Calcium and/or vitamin D3 supplementation do not appear to appreciably change crypt morphology in the normal colorectal mucosa of sporadic adenoma patients. These results, taken together with previous findings, support the use of molecular phenotypic over morphologic pre-neoplastic biomarkers of risk for colorectal neoplasms. © 2013 Wiley Periodicals, Inc.

WNT signaling controls expression of pro-apoptotic BOK and BAX in intestinal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeilstra, Jurrit; Joosten, Sander P.J.; Wensveen, Felix M.

Research highlights: {yields} Intestinal adenomas initiated by aberrant activation of the WNT pathway displayed an increased sensitivity to apoptosis. {yields} Expression profiling of apoptosis-related genes in Apc{sup Min/+} mice revealed the differential expression of pro-apoptotic Bok and Bax. {yields} APC-mutant adenomatous crypts in FAP patients showed strongly increased BAX immunoreactivity. {yields} Blocking of {beta}-catenin/TCF-4-mediated signaling in colon cancer cells reduced the expression of BOK and BAX. -- Abstract: In a majority of cases, colorectal cancer is initiated by aberrant activation of the WNT signaling pathway. Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or {beta}-catenin causesmore » constitutively active {beta}-catenin/TCF-mediated transcription, driving the transformation of intestinal crypts to cancer precursor lesions, called dysplastic aberrant crypt foci. Deregulated apoptosis is a hallmark of adenomatous colon tissue. However, the contribution of WNT signaling to this process is not fully understood. We addressed this role by analyzing the rate of epithelial apoptosis in aberrant crypts and adenomas of the Apc{sup Min/+} mouse model. In comparison with normal crypts and adenomas, aberrant crypts displayed a dramatically increased rate of apoptotic cell death. Expression profiling of apoptosis-related genes along the crypt-villus axis and in Apc mutant adenomas revealed increased expression of two pro-apoptotic Bcl-2 family members in intestinal adenomas, Bok and Bax. Analysis of the colon of familial adenomatous polyposis (FAP) patients along the crypt-to-surface axis, and of dysplastic crypts, corroborated this expression pattern. Disruption of {beta}-catenin/TCF-4-mediated signaling in the colorectal cancer cell line Ls174T significantly decreased BOK and BAX expression, confirming WNT-dependent regulation in intestinal epithelial cells. Our results suggest a feedback mechanism by which uncontrolled epithelial cell proliferation in the stem cell compartment can be counterbalanced by an increased propensity to undergo cell death.« less

Cancer emerging from the recurrence of sessile serrated adenoma/polyp resected endoscopically 5 years ago.

PubMed

Chino, A; Nagayama, S; Ishikawa, H; Morishige, K; Kishihara, T; Arai, M; Sugiura, Y; Motoi, N; Yamamoto, N; Tamegai, Y; Igarashi, M

2016-01-01

Since the serrated neoplastic pathway has been regarded as an important pathway of colorectal carcinogenesis, few reports have been published on clinical cases of cancer derived from sessile serrated adenoma/polyp, especially on recurrence after resected sessile serrated adenoma/polyp. An elderly woman underwent endoscopic mucosal resection of a flat elevated lesion, 30 mm in diameter, in the ascending colon; the histopathological diagnosis at that time was a hyperplastic polyp, now known as sessile serrated adenoma/polyp. Five years later, cancer due to the malignant transformation of the sessile serrated adenoma/polyp was detected at the same site. The endoscopic diagnosis was a deep invasive carcinoma with a remnant sessile serrated adenoma/polyp component. The carcinoma was surgically removed, and the pathological diagnosis was an adenocarcinoma with sessile serrated adenoma/polyp, which invaded the muscularis propria. The surgically removed lesion did not have a B-RAF mutation in either the sessile serrated adenoma/polyp or the carcinoma; moreover, the initial endoscopically resected lesion also did not have a B-RAF mutation. Immunohistochemistry confirmed negative MLH1 protein expression in only the cancer cells. Lynch syndrome was not detected on genomic examination. The lesion was considered to be a cancer derived from sessile serrated adenoma/polyp recurrence after endoscopic resection, because both the surgically and endoscopically resected lesions were detected at the same location and had similar pathological characteristics, with a serrated structure and low-grade atypia. Furthermore, both lesions had a rare diagnosis of a sessile serrated adenoma/polyp without B-RAF mutation. This report highlights the need for the follow-up colonoscopy after endoscopic resection and rethinking our resection procedures to improve treatment. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Development and validation of quality standards for colonoscopy].

PubMed

Sánchez Del Río, Antonio; Baudet, Juan Salvador; Naranjo Rodríguez, Antonio; Campo Fernández de Los Ríos, Rafael; Salces Franco, Inmaculada; Aparicio Tormo, Jose Ramón; Sánchez Muñoz, Diego; Llach, Joseph; Hervás Molina, Antonio; Parra-Blanco, Adolfo; Díaz Acosta, Juan Antonio

2010-01-30

Before starting programs for colorectal cancer screening it is necessary to evaluate the quality of colonoscopy. Our objectives were to develop a group of quality indicators of colonoscopy easily applicable and to determine the variability of their achievement. After reviewing the bibliography we prepared 21 potential indicators of quality that were submitted to a process of selection in which we measured their facial validity, content validity, reliability and viability of their measurement. We estimated the variability of their achievement by means of the coefficient of variability (CV) and the variability of the achievement of the standards by means of chi(2). Six indicators overcome the selection process: informed consent, medication administered, completed colonoscopy, complications, every polyp removed and recovered, and adenoma detection rate in patients older than 50 years. 1928 colonoscopies were included from eight endoscopy units. Every unit included the same number of colonoscopies selected by means of simple random sampling with substitution. There was an important variability in the achievement of some indicators and standards: medication administered (CV 43%, p<0.01), complications registered (CV 37%, p<0.01), every polyp removed and recovered (CV 12%, p<0.01) and adenoma detection rate in older than fifty years (CV 2%, p<0.01). We have validated six quality indicators for colonoscopy which are easily measurable. An important variability exists in the achievement of some indicators and standards. Our data highlight the importance of the development of continuous quality improvement programmes for colonoscopy before starting colorectal cancer screening. Copyright (c) 2009 Elsevier España, S.L. All rights reserved.

Circulating Biomarkers of Gut Barrier Function: Correlates and Nonresponse to Calcium Supplementation among Colon Adenoma Patients.

PubMed

Yang, Baiyu; Bostick, Roberd M; Tran, Hao Quang; Gewirtz, Andrew T; Campbell, Peter T; Fedirko, Veronika

2016-02-01

Gut barrier dysfunction contributes to several gastrointestinal disorders, including colorectal cancer, but factors associated with intestinal hyperpermeability have been minimally studied in humans. We tested the effects of two doses of calcium (1.0 or 2.0 g/d) on circulating biomarkers of gut permeability [anti-flagellin and anti-lipopolysaccharide (LPS) Ig, measured via ELISA] over a 4-month treatment period among colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193), and evaluated the factors associated with baseline levels of these biomarkers. Baseline concentrations of anti-flagellin IgA and anti-LPS IgA were, respectively, statistically significantly proportionately higher by 11.8% and 14.1% among men, 31.3% and 39.8% among those with a body mass index ≥ 35 kg/m(2), and 19.9% and 22.0% among those in the upper relative to the lowest sex-specific tertile of waist circumference. A combined permeability score (the summed optical densities of all four biomarkers) was 24.3% higher among women in the upper tertile of plasma C-reactive protein (Ptrend < 0.01). We found no appreciable effects of supplemental calcium on anti-flagellin or anti-LPS Igs. Our results suggest that (i) men and those with higher adiposity may have greater gut permeability, (ii) gut permeability and systemic inflammation may be directly associated with one another, and (iii) supplemental calcium may not modify circulating levels of gut permeability biomarkers within 4 months. Our findings may improve the understanding of the factors that influence gut permeability to inform development of treatable biomarkers of risk for colorectal cancer and other health outcomes. ©2015 American Association for Cancer Research.

N-Acetyltransferase Polymorphism and Risk of Colorectal Adenoma and Cancer: A Pooled Analysis of Variations from 59 Studies

PubMed Central

Wang, Xiaoxue; Chen, Yizhi; Li, Rong; Zhang, Ying; Luo, Rongcheng

2012-01-01

Background There have been an increasing number of studies with evidence suggesting that the N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) genotypes may be implicated in the development of colorectal cancer (CRC) and colorectal adenoma (CRA). So far the published data on this association has remained controversial, however. We performed a meta-analysis of case-cohort and case-control studies using a subset of the published data, with an aim to derive a better understanding of the underlying relationship. Methods/Principal Findings A literature search was performed using Medline database for relevant studies published through October 31, 2011. A total of 39 publications were selected for this meta-analysis, including 11,724 cases and 16,215 controls for CRC, and 3,701 cases and 5,149 controls for CRA. In our pooled analysis of all these studies, the results of our meta-analysis suggested that the NAT1 genotype was not significantly associated with an elevated CRC risk (OR 0.99, 95% CI 0.91–1.07). We also found that individuals with the rapid NAT2 genotype did have an elevated risk of CRC (OR 1.07, 95% CI 1.01–1.13). There was no evidence for an association between the NAT1 and 2 rapid genotype and an elevated CRA risk (NAT1: OR 1.14, 95% CI 0.99–1.29; NAT2: OR 0.94, 95% CI 0.86–1.03). Conclusion This meta-analysis suggests that individuals with NAT2 genotype had an elevated risk of CRC. There was no evidence for the association between NAT1 and 2 rapid genotype and CRA risk. PMID:22905173

The Stool DNA Test is More Accurate than the Plasma Septin 9 Test in Detecting Colorectal Neoplasia

PubMed Central

Ahlquist, David A.; Taylor, William R.; Mahoney, Douglas W.; Zou, Hongzhi; Domanico, Michael; Thibodeau, Stephen N.; Boardman, Lisa A.; Berger, Barry M.; Lidgard, Graham P.

2014-01-01

Background & Aims Several noninvasive tests have been developed for colorectal cancer (CRC) screening. We compared the sensitivities of a multi-marker test for stool DNA (sDNA) and a plasma test for methylated Septin 9 (SEPT9) in identifying patients with large adenomas or CRC. Methods We analyzed paired stool and plasma samples from 30 patients with CRC and 22 with large adenomas from Mayo Clinic archives. Stool (n=46) and plasma (n=49) samples from age- and sex-matched patients with normal colonoscopy results were used as controls. The sDNA test is an assay for methylated BMP3, NDRG4, vimentin, and TFPI2; mutant KRAS; the β-actin gene, and quantity of hemoglobin (by the porphyrin method). It was performed blindly at Exact Sciences (Madison WI); the test for SEPT9 was performed at ARUP Laboratories (Salt Lake City UT). Results were considered positive based on the manufacturer's specificity cutoff values of 90% and 89%, respectively. Results The sDNA test detected adenomas (median 2 cm, range 1–5 cm) with 82% sensitivity (95% confidence interval [CI], 60%–95%); SEPT9 had 14% sensitivity (95% CI, 3%–35%; P=.0001). The sDNA test identified patients with CRC with 87% sensitivity (95% CI, 69%–96%); SEPT9 had 60% sensitivity (95% CI, 41%–77%; P=.046). The sDNA test identified patients with stage I–III CRC with 91% sensitivity (95% CI, 71%–99%); SEPT9 had 50% sensitivity (95% CI, 28%–72%; P=.013); for stage IV CRC, sensitivity values were 75% (95% CI, 35%–97%) and 88% (95% CI, 47%–100%), respectively (P=.56). False-positive rates were 7% for the sDNA test and 27% for SEPT9. Conclusions Based on analyses of paired samples, the sDNA test detects non-metastatic CRC and large adenomas with significantly greater levels of sensitivity than the SEPT9 test. These findings might be used to modify approaches for CRC prevention and early detection. PMID:22019796

Predictive cytogenetic biomarkers for colorectal neoplasia in medium risk patients

PubMed Central

Ionescu, EM; Nicolaie, T; Ionescu, MA; Becheanu, G; Andrei, F; Diculescu, M; Ciocirlan, M

2015-01-01

Rationale: DNA damage and chromosomal alterations in peripheral lymphocytes parallels DNA mutations in tumor tissues. Objective: The aim of our study was to predict the presence of neoplastic colorectal lesions by specific biomarkers in “medium risk” individuals (age 50 to 75, with no personal or family of any colorectal neoplasia). Methods and Results: We designed a prospective cohort observational study including patients undergoing diagnostic or opportunistic screening colonoscopy. Specific biomarkers were analyzed for each patient in peripheral lymphocytes - presence of micronuclei (MN), nucleoplasmic bridges (NPB) and the Nuclear Division Index (NDI) by the cytokinesis-blocked micronucleus assay (CBMN). Of 98 patients included, 57 were “medium risk” individuals. MN frequency and NPB presence were not significantly different in patients with neoplastic lesions compared to controls. In “medium risk” individuals, mean NDI was significantly lower for patients with any neoplastic lesions (adenomas and adenocarcinomas, AUROC 0.668, p 00.5), for patients with advanced neoplasia (advanced adenoma and adenocarcinoma, AUROC 0.636 p 0.029) as well as for patients with adenocarcinoma (AUROC 0.650, p 0.048), for each comparison with the rest of the population. For a cut-off of 1.8, in “medium risk” individuals, an NDI inferior to that value may predict any neoplastic lesion with a sensitivity of 97.7%, an advanced neoplastic lesion with a sensitivity of 97% and adenocarcinoma with a sensitivity of 94.4%. Discussion: NDI score may have a role as a colorectal cancer-screening test in “medium risk” individuals. Abbreviations: DNA = deoxyribonucleic acid; CRC = colorectal cancer; EU = European Union; WHO = World Health Organization; FOBT = fecal occult blood test; CBMN = cytokinesis-blocked micronucleus assay; MN = micronuclei; NPB = nucleoplasmic bridges; NDI = Nuclear Division Index; FAP = familial adenomatous polyposis; HNPCC = hereditary non-polypoid colorectal cancer; IBD = inflammatory bowel diseases; ROC = receiver operating characteristics; AUROC = area under the receiver operating characteristics curve. PMID:26351547

The first 2 years of colorectal cancer screening in Ferrara, Italy.

PubMed

Matarese, Vincenzo G; Feo, Carlo Vittorio; Lanza, Giovanni; Fusetti, Nadia; Carpanelli, Maria Cristina; Cataldo, Serena; Cifalà, Viviana; Ferretti, Stefano; Gafà, Roberta; Marzola, Marina; Montanari, Enrica; Palmonari, Caterina; Simone, Loredana; Trevisani, Lucio; Stockbrugger, Reinhold; Gullini, Sergio

2011-05-01

We report on the first screening round in the District of Ferrara, a region of Emilia-Romagna, carried out between March 2005 and March 2007 to illustrate the effort of colorectal cancer (CRC) screening from administration and information to therapy and follow-up. After invitation of 38 344 persons aged 50-69 years (28.5%), 19 480 (50.8%) accepted the immunological faecal occult blood test, with 1 149 (6%) resulting positive. One thousand and one individuals (88.2%) who tested positive for immunological faecal occult blood test accepted examination by either colonoscopy (99.5%) or barium enema (0.5%). Out of 996 screenees having a colonoscopy, 231 had low-risk adenomas (23.2%) and 239 had high-risk adenomas (24%), and were treated endoscopically (96%) or surgically (4%). Ninety-one cancers were diagnosed in 9.1% of colonoscopies (Dukes stadia: A, 58.2%; B, 19.8%; C, 18.7%; D, 3.3%). Fourteen cancers (all in polyps) were treated endoscopically, and the remaining 77 were treated by surgery. One Dukes B patient and 13 of 17 Dukes C patients received adjuvant chemotherapy. Three Dukes D patients had chemotherapy only. During the 2-year study period, 87 screenees had a follow-up colonoscopy: no neoplasia was found in 35 patients initially diagnosed with cancer; low-risk adenomas were found in 31 of 52 patients with initial high-risk adenomas. In conclusion, the first CRC screening round in Ferrara was easy to organize, had a high acceptance, and detected 91 cancers (78% of which were in Dukes stages A and B, compared with only 40% in sporadic CRC in the same background population). Chemotherapy was necessary in 17 cases. This report may motivate other health authorities to initiate CRC screening campaigns.

Metformin therapy and the risk of colorectal adenoma in patients with type 2 diabetes: A meta-analysis

PubMed Central

Hou, Yi-Chao; Hu, Qiang; Huang, Jiao; Fang, Jing-Yuan; Xiong, Hua

2017-01-01

Background Existing data evaluating the impact of metformin on the colorectal adenoma (CRA) risk in patients suffering from type 2 diabetes (T2D) are limited and controversial. We therefore summarized the studies currently available and assessed the relationship between metformin treatment and risk of CRA in T2D patients. Methods We systematically searched databases for eligible studies that explored the impact of metformin treatment on the occurrence of CRA in T2D patients from inception to June 2016. The summary odds ratio (OR) estimates with their 95% confidence interval (CI) were derived using random-effect, generic inverse variance methods. Sensitivity analysis and subgroup analysis were performed. Results Seven studies involving 7178 participants met the inclusion criteria. The pooling showed that metformin therapy has a 27% decrease in the CRA risk (OR, 0.73; 95% CI, 0.58 - 0.90). In subgroup analysis, we detected that metformin exhibits significant chemoprevention effects in Asia region (OR, 0.68; 95% CI, 0.48 - 0.96). Similar results were identified in both studies with adjusted ORs and high-quality studies (OR, 0.66; 95% CI, 0.50 - 0.86 and OR, 0.70; 95% CI, 0.58 - 0.84, respectively). Of note, an inverse relationship was noted that metformin therapy may result in a significant decrease in the advanced adenoma risk (OR, 0.52; 95% CI, 0.38 - 0.72). Low heterogeneity was observed, however, the results remained robust in multiplesensitivity analyses. Conclusions This meta-analysis indicates that metformin therapy is correlated with a significant decrease in the risk of CRA and advanced adenoma in T2D patients. Further confirmatory studies are warranted. PMID:27903961

[Serrated polyps and their association with synchronous advanced colorectal neoplasia].

PubMed

Urman, Jesús; Gomez, Marta; Basterra, Marta; Mercado, María Del Rosario; Montes, Marta; Gómez Dorronsoro, Marisa; Garaigorta, Maitane; Fraile, María; Rubio, Eva; Aisa, Gregorio; Galbete, Arkaitz

2016-11-01

Large serrated polyps (SP), proximal SP, SP with dysplasia and the presence of multiple sessile serrated adenomas/polyps (SSA/P), which we refer to as SP with increased risk of metachronous lesions (SPIRML), have been associated with an increased risk of advanced colon lesions on follow-up. It is unclear, however, whether SPIRML are also associated with an increased risk of synchronous advanced colorectal neoplasia (ACN). The aim of this study was to estimate the prevalence of SPIRML and to evaluate the association between SPIRML and synchronous ACN. A cross-sectional population-based study in all patients (1,538) with histological diagnosis of SP obtained from colonoscopies, sigmoidoscopies and colonic surgery performed in Navarra Health Service hospitals (Spain) in 2011. Demographic parameters and synchronous colonic lesions (adenomas, advanced adenomas [AA] and ACN) were analyzed. One fourth of the sample (384 patients) presented SPIRML. These were older patients, with a slight predominance of women, and with no differences in body mass index (BMI) compared to patients without SPIRML. In the univariate analysis, patients with SPIRML showed an increased risk of adenoma, AA and ACN. In the multivariate analysis, the SPIRML group had a higher risk of synchronous AA and ACN (odds ratio [OR]: 2.38 [1.77-3.21] and OR: 2.29 [1.72-3.05], respectively); in the case of ACN, this risk was statistically significant in both locations (proximal or distal), with OR slightly higher for the proximal location. Different subtypes of SPIRML had a higher risk of AA and synchronous NA. SPIRML were common in patients with SP, and their presence was associated with an increased risk of synchronous ACN. Copyright © 2016 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

Atrial Fibrillation and Colonic Neoplasia in African Americans.

PubMed

Nouraie, Mehdi; Kansal, Vandana; Belfonte, Cassius; Ghazvini, Mohammad; Haidari, Tahmineh; Shahnazi, Anahita; Brim, Hassan; Soliman, Elsayed Z; Ashktorab, Hassan

2015-01-01

Colorectal cancer (CRC) and atrial fibrillation/flutter (AF) share several risk factors including increasing age and obesity. However, the association between CRC and AF has not been thoroughly examined, especially in African Americans. In this study we aimed to assess the prevalence of AF and its risk factors in colorectal neoplasia in an African American. We reviewed records of 527 African American patients diagnosed with CRC and 1008 patients diagnosed with benign colonic lesions at Howard University Hospital from January 2000 to December 2012. A control group of 731 hospitalized patients without any cancer or colonic lesion were randomly selected from the same time and age range, excluding patients who had diagnosis of both CRC and/or adenoma. The presence or absence of AF was based upon ICD-9 code documentation. The prevalence of AF in these three groups was compared by multivariate logistic regression. The prevalence of AF was highest among CRC patients (10%) followed by adenoma patients (7.2%) then the control group (5.4%, P for trend = 0.002). In the three groups of participants, older age (P<0.008) and heart failure (P<0.001) were significantly associated with higher risk of AF. After adjusting for these risk factors, CRC (OR: 1.4(95%CI):0.9-2.2, P = 0.2) and adenoma (OR: 1.1(95%CI):0.7-1.6, P = 0.7) were not significantly associated AF compared to control group. AF is highly prevalent among CRC patients; 1 in 10 patients had AF in our study. The predictors of AF in CRC was similar to that in adenoma and other patients after adjustment for potential confounders suggesting that the increased AF risk in CRC is explained by higher prevalence of AF risk factors.

[Analysis of community colorectal cancer screening in 50-74 years old people in Guangzhou, 2015-2016].

PubMed

Li, Y; Liu, H Z; Liang, Y R; Lin, G Z; Li, K; Dong, H; Xu, H; Wang, M

2018-01-10

Objective: To analyze the effect of colorectal cancer screening in the general population in Guangzhou, and provide evidence for the for development of colorectal cancer screening policy and strategy. Methods: The data of colorectal cancer screening in Guangzhou during 2015- 2016 were collected. The participation, the positive rate of fecal occult blood test, the detection rate of colonoscopy and screening effect of colonoscopy were evaluated. Results: A total of 220 834 residents aged 50-74 years received the screening, and the positive rate of the screening was 16.77% (37 040 cases). Colonoscopy was performed for 7 821 cases (21.12%). Colorectal lesions were found in 4 126 cases (52.76%), of which 614 (7.85%) and 73 (0.93%) and 230 (2.94%) were identified as advanced adenoma, severe dysplasia lesions and colorectal cancers, respectively. The detection rates of all colorectal lesions were higher in men than in women (all P <0.01). The diagnostic rate of early lesion was 87.24%, and 99 early cancer cases were found, accounting for 46.26% of the total cases. The overall screening detection rate of colorectal cancer was 104.15/100 000, higher than the incidence rate (81.18/100 000) in colorectal cancer surveillance ( P <0.001), but age group <70 years had higher detection rate, age group ≥70 years had higher incidence rate. Conclusions: The colorectal cancer screening strategy in Guangzhou is effective in the detection of the population at high risk, increase the detection rate of colorectal lesions, early diagnosis rate of precancerous lesions and diagnosis rate of early colorectal cancer. The benefit in those aged ≤69 years was more obvious than that in those aged 70-74 years. It is necessary to improve the compliancy of colorectal cancer screening in population at high risk.

Prospective evaluation of 64 serum autoantibodies as biomarkers for early detection of colorectal cancer in a true screening setting.

PubMed

Chen, Hongda; Werner, Simone; Butt, Julia; Zörnig, Inka; Knebel, Phillip; Michel, Angelika; Eichmüller, Stefan B; Jäger, Dirk; Waterboer, Tim; Pawlita, Michael; Brenner, Hermann

2016-03-29

Novel blood-based screening tests are strongly desirable for early detection of colorectal cancer (CRC). We aimed to identify and evaluate autoantibodies against tumor-associated antigens as biomarkers for early detection of CRC. 380 clinically identified CRC patients and samples of participants with selected findings from a cohort of screening colonoscopy participants in 2005-2013 (N=6826) were included in this analysis. Sixty-four serum autoantibody markers were measured by multiplex bead-based serological assays. A two-step approach with selection of biomarkers in a training set, and validation of findings in a validation set, the latter exclusively including participants from the screening setting, was applied. Anti-MAGEA4 exhibited the highest sensitivity for detecting early stage CRC and advanced adenoma. Multi-marker combinations substantially increased sensitivity at the price of a moderate loss of specificity. Anti-TP53, anti-IMPDH2, anti-MDM2 and anti-MAGEA4 were consistently included in the best-performing 4-, 5-, and 6-marker combinations. This four-marker panel yielded a sensitivity of 26% (95% CI, 13-45%) for early stage CRC at a specificity of 90% (95% CI, 83-94%) in the validation set. Notably, it also detected 20% (95% CI, 13-29%) of advanced adenomas. Taken together, the identified biomarkers could contribute to the development of a useful multi-marker blood-based test for CRC early detection.

Referring patients to nurses: Outcomes and evaluation of a nurse flexible sigmoidoscopy training program for colorectal cancer screening

PubMed Central

Dobrow, Mark J; Cooper, Mary Anne; Gayman, Karen; Pennington, Jason; Matthews, Joanne; Rabeneck, Linda

2007-01-01

Colorectal cancer is a significant health burden. Several screening options exist that can detect colorectal cancer at an early stage, leading to a more favourable prognosis. However, despite years of knowledge on best practice, screening rates are still very low in Canada, particularly in Ontario. The present paper reports on efforts to increase the flexible sigmoidoscopy screening capacity in Ontario by training nurses to perform this traditionally physician-performed procedure. Drawing on American, British and local experience, a professional regulatory framework was established, and training curriculum and assessment criteria were developed. Training was initiated at Princess Margaret Hospital and Sunnybrook and Women’s College Health Sciences Centre in Toronto, Ontario. (During the study, Sunnybrook and Women’s College Health Sciences Centre was deamalgamated into two separate hospitals: Women’s College Hospital and Sunnybrook Health Sciences Centre.) Six registered nurses participated in didactic, simulator and practical training. These nurses performed a total of 77 procedures in patients, 23 of whom had polyps detected and biopsied. Eight patients were advised to undergo colonoscopy because they had one or more neoplastic polyps. To date, six of these eight patients have undergone colonoscopy, one patient has moved out of the province and another patient is awaiting the procedure. Classifying the six patients according to the most advanced polyp histology, one patient had a negative colonoscopy (no polyps found), one patient’s polyps were hyperplastic, one had a tubular adenoma, two had advanced neoplasia (tubulovillous adenomas) and one had adenocarcinoma. All these lesions were excised completely at colonoscopy. Overall, many difficulties were anticipated and addressed in the development of the training program; ultimately, the project was affected most directly by challenges in encouraging family physicians to refer patients to the program. As health human resource strategies continue to evolve, it is believed that lessons learned from experience make an important contribution to the knowledge of how nontraditional health services can be organized and delivered. PMID:17505566

The Effect of Right Colon Retroflexion on Adenoma Detection: A Systematic Review and Meta-analysis.

PubMed

Cohen, Jonah; Grunwald, Douglas; Grossberg, Laurie B; Sawhney, Mandeep S

2017-10-01

Although colonoscopy with polypectomy can prevent up to 80% of colorectal cancers, a significant adenoma miss rate still exists, particularly in the right colon. Previous studies addressing right colon retroflexion have revealed discordant evidence regarding the benefit of this maneuver on adenoma detection with concomitant concerns about safety and rates of maneuver success. In this meta-analysis, we sought to determine the effect of right colon retroflexion on improving adenoma detection compared with conventional colonoscopy without retroflexion, as well as determine the rates of retroflexion maneuver success and adverse events. Multiple databases including MEDLINE, Embase, and Web of Science were searched for studies on right colon retroflexion and its impact on adenoma detection compared with conventional colonoscopy. Pooled analyses of adenoma detection and retroflexion success were based on mixed-effects and random-effects models with heterogeneity analyses. Eight studies met the inclusion criteria (N=3660). The primary analysis comparing colonoscopy with right-sided retroflexion versus conventional colonoscopy to determine the per-adenoma miss rate in the right colon was 16.9% (95% confidence interval, 12.5%-22.5%). The overall rate of successful retroflexion was 91.9% (95% confidence interval, 86%-95%) and rate of adverse events was 0.03%. Colonoscopy with right-sided retroflexion significantly increases the detection of adenomas in the right colon compared with conventional colonoscopy with a high rate of maneuver success and small risk of adverse events. Thus, reexamination of the right colon in retroflexed view should be strongly considered in future standard of care colonoscopy guidelines for quality improvement in colon cancer prevention.

Multitarget stool DNA tests increases colorectal cancer screening among previously noncompliant Medicare patients

PubMed Central

Prince, Mark; Lester, Lynn; Chiniwala, Rupal; Berger, Barry

2017-01-01

AIM To determine the uptake of noninvasive multitarget stool DNA (mt-sDNA) in a cohort of colorectal cancer (CRC) screening non-compliant average-risk Medicare patients. METHODS This cross sectional primary care office-based study examined mt-sDNA uptake in routine clinical practice among 393 colorectal cancer screening non-compliant Medicare patients ages 50-85 ordered by 77 physicians in a multispecialty group practice (USMD Physician Services, Dallas, TX) from October, 2014-September, 2015. Investigators performed a Health Insurance Portability and Accountability Act compliant retrospective review of electronic health records to identify mt-sDNA use in patients who were either > 10 years since last colonoscopy and/or > 1 year since last fecal occult blood test. Test positive patients were advised to get diagnostic colonoscopy and thereafter patients were characterized by the most clinically significant lesion documented on histopathology of biopsies or excisional tissue. Descriptive statistics were employed. Key outcome measures included mt-sDNA compliance and diagnostic colonoscopy compliance on positive cases. RESULTS Over 12 mo, 77 providers ordered 393 mt-sDNA studies with 347 completed (88.3% compliance). Patient mean age was 69.8 (50-85) and patients were 64% female. Mt-sDNA was negative in 85.3% (296/347) and positive in 14.7% (51/347). Follow-up colonoscopy was performed in 49 positive patients (96.1% colonoscopy compliance) with two patients lost to follow up. Index findings included: colon cancer (4/49, 8.2%), advanced adenomas (21/49, 42.9%), non-advanced adenomas (15/49, 30.6%), and negative results (9/49, 18.4%). The positive predictive value for advanced colorectal lesions was 51.0% and for any colorectal neoplasia was 81.6%. The mean age of patients with colorectal cancer was 70.3 and all CRC's were localized Stage I (2) and Stage II (2), three were located in the proximal colon and one was located in the distal colon. CONCLUSION Mt-sDNA provided medical benefit to screening noncompliant Medicare population. High compliance with mt-sDNA and subsequent follow-up diagnostic colonoscopy identified patients with clinically critical advanced colorectal neoplasia. PMID:28210082

Multitarget stool DNA tests increases colorectal cancer screening among previously noncompliant Medicare patients.

PubMed

Prince, Mark; Lester, Lynn; Chiniwala, Rupal; Berger, Barry

2017-01-21

To determine the uptake of noninvasive multitarget stool DNA (mt-sDNA) in a cohort of colorectal cancer (CRC) screening non-compliant average-risk Medicare patients. This cross sectional primary care office-based study examined mt-sDNA uptake in routine clinical practice among 393 colorectal cancer screening non-compliant Medicare patients ages 50-85 ordered by 77 physicians in a multispecialty group practice (USMD Physician Services, Dallas, TX) from October, 2014-September, 2015. Investigators performed a Health Insurance Portability and Accountability Act compliant retrospective review of electronic health records to identify mt-sDNA use in patients who were either > 10 years since last colonoscopy and/or > 1 year since last fecal occult blood test. Test positive patients were advised to get diagnostic colonoscopy and thereafter patients were characterized by the most clinically significant lesion documented on histopathology of biopsies or excisional tissue. Descriptive statistics were employed. Key outcome measures included mt-sDNA compliance and diagnostic colonoscopy compliance on positive cases. Over 12 mo, 77 providers ordered 393 mt-sDNA studies with 347 completed (88.3% compliance). Patient mean age was 69.8 (50-85) and patients were 64% female. Mt-sDNA was negative in 85.3% (296/347) and positive in 14.7% (51/347). Follow-up colonoscopy was performed in 49 positive patients (96.1% colonoscopy compliance) with two patients lost to follow up. Index findings included: colon cancer (4/49, 8.2%), advanced adenomas (21/49, 42.9%), non-advanced adenomas (15/49, 30.6%), and negative results (9/49, 18.4%). The positive predictive value for advanced colorectal lesions was 51.0% and for any colorectal neoplasia was 81.6%. The mean age of patients with colorectal cancer was 70.3 and all CRC's were localized Stage I (2) and Stage II (2), three were located in the proximal colon and one was located in the distal colon. Mt-sDNA provided medical benefit to screening noncompliant Medicare population. High compliance with mt-sDNA and subsequent follow-up diagnostic colonoscopy identified patients with clinically critical advanced colorectal neoplasia.

[Cost-effectiveness analysis on colorectal cancer screening program].

PubMed

Huang, Q C; Ye, D; Jiang, X Y; Li, Q L; Yao, K Y; Wang, J B; Jin, M J; Chen, K

2017-01-10

Objective: To evaluate the cost-effectiveness of colorectal cancer screening program in different age groups from the view of health economics. Methods: The screening compliance rates, detection rates in different age groups were calculated by using the data from colorectal cancer screening program in Jiashan county, Zhejiang province. The differences in indicator among age groups were analyzed with χ (2) test or trend χ (2) test. The ratios of cost to the number of case were calculated according to cost statistics. Results: The detection rates of immunochemical fecal occult blood test (iFOBT) positivity, advanced adenoma and colorectal cancer and early stage cancer increased with age, while the early diagnosis rates were negatively associated with age. After exclusion the younger counterpart, the cost-effectiveness of individuals aged >50 years could be reduced by 15 %- 30 % . Conclusion: From health economic perspective, it is beneficial to start colorectal cancer screening at age of 50 years to improve the efficiency of the screening.

A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans.

PubMed

Bongers, Gerold; Muniz, Luciana R; Pacer, Michelle E; Iuga, Alina C; Thirunarayanan, Nanthakumar; Slinger, Erik; Smit, Martine J; Reddy, E Premkumar; Mayer, Lloyd; Furtado, Glaucia C; Harpaz, Noam; Lira, Sergio A

2012-09-01

Epithelial cancers can be initiated by activating mutations in components of the mitogen-activated protein kinase signaling pathway such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or epidermal growth factor receptor (EGFR). Human intestinal serrated polyps are a heterogeneous group of benign lesions, but some progress to colorectal cancer. Tumors that arise from these polyps frequently contain activating mutations in BRAF or KRAS, but little is known about the role of EGFR activation in their development. Polyp samples were obtained from adults during screening colonoscopies at Mount Sinai Hospital in New York. We measured levels of EGFR protein and phosphorylation in human serrated polyps by immunohistochemical and immunoblot analyses. We generated transgenic mice that express the ligand for EGFR, Heparin-binding EGF-like growth factor (HB-EGF), in the intestine. EGFR and the extracellular-regulated kinases (ERK)1/2 were phosphorylated in serrated areas of human hyperplastic polyps (HPPs), sessile serrated adenomas, and traditional serrated adenomas. EGFR and ERK1/2 were phosphorylated in the absence of KRAS or BRAF activating mutations in a subset of HPP. Transgenic expression of the EGFR ligand HB-EGF in the intestines of mice promoted development of small cecal serrated polyps. Mice that expressed a combination of HB-EGF and US28 (a constitutively active, G-protein-coupled receptor that increases processing of HB-EGF from the membrane) rapidly developed large cecal serrated polyps. These polyps were similar to HPPs and had increased phosphorylation of EGFR and ERK1/2 within the serrated epithelium. Administration of pharmacologic inhibitors of EGFR or MAPK to these transgenic mice significantly reduced polyp development. Activation of EGFR signaling in the intestine of mice promotes development of serrated polyps. EGFR signaling also is activated in human HPPs, sessile serrated adenomas, and traditional serrated adenomas. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

25-hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case-control versus nested case-control studies.

PubMed

Grant, William B

2015-02-01

Existing literature includes concerns regarding reliability of case-control studies of breast cancer incidence with respect to 25-hydroxyvitamin D (25(OH)D) concentrations. For breast cancer, only case-control studies consistently find inverse correlations between 25(OH)D and breast cancer. However, for colorectal cancer, nested case-control studies find significant inverse correlations with respect to 25(OH)D concentrations at baseline for mean follow-up times of 7 years. This is a review of results currently existing in literature. I provide evidence that 25(OH)D concentration values are only useful for short follow-up times for breast cancer since it develops rapidly. To support the robust nature of breast cancer case-control studies, I show that results from 11 studies from seven countries align in a robust power-law fit to the odds ratio versus mean 25(OH)D concentrations. Case-control studies of breast cancer incidence rates provide reliable results. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

An epitope localized in c-Src negative regulatory domain is a potential marker in early stage of colonic neoplasms.

PubMed

Sakai, T; Kawakatsu, H; Fujita, M; Yano, J; Owada, M K

1998-02-01

In previous work, we established a new monoclonal antibody that specifically recognizes the active form of c-Src tyrosine kinase (Kawakatsu et al, 1996). To determine whether c-Src is active in colorectal tumorigenesis, we examined the expression of an active form of c-Src in human normal mucosa, hyperplastic polyps, adenomas, and adenocarcinomas. The tissue distribution of the active form of c-Src was studied by immunohistochemistry using this antibody, termed Clone 28. Among 66 cases of adenoma tested, 61 (92%) showed positive staining (adenoma with mild atypia, 3 of 3; adenoma with moderate atypia, 38 of 42; adenoma with severe atypia, 20 of 21). In contrast to the frequent and intense staining in adenomas, adenocarcinoma showed weak staining with less frequency in 4 of 16 (25%) cases. The number of specimens with positive staining in well- and moderately differentiated adenocarcinomas was limited to an early stage. The active form of c-Src mainly localized to the nuclear membrane and the perinuclear region. These results provide the first direct evidence that the activation of c-Src appears to be an early event in colonic carcinogenesis in situ. The findings of the present study thus allow us to propose a molecular mechanism involving c-Src activation in the process of malignant transformation of the human colonic neoplastic cells.

Effect of diet, life style, and other environmental/chemopreventive factors on colorectal cancer development, and assessment of the risks.

PubMed

Ahmed, Farid E

2004-01-01

This review presents a comprehensive, evenhanded evaluation of the evidence from experimental, in vitro and human studies associating environmental and therapeutic factors with risk of colorectal cancer. Life styles correlated with the greatest increase in colorectal cancer risk are the ones that typify a diet rich in fat and calories, alcohol drinking and tobacco smoking, and low intake of vegetable, fruits and fibers, referred to as a "western diet," as well as sedentary style (i.e., no- or low-exercise). This kind of life style has also been associated with other chronic diseases (other cancers, obesity, dyslipedemia, diabetes, hypertension cardiovascular, and hypertension). The evidence does not implicated red meat as a risk factor, and fiber has been shown to protect against colorectal adenomas and carcinomas. Calcium, vitamin D, folate, and some antioxidant vitamins and minerals (gamma-tocopherol and selenium) have protective effects, and daily exercise for > or =30 min results in a significant decrease in risk. Estrogen use (hormone replacement therapy) substantially reduces colorectal cancer risk in postmenopausal women. Nonsteroidal anti-inflammatory drugs (e.g., aspirin) in excessive doses is protective, especially in high risk populations, but the side effects of its use and cost incurred due to its continued intake over long periods must be carefully scrutinized before any recommendations are made for the general public.

Diet and lifestyle intervention among patients with colorectal adenomas: rationale and design of a Malaysian study.

PubMed

Kandiah, Mirnalini; Ramadas, Amutha; Shariff, Zalilah Mohd; Yusof, Rokiah Mohd; Gul, Yunus Gul Alif

2005-01-01

Comprehensive evaluation of the large body of consistent evidence from laboratory, epidemiologic and clinical studies has led to the conclusion that modification of the dietary and lifestyle patterns of populations has considerable potential for reducing cancer risk. This paper describes a randomized-controlled trial involving a diet and lifestyle intervention for patients with history of colorectal adenomas. The primary aim of this trial is to evaluate the effectiveness of the intervention with reference to recurrence of adenomatous polyps over a two year period--the first year being the intervention period and the second year of the study allowing for post-intervention follow-up. Subjects found to fit the inclusion criteria are recruited and randomized to two groups: the intervention group and the control group. The intervention group subjects will attend a monthly lecture-discussion session for 10 months and small group counseling on modification of lifestyle behavior and diet as well as receive educational materials which were adapted from the WCRF Diet and Health Recommendations for Cancer Prevention. Control subjects will be provided with the usual care given to such patients. One hundred and sixteen patients who were diagnosed with colorectal adenomatous polyps in the previous twelve months at the Hospital Kuala Lumpur have already been enrolled in this trial. Baseline data collection is on-going.

Fecal Microbiota Characteristics of Patients with Colorectal Adenoma Detected by Screening: A Population-based Study

PubMed Central

Goedert, James J.; Gong, Yangming; Hua, Xing; Zhong, Huanzi; He, Yimin; Peng, Peng; Yu, Guoqin; Wang, Wenjing; Ravel, Jacques; Shi, Jianxin; Zheng, Ying

2015-01-01

Background Screening for colorectal cancer (CRC) and precancerous colorectal adenoma (CRA) can detect curable disease. However, participation in colonoscopy and sensitivity of fecal heme for CRA are low. Methods Microbiota metrics were determined by Illumina sequencing of 16S rRNA genes amplified from DNA extracted from feces self-collected in RNAlater. Among fecal immunochemical test-positive (FIT +) participants, colonoscopically-defined normal versus CRA patients were compared by regression, permutation, and random forest plus leave-one-out methods. Findings Of 95 FIT + participants, 61 had successful fecal microbiota profiling and colonoscopy, identifying 24 completely normal patients, 20 CRA patients, 2 CRC patients, and 15 with other conditions. Phylum-level fecal community composition differed significantly between CRA and normal patients (permutation P = 0.02). Rank phylum-level abundance distinguished CRA from normal patients (area under the curve = 0.767, permutation P = 0.006). CRA prevalence was 59% in phylum-level cluster B versus 20% in cluster A (exact P = 0.01). Most of the difference reflected 3-fold higher median relative abundance of Proteobacteria taxa (Wilcoxon signed-rank P = 0.03, positive predictive value = 67%). Antibiotic exposure and other potential confounders did not affect the associations. Interpretation If confirmed in larger, more diverse populations, fecal microbiota analysis might be employed to improve screening for CRA and ultimately to reduce mortality from CRC. PMID:26288821

Serrated Lesions of the Colorectum: Review and Recommendations From an Expert Panel

PubMed Central

Rex, Douglas K.; Ahnen, Dennis J.; Baron, John A.; Batts, Kenneth P.; Burke, Carol A.; Burt, Randall W.; Goldblum, John R.; Guillem, José G.; Kahi, Charles J.; Kalady, Matthew F.; O’Brien, Michael J; Odze, Robert D.; Ogino, Shuji; Parry, Susan; Snover, Dale C.; Torlakovic, Emina Emilia; Wise, Paul E.; Young, Joanne; Church, James

2012-01-01

Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers. Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to World Health Organization criteria as hyperplastic polyps, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premaligant lesions, but SSA/P is the principle serrated precursor of colorectal cancers. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid > 5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives. PMID:22710576

Serrated lesions of the appendix: a morphologic and immunohistochemical appraisal.

PubMed

Bellizzi, Andrew M; Rock, Jonathan; Marsh, William L; Frankel, Wendy L

2010-04-01

We performed a histologic and immunohistochemical assessment of 53 noninvasive appendiceal epithelial proliferations, appropriating terminology and using markers shown useful in differentiating serrated colorectal polyps. These were classified as hyperplastic polyp (HP), sessile serrated adenoma (SSA), mixed serrated and adenomatous lesion (MSAL), mucinous cystadenoma (MCA), or conventional adenoma (CAD). Immunohistochemical analysis for cytokeratin (CK) 20, Ki-67, MUC6, and beta-catenin was performed. Diagnoses were as follows: HP, 6; SSA, 12; HP vs SSA, 3; MSAL, 16; MCA, 14; and CAD, 2. All HPs showed expanded (beyond surface) CK20 and expanded or normal (base) Ki-67; 1 was MUC6+. Most SSAs and MSALs were CK20-expanded or expanded with random expression in deep crypts (Ex/I) and Ki-67-expanded, Ex/I (expanded with asymmetry), or normal. All SSAs and 8 of 16 MSALs were MUC6+. CADs were CK20-Ex/I, Ki-67-Ex, and MUC6-; 1 showed nuclear beta-catenin expression. Serrated appendiceal lesions can be categorized using colorectal terminology. MUC6 is associated with SSA morphologic features. Similar immunohistochemical patterns in SSA and MSAL suggest a link between these lesions.

A transposon-based genetic screen in mice identifies genes altered in colorectal cancer.

PubMed

Starr, Timothy K; Allaei, Raha; Silverstein, Kevin A T; Staggs, Rodney A; Sarver, Aaron L; Bergemann, Tracy L; Gupta, Mihir; O'Sullivan, M Gerard; Matise, Ilze; Dupuy, Adam J; Collier, Lara S; Powers, Scott; Oberg, Ann L; Asmann, Yan W; Thibodeau, Stephen N; Tessarollo, Lino; Copeland, Neal G; Jenkins, Nancy A; Cormier, Robert T; Largaespada, David A

2009-03-27

Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN, and SMAD4. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2.

Crosstalk between peroxisome proliferator-activated receptor δ and VEGF stimulates cancer progression

PubMed Central

Wang, Dingzhi; Wang, Haibin; Guo, Yong; Ning, Wei; Katkuri, Sharada; Wahli, Walter; Desvergne, Beatrice; Dey, Sudhansu K.; DuBois, Raymond N.

2006-01-01

Peroxisome proliferator-activated receptor (PPAR) δ is a member of the nuclear hormone receptor superfamily. PPARδ may ameliorate metabolic diseases such as obesity and diabetes. However, PPARδ's role in colorectal carcinogenesis remains controversial. Here, we present genetic and pharmacologic evidence demonstrating that deletion of PPARδ decreases intestinal adenoma growth in ApcMin/+ mice and inhibits tumor-promoting effects of a PPARδ agonist GW501516. More importantly, we found that activation of PPARδ up-regulated VEGF in colon carcinoma cells. VEGF directly promotes colon tumor epithelial cell survival through activation of PI3K–Akt signaling. These results not only highlight concerns about the use of PPARδ agonists for treatment of metabolic disorders in patients who are at high risk for colorectal cancer, but also support the rationale for developing PPARδ antagonists for prevention and/or treatment of cancer. PMID:17148604

Subtypes of the Type II Pit Pattern Reflect Distinct Molecular Subclasses in the Serrated Neoplastic Pathway.

PubMed

Aoki, Hironori; Yamamoto, Eiichiro; Yamano, Hiro-O; Sugai, Tamotsu; Kimura, Tomoaki; Tanaka, Yoshihito; Matsushita, Hiro-O; Yoshikawa, Kenjiro; Takagi, Ryo; Harada, Eiji; Nakaoka, Michiko; Yoshida, Yuko; Harada, Taku; Sudo, Gota; Eizuka, Makoto; Yorozu, Akira; Kitajima, Hiroshi; Niinuma, Takeshi; Kai, Masahiro; Nojima, Masanori; Suzuki, Hiromu; Nakase, Hiroshi

2018-03-15

Colorectal serrated lesions (SLs) are important premalignant lesions whose clinical and biological features are not fully understood. We aimed to establish accurate colonoscopic diagnosis and treatment of SLs through evaluation of associations among the morphological, pathological, and molecular characteristics of SLs. A total of 388 premalignant and 18 malignant colorectal lesions were studied. Using magnifying colonoscopy, microsurface structures were assessed based on Kudo's pit pattern classification system, and the Type II pit pattern was subcategorized into classical Type II, Type II-Open (Type II-O) and Type II-Long (Type II-L). BRAF/KRAS mutations and DNA methylation of CpG island methylator phenotype (CIMP) markers (MINT1, - 2, - 12, - 31, p16, and MLH1) were analyzed through pyrosequencing. Type II-O was tightly associated with sessile serrated adenoma/polyps (SSA/Ps) with BRAF mutation and CIMP-high. Most lesions with simple Type II or Type II-L were hyperplastic polyps, while mixtures of Type II or Type II-L plus more advanced pit patterns (III/IV) were characteristic of traditional serrated adenomas (TSAs). Type II-positive TSAs frequently exhibited BRAF mutation and CIMP-low, while Type II-L-positive TSAs were tightly associated with KRAS mutation and CIMP-low. Analysis of lesions containing both premalignant and cancerous components suggested Type II-L-positive TSAs may develop into KRAS-mutated/CIMP-low/microsatellite stable cancers, while Type II-O-positive SSA/Ps develop into BRAF-mutated/CIMP-high/microsatellite unstable cancers. These results suggest that Type II subtypes reflect distinct molecular subclasses in the serrated neoplasia pathway and that they could be useful hallmarks for identifying SLs at high risk of developing into CRC.

FICE in Predicting Colorectal Flat Lesion Histology.

PubMed

Akarsu, Cevher; Sahbaz, Nuri A; Dural, Ahmet C; Kones, Osman; Binboga, Sinan; Kabuli, Hamit A; Gumusoglu, Alpen Y; Alis, Halil

2017-01-01

Colonoscopy is the gold standard for detection of polyps and is preventive against colorectal cancers. Flat adenomas are small, superficial lesions and have a high rate of going undetected during conventional white-light endoscopy. This article adds to the scant body of literature in English regarding in vivo detection and diagnosis of flat adenomas using Fujinon intelligent color enhancement (FICE) system. In this study, we investigated the diagnosis of flat lesions via the FICE endoscopy system and in vivo histologic diagnostic estimations of flat lesions. This prospective study was conducted in patients who underwent colonoscopy that found flat adenomas. Lesions were classified morphologically with regard to the Paris Classification and sent for histopathologic examination after in vivo histologic diagnostic estimations were made according to Kudo's pit pattern classification. The positive predictive value (PPV), negative predictive value (NPV), specificity, sensitivity, and accuracy of in vivo endoscopic diagnostic estimations of flat lesions with the FICE system were analyzed. A total of 217 flat lesions were identified in 137 patients. Of the lesions, 85.7% were Paris type 0-IIa, and 59.4% were Kudo pit pattern type III. When the FICE diagnostic estimations of flat lesions and final pathology results were considered, PPV was 68.5%, NPV value was 89.6%, sensitivity was 94.7%, specificity was 50.9%, and accuracy was 74.2%. Biologic importance of flat lesions is obscure, as they are usually missed during colonoscopy. The use of novel endoscopic techniques may improve their detection and diagnosis rates.

Nonbleeding adenomas: Evidence of systematic false-negative fecal immunochemical test results and their implications for screening effectiveness-A modeling study.

PubMed

van der Meulen, Miriam P; Lansdorp-Vogelaar, Iris; van Heijningen, Else-Mariëtte B; Kuipers, Ernst J; van Ballegooijen, Marjolein

2016-06-01

If some adenomas do not bleed over several years, they will cause systematic false-negative fecal immunochemical test (FIT) results. The long-term effectiveness of FIT screening has been estimated without accounting for such systematic false-negativity. There are now data with which to evaluate this issue. The authors developed one microsimulation model (MISCAN [MIcrosimulation SCreening ANalysis]-Colon) without systematic false-negative FIT results and one model that allowed a percentage of adenomas to be systematically missed in successive FIT screening rounds. Both variants were adjusted to reproduce the first-round findings of the Dutch CORERO FIT screening trial. The authors then compared simulated detection rates in the second screening round with those observed, and adjusted the simulated percentage of systematically missed adenomas to those data. Finally, the authors calculated the impact of systematic false-negative FIT results on the effectiveness of repeated FIT screening. The model without systematic false-negativity simulated higher detection rates in the second screening round than observed. These observed rates could be reproduced when assuming that FIT systematically missed 26% of advanced and 73% of nonadvanced adenomas. To reduce the false-positive rate in the second round to the observed level, the authors also had to assume that 30% of false-positive findings were systematically false-positive. Systematic false-negative FIT testing limits the long-term reduction of biennial FIT screening in the incidence of colorectal cancer (35.6% vs 40.9%) and its mortality (55.2% vs 59.0%) in participants. The results of the current study provide convincing evidence based on the combination of real-life and modeling data that a percentage of adenomas are systematically missed by repeat FIT screening. This impairs the efficacy of FIT screening. Cancer 2016;122:1680-8. © 2016 American Cancer Society. © 2016 American Cancer Society.

Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis.

PubMed

Perkins, Sarah; Verschoyle, Richard D; Hill, Kirsti; Parveen, Ifat; Threadgill, Michael D; Sharma, Ricky A; Williams, Marion L; Steward, William P; Gescher, Andreas J

2002-06-01

Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/+ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/+ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated. Levels of curcumin and metabolites were determined by high-performance liquid chromatography in plasma, tissues, and feces of mice after either long-term ingestion of dietary curcumin or a single dose of [(14)C]curcumin (100 mg/kg) via the i.p. route. Whereas curcumin at 0.1% in the diet was without effect, at 0.2 and 0.5%, it reduced adenoma multiplicity by 39 and 40%, respectively, compared with untreated mice. Hematocrit values in untreated Min/+ mice were drastically reduced compared with those in wild-type C57Bl/6J mice. Dietary curcumin partially restored the suppressed hematocrit. Traces of curcumin were detected in the plasma. Its concentration in the small intestinal mucosa, between 39 and 240 nmol/g of tissue, reflects differences in dietary concentration. [(14)C]Curcumin disappeared rapidly from tissues and plasma within 2-8 h after dosing. Curcumin may be useful in the chemoprevention of human intestinal malignancies related to Apc mutations. The comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. A clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation.

Transanal endoscopic surgery using a single access port: a practical tool in the surgeon's toybox.

PubMed

Gorgun, I E; Gorgun, I Emre; Aytac, Erman; Costedio, Meagan M; Erem, Hasan H; Valente, Michael A; Stocchi, Luca

2014-03-01

Large polyps and early carcinomas of the rectum may be excised with transanal endoscopic surgery (TES). Single-port techniques are emerging in the field of colorectal surgery and have been adapted to many colorectal procedures so far. In this article, we aimed to present our initial experience with TES using a single access port with its technical details. Patients undergoing TES using a single access port between July 2010 and January 2013 were included in the study. Patient demographics, operative technique, and both operative and postoperative outcomes were evaluated and presented. A total of 12 patients (ten males) were included in our study. The median age was 63.5 years (50-84), median American Society of Anesthesiologists (ASA) score was 3 (2-4), and median body mass index was 28.8 kg/m(2) (17.4-55.6). Median operating time was 79 min (43-261). Histopathological diagnoses were as follows: tubulovillous adenoma (n = 6), tubular adenoma (n = 4), adenocarcinoma (n = 1), and neuroendocrine tumor (n = 1). Five patients were sent home on the day of surgery and the median postoperative hospital stay was 1 day (0-38). Median estimated blood loss was 22.5 ml (5-150). A transient urinary retention was developed in one patient postoperatively, and two patients had postoperative bleeding. The first of these patients with a long history of anticoagulant usage had rectal bleeding 13 days after surgery, which was successfully managed with medical treatment. The second patient was morbidly obese, had multiple comorbidities, and had rectal bleeding on postoperative day 7 which was managed with local epinephrine injection. He suffered unrelated cardiac death on postoperative day 38. TES is safe and feasible when using a single port and in the standard laparoscopic setting. The single-port technique may play a major role in the widespread utilization of TES as a treatment for large adenomas and early rectal cancers.

Faecal immunochemical tests versus guaiac faecal occult blood tests: what clinicians and colorectal cancer screening programme organisers need to know.

PubMed

Tinmouth, Jill; Lansdorp-Vogelaar, Iris; Allison, James E

2015-08-01

Although colorectal cancer (CRC) is a common cause of cancer-related death, it is fortunately amenable to screening with faecal tests for occult blood and endoscopic tests. Despite the evidence for the efficacy of guaiac-based faecal occult blood tests (gFOBT), they have not been popular with primary care providers in many jurisdictions, in part because of poor sensitivity for advanced colorectal neoplasms (advanced adenomas and CRC). In order to address this issue, high sensitivity gFOBT have been recommended, however, these tests are limited by a reduction in specificity compared with the traditional gFOBT. Where colonoscopy is available, some providers have opted to recommend screening colonoscopy to their patients instead of faecal testing, as they believe it to be a better test. Newer methods for detecting occult human blood in faeces have been developed. These tests, called faecal immunochemical tests (FIT), are immunoassays specific for human haemoglobin. FIT hold considerable promise over the traditional guaiac methods including improved analytical and clinical sensitivity for CRC, better detection of advanced adenomas, and greater screenee participation. In addition, the quantitative FIT are more flexible than gFOBT as a numerical result is reported, allowing customisation of the positivity threshold. When compared with endoscopy, FIT are less sensitive for the detection of advanced colorectal neoplasms when only one time testing is applied to a screening population; however, this is offset by improved participation in a programme of annual or biennial screens and a better safety profile. This review will describe how gFOBT and FIT work and will present the evidence that supports the use of FIT over gFOBT, including the cost-effectiveness of FIT relative to gFOBT. Finally, specific issues related to FIT implementation will be discussed, particularly with respect to organised CRC screening programmes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

[Aspirin and colorectal cancer].

PubMed

Grancher, Adrien; Michel, Pierre; Di Fiore, Frédéric; Sefrioui, David

2018-02-01

Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti-inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH(2)-terminal kinase during human colorectal carcinogenesis.

PubMed

Yamagata, Hideo; Matsuzaki, Koichi; Mori, Shigeo; Yoshida, Katsunori; Tahashi, Yoshiya; Furukawa, Fukiko; Sekimoto, Go; Watanabe, Toshihiko; Uemura, Yoshiko; Sakaida, Noriko; Yoshioka, Kazuhiko; Kamiyama, Yasuo; Seki, Toshihito; Okazaki, Kazuichi

2005-01-01

Conversion of normal epithelial cells to tumors is associated with a shift in transforming growth factor-beta (TGF-beta) function: reduction of tumor suppressor activity and increase of oncogenic activity. However, specific mechanisms of this functional alteration during human colorectal carcinogenesis remain to be elucidated. TGF-beta signaling involves Smad2/3 phosphorylated at linker regions (pSmad2/3L) and COOH-terminal regions (pSmad2/3C). Using antibodies specific to each phosphorylation site, we herein showed that Smad2 and Smad3 were phosphorylated at COOH-terminal regions but not at linker regions in normal colorectal epithelial cells and that pSmad2/3C were located predominantly in their nuclei. However, the linker regions of Smad2 and Smad3 were phosphorylated in 31 sporadic colorectal adenocarcinomas. In particular, late-stage invasive and metastatic cancers typically showed a high degree of phosphorylation of Smad2/3L. Their extent of phosphorylation in 11 adenomas was intermediate between those in normal epithelial cells and adenocarcinomas. Whereas pSmad2L remained in the cytoplasm, pSmad3L was located exclusively in the nuclei of Ki-67-immunoreactive adenocarcinomas. In contrast, pSmad3C gradually decreased as the tumor stage progressed. Activated c-Jun NH(2)-terminal kinase in cancers could directly phosphorylate Smad2/3L. Although Mad homology 2 region sequencing in the Smad4 gene revealed a G/A substitution at codon 361 in one adenocarcinoma, the mutation did not correlate with phosphorylation. No mutations in the type II TGF-beta receptor and Smad2 genes were observed in the tumors. In conclusion, pSmad3C, which favors tumor suppressor activity of TGF-beta, was found to decrease, whereas c-Jun NH(2)-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence.

Effects of calcium and vitamin D3 on transforming growth factors in rectal mucosa of sporadic colorectal adenoma patients: a randomized controlled trial.

PubMed

Tu, Huakang; Flanders, W Dana; Ahearn, Thomas U; Daniel, Carrie R; Gonzalez-Feliciano, Amparo G; Long, Qi; Rutherford, Robin E; Bostick, Roberd M

2015-04-01

Transforming growth factor alpha (TGFα) and TGFβ1 are growth-promoting and -inhibiting autocrine/paracrine growth factors, respectively, that may (1) affect risk for colorectal cancer and (2) be modifiable by anti-proliferative exposures. The effects of supplemental calcium and vitamin D3 on these two markers in the normal-appearing colorectal mucosa in humans are unknown. We conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n = 92; 23/treatment group) of calcium 2 g and/or vitamin D3 800 IU/d versus placebo over 6 mo. TGFα and TGFβ1 expression was measured in biopsies of normal-appearing rectal mucosa using automated immunohistochemistry and quantitative image analysis at baseline and 6-mo follow-up. In the calcium, vitamin D3 , and calcium plus vitamin D3 groups relative to the placebo group (1) the mean overall expression of TGFβ1 increased by 14% (P= 0.25), 19% (P = 0.17), and 22% (P = 0.09); (2) the ratio of TGFα expression in the upper 40% (differentiation zone) to that in the lower 60 (proliferation zone) of the crypts decreased by 34% (P = 0.11), 31% (P = 0.22), and 26% (P = 0.33); and (3) the TGFα/TGFβ1 ratio in the upper 40% of the crypts decreased by 28% (P = 0.09), 14% (P = 0.41), and 22% (P = 0.24), respectively. These preliminary results, although not statistically significant, suggest that supplemental calcium and vitamin D3 may increase TGFβ1 expression and shift TGFα expression downward from the differentiation to the proliferation zone in the crypts in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, and support further investigation in a larger clinical trial. © 2013 Wiley Periodicals, Inc.

Sensitivity and specificity of CT colonography for the detection of colonic neoplasia after positive faecal occult blood testing: systematic review and meta-analysis.

PubMed

Plumb, Andrew A; Halligan, Steve; Pendsé, Douglas A; Taylor, Stuart A; Mallett, Susan

2014-05-01

CT colonography (CTC) is recommended after positive faecal occult blood testing (FOBt) when colonoscopy is incomplete or infeasible. We aimed to estimate the sensitivity and specificity of CTC for colorectal cancer and adenomatous polyps following positive FOBt via systematic review. The MEDLINE, EMBASE, AMED and Cochrane Library databases were searched for CTC studies reporting sensitivity and specificity for colorectal cancer and adenomatous polyps. Included subjects had tested FOBt-positive by guaiac or immunochemical methods. Per-patient detection rates were summarized via forest plots. Meta-analysis of sensitivity and specificity was conducted using a bivariate random effects model and the average operating point calculated. Of 538 articles considered, 5 met inclusion criteria, describing results from 622 patients. Research study quality was good. CTC had a high per-patient average sensitivity of 88.8 % (95 % CI 83.6 to 92.5 %) for ≥6 mm adenomas or colorectal cancer, with low between-study heterogeneity. Specificity was both more heterogeneous and lower, at an average of 75.4 % (95 % CI 58.6 to 86.8 %). Few studies have investigated CTC in FOBt-positive individuals. CTC is sensitive at a ≥6 mm threshold but specificity is lower and variable. Despite the limited data, these results suggest that CTC may adequately substitute for colonoscopy when the latter is undesirable. • FOBt is the most common mass screening test for colorectal cancer. • Few studies evaluate CT colonography after positive FOBt. • CTC is approximately 89 % sensitive for ≥6 mm adenomas/cancer in this setting. • Specificity is lower, at approximately 75 %, and more variable. • CT colonography is a good alternative when colonoscopy is undesirable.

Detection of colorectal neoplasia: Combination of eight blood-based, cancer-associated protein biomarkers.

PubMed

Wilhelmsen, Michael; Christensen, Ib J; Rasmussen, Louise; Jørgensen, Lars N; Madsen, Mogens R; Vilandt, Jesper; Hillig, Thore; Klaerke, Michael; Nielsen, Knud T; Laurberg, Søren; Brünner, Nils; Gawel, Susan; Yang, Xiaoqing; Davis, Gerard; Heijboer, Annemieke; Martens, Frans; Nielsen, Hans J

2017-03-15

Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3 and TIMP-1 were determined in EDTA-plasma using the Abbott ARCHITECT® automated immunoassay platform. Primary endpoints were detection of (i) CRC and high-risk adenoma and (ii) CRC. Logistic regression was performed. Final reduced models were constructed selecting the four biomarkers with the highest likelihood scores. Subjects (N = 4,698) were consecutively included during 2010-2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer and 193 rectal cancer. Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1,342 had nonneoplastic bowell disease and 1,978 subjects had 'clean' colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in the selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the two endpoints; AUCs were 0.76 and 0.84, respectively. The postive predictive value at 90% sensitivity was 25% for endpoint 1 and the negative predictive value was 93%. For endpoint 2, the postive predictive value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC. © 2016 UICC.

A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in normal mucosa of colorectal adenoma patients.

PubMed

Ahearn, Thomas U; McCullough, Marjorie L; Flanders, W Dana; Long, Qi; Sidelnikov, Eduard; Fedirko, Veronika; Daniel, Carrie R; Rutherford, Robin E; Shaukat, Aasma; Bostick, Roberd M

2011-01-15

In cancer cell lines and rodent models, calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes, CYP27B1 and CYP24A1; however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2×2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d elemental calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months (n=92; 23 per group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal appearing rectal mucosa were detected by standardized, automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group, CaR expression increased 27% (P=0.03) and CYP24A1 expression decreased 21% (P=0.79). In the vitamin D3-supplemented group, CaR expression increased 39% (P=0.01) and CYP27B1 expression increased 159% (P=0.06). In patients supplemented with both calcium and vitamin D3, VDR expression increased 19% (P=0.13) and CaR expression increased 24% (P=0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, preneoplastic risk biomarkers for colorectal neoplasms. © 2010 AACR.

Absence of non-alcoholic fatty liver disease in the presence of insulin resistance is a strong predictor for colorectal carcinoma

PubMed Central

Basyigit, Sebahat; Uzman, Metin; Kefeli, Ayse; Sapmaz, Ferdane Pirincci; Yeniova, Abdullah Ozgür; Nazligul, Yasar; Asiltürk, Zeliha

2015-01-01

Background: Colorectal carcinoma (CRC) and non-alcoholic fatty liver disease (NAFLD) share common risk factors. Insulin resistance (IR) has an important role in both diseases. It has been speculated that the prevalence of colorectal neoplasms might be increased in patients with NAFLD. However, It is unclear whether NAFLD is an actual risk factor or any association is incidental coexistance due to the role of IR in both disease. We aimed to assess the risk for CRC in patients with NAFLD in relation to IR. Method: This study was designed prospectively and cross-sectionally. We determined NAFLD by ultrasonography and measured IR by the homeostatic model of assessment-insulin resistance model. Results: The prevalences of CRC and adenoma were shown to be significantly higher in patients with IR (respectively; P: 0.005, P: 0.008). But prevalence of CRC was found to be significantly lower in subjects with NAFLD (P: 0.001). On multivariate logistic regression analysis, the risks of colorectal adenoma and carcinoma were significantly associated with the presence of IR (respectively; OR: 2.338, 95% CI: 1.080-4.993, P: 0.003 and : 5.023, 95% CI: 1.789-9.789, P: 0.001). The risk for CRC was significantly associated with the absence of NAFLD (OR: 7.380, 95% CI: 3.069-7.961, P: 0.010). The absence of NAFLD in the presence of IR was associated with significantly high risk for CRC (OR: 5.218, 95% CI: 1.538-7.448, P: 0.017). Conclusion: The risk of CRC can increased in subjects with IR but without NAFLD. The absence of NAFLD in the presence of IR may predict the CRC. PMID:26770473

Effects of Supplemental Vitamin D and Calcium on Normal Colon Tissue and Circulating Biomarkers of Risk for Colorectal Neoplasms

PubMed Central

Bostick, Roberd M.

2015-01-01

This brief review, based on an invited presentation at the 17th Workshop on Vitamin D, is to summarize a line of the author’s research that has been directed at the intertwined missions of clarifying and/or developing vitamin D and calcium and as preventive agents against colorectal cancer in humans, understanding the mechanisms by which these agents may reduce risk for the disease, and developing ‘treatable’ biomarkers of risk for colorectal cancer. The biological plausibility and observational and clinical trial evidence for vitamin D and calcium in reducing risk for colorectal neoplasms, the development of pre-neoplastic biomarkers of risk for colorectal neoplasms, and the clinical trial findings from the author’s research group on the efficacy of vitamin D and calcium in modulating these biomarkers are summarized. Regarding the latter, we tested the efficacy of 800 IU (20 µg) of vitamin D3 and 2.0g of calcium daily, alone and combined vs. placebo over 6 months on modulating normal colon tissue and circulating hypothesis-based biomarkers of risk for colorectal neoplasms in a randomized, double-blind, placebo-controlled, 2×2 factorial design clinical trial (n = 92). The tissue-based biomarkers were measured in biopsies of normal-appearing rectal mucosa using immunohistochemistry with quantitative image analysis, and a panel of circulating inflammation markers was measured using enzyme-linked immunoassays (ELISA). Statistically significant proportional tissue increases in the vitamin D group relative to the placebo group were found in bax (51%), p21 (141%), APC (48%), E-cadherin (78%), MSH2 (179%), the CaSR (39%), and CYP27B1 (159%). In blood, there was a 77% statistically significant decrease in a summary inflammation z-score. The findings for calcium were similar to those for vitamin D. These findings indicate that supplemental vitamin D3 or calcium can favorably modulate multiple normal colon tissue and circulating hypothesis-based biomarkers of risk for colorectal neoplasms in sporadic colorectal adenoma patients. PMID:25597952

Effects of supplemental vitamin D and calcium on normal colon tissue and circulating biomarkers of risk for colorectal neoplasms.

PubMed

Bostick, Roberd M

2015-04-01

This brief review, based on an invited presentation at the 17th Workshop on Vitamin D, is to summarize a line of the author's research that has been directed at the intertwined missions of clarifying and/or developing vitamin D and calcium as preventive agents against colorectal cancer in humans, understanding the mechanisms by which these agents may reduce risk for the disease, and developing 'treatable' biomarkers of risk for colorectal cancer. The biological plausibility and observational and clinical trial evidence for vitamin D and calcium in reducing risk for colorectal neoplasms, the development of pre-neoplastic biomarkers of risk for colorectal neoplasms, and the clinical trial findings from the author's research group on the efficacy of vitamin D and calcium in modulating these biomarkers are summarized. Regarding the latter, we tested the efficacy of 800 IU (20μg) of vitamin D3 and 2.0g of calcium daily, alone and combined vs. placebo over 6 months on modulating normal colon tissue and circulating hypothesis-based biomarkers of risk for colorectal neoplasms in a randomized, double-blind, placebo-controlled, 2×2 factorial design clinical trial (n=92). The tissue-based biomarkers were measured in biopsies of normal-appearing rectal mucosa using immunohistochemistry with quantitative image analysis, and a panel of circulating inflammation markers was measured using enzyme-linked immunoassays (ELISA). Statistically significant proportional tissue increases in the vitamin D group relative to the placebo group were found in bax (51%), p21 (141%), APC (48%), E-cadherin (78%), MSH2 (179%), the CaSR (39%), and CYP27B1 (159%). In blood, there was a 77% statistically significant decrease in a summary inflammation z-score. The findings for calcium were similar to those for vitamin D. These findings indicate that supplemental vitamin D3 or calcium can favorably modulate multiple normal colon tissue and circulating hypothesis-based biomarkers of risk for colorectal neoplasms in sporadic colorectal adenoma patients. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prospective evaluation of 64 serum autoantibodies as biomarkers for early detection of colorectal cancer in a true screening setting

PubMed Central

Chen, Hongda; Werner, Simone; Butt, Julia; Zörnig, Inka; Knebel, Phillip; Michel, Angelika; Eichmüller, Stefan B.; Jäger, Dirk; Waterboer, Tim; Pawlita, Michael; Brenner, Hermann

2016-01-01

Novel blood-based screening tests are strongly desirable for early detection of colorectal cancer (CRC). We aimed to identify and evaluate autoantibodies against tumor-associated antigens as biomarkers for early detection of CRC. 380 clinically identified CRC patients and samples of participants with selected findings from a cohort of screening colonoscopy participants in 2005–2013 (N=6826) were included in this analysis. Sixty-four serum autoantibody markers were measured by multiplex bead-based serological assays. A two-step approach with selection of biomarkers in a training set, and validation of findings in a validation set, the latter exclusively including participants from the screening setting, was applied. Anti-MAGEA4 exhibited the highest sensitivity for detecting early stage CRC and advanced adenoma. Multi-marker combinations substantially increased sensitivity at the price of a moderate loss of specificity. Anti-TP53, anti-IMPDH2, anti-MDM2 and anti-MAGEA4 were consistently included in the best-performing 4-, 5-, and 6-marker combinations. This four-marker panel yielded a sensitivity of 26% (95% CI, 13–45%) for early stage CRC at a specificity of 90% (95% CI, 83–94%) in the validation set. Notably, it also detected 20% (95% CI, 13–29%) of advanced adenomas. Taken together, the identified biomarkers could contribute to the development of a useful multi-marker blood-based test for CRC early detection. PMID:26909861

Correlation between adenoma detection rate in colonoscopy- and fecal immunochemical testing-based colorectal cancer screening programs.

PubMed

Cubiella, Joaquín; Castells, Antoni; Andreu, Montserrat; Bujanda, Luis; Carballo, Fernando; Jover, Rodrigo; Lanas, Ángel; Morillas, Juan Diego; Salas, Dolores; Quintero, Enrique

2017-03-01

The adenoma detection rate (ADR) is the main quality indicator of colonoscopy. The ADR recommended in fecal immunochemical testing (FIT)-based colorectal cancer screening programs is unknown. Using the COLONPREV (NCT00906997) study dataset, we performed a post-hoc analysis to determine if there was a correlation between the ADR in primary and work-up colonoscopy, and the equivalent figure to the minimal 20% ADR recommended. Colonoscopy was performed in 5722 individuals: 5059 as primary strategy and 663 after a positive FIT result (OC-Sensor™; cut-off level 15 µg/g of feces). We developed a predictive model based on a multivariable lineal regression analysis including confounding variables. The median ADR was 31% (range, 14%-51%) in the colonoscopy group and 55% (range, 21%-83%) in the FIT group. There was a positive correlation in the ADR between primary and work-up colonoscopy (Pearson's coefficient 0.716; p  < 0.001). ADR in the FIT group was independently related to ADR in the colonoscopy group: regression coefficient for colonoscopy ADR, 0.71 ( p  = 0.009); sex, 0.09 ( p  = 0.09); age, 0.3 ( p  = 0.5); and region 0.00 ( p  = 0.9). The equivalent figure to the 20% ADR was 45% (95% confidence interval, 35%-56%). ADR in primary and work-up colonoscopy of a FIT-positive result are positively and significantly correlated.

Correlation between adenoma detection rate in colonoscopy- and fecal immunochemical testing-based colorectal cancer screening programs

PubMed Central

Castells, Antoni; Andreu, Montserrat; Bujanda, Luis; Carballo, Fernando; Jover, Rodrigo; Lanas, Ángel; Morillas, Juan Diego; Salas, Dolores; Quintero, Enrique

2016-01-01

Background The adenoma detection rate (ADR) is the main quality indicator of colonoscopy. The ADR recommended in fecal immunochemical testing (FIT)-based colorectal cancer screening programs is unknown. Methods Using the COLONPREV (NCT00906997) study dataset, we performed a post-hoc analysis to determine if there was a correlation between the ADR in primary and work-up colonoscopy, and the equivalent figure to the minimal 20% ADR recommended. Colonoscopy was performed in 5722 individuals: 5059 as primary strategy and 663 after a positive FIT result (OC-Sensor™; cut-off level 15 µg/g of feces). We developed a predictive model based on a multivariable lineal regression analysis including confounding variables. Results The median ADR was 31% (range, 14%–51%) in the colonoscopy group and 55% (range, 21%–83%) in the FIT group. There was a positive correlation in the ADR between primary and work-up colonoscopy (Pearson’s coefficient 0.716; p < 0.001). ADR in the FIT group was independently related to ADR in the colonoscopy group: regression coefficient for colonoscopy ADR, 0.71 (p = 0.009); sex, 0.09 (p = 0.09); age, 0.3 (p = 0.5); and region 0.00 (p = 0.9). The equivalent figure to the 20% ADR was 45% (95% confidence interval, 35%–56%). Conclusions ADR in primary and work-up colonoscopy of a FIT-positive result are positively and significantly correlated. PMID:28344793

RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers.

PubMed

Fennell, Lochlan J; Clendenning, Mark; McKeone, Diane M; Jamieson, Saara H; Balachandran, Samanthy; Borowsky, Jennifer; Liu, John; Kawamata, Futoshi; Bond, Catherine E; Rosty, Christophe; Burge, Matthew E; Buchanan, Daniel D; Leggett, Barbara A; Whitehall, Vicki L J

2018-01-01

The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable (MSI) colorectal cancers. This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome. The entire coding region of RNF43 was Sanger sequenced in 24 colorectal cancers from 23 patients who either (i) carried a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH6, MSH2, PMS2), or (ii) showed immunohistochemical loss of expression of one or more of the DNA mismatch repair proteins, was BRAF wild type at V600E, were under 60 years of age at diagnosis, and demonstrated no promoter region methylation for MLH1 in tumor DNA. A validation cohort of 44 colorectal cancers from mismatch repair germline mutation carriers from the Australasian Colorectal Cancer Family Registry (ACCFR) were sequenced for the most common truncating mutation hotspots (X117 and X659). RNF43 mutations were found in 9 of 24 (37.5%) Lynch syndrome colorectal cancers. The majority of mutations were frameshift deletions in the G659 G7 repeat tract (29%); 2 cancers (2/24, 8%) from the one patient harbored frameshift mutations at codon R117 (C6 repeat tract) within exon 3. In the ACCFR validation cohort, RNF43 hotspot mutations were identified in 19/44 (43.2%) of samples, which was not significantly different to the initial series. The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic MSI colorectal cancers. These findings identify further genetic differences between sporadic and hereditary colorectal cancers. This may be because Lynch Syndrome cancers commonly arise in colorectal adenomas already bearing the APC mutation, whereas sporadic microsatellite unstable colorectal cancers arise from serrated polyps typically lacking APC mutation, decreasing the selection pressure on other WNT signaling related loci in Lynch syndrome.

CT Colonographic Screening of Patients With a Family History of Colorectal Cancer: Comparison With Adults at Average Risk and Implications for Guidelines.

PubMed

Pickhardt, Perry J; Mbah, Ifeanyi; Pooler, B Dustin; Chen, Oliver T; Hinshaw, J Louis; Weiss, Jennifer M; Kim, David H

2017-04-01

The purposes of this study were to compare rates of lesion detection at CT colonographic (CTC) screening of adults without symptoms who had and who did not have a family history of colorectal cancer according to American Cancer Society guidelines and to consider the clinical implications. Over 134 months, consecutively registered CTC cohorts of adults without symptoms who had (n = 156; 88 [56.4%] women; 68 [43.6%] men; mean age, 56.3 years) and who did not have (n = 8857; 4757 [53.7%] women; 4100 [46.3%] men; mean age, 56.6 years) an American Cancer Society-defined family history of colorectal cancer (first-degree relative with diagnosis before age 60 years or two first-degree relatives with diagnosis at any age) were compared for relevant colorectal findings. For the family history versus no family history cohorts, the frequency of all nondiminutive polyps (≥ 6 mm) reported at CTC was 23.7% versus 15.5% (p = 0.007); small polyps (6-9 mm), 13.5% versus 9.1% (p = 0.068); and large polyps (≥ 10 mm), 10.2% versus 6.5% (p = 0.068). The rate of referral for colonoscopy was greater for the family history cohort (16.0% vs 10.5%; p = 0.035). However, the frequencies of proven advanced adenoma (4.5% vs 3.2%; p = 0.357), nonadvanced adenoma (5.1% vs 2.6%; p = 0.070), and cancer (0.0% vs 0.4%; p = 0.999) were not significantly increased. The difference in positive rates between the two cohorts (11.5% vs 4.3%; p < 0.001) was primarily due to nonneoplastic findings of no colorectal cancer relevance, such as small hyperplastic polyps, diverticular disease, and false-positive CTC findings. Although the overall CTC-positive and colonoscopy referral rates were higher in the family history cohort, the clinically relevant frequencies of advanced neoplasia and cancer were not sufficiently increased to preclude CTC screening. These findings support the use of CTC as a front-line screening option in adults with a family history of colorectal cancer.

Serrated and adenomatous polyp detection increases with longer withdrawal time: results from the New Hampshire Colonoscopy Registry.

PubMed

Butterly, Lynn; Robinson, Christina M; Anderson, Joseph C; Weiss, Julia E; Goodrich, Martha; Onega, Tracy L; Amos, Christopher I; Beach, Michael L

2014-03-01

Detection and removal of adenomas and clinically significant serrated polyps (CSSPs) is critical to the effectiveness of colonoscopy in preventing colorectal cancer. Although longer withdrawal time has been found to increase polyp detection, this association and the use of withdrawal time as a quality indicator remains controversial. Few studies have reported on withdrawal time and serrated polyp detection. Using data from the New Hampshire Colonoscopy Registry, we examined how an endoscopist's withdrawal time in normal colonoscopies affects adenoma and serrated polyp detection. We analyzed 7,996 colonoscopies performed in 7,972 patients between 2009 and 2011 by 42 endoscopists at 14 hospitals, ambulatory surgery centers, and community practices. CSSPs were defined as sessile serrated polyps and hyperplastic polyps proximal to the sigmoid. Adenoma and CSSP detection rates were calculated based on median endoscopist withdrawal time in normal exams. Regression models were used to estimate the association of increased normal withdrawal time and polyp, adenoma, and CSSP detection. Polyp and adenoma detection rates were highest among endoscopists with 9 min median normal withdrawal time, and detection of CSSPs reached its highest levels at 8-9 min. Incident rate ratios for adenoma and CSSP detection increased with each minute of normal withdrawal time above 6 min, with maximum benefit at 9 min for adenomas (1.50, 95% confidence interval (CI) (1.21, 1.85)) and CSSPs (1.77, 95% CI (1.15, 2.72)). When modeling was used to set the minimum withdrawal time at 9 min, we predicted that adenomas and CSSPs would be detected in 302 (3.8%) and 191 (2.4%) more patients. The increase in detection was most striking for the CSSPs, with nearly a 30% relative increase. A withdrawal time of 9 min resulted in a statistically significant increase in adenoma and serrated polyp detection. Colonoscopy quality may improve with a median normal withdrawal time benchmark of 9 min.

Snaring large serrated polyps.

PubMed

Liang, Jennifer; Kalady, Matthew F; Church, James

2013-05-01

Serrated polyps of the large bowel are potentially premalignant, difficult to see, but important to remove. Few studies describe the technique or outcomes of serrated polypectomy. We sought to present outcomes of a series of polypectomies of large serrated polyps in comparison to a series of endoscopic resections of large adenomas. This retrospective, comparative, single endoscopist study was performed in an outpatient colonoscopy department of a tertiary referral medical center. Patients had outpatient colonoscopy where a large (≥2 cm) serrated polyp or adenoma was removed. Outcomes were completeness of excision and complications of polypectomy. A database of endoscopic polypectomies was reviewed. Polypectomy of large serrated polyps was compared with polypectomy of large adenomas. There were 132 large serrated polyps in 112 patients and 563 adenomas in 428 patients. More serrated polyps were right sided (120 of 130, 92.3 %, vs. 379 of 563, 67 %) (p < 0.0001). The serrated polyps were smaller than the adenomas (mean 25.5 ± 7.9 mm standard deviation) versus 36.8 ± 16.9 mm standard deviation (p < 0.001). There were four complications of serrated polypectomy in four patients (4 % of polyps, 5 % of patients): three postpolypectomy bleeds and one postpolypectomy syndrome. There were 33 complications of adenoma removal (31 postpolypectomy bleeding and two postpolypectomy syndrome) (6.9 % of polyps, p = 0.376, 8.4 % of patients, p = 0.371). On follow-up, 36 of 51 patients (71 %) with serrated polyps had metachronous lesions compared to 133 of 298 patients (45 %) with adenomas (p < 0.0001). There were fewer residual polyps in the serrated group (4 of 47 vs. 64 of 298, p = 0.001). Removal of large serrated colorectal polyps is no more complicated than polypectomy of similarly sized adenomas. However, large serrated polyps have a higher rate of metachronous polyps than similarly sized adenomas and surveillance should be adapted to reflect these findings.

The role of APC in WNT pathway activation in serrated neoplasia.

PubMed

Borowsky, Jennifer; Dumenil, Troy; Bettington, Mark; Pearson, Sally-Ann; Bond, Catherine; Fennell, Lochlan; Liu, Cheng; McKeone, Diane; Rosty, Christophe; Brown, Ian; Walker, Neal; Leggett, Barbara; Whitehall, Vicki

2018-03-01

Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of β-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear β-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas.

Parameters of Glucose and Lipid Metabolism Affect the Occurrence of Colorectal Adenomas Detected by Surveillance Colonoscopies

PubMed Central

Kim, Nam Hee; Suh, Jung Yul; Park, Jung Ho; Park, Dong Il; Cho, Yong Kyun; Sohn, Chong Il; Choi, Kyuyong

2017-01-01

Purpose Limited data are available regarding the associations between parameters of glucose and lipid metabolism and the occurrence of metachronous adenomas. We investigated whether these parameters affect the occurrence of adenomas detected on surveillance colonoscopy. Materials and Methods This longitudinal study was performed on 5289 subjects who underwent follow-up colonoscopy between 2012 and 2013 among 62171 asymptomatic subjects who underwent an initial colonoscopy for a health check-up between 2010 and 2011. The risk of adenoma occurrence was assessed using Cox proportional hazards modeling. Results The mean interval between the initial and follow-up colonoscopy was 2.2±0.6 years. The occurrence of adenomas detected by the follow-up colonoscopy increased linearly with the increasing quartiles of fasting glucose, hemoglobin A1c (HbA1c), insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglycerides measured at the initial colonoscopy. These associations persisted after adjusting for confounding factors. The adjusted hazard ratios for adenoma occurrence comparing the fourth with the first quartiles of fasting glucose, HbA1c, insulin, HOMA-IR, and triglycerides were 1.50 [95% confidence interval (CI), 1.26–1.77; ptrend<0.001], 1.22 (95% CI, 1.04–1.43; ptrend=0.024), 1.22 (95% CI, 1.02–1.46; ptrend=0.046), 1.36 (95% CI, 1.14–1.63; ptrend=0.004), and 1.19 (95% CI, 0.99–1.42; ptrend=0.041), respectively. In addition, increasing quartiles of low-density lipoprotein-cholesterol and apolipoprotein B were associated with an increasing occurrence of adenomas. Conclusion The levels of parameters of glucose and lipid metabolism were significantly associated with the occurrence of adenomas detected on surveillance colonoscopy. Improving the parameters of glucose and lipid metabolism through lifestyle changes or medications may be helpful in preventing metachronous adenomas. PMID:28120565

No evidence of decreased risk of colorectal adenomas with white meat, poultry, and fish intake: a meta-analysis of observational studies.

PubMed

Xu, Bin; Sun, Jing; Sun, Yunwei; Huang, Liya; Tang, Yuming; Yuan, Yaozong

2013-04-01

Observational studies on the association between white meat (including fish and poultry) intake and the risk of colorectal adenoma (CRA), the precursor of colorectal cancer, have reported mixed results. To provide a quantitative assessment of this association, we summarized the evidence from observational studies. Relevant studies published on or before April 30, 2012 were identified from MEDLINE and EMBASE. Summary effect size estimates with 95% confidence intervals (CIs) were calculated with a random-effects model. Between-study heterogeneity was assessed using the Cochran Q and I(2) statistics. A total of 23 publications from 21 independent studies (16 case-control and 5 cohort studies) were included in this meta-analysis. Based on high versus low analysis, the summary effect size estimate of CRA was 0.96 (95% CI, 0.84-1.09) for white meat intake, 0.98 (95% CI, 0.80-1.19) for fish intake, and 0.98 (95% CI, 0.80-1.18) for poultry intake. Subgroup analyses revealed that the null associations of CRA with intake of white meat (fish/poultry) were independent of geographic locations, study design, type of food frequency questionnaire, number of cases, and adjustments for confounders, such as body mass index, use of nonsteroidal anti-inflammatory drugs, dietary energy intake, smoking, and physical activity. Intake of white meat (fish/poultry) is not associated with the risk of CRA. Copyright © 2013 Elsevier Inc. All rights reserved.

Serum concentrations of fatty acids and colorectal adenoma risk: a case-control study in Japan.

PubMed

Ghadimi, Reza; Kuriki, Kiyonori; Tsuge, Shinji; Takeda, Emiru; Imaeda, Nahomi; Suzuki, Sadao; Sawai, Asuka; Takekuma, Kiyoshi; Hosono, Akihiro; Tokudome, Yuko; Goto, Chiho; Esfandiary, Imaneh; Nomura, Hisashi; Tokudome, Shinkan

2008-01-01

Epidemiologic studies of n-3 fatty acids (FAs) and risk of colorectal cancer have generated inconsistent results, and relations with precursor colorectal adenomas (CRA) have not been evaluated in detail. We here focused on possible associations of serum FAs with CRA in the Japanese population. We conducted a case-control study of 203 asymptomatic CRA cases (148 men, 55 women) and 179 healthy controls (67 men, 112 women) during 1997-2003 in Nagoya, Japan. Baseline information was obtained using a lifestyle questionnaire and serum FA levels were measured by gas chromatography. A non-significant inverse association with CRA was observed for eicosapentaenoic acid (EPA) among women. Moreover, the concentrations of docosahexaenoeic acid (DHA), a major component of n-3 highly-unsaturated FAs (HUFAs), were significantly lower in cases in both sexes. In addition, serum concentrations of total FAs, saturated FAs (SFAs) and mono-unsaturated FAs (MUFAs) had strong positive links with CRA risk. In contrast, arachidonic acid (AA) and DHA were inversely related, with 66% and 59% risk reduction, respectively. Ratios of SFAs/n-3 PUFAs and SFAs/n-3 HUFAs exhibited significant positive relations with CRA risk but there was no clear link with n-6 PUFAs/n-3 PUFAs. Our findings suggest a promoting influence of SFAs and MUFAs along with a protective effect of DHA on CRA risk. However, further research is needed to investigate the observed discrepancy with the generally accepted roles of the AA cascade in carcinogenesis.

Helicobacter pylori and colorectal neoplasia: Is there a causal link?

PubMed Central

Papastergiou, Vasilios; Karatapanis, Stylianos; Georgopoulos, Sotirios D

2016-01-01

Ever since Helicobacter pylori (H. pylori) was recognized as an infectious cause of gastric cancer, there has been increasing interest in examining its potential role in colorectal carcinogenesis. Data from case-control and cross-sectional studies, mostly relying on hospital-based samples, and several meta-analyses have shown a positive statistical relationship between H. pylori infection and colorectal neoplasia. However, the possibility exists that the results have been influenced by bias, including the improper selection of patients and disparities with respect to potential confounders. While the evidence falls short of a definitive causal link, it appears that infection with H. pylori/H. pylori-related gastritis is associated with an increased, although modest, risk of colorectal adenoma and cancer. The pathogenic mechanisms responsible for this association remain uncertain. H. pylori has been detected in colorectal malignant tissues; however, the possibility that H. pylori is a direct activator of colonic carcinogenesis remains purely hypothetical. On the other hand, experimental data have indicated a series of potential oncogenic interactions between these bacteria and colorectal mucosa, including induction and perpetuation of inflammatory responses, alteration of gut microflora and release of toxins and/or hormonal mediators, such as gastrin, which may contribute to tumor formation. PMID:26811614

History, evolution, and current status of radiologic imaging tests for colorectal cancer screening.

PubMed

Levine, Marc S; Yee, Judy

2014-11-01

Colorectal cancer screening is thought to be an effective tool with which to reduce the mortality from colorectal cancer through early detection and removal of colonic adenomas and early colon cancers. In this article, we review the history, evolution, and current status of imaging tests of the colon-including single-contrast barium enema, double-contrast barium enema, computed tomographic (CT) colonography, and magnetic resonance (MR) colonography-for colorectal cancer screening. Despite its documented value in the detection of colonic polyps, the double-contrast barium enema has largely disappeared as a screening test because it is widely perceived as a labor-intensive, time-consuming, and technically demanding procedure. In the past decade, the barium enema has been supplanted by CT colonography as the major imaging test in colorectal cancer screening in the United States, with MR colonography emerging as another viable option in Europe. Although MR colonography does not require ionizing radiation, the radiation dose for CT colonography has decreased substantially, and regular screening with this technique has a high benefit-to-risk ratio. In recent years, CT colonography has been validated as an effective tool for use in colorectal cancer screening that is increasingly being disseminated.

EGFR Overexpressed in Colonic Neoplasia Can be Detected on Wide-Field Endoscopic Imaging.

PubMed

Zhou, Juan; Joshi, Bishnu P; Duan, Xiyu; Pant, Asha; Qiu, Zhen; Kuick, Rork; Owens, Scott R; Wang, Thomas D

2015-07-16

Colorectal cancer initially lies dormant as dysplasia, a premalignant state that provides an opportunity for early cancer detection. Dysplasia can be flat in morphology, focal in size, and patchy in distribution, and thus it appears "invisible" on conventional wide-field endoscopy. We aim to develop and validate a peptide that is specific for epidermal growth factor receptor (EGFR), a cell surface target that is overexpressed in colonic adenomas and is readily accessible for imaging. We expressed and purified the extracellular domain of EGFR for use with phage display to identify a peptide QRHKPRE that binds to domain 2 of this target. A near-infrared fluorescence endoscope was used to perform in vivo imaging to validate specific peptide binding to spontaneous colonic adenomas in a mouse model with topical administration. We also validated specific peptide binding to human colonic adenomas on immunohistochemistry and immunofluorescence. After labeling with Cy5.5, we validated specific peptide binding to EGFR on knockdown and competition studies. Peptide binding to cells occurred within 2.46 min and had an affinity of 50 nm. No downstream signaling was observed. We measured a target-to-background ratio of 4.0±1.7 and 2.7±0.7, for polyps and flat lesions, respectively. On immunofluorescence of human colonic specimens, greater intensity from peptide binding to dysplasia than normal was found with a 19.4-fold difference. We have selected and validated a peptide that can be used as a specific contrast agent to identify colonic adenomas that overexpress EGFR in vivo on fluorescence endoscopy.

Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas

PubMed Central

Montazeri, Zahra; Theodoratou, Evropi; Nyiraneza, Christine; Timofeeva, Maria; Chen, Wanjing; Svinti, Victoria; Sivakumaran, Shanya; Gresham, Gillian; Cubitt, Laura; Carvajal-Carmona, Luis; Bertagnolli, Monica M; Zauber, Ann G; Tomlinson, Ian; Farrington, Susan M; Dunlop, Malcolm G; Campbell, Harry; Little, Julian

2018-01-01

Background Low penetrance genetic variants, primarily single nucleotide polymorphisms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from colorectal adenomas (CRA). Here, we report the first comprehensive field synopsis that catalogues all genetic association studies on CRA, with a parallel online database (http://www.chs.med.ed.ac.uk/CRAgene/). Methods We performed a systematic review, reviewing 9750 titles and then extracted data from 130 publications reporting on 181 polymorphisms in 74 genes. We conducted meta-analyses to derive summary effect estimates for 37 polymorphisms in 26 genes. We applied the Venice criteria and Bayesian False Discovery Probability (BFDP) to assess the levels of the credibility of associations. Results We considered the association with the rs6983267 variant at 8q24 as “highly credible”, reaching genome wide statistical significance in at least one meta-analysis model. We identified “less credible” associations (higher heterogeneity, lower statistical power, BFDP>0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V (rs1801133), TP53 c.215C>G p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes. For the remaining 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations. Conclusions The limited number of credible associations between low penetrance genetic variants and CRA reflects the lower volume of evidence and associated lack of statistical power to detect associations of the magnitude typically observed for genetic variants and chronic diseases. The CRAgene database provides context for CRA genetic association data and will help inform future research directions. PMID:26451011

Construction of a multiplex mutation hot spot PCR panel: the first step towards colorectal cancer genotyping on the GS Junior platform.

PubMed

Péterfia, Bálint; Kalmár, Alexandra; Patai, Árpád V; Csabai, István; Bodor, András; Micsik, Tamás; Wichmann, Barnabás; Egedi, Krisztina; Hollósi, Péter; Kovalszky, Ilona; Tulassay, Zsolt; Molnár, Béla

2017-01-01

Background: To support cancer therapy, development of low cost library preparation techniques for targeted next generation sequencing (NGS) is needed. In this study we designed and tested a PCR-based library preparation panel with limited target area for sequencing the top 12 somatic mutation hot spots in colorectal cancer on the GS Junior instrument. Materials and Methods: A multiplex PCR panel was designed to amplify regions of mutation hot spots in 12 selected genes ( APC, BRAF, CTNNB1, EGFR, FBXW7, KRAS, NRAS, MSH6, PIK3CA, SMAD2, SMAD4, TP53 ). Amplicons were sequenced on a GS Junior instrument using ligated and barcoded adaptors. Eight samples were sequenced in a single run. Colonic DNA samples (8 normal mucosa; 33 adenomas; 17 adenocarcinomas) as well as HT-29 and Caco-2 cell lines with known mutation profiles were analyzed. Variants found by the panel on APC, BRAF, KRAS and NRAS genes were validated by conventional sequencing. Results: In total, 34 kinds of mutations were detected including two novel mutations ( FBXW7 c.1740:C>G and SMAD4 c.413C>G) that have not been recorded in mutation databases, and one potential germline mutation ( APC ). The most frequently mutated genes were APC, TP53 and KRAS with 30%, 15% and 21% frequencies in adenomas and 29%, 53% and 29% frequencies in carcinomas, respectively. In cell lines, all the expected mutations were detected except for one located in a homopolymer region. According to re-sequencing results sensitivity and specificity was 100% and 92% respectively. Conclusions: Our NGS-based screening panel denotes a promising step towards low cost colorectal cancer genotyping on the GS Junior instrument. Despite the relatively low coverage, we discovered two novel mutations and obtained mutation frequencies comparable to literature data. Additionally, as an advantage, this panel requires less template DNA than sequence capture colon cancer panels currently available for the GS Junior instrument.

The variation trends of SFRP2 methylation of tissue, feces, and blood detection in colorectal cancer development.

PubMed

Sui, Chengguang; Ma, Jianzhong; Chen, Qun; Yang, Yang

2016-07-01

The susceptibility of secreted frizzled-related protein 2 (SFRP2) methylation in colorectal cancer (CRC) has been studied previously. The aim of this study was to determine the risk sizes and variation trends of SFRP2 methylation in CRC development in Chinese populations. Subgroup meta-analysis and the least-squares curve-fitting method were carried out to analyze the risk of SFRP2 methylation in tissue, feces, and blood detection from 2221 samples, including a total of 1103 cases of CRC, 459 cases of adenoma, 257 cases of polyps, and 402 controls. The data showed that odds ratios (95% confidence intervals) between CRC and controls for tissue, feces, and blood detection were 334.01 (104.42-1068.39), 63.76 (20.62-197.63), and 133.75 (18.32-976.32), respectively. There were also significant differences between tissue and feces or blood as well as between feces and blood methylation frequency. These results showed that the risk size in tissue was much greater than that in feces and that in blood. The results pointed out that three curves in tissue, feces, and blood detection described the variation trends of methylation incidence from the control to polyp, to adenoma and to CRC, and that the variation trend of the risk size of SFRP2 methylation was synchronized with the histological evolution process of CRC. The variation trend of the risk size of SFRP2 methylation incidence is consistent with the histological evolution process of CRC. The susceptibility to SFRP2 methylation is an important biomarker in the study of early diagnosis of CRC and high-risk patients.

Black Raspberries Enhance Natural Killer Cell Infiltration into the Colon and Suppress the Progression of Colorectal Cancer

PubMed Central

Pan, Pan; Kang, Siwen; Wang, Youwei; Liu, Ka; Oshima, Kiyoko; Huang, Yi-Wen; Zhang, Jianying; Yearsley, Martha; Yu, Jianhua; Wang, Li-Shu

2017-01-01

Natural killer (NK) cells are an essential component of innate immunity against cancer development. Many studies have been conducted to evaluate immune-modulating effects using dietary compounds. Our laboratory has been investigating the chemopreventive potential of black raspberries (BRBs) and previously demonstrated their beneficial modulation of genetic and epigenetic biomarkers in patients with colorectal cancer (CRC). The current study investigated their potential on modulating NK cells. To avoid the excessive inflammation caused by the dextran sulfate sodium (DSS) treatment that leads to colitis, we treated the mice with overnight DSS so that it would slightly irritate the colon but still promote colon carcinogenesis with 100% incidence in both the ApcMin/+ mice and azoxymethane (AOM)-treated mice. A significant decrease of tissue-infiltrating NK cells along the progression of microadenoma-to-adenoma and adenoma-to-adenocarcinoma was observed in the ApcMin/+/DSS and AOM/DSS mice, respectively. Depletion of NK cells significantly promoted the development of CRC, suggesting a critical role of NK cells in combating CRC progression. BRBs significantly suppressed the CRC progression and increased the number of tissue-infiltrating NK cells in both mouse models. Moreover, we further determined BRBs’ effects on NK cells in the human biopsy specimens collected from our previously completed clinical trial, in which CRC patients consumed BRBs for an average of 4 weeks during a presurgical window. We observed an increased number and an enhanced cytotoxicity of NK cells by BRB intervention. The current study provides evidence that BRBs have the potential to enhance the tumor immunesurveillance of NK cells that can be beneficial in the setting of CRC prevention and treatment. PMID:28861089

Different surgical strategies in the treatment of familial adenomatous polyposis: what's the role of the ileorectal anastomosis?

PubMed

Wolthuis, Albert M; Leonard, Daniel; Kartheuser, Alex; Bruyninx, Luc; Van De Stadt, Jean; Van Cutsem, Eric; D'Hoore, André

2011-09-01

Prophylactic (procto-) colectomy is the treatment of choice to reduce the risk of colorectal cancer in FAP patients with multiple adenomas. Because patients present at young age, rectum-sparing surgery is sometimes advocated, so that there is no pelvic dissection with impact on quality of life, preserved pelvic innervation and sexual function and fertility. The main disadvantage of a total colectomy with an ileorectal anastomosis (IRA) is a rectal cancer risk of 50% at the age of 50 years and a cumulative risk of 25.8% after 25 years of follow-up. Therefore, this procedure should be reserved for patients with an unaffected rectum. There should be no discussion to perform a primary IPAA in patients with multiple rectal adenomas (> 20) or those with a severe dysplastic or large (> 3 cm) rectal adenoma or a cancer elsewhere in the colon. A patient with an IRA should undergo yearly follow-up by rectoscopy.

Optical spectroscopy combined with high-resolution magnetic resonance imaging for digestive wall assessment: endoluminal bimodal probe conception and characterization in vitro, on organic sample and in vivo on a rabbit

NASA Astrophysics Data System (ADS)

Ramgolam, Anoop; Sablong, Raphaël; Lafarge, Lionel; Saint-Jalmes, Hervé; Beuf, Olivier

2011-11-01

Colorectal cancer is a major health issue worldwide. Conventional white light endoscopy (WLE) coupled to histology is considered as the gold standard today and is the most widespread technique used for colorectal cancer diagnosis. However, during the early stages, colorectal cancer is very often characterized by flat adenomas which develop just underneath the mucosal surface. The use of WLE, which is heavily based on the detection of morphological changes, becomes quite delicate due to subtle or quasi-invisible morphological changes of the colonic lining. Several techniques are currently being investigated in the scope of providing new tools that would allow such a diagnostic or assist actual techniques in so doing. We hereby present a novel technique where high spatial resolution MRI is combined with autofluorescence and reflectance spectroscopy in a bimodal endoluminal probe to extract morphological data and biochemical information, respectively. The design and conception of the endoluminal probe are detailed and the promising preliminary results obtained in vitro (home-built phantom containing eosin and rhodamine B), on an organic sample (the kiwi fruit) and in vivo on a rabbit are presented and discussed.

Genome-wide Analysis of Germline CNPs and SNPs in Prostate Cancer

DTIC Science & Technology

2010-03-01

colorectal adenomas. Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15992-7. 12) Iliopoulos D, Guler G, Han SY, Druck T, Ottey M, McCorkell KA...SNPs and copy number variation. Nat Genet. 2008 Oct;40(10):1166-74. 17) Qin HR, Iliopoulos D, Semba S, Fabbri M, Druck T, Volinia S, Croce CM

Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers

PubMed Central

Georgitsi, M; Karhu, A; Winqvist, R; Visakorpi, T; Waltering, K; Vahteristo, P; Launonen, V; Aaltonen, L A

2007-01-01

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently identified in individuals with pituitary adenoma predisposition (PAP). These patients have prolactin (PRL) or growth hormone (GH) oversecreting pituitary adenomas, the latter exhibiting acromegaly or gigantism. Loss-of-heterozygosity (LOH) analysis revealed that AIP is lost in PAP tumours, suggesting that it acts as a tumour-suppressor gene. Aryl hydrocarbon receptor interacting protein is involved in several pathways, but it is best characterised as a cytoplasmic partner of the aryl hydrocarbon receptor (AHR). To examine the possible role of AIP in the genesis of common cancers, we performed somatic mutation screening in a series of 373 colorectal cancers (CRCs), 82 breast cancers, and 44 prostate tumour samples. A missense R16H (47G>A) change was identified in two CRC samples, as well as in the respective normal tissues, but was absent in 209 healthy controls. The remaining findings were silent, previously unreported, changes of the coding, non-coding, or untranslated regions of AIP. These results suggest that somatic AIP mutations are not common in CRC, breast, and prostate cancers. PMID:17242703

High definition plus colonoscopy combined with i-scan tone enhancement vs. high definition colonoscopy for colorectal neoplasia: A randomized trial.

PubMed

Hoffman, Arthur; Loth, Linn; Rey, Johannes Wilhelm; Rahman, Fareed; Goetz, Martin; Hansen, Torsten; Tresch, Achim; Niederberger, Theresa; Galle, Peter Robert; Kiesslich, Ralf

2014-11-01

High definition endoscopy is the accepted standard in colonoscopy. However, an important problem is missed polyps. Our objective was to assess the additional adenoma detection rate between high definition colonoscopy with tone enhancement (digital chromoendoscopy) vs. white light high definition colonoscopy. In this prospective randomized trial patients were included to undergo a tandem colonoscopy. The first exam was a white light colonoscopy with removal of all visualized polyps. The second examination was randomly assigned in a 1:1 ratio as either again white light colonoscopy (Group A) or colonoscopy with tone enhancement (Group B). Primary endpoint was the adenoma detection rate during the second withdrawal (sample size calculation - 40 per group). 67 lesions (Group A: n=34 vs. Group B: n=33) in 80 patients (mean age 61 years, male 64%) were identified on the first colonoscopy. The second colonoscopy detected 78 additional lesions: n=60 with tone enhancement vs. n=18 with white light endoscopy (p<0.001). Tone enhancement found more additional adenomas (A n=20 vs. B n=6, p=0.006) and identified significantly more missed adenomas per subject (0.5 vs. 0.15, p=0.006). High definition plus colonoscopy with tone enhancement detected more adenomas missed by white light colonoscopy. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype

PubMed Central

Toyota, Minoru; Ohe-Toyota, Mutsumi; Ahuja, Nita; Issa, Jean-Pierre J.

2000-01-01

Colorectal cancers (CRCs) are characterized by multiple genetic (mutations) and epigenetic (CpG island methylation) alterations, but it is not known whether these evolve independently through stochastic processes. We have recently described a novel pathway termed CpG island methylator phenotype (CIMP) in CRC, which is characterized by the simultaneous methylation of multiple CpG islands, including several known genes, such as p16, hMLH1, and THBS1. We have now studied mutations in K-RAS, p53, DPC4, and TGFβRII in a panel of colorectal tumors with or without CIMP. We find that CIMP defines two groups of tumors with significantly different genetic lesions: frequent K-RAS mutations were found in CIMP+ CRCs (28/41, 68%) compared with CIMP− cases (14/47, 30%, P = 0.0005). By contrast, p53 mutations were found in 24% (10/41) of CIMP+ CRCs vs. 60% (30/46) of CIMP− cases (P = 0.002). Both of these differences were independent of microsatellite instability. These interactions between CIMP, K-RAS mutations, and p53 mutations were preserved in colorectal adenomas, suggesting that they occur early in carcinogenesis. The distinct combinations of epigenetic and genetic alterations in each group suggest that activation of oncogenes and inactivation of tumor suppressor genes is related to the underlying mechanism of generating molecular diversity in cancer, rather than simply accumulate stochastically during cancer development. PMID:10639144

UK guidance for the pathological reporting of serrated lesions of the colorectum.

PubMed

Bateman, Adrian C; Shepherd, Neil A

2015-08-01

Bowel cancer screening programmes have highlighted to endoscopists and clinicians the spectrum of serrated colorectal lesions. One of the most significant developments has been the recognition that sessile serrated lesions (SSLs), while bearing histological resemblance to hyperplastic polyps (HPs), may be associated with the enhanced development of epithelial dysplasia and colorectal adenocarcinoma. Different minimum criteria exist for the diagnosis of SSLs and their differentiation from HPs. Furthermore, the spectrum of terminology used to describe the entire range of serrated lesions is wide. This variability has impaired interobserver agreement during their histopathological assessment. Here, we provide guidance for the histopathological reporting of serrated lesions, including a simplified nomenclature system. Essentially, we recommend use of the following terms: HP, SSL, SSL with dysplasia, traditional serrated adenoma (TSA) and mixed polyp. It is hoped that this standardisation of nomenclature will facilitate studies of the biological significance of serrated lesions in terms of the relative risk of disease progression. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention

PubMed Central

Liskay, R.Michael

2014-01-01

Although Apc mutation is widely considered an initiating event in colorectal cancer, little is known about the earliest stages of tumorigenesis following sporadic Apc loss. Therefore, we have utilized a novel mouse model that facilitates the sporadic inactivation of Apc via frameshift reversion of Cre in single, isolated cells and subsequently tracks the fates of Apc-deficient intestinal cells. Our results suggest that consistent with Apc being a ‘gatekeeper’, loss of Apc early in life during intestinal growth leads to adenomas or increased crypt fission, manifested by fields of mutant but otherwise normal-appearing crypts. In contrast, Apc loss occurring later in life has minimal consequences, with mutant crypts being less prone to either increased crypt fission or adenoma formation. Using the stem cell-specific Lgr5-CreER mouse, we generated different sized fields of Apc-deficient crypts via independent recombination events and found that field size correlates with progression to adenoma. To evaluate this early stage prior to adenoma formation as a therapeutic target, we examined the chemopreventive effects of sulindac on Apc-deficient occult crypt fission. We found that sulindac treatment started early in life inhibits the morphologically occult spread of Apc-deficient crypts and thus reduces adenoma numbers. Taken together these results suggest that: (i) earlier Apc loss promotes increased crypt fission, (ii) a field of Apc-deficient crypts, which can form via occult crypt fission or independent neighboring events, is an important intermediate between loss of Apc and adenoma formation and (iii) normal-appearing Apc-deficient crypts are potential unappreciated targets for cancer screening and chemoprevention. PMID:23996931

Epidemiology of goblet cell and microvesicular hyperplastic polyps.

PubMed

Qazi, Taha M; O'Brien, Michael J; Farraye, Francis A; Gould, Ryan W; Chen, Clara A; Schroy, Paul C

2014-12-01

Serrated polyps compromise both typical hyperplastic polyps as well as sessile serrated adenomas and dysplastic serrated polyps. Hyperplastic polyps exhibit two histological patterns: microvesicular hyperplastic polyps (MVHPs) and goblet cell hyperplastic polyps (GCHPs). MVHPs and GCHPs differ in their molecular signature. MVHPs have been frequently found to have the BRAF(V600E) mutation as well as aberrant methylation. In contrast, GCHPs have been associated with the KRAS mutation (KRAS-mut), which are infrequently seen in dysplastic serrated sessile adenomas. The particular risk factors that are associated with development of the types of hyperplastic polyps have not been previously studied. The purpose of this study is to characterize the associations between particular risk factors and the development of goblet cell or microvesicular hyperplastic polyps. We conducted a cross-sectional analysis of 3,543 asymptomatic, mostly average risk patients 50 and 79 years of age undergoing open-access screening colonoscopy between March 2005 and January 2012. Each patient was given a survey regarding 25 reputed risk factors for colorectal neoplasia and the responses were correlated with findings at colonoscopy. Associations between putative risk factors for colorectal neoplasia and MVHPs and GSHPs were examined using multiple logistic regression. MVHPS and GCHPs were identified in 5.3% and 8.7% of patients, respectively. The results of the statistical analysis indicate that a history of smoking greater than 20 years is associated with an increased risk of MVHPs (P<0.005) and GCHPs (P<0.005). An elevated BMI >30 kg/m(2) was also associated with the presence of MVHP at colonoscopy (P<0.005). Blacks and Asians appear to be protected from the development of MVHPs. In contrast, there was a positive association with the presence of GCHP at colonoscopy in blacks. The study suggests that the development of the distinct histological types of hyperplastic polyps are associated with distinct modifiable and non-modifiable lifestyle factors.

Strategies to Increase Adenoma Detection Rates.

PubMed

Brand, Eelco C; Wallace, Michael B

2017-03-01

The adenoma detection rate (ADR), i.e., the proportion of average risk patients with at least one adenoma detected during screening colonoscopy, is inversely associated with the development of interval colorectal cancer. Increasing the ADR is therefore an important proxy for increase in quality and efficacy of (screening) colonoscopy. Several potentially modifiable factors, such as, procedural and technological factors, and quality improvement programs, and their effect on the ADR will be reviewed. Procedural factors, such as, bowel preparation, withdrawal time, and position changes of the patient are associated with the ADR. While the relation of others, such as inspection during insertion, use of antispasmodic agents, and second inspection in the proximal colon, with the ADR is not completely clear. Many new colonoscopy technologies have been evaluated over recent years and are still under evaluation, but no unequivocal positive effect on the ADR has been observed in randomized trials that have mostly been performed by experienced endoscopists with high baseline ADRs. Several quality improvement programs have been evaluated and seem to have a positive effect on endoscopists' ADR. Increase in ADR is important for the protective benefit of colonoscopy. There are now extensive methods to measure, benchmark, and improve ADR but increased awareness of these is critical. We have provided an overview of potential factors that can be used to increase personal ADRs in every day practice.

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche.

PubMed

Davis, Hayley; Irshad, Shazia; Bansal, Mukesh; Rafferty, Hannah; Boitsova, Tatjana; Bardella, Chiara; Jaeger, Emma; Lewis, Annabelle; Freeman-Mills, Luke; Giner, Francesc Castro; Rodenas-Cuadrado, Pedro; Mallappa, Sreelakshmi; Clark, Susan; Thomas, Huw; Jeffery, Rosemary; Poulsom, Richard; Rodriguez-Justo, Manuel; Novelli, Marco; Chetty, Runjan; Silver, Andrew; Sansom, Owen James; Greten, Florian R; Wang, Lai Mun; East, James Edward; Tomlinson, Ian; Leedham, Simon John

2015-01-01

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

Clonal evolution of colorectal cancer in IBD.

PubMed

Choi, Chang-Ho R; Bakir, Ibrahim Al; Hart, Ailsa L; Graham, Trevor A

2017-04-01

Optimizing the management of colorectal cancer (CRC) risk in IBD requires a fundamental understanding of the evolutionary process underpinning tumorigenesis. In IBD, clonal evolution begins long before the development of overt neoplasia, and is probably accelerated by the repeated cycles of epithelial wounding and repair that are characteristic of the condition. Here, we review the biological drivers of mutant clone selection in IBD with particular reference to the unique histological architecture of the intestinal epithelium coupled with the inflammatory microenvironment in IBD, and the unique mutation patterns seen in IBD-driven neoplasia when compared with sporadic adenomas and CRC. How these data can be leveraged as evolutionary-based biomarkers to predict cancer risk is discussed, as well as how the efficacy of CRC surveillance programmes and the management of dysplasia can be improved. From a research perspective, the longitudinal surveillance of patients with IBD provides an under-exploited opportunity to investigate the biology of the human gastrointestinal tract over space and time.

Colorectal cancer chemoprevention: the potential of a selective approach.

PubMed

Ben-Amotz, Oded; Arber, Nadir; Kraus, Sarah

2010-10-01

Colorectal cancer (CRC) is a leading cause of cancer death, and therefore demands special attention. Novel recent approaches for the chemoprevention of CRC focus on selective targeting of key pathways. We review the study by Zhang and colleagues, evaluating a selective approach targeting APC-deficient premalignant cells using retinoid-based therapy and TNF-related apoptosis-inducing ligand (TRAIL). This study demonstrates that induction of TRAIL-mediated death signaling contributes to the chemopreventive value of all-trans-retinyl acetate (RAc) by sensitizing premalignant adenoma cells for apoptosis without affecting normal cells. We discuss these important findings, raise few points that deserve consideration, and may further contribute to the development of RAc-based combination therapies with improved efficacy. The authors clearly demonstrate a synergistic interaction between TRAIL, RAc and APC, which leads to the specific cell death of premalignant target cells. The study adds to the growing body of literature related to CRC chemoprevention, and provides solid data supporting a potentially selective approach for preventing CRC using RAc and TRAIL.

Endoscopic full-thickness resection in the colorectum with a novel over-the-scope device: first experience.

PubMed

Schmidt, Arthur; Bauerfeind, Peter; Gubler, Christoph; Damm, Michael; Bauder, Markus; Caca, Karel

2015-08-01

Endoscopic full-thickness resection (EFTR) in the lower gastrointestinal tract may be a valuable therapeutic and diagnostic approach for a variety of indications. Although feasibility of EFTR has been demonstrated, there is a lack of safe and effective endoscopic devices for routine use. The aim of this study was to investigate the efficacy and safety of a novel over-the-scope device for colorectal EFTR. Between July 2012 and July 2014, 25 patients underwent EFTR at two tertiary referral centers. All resections were performed using the full-thickness resection device (FTRD; Ovesco Endoscopy, Tübingen, Germany). Data were collected retrospectively. Indications for EFTR were: recurrent or incompletely resected adenoma with nonlifting sign (n = 11), untreated adenoma and nonlifting sign (n = 2), adenoma involving the appendix (n = 5), flat adenoma in a patient with coagulopathy (n = 1), diagnostic re-resection after incomplete resection of a T1 carcinoma (n = 2), adenoma involving a diverticulum (n = 1), submucosal tumor (n = 2), and diagnostic resection in a patient with suspected Hirschsprung's disease (n = 1). In one patient, the lesion could not be reached because of a sigmoid stenosis. In the other patients, resection of the lesion was macroscopically complete and en bloc in 20/24 patients (83.3 %). The mean diameter of the resection specimen was 24 mm (range 12 - 40 mm). The R0 resection rate was 75.0 % (18/24), and full-thickness resection was histologically confirmed in 87.5 %. No perforations or major bleeding were observed during or after resection. Two patients developed postpolypectomy syndrome, which was managed with antibiotic therapy. Full-thickness resection in the lower gastrointestinal tract with the novel FTRD was feasible and effective. Prospective studies are needed to further evaluate the device and technique. © Georg Thieme Verlag KG Stuttgart · New York.

A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma.

PubMed

Kimura, Tomoaki; Yamamoto, Eiichiro; Yamano, Hiro-O; Suzuki, Hiromu; Kamimae, Seiko; Nojima, Masanori; Sawada, Takeshi; Ashida, Masami; Yoshikawa, Kenjiro; Takagi, Ryo; Kato, Ryusuke; Harada, Taku; Suzuki, Ryo; Maruyama, Reo; Kai, Masahiro; Imai, Kohzoh; Shinomura, Yasuhisa; Sugai, Tamotsu; Toyota, Minoru

2012-03-01

Sessile serrated adenomas (SSAs) are known to be precursors of sporadic colorectal cancers (CRCs) with microsatellite instability (MSI), and to be tightly associated with BRAF mutation and the CpG island methylator phenotype (CIMP). Consequently, colonoscopic identification of SSAs has important implications for preventing CRCs, but accurate endoscopic diagnosis is often difficult. Our aim was to clarify which endoscopic findings are specific to SSAs. The morphological, histological and molecular features of 261 specimens from 226 colorectal tumors were analyzed. Surface microstructures were analyzed using magnifying endoscopy. Mutation in BRAF and KRAS was examined by pyrosequencing. Methylation of p16, IGFBP7, MLH1 and MINT1, -2, -12 and -31 was analyzed using bisulfite pyrosequencing. Through retrospective analysis of a training set (n=145), we identified a novel surface microstructure, the Type II open-shape pit pattern (Type II-O), which was specific to SSAs with BRAF mutation and CIMP. Subsequent prospective analysis of an independent validation set (n=116) confirmed that the Type II-O pattern is highly predictive of SSAs (sensitivity, 65.5%; specificity, 97.3%). BRAF mutation and CIMP occurred with significant frequency in Type II-O-positive serrated lesions. Progression of SSAs to more advanced lesions was associated with further accumulation of aberrant DNA methylation and additional morphological changes, including the Type III, IV and V pit patterns. Our results suggest the Type II-O pit pattern is a useful hallmark of the premalignant stage of CRCs with MSI and CIMP, which could serve to improve the efficacy of colonoscopic surveillance.

Red and processed meat intake and risk of colorectal adenomas: a meta-analysis of observational studies.

PubMed

Xu, Xiaodong; Yu, Enda; Gao, Xianhua; Song, Ning; Liu, Lianjie; Wei, Xubiao; Zhang, Wei; Fu, Chuangang

2013-01-15

Inconsistent results regarding the association between red and processed meat intake and the risk of colorectal adenoma (CRA), the precursor of colorectal cancer (CRC), have been reported. To provide a quantitative assessment of this association, we summarized the evidence from observational studies. Relevant studies were identified in MEDLINE and EMBASE until December 31, 2011. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were pooled with a random-effects model. Between-study heterogeneity was assessed using the Cochran's Q and I(2) statistics. A total of 21 studies (16 case-control studies and five cohort/nested case-control studies) were included in this meta-analysis. The SRRs of CRA were 1.36 (95% CI = 1.17-1.58) for every 100 g/day increase in red meat intake, and 1.24 (95% CI = 1.12-1.36) for the highest versus the lowest level of red meat intake. Nonlinear dose-response meta-analysis indicated that CRA risk increased approximately linearly with increasing intake of red meat up to ~ 90 g/day, where the curve reached its plateau. Subgrouped analyses revealed that the increased risk of CRA with intake of red meat was independent of geographic locations, design and confounders. The SRRs of CRA was 1.28 (95% CI = 1.03-1.60) for per 50 g/day increase in processed meat intake, and 1.17 (95% CI = 1.08-1.26) for the highest versus the lowest level of processed meat intake. Increased intake of red and processed meat is associated with significantly increased risk of CRA. Copyright © 2012 UICC.

Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma.

PubMed

Chen, Hui-Min; Yu, Ya-Nan; Wang, Ji-Lin; Lin, Yan-Wei; Kong, Xuan; Yang, Chang-Qing; Yang, Li; Liu, Zhan-Ju; Yuan, Yao-Zong; Liu, Fei; Wu, Jian-Xin; Zhong, Liang; Fang, Dian-Chun; Zou, Weiping; Fang, Jing-Yuan

2013-05-01

Accumulating evidence indicates that diet is one of the most important environmental factors involved in the progression from advanced colorectal adenoma (A-CRA) to colorectal cancer. We evaluated the possible effects of dietary fiber on the fecal microbiota of patients with A-CRA. Patients with a diagnosis of A-CRA by pathological examination were enrolled in the A-CRA group. Patients with no obvious abnormalities or histopathological changes were enrolled in the healthy control (HC) group. Dietary fiber intake was assessed in all patients. Short-chain fatty acids (SCFAs) in feces were detected by gas chromatography. The fecal microbiota community was analyzed by 454 pyrosequencing based on 16S ribosomal RNA. Lower dietary fiber patterns and consistently lower SCFA production were observed in the A-CRA group (n = 344). Principal component analysis showed distinct differences in the fecal microbiota communities of the 2 groups. Clostridium, Roseburia, and Eubacterium spp. were significantly less prevalent in the A-CRA group (n = 47) than in the HC group (n = 47), whereas Enterococcus and Streptococcus spp. were more prevalent in the A-CRA group (n = 47) (all P < 0.05). Butyrate and butyrate-producing bacteria were more prevalent in a subgroup of HC subjects with a high fiber intake than in those in both the low-fiber HC subgroup and the high-fiber A-CRA subgroup (all P < 0.05). A high-fiber dietary pattern and subsequent consistent production of SCFAs and healthy gut microbiota are associated with a reduced risk of A-CRA. This trial was registered at www.chictr.org as ChiCTR-TRC-00000123.

Somatic APC mosaicism and oligogenic inheritance in genetically unsolved colorectal adenomatous polyposis patients.

PubMed

Ciavarella, Michele; Miccoli, Sara; Prossomariti, Anna; Pippucci, Tommaso; Bonora, Elena; Buscherini, Francesco; Palombo, Flavia; Zuntini, Roberta; Balbi, Tiziana; Ceccarelli, Claudio; Bazzoli, Franco; Ricciardiello, Luigi; Turchetti, Daniela; Piazzi, Giulia

2018-03-01

Germline variants in the APC gene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3 genes and somatic APC mosaicism have been reported as alternative causes of polyposis. However, ~30-50% of cases of polyposis remain genetically unsolved. Thus, the aim of this study was to investigate the genetic causes of unexplained adenomatous polyposis. Eight sporadic cases with >20 adenomatous polyps by 35 years of age or >50 adenomatous polyps by 55 years of age, and no causative germline variants in APC and/or MutYH, were enrolled from a cohort of 56 subjects with adenomatous colorectal polyposis. APC gene mosaicism was investigated on DNA from colonic adenomas by Sanger sequencing or Whole Exome Sequencing (WES). Mosaicism extension to other tissues (peripheral blood, saliva, hair follicles) was evaluated using Sanger sequencing and/or digital PCR. APC second hit was investigated in adenomas from mosaic patients. WES was performed on DNA from peripheral blood to identify additional polyposis candidate variants. We identified APC mosaicism in 50% of patients. In three cases mosaicism was restricted to the colon, while in one it also extended to the duodenum and saliva. One patient without APC mosaicism, carrying an APC in-frame deletion of uncertain significance, was found to harbor rare germline variants in OGG1, POLQ, and EXO1 genes. In conclusion, our restrictive selection criteria improved the detection of mosaic APC patients. In addition, we showed for the first time that an oligogenic inheritance of rare variants might have a cooperative role in sporadic colorectal polyposis onset.

Prevalence of colorectal neoplasia among young African Americans and Hispanic Americans

PubMed Central

Ashktorab, Hassan; Paydar, Mansour; Namin, Hassan Hassanzadeh; Sanderson, Andrew; Begum, Rehana; Brim, Hassan; Panchal, Heena; Lee, Edward; Kibreab, Angesom; Nouraie, Mehdi; Laiyemo, Adeyinka O.

2014-01-01

Background The disproportionately higher incidence of, and mortality from colorectal cancer (CRC) among African Americans (AA) led the American College of Gastroenterology to recommend screening starting at age 45 in 2005. Aim To determine the prevalence of colorectal neoplasia among 40–49 years old inner city African Americans (AA) and Hispanic Americans (HA). Methods We reviewed the medical records of 2435 inner city AA and HA who underwent colonoscopy regardless of indication and compared the prevalence of colorectal neoplasia between AA and HA patients. We used logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI). Results There were 2,163 AA and 272 HA. There were 57% women in both groups. A total of 158 (7%) AA and 9 (3%) HA (P = 0.014) underwent the procedures for CRC screening. When compared to HA, AA had higher prevalence of any polyp (35% versus 18%, OR = 2.53; 95% CI: 1.82–3.52). Overall, AA had higher prevalence of colorectal neoplasia (adenoma and cancer) when compared to HA (16% versus 10%; OR = 1.68; 95% CI: 1.10–2.56). Conclusion We observed a higher frequency of colorectal neoplasia among 40–49 year-old AA as compared to HA suggesting an increased susceptibility to CRC risk in this population. PMID:24193352

Advance in plasma SEPT9 gene methylation assay for colorectal cancer early detection

PubMed Central

Wang, Yu; Chen, Pei-Min; Liu, Rong-Bin

2018-01-01

This review article summarizes the research advances of the plasma-based SEPT9 gene methylation assay for the clinical detection of colorectal cancer and its limitations. Colorectal cancer is a common malignancy with a poor prognosis and a high mortality, for which early detection and diagnosis are particularly crucial for the high-risk groups. Increasing evidence supported that SEPT9 gene methylation is associated with the pathogenesis of colorectal cancer and that detecting the level of methylation of SEPT9 in the peripheral blood can be used for screening of colorectal cancer in susceptible populations. In recent years, the data obtained in clinical studies demonstrated that the SEPT9 gene methylation assay has a good diagnostic performance with regard to both sensitivity and specificity with the advantage of better acceptability, convenience and compliance with serological testing compared with fecal occult blood tests and carcinoembryonic antigen for colorectal cancer (CRC). Furthermore, the combination of multiple methods or markers has become a growing trend for CRC detection and screening. Nevertheless, the clinical availability of the methylated SEPT9 assay is still limited because of the large degree of sample heterogeneity caused by demographic characteristics, pathological features, comorbidities and/or technique selection. Another factor is the cost-effectiveness of colorectal cancer screening strategies that hinders its large-scale application. In addition, improvements in its accuracy in detecting adenomas and premalignant polyps are required. PMID:29375744

Advance in plasma SEPT9 gene methylation assay for colorectal cancer early detection.

PubMed

Wang, Yu; Chen, Pei-Min; Liu, Rong-Bin

2018-01-15

This review article summarizes the research advances of the plasma-based SEPT9 gene methylation assay for the clinical detection of colorectal cancer and its limitations. Colorectal cancer is a common malignancy with a poor prognosis and a high mortality, for which early detection and diagnosis are particularly crucial for the high-risk groups. Increasing evidence supported that SEPT9 gene methylation is associated with the pathogenesis of colorectal cancer and that detecting the level of methylation of SEPT9 in the peripheral blood can be used for screening of colorectal cancer in susceptible populations. In recent years, the data obtained in clinical studies demonstrated that the SEPT9 gene methylation assay has a good diagnostic performance with regard to both sensitivity and specificity with the advantage of better acceptability, convenience and compliance with serological testing compared with fecal occult blood tests and carcinoembryonic antigen for colorectal cancer (CRC). Furthermore, the combination of multiple methods or markers has become a growing trend for CRC detection and screening. Nevertheless, the clinical availability of the methylated SEPT9 assay is still limited because of the large degree of sample heterogeneity caused by demographic characteristics, pathological features, comorbidities and/or technique selection. Another factor is the cost-effectiveness of colorectal cancer screening strategies that hinders its large-scale application. In addition, improvements in its accuracy in detecting adenomas and premalignant polyps are required.

Traditional serrated adenoma (TSA): morphological questions, queries and quandaries.

PubMed

Chetty, Runjan

2016-01-01

Traditional serrated adenoma (TSA) is an uncommon type of serrated adenoma that can be a precursor to biologically aggressive colorectal cancer that invokes the serrated (accelerated) pathway. The purpose of this review is to address some of the more contentious issues around nomenclature, diagnostic criteria, histological variants, coexistence with other polyp types, the occurrence of dysplasia and the differential diagnosis. While the vast majority of TSAs are exophytic villiform polyps composed of deeply eosinophilic cells, flat top luminal serrations and numerous ectopic crypt foci, histological variants include flat TSA, filiform TSA and one composed of large numbers of mucin-containing cells. It is unlikely that there is any biological difference between the histological variants. There is a contention that TSAs are not dysplastic ab initio and that the majority do not show cytological atypia. Two types of dysplasia are associated with TSA. Serrated dysplasia is less well recognised and less commonly encountered than adenomatous dysplasia. TSA with dysplasia must be separated from TSA with coexisting conventional adenoma. TSA is a characteristic polyp that may be extremely exophytic, flat or composed of mucin-rich cells and is typified by numerous ectopic crypt foci. They may coexist with other serrated polyps and conventional adenomas. Approximately 20-25% will be accompanied by adenomatous dysplasia. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Frequency of papillary tubal hyperplasia (PTH), salpingoliths and transition from adenoma to borderline ovarian tumors (BOT): A systematic analysis of 74 BOT with different histologic types.

PubMed

Horn, Lars-Christian; Angermann, Karolin; Hentschel, Bettina; Einenkel, Jens; Höhn, Anne Kathrin

2017-04-01

Borderline ovarian tumors (BOT) arise from cystadenomas and represent a transition step within the development of low-grade ovarian carcinomas (Type I tumors). That pathway mirrors the adenoma-to-carcinoma sequence known for colorectal cancer. It has been suggested that papillary tubal hyperplasia (PTH) and salpingoliths may be associated with the development of BOT. To evaluate the frequency of the presence of benign cystadenoma and its transition to BOT in a given patient as well as the presence of PTH and salpingoliths we re-valuated in 74 consecutive cases of BOT with different histologic types. The majority of cases represented serous-BOT (60.8%), followed by mucinous BOT (25.7%), other histologic types were rare. 86.5% showed an adenoma-BOT sequence, which was seen in all mucinous BOT but was missed in 15.6% of serous BOT. Two cases had salpingoliths without associated PTH. PTH was seen in four out of the 74 (5.4%) BOT and occurred only in cases with serous histology. The vast majority of BOT represent a transition from benign cystadenoma to BOT in cases with mucinous and serous histology. Salpingoliths are rarely seen in association with BOT and occurred exclusively in BOT with serous histology. PTH may represent a distinct lesion but is rarely seen in association with BOT, especially in those with non-serous histology. Further studies are needed to evaluate the frequency and pathogenetic association of PTH with BOT. Copyright © 2017 Elsevier GmbH. All rights reserved.

APC10.1 cells as a model for assessing the efficacy of potential chemopreventive agents in the Apc(Min) mouse model in vivo.

PubMed

Sale, Stewart; Fong, Isabel L; de Giovanni, Carla; Landuzzi, Lorena; Brown, Karen; Steward, William P; Gescher, Andreas J

2009-11-01

Apc(Min) mice are widely used for mechanism and efficacy studies associated with the development of chemopreventive agents. APC10.1 cells have been derived from Apc(Min) mouse adenomas and retain the heterozygous Apc genotype. We tested the hypothesis that this cell type may provide an in vitro model to predict chemopreventive activity of agents in the Apc(Min) mouse in vivo. The growth inhibitory properties of 14 putative colorectal cancer chemopreventive agents, tricin, apigenin, 3',4',5',5,7-pentamethoxyflavone, resveratrol, curcumin, 3,4-methylenedioxy-3',4',5'-trimethoxychalcone (DMU135), 3,4,5,4'-tetramethoxystilbene (DMU212), celecoxib, aspirin, piroxicam, all-trans-retinoic acid, difluoromethylornithine (DFMO), quercetin and cyanidin-3-glucoside, were studied in this cell line, and the IC(50) values were calculated. The IC(50) values were plotted against previously published data of reduction of adenoma numbers caused by these agents in Apc(Min) mice. The correlation co-efficient was 0.678 (p<0.01), suggesting that there was a tentative correlation between the ability to inhibit the growth of APC10.1 cells and the ability to delay adenoma development in vivo. If this relationship is supported by using further agents, APC10.1 cells may serve in the future as an initial screen to prioritise compounds for assessing chemopreventive efficacy in Apc(Min) mice in vivo. Such a screen could reduce the number of animals required to find active agents, help reduce costs and increase throughput.

Search for novel circulating cancer chemopreventive biomarkers of dietary rice bran intervention in Apc(Min) mice model of colorectal carcinogenesis, using proteomic and metabolic profiling strategies.

PubMed

Norris, Leonie; Malkar, Aditya; Horner-Glister, Emma; Hakimi, Amirmansoor; Ng, Leong L; Gescher, Andreas J; Creaser, Colin; Sale, Stewart; Jones, Donald J L

2015-09-01

There is strong epidemiological evidence indicating that consumption by humans of whole-grain foods including rice bran may be associated with a low incidence of cancer, especially in the colorectum. Molecular processes associated with cancer development may be retarded by fiber consumption. Consequently, intervention with dietary fiber might be suitable as a cancer chemoprevention strategy in high-risk populations. Here, we searched for putative molecular mechanism-based efficacy biomarkers of rice fiber consumption in the plasma of mice characterized by a genetic propensity to develop gastrointestinal adenomas. The hypothesis was tested that metabolic and proteomic changes in blood reflect the chemopreventive activity of rice bran. Apc(Min) mice received diet supplemented with rice bran at 5, 15, and 30%. Blood and tissue samples were taken. Plasma was subjected to MS-based proteomic and metabolic profiling analyses as well as assessment of hematocrit values. Gastrointestinal tracts were removed and adenomas were counted and their size was measured so that total tumor burden could be calculated. The hypothesis was tested that metabolic and proteomic changes in blood reflect chemopreventive activity. Rice bran consumption reduced adenoma burden and number in a dose-related fashion when compared to controls. Metabolic profiling data demonstrated strong clustering of the groups indicating that metabolic pathways are perturbed. Proteomic analysis identified adiponectin as a molecule that was significantly altered, which may play a role in tumor suppression. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cancer in an unexpected site post pouch surgery for familial adenomatous polyposis (FAP).

PubMed

Alwahbi, Omar A; Abduljabbar, Alaa S; Anwer, Lucman A

2018-01-01

Familial Adenomatous Polyposis (FAP) is a hereditary condition characterized by multiple colorectal adenomatous polyps. FAP is the most common adenomatous polyposis syndrome. Restorative proctocolectomy is the most commonly performed surgical procedure performed for patients suffering from FAP with different options for anastomosis, namely ileorectal anastomosis (IRA) or ileal pouch anal anastomosis (IPAA). The occurrence of adenomas is a common finding during follow up and surveillance post surgery for these patients. Although there are a few cases of carcinoma that were namely at the anal transitional zone (ATZ), there are only a few cases of ileal pouch related adenocarcinoma reported. This work has been reported in line with the SCARE criteria (Agha et al., 2016) [1]. We report a case of a 34-year-old man diagnosed with FAP who underwent proctocolectomy with IPAA, and subsequently referred to our center, who, despite appropriate measures and surveillance, developed adenocarcinoma in the ileal pouch. Restorative proctocolectomy for Familial Adenomatous Polyposis (FAP) is the mainstay of treatment. There are different surgical options, each with its own set of advantages and disadvantages. The most favored option is proctocolectomy with ileal pouch anal anastomosis (IPAA) due to because it involves resection of the rectum. Despite these interventions, adenomas and/or carcinomas have been reported on follow up post surgery. Although the risk of developing adenomas or carcinomas in the ileal pouch post proctocolectomy with IPAA is low it should not be neglected as cancer occurrence or recurrence is unpredictable even with appropriate measures. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Multicentric GISCoR Study "intensive clinical follow-up versus surgical radicalization after complete endoscopic polypectomy of a malignant adenoma" (SEC-GISCoR).

PubMed

Andreoni, Bruno; Camellini, Lorenzo; Sonzogni, Angelica; Crosta, Cristiano; Pirola, Maria Elena; Corbellini, Carlo

2011-09-01

Colorectal cancer screening programs result in an early diagnosis of the disease. In 2007, 250 malignant polyps were identified in Lombardy, out of 1,329 screen-detected colorectal carcinomas. The Italian Group for Colorectal Cancer (GISCoR) promoted the multicentric study "Endoscopic Follow-up versus Surgical Radicalization of Malignant Polyps after Complete Endoscopic Polypectomy" (SEC-GISCoR). The protocol was a multicentric, prospective, observational, non-randomized study. It included patients diagnosed a colorectal malignant adenoma, after complete endoscopic removal. From November 2005 to September 2009, three participating centers enrolled 120 patients with malignant polyps after "complete" endoscopic polypectomy; malignant polyps were classified as "low risk" or "high risk". The study had two arms: "Intensive follow-up" (42 patients: 32 with low-risk and 10 with high-risk polyps) and "Surgical radicalization" (78 patients: 5 with low-risk and 73 with high-risk polyps). Data were collected using an online CRF. Overall, 37/120 polyps (30.8%) were low risk and 83/120 (69.2%) were high risk. 42 out of 120 patients (35%) were enrolled in the "clinical follow-up" arm, while 78/120 (65%) entered the surgery arm. In 15 cases, patients were not enrolled in the correct arm, according to the criteria agreed upon before starting the study. There still is a high incidence (11.5%) of pathological mismatches. No clinical event was reported in 2.9 years of follow-up. In conclusion, some differences emerged in the management of patients with malignant polyps among participating centers (p < 0.001), mismatches can be explained by high surgical risk or patient's choice. Only in 5 cases (4.2%), did data analysis not allow to exactly determine the reason for a choice different from protocol criteria. The availability of new risk factors and the evidence of pathological mismatches confirmed the need for future studies on this issue.

MLH1-93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation.

PubMed

Fennell, Lochlan J; Jamieson, Saara; McKeone, Diane; Corish, Tracie; Rohdmann, Megan; Furner, Tori; Bettington, Mark; Liu, Cheng; Kawamata, Futoshi; Bond, Catherine; Van De Pols, Jolieke; Leggett, Barbara; Whitehall, Vicki

2018-01-05

Sessile serrated adenomas with BRAF mutation progress rapidly to cancer following the development of dysplasia (SSAD). Approximately 75% of SSADs methylate the mismatch repair gene MLH1, develop mismatch repair deficiency and the resultant cancers have a good prognosis. The remaining SSADs and BRAF mutant traditional serrated adenomas (TSA) develop into microsatellite stable cancers with a poor prognosis. The reason for this dichotomy is unknown. In this study, we assessed the genotypic frequency of the MLH1-93 polymorphism rs1800734 in SSADs and TSAs to determine if the uncommon variant A allele predisposes to MLH1 promoter hypermethylation. We performed genotyping for the MLH1-93 polymorphism, quantitative methylation specific PCR, and MLH1 immunohistochemistry on 124 SSAD, 128 TSA, 203 BRAF mutant CRCs and 147 control subjects with normal colonoscopy. The minor A allele was significantly associated with a dose dependent increase in methylation at the MLH1 promoter in SSADs (p = 0.022). The AA genotype was only observed in SSADs with MLH1 loss. The A allele was also overrepresented in BRAF mutant cancers with MLH1 loss. Only one of the TSAs showed loss of MLH1 and the overall genotype distribution in TSAs did not differ from controls. The MLH1-93 AA genotype is significantly associated with promoter hypermethylation and MLH1 loss in the context of SSADs. BRAF mutant microsatellite stable colorectal cancers with the AA genotype most likely arise in TSAs since the A allele does not predispose to methylation in this context.

IGF2 differentially methylated region hypomethylation in relation to pathological and molecular features of serrated lesions

PubMed Central

Naito, Takafumi; Nosho, Katsuhiko; Ito, Miki; Igarashi, Hisayoshi; Mitsuhashi, Kei; Yoshii, Shinji; Aoki, Hironori; Nomura, Masafumi; Sukawa, Yasutaka; Yamamoto, Eiichiro; Adachi, Yasushi; Takahashi, Hiroaki; Hosokawa, Masao; Fujita, Masahiro; Takenouchi, Toshinao; Maruyama, Reo; Suzuki, Hiromu; Baba, Yoshifumi; Imai, Kohzoh; Yamamoto, Hiroyuki; Ogino, Shuji; Shinomura, Yasuhisa

2014-01-01

AIM: To investigate insulin-like growth factor 2 (IGF2) differentially methylated region (DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions. METHODS: To accurately analyze the association between the histological types and molecular features of each type of serrated lesion, we consecutively collected 1386 formalin-fixed paraffin-embedded tissue specimens that comprised all histological types [hyperplastic polyps (HPs, n = 121), sessile serrated adenomas (SSAs, n = 132), traditional serrated adenomas (TSAs, n = 111), non-serrated adenomas (n = 195), and colorectal cancers (CRCs, n = 827)]. We evaluated the methylation levels of IGF2 DMR0 and long interspersed nucleotide element-1 (LINE-1) in HPs (n = 115), SSAs (n = 120), SSAs with cytological dysplasia (n = 10), TSAs (n = 91), TSAs with high-grade dysplasia (HGD) (n = 15), non-serrated adenomas (n = 80), non-serrated adenomas with HGD (n = 105), and CRCs (n = 794). For the accurate quantification of the relative methylation levels (scale 0%-100%) of IGF2 DMR0 and LINE-1, we used bisulfite pyrosequencing method. Tumor specimens were analyzed for microsatellite instability, KRAS (codons 12 and 13), BRAF (V600E), and PIK3CA (exons 9 and 20) mutations; MLH1 and MGMT methylation; and IGF2 expression by immunohistochemistry. RESULTS: The distribution of the IGF2 DMR0 methylation level in 351 serrated lesions and 185 non-serrated adenomas (with or without HGD) was as follows: mean 61.7, median 62.5, SD 18.0, range 5.0-99.0, interquartile range 49.5-74.4. The IGF2 DMR0 methylation level was divided into quartiles (Q1 ≥ 74.5, Q2 62.6-74.4, Q3 49.6-62.5, Q4 ≤ 49.5) for further analysis. With regard to the histological type, the IGF2 DMR0 methylation levels of SSAs (mean ± SD, 73.1 ± 12.3) were significantly higher than those of HPs (61.9 ± 20.5), TSAs (61.6 ± 19.6), and non-serrated adenomas (59.0 ± 15.8) (P < 0.0001). The IGF2 DMR0 methylation level was inversely correlated with the IGF2 expression level (r = -0.21, P = 0.0051). IGF2 DMR0 hypomethylation was less frequently detected in SSAs compared with HPs, TSAs, and non-serrated adenomas (P < 0.0001). Multivariate logistic regression analysis also showed that IGF2 DMR0 hypomethylation was inversely associated with SSAs (P < 0.0001). The methylation levels of IGF2 DMR0 and LINE-1 in TSAs with HGD (50.2 ± 18.7 and 55.7 ± 5.4, respectively) were significantly lower than those in TSAs (61.6 ± 19.6 and 58.8 ± 4.7, respectively) (IGF2 DMR0, P = 0.038; LINE-1, P = 0.024). CONCLUSION: IGF2 DMR0 hypomethylation may be an infrequent epigenetic alteration in the SSA pathway. Hypomethylation of IGF2 DMR0 and LINE-1 may play a role in TSA pathway progression. PMID:25110432

The Smad4/PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma.

PubMed

Chung, Yumin; Wi, Young Chan; Kim, Yeseul; Bang, Seong Sik; Yang, Jung-Ho; Jang, Kiseok; Min, Kyueng-Whan; Paik, Seung Sam

2018-01-01

Smad4 and PTEN are prognostic indicators for various tumor types. Smad4 regulates tumor suppression, whereas PTEN inhibits cell proliferation. We analyzed and compared the performance of Smad4 and PTEN for predicting the prognosis of patients with colorectal adenocarcinoma. Combined expression patterns based on Smad4+/- and PTEN+/- status were evaluated by immunostaining using a tissue microarray of colorectal adenocarcinoma. The relationships between the protein expression and clinicopathological variables were analyzed. Smad4-/PTEN- status was most frequently observed in metastatic adenocarcinoma, followed by primary adenocarcinoma and tubular adenoma (p<.001). When Smad4-/PTEN- and Smad4+/PTEN+ groups were compared, Smad4-/PTEN- status was associated with high N stage (p=.018) and defective mismatch repair proteins (p=.006). Significant differences in diseasefree survival and overall survival were observed among the three groups (Smad4+/PTEN+, Smad4-/PTEN+ or Smad4+/PTEN-, and Smad4-/PTEN-) (all p<.05). Concurrent loss of Smad4 and PTEN may lead to more aggressive disease and poor prognosis in patients with colorectal adenocarcinoma compared to the loss of Smad4 or PTEN alone.

[Prevalence of altered mismatch repair protein nuclear expression detected by immunohistochemistry on adenomas with high-grade dysplasia and features associated with this risk in a population-based study].

PubMed

Basterra, Marta; Gomez, Marta; Mercado, María Del Rosario; Irisarri, Rebeca; Amorena, Edurne; Arrospide, Arantzazu; Montes, Marta; Aisa, Gregorio; Cambra, Koldo Iñaki; Urman, Jesús

2016-10-01

Alteration of mismatch repair system protein expression detected by immunohistochemistry (IHQ) in tumoural tissue is a useful technique for Lynch Syndrome (LS) screening. A recent review proposes LS screening through immunohistochemical study not only in all diagnosed cases of colorectal cancer (CRC) but also in advanced adenomas, especially in young patients. To assess the prevalence of altered IHQ carried out in all adenomas with high-grade dysplasia (HGD) diagnosed in our community in 2011, as well as the variables associated with this alteration. We included all the cases of adenomatous polyps with HGD diagnosed in the three public pathology laboratories of Navarre during 2011 and performed a statistical study to assess the association between different patient and lesion characteristics and altered IHQ results. A total of 213 colonic adenomas with HGD were diagnosed, and 26 (12.2%) cases were excluded from the final analysis (2 known LS, 22 without IHQ study and 2 with inconclusive IHQ studies). The final number of adenomas included was 187. Pathologic results were found in 10 cases (5.35%)-6 cases in MLH1 and PMS2, 2 cases in PMS2, 1 case in MSH6 and 1 case in MSH2 and MSH6. The factors showing a statistically significant association with the presence of abnormal proteins were the synchronous presence of CRC, the presence of only one advanced adenoma, proximal location of HGD and age <50 years. The percentage of pathologic nuclear expression found in IHQ is high. Consequently, screening of all diagnosed HGD could be indicated, especially in young patients, with a single AA and proximal HGD. Copyright © 2015 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

MicroRNA signatures of colonic polyps on screening and histology

PubMed Central

Tsikitis, Vassiliki L.; Potter, Amiee; Mori, Motomi; Buckmeier, Julie A.; Preece, Christina R.; Harrington, Christina A.; Bartley, Angela N.; Bhattacharyya, Achyut K.; Hamilton, Stanley R.; Lance, M. Peter; Thompson, Patricia A.

2016-01-01

Colorectal cancer (CRC) and adenoma adjacent to cancer exhibit distinct microRNA (miR) alterations in an apparent mucosa-to-adenocarcinoma sequence. The pattern of microRNAs in screen-detected polyps in relation to histologic features and cancer risk has not been investigated. miR expression analysis was performed on normal mucosa (NM), hyperplastic polyps (HPs), tubular adenomas (TAs), tubulovillous adenomas or high-grade dysplasia (TVHGs), and serrated polyps (sessile serrated adenoma/polyps, SSA/Ps, and traditional serrated adenomas, TSAs) in biopsy specimens from 109 patients undergoing screening/surveillance colonoscopy. Generalized linear models were used to identify differentially expressed miRs by histologic type and logistic regression to identify miR predictors of histopathology. False discovery rate (FDR) was used to control for multiple comparisons. We identified 99 miRs differing in at least one of five histopathologic groups (FDR ≤ 0.05). In a comparison of HPNM vs. TVHG, the top most up- and down-regulated miRs in HPNM included miR-145, -143, -107, -194, and -26a (upregulated), and miR-663, -1268, -320b, -1275, and -320b (down-regulated) (FDR P-value < 0.05). miR-145 and -619 showed high accuracy to discriminate low- from high-risk polyps without serrated histology (TVHG vs. HPNM+TA) (CI= 95.6%), whereas miRs-124, -143, and -30a showed high accuracy of separating high-risk polyps (TVHG+TSA) from low-risk polyps (HPNM+TA+SSA/P) (CI=96.0%). For TSAs, miRs-125b and -199a were uniquely downregulated relative to HPNMs, and miR-335, -222 and -214 discriminated between non-serrated and serrated histology. Our data support the presence of CRC-associated miR alterations in screen-detected adenomas that may be useful for risk stratification for surveillance interval planning. PMID:27658891

Erlotinib Hydrochloride in Treating Patients With Stage I-III Colorectal Cancer or Adenoma

ClinicalTrials.gov

2014-12-22

Adenomatous Polyp; Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage I Colon Cancer; Stage I Rectal Cancer; Stage IIA Colon Cancer; Stage IIA Rectal Cancer; Stage IIB Colon Cancer; Stage IIB Rectal Cancer; Stage IIC Colon Cancer; Stage IIC Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer

Blood test using surface-enhanced Raman spectroscopy with colloidal silver nanoparticle substrate to detect polyps and colorectal cancer (Conference Presentation)

NASA Astrophysics Data System (ADS)

Wang, Wenbo; Feng, Shangyuan; Tai, Isabella T.; Chen, Guannan; Chen, Rong; Zeng, Haishan

2016-03-01

Colorectal cancer (CRC) is the third most common type of cancer and forth leading cause of cancer-related death. Early diagnosis is the key to long-term patient survival. Programmatic screening for the general population has shown to be cost-effective in reducing the incidence and mortality from CRC. Current CRC screening strategy relies on a broad range of test techniques such as fecal based tests and endoscopic exams. Occult blood tests like fecal immunochemical test is a cost effective way to detect CRC but have limited diagnostic values in detecting adenomatous polyp, the most treatable precursor to CRC. In the present work, we proposed the use of surface enhanced Raman spectroscopy (SERS) with silver nanoparticles as substrate to analyze blood plasma for detecting both CRC and adenomatous polyps. Blood plasma samples collected from healthy subjects and patients diagnosed with adenomas and CRC were prepared with nanoparticles and measured using a real-time fiber optic probe based Raman system. The collected SERS spectra are analyzed with partial least squares-discriminant analysis. Classification of normal versus CRC plus adenomatous polyps achieved diagnostic sensitivity of 86.4% and specificity of 80%. This exploratory study suggests that blood plasma SERS analysis has potential to become a screening test for detecting both CRC and adenomas.

Fluorescent and scattering contrast agents in a mouse model of colorectal cancer

NASA Astrophysics Data System (ADS)

Winkler, Amy M.; Rice, Photini F. S.; Troutman, Timothy S.; Backer, Marina V.; Backer, Joseph M.; Drezek, Rebekah A.; Romanowski, Marek; Barton, Jennifer K.

2008-02-01

In previous work we have demonstrated the utility of laser-induced fluorescence (LIF) and optical coherence tomography (OCT) to identify adenoma in mouse models of colorectal cancer with high sensitivity and specificity. However, improved sensitivity to early disease, as well as the ability to distinguish confounders (e.g. fecal contamination, natural variations in mucosal thickness), is desired. In this study, we investigated the signal enhancement of fluorescent and scattering contrast agents in the colons of AOM-treated mice. The fluorescent tracer scVEGF/Cy, targeted to receptors for vascular endothelial growth factor, was visualized on a dual modality OCT/LIF endoscopic system with 1300-nm center wavelength OCT source and 635-nm LIF excitation. Scattering agents were tested with an 890-nm center wavelength endoscopic OCT system. Agents included nanoshells, 120-nm in diameter, and nanorods, 20-nm in diameter by 80-nm in length. Following imaging, colons were excised. Tissue treated with fluorophore was imaged on an epifluorescence microscope. Histological sections were obtained and stained with H&E and silver enhancer to verify disease and identify regions of gold uptake, respectively. Non-specific signal enhancement was observed with the scattering contrast agents. Specificity for adenoma was seen with the scVEGF/Cy dye.

A novel pathogenic splice acceptor site germline mutation in intron 14 of the APC gene in a Chinese family with familial adenomatous polyposis.

PubMed

Wang, Dan; Liang, Shengyun; Zhang, Zhao; Zhao, Guoru; Hu, Yuan; Liang, Shengran; Zhang, Xipeng; Banerjee, Santasree

2017-03-28

Familial adenomatous polyposis (FAP) is an autosomal dominant precancerous condition, clinically characterized by the presence of multiple colorectal adenomas or polyps. Patients with FAP has a high risk of developing colorectal cancer (CRC) from these colorectal adenomatous polyps by the mean age of diagnosis at 40 years. Germline mutations of the APC gene cause familial adenomatous polyposis (FAP). Colectomy has recommended for the FAP patients with significant polyposis. Here, we present a clinical molecular study of a four generation Chinese family with FAP. Clinical diagnosis of FAP has been done according to the phenotype, family history and medical records. Patient's blood samples were collected and genomic DNA was extracted. In order to identify the pathogenic mutation underlying the disease phenotype targeted next-generation sequencing and confirmatory sanger sequencing has undertaken. Targeted next generation sequencing identified a novel heterozygous splice-acceptor site mutation [c.1744-1G>A] in intron 14 of APC gene, which is co-segregated with the FAP phenotypes in the proband and amongst all the affected family members. This mutation is not present in unaffected family members and in normal healthy controls of same ethnic origin. According to the LOVD database for Chinese colorectal cancer patients, in Chinese population, 60% of the previously reported APC gene mutations causes FAP, are missense mutations. This novel splice-acceptor site mutation causing FAP in this Chinese family expands the germline mutation spectrum of the APC gene in the Chinese population.

A randomised tandem colonoscopy trial of narrow band imaging versus white light examination to compare neoplasia miss rates.

PubMed

Kaltenbach, T; Friedland, S; Soetikno, R

2008-10-01

Colonoscopy, the "gold standard" screening test for colorectal cancer (CRC), has known diagnostic limitations. Advances in endoscope technology have focused on improving mucosal visualisation. In addition to increased angle of view and resolution features, recent colonoscopes have non-white-light optics, such as narrow band imaging (NBI), to enhance image contrast. We aimed to study the neoplasia diagnostic characteristics of NBI, by comparing the neoplasm miss rate when the colonoscopy was performed under NBI versus white light (WL). Randomised controlled trial. US Veterans hospital. Elective colonoscopy adults. We randomly assigned patients to undergo a colonoscopic examination using NBI or WL. All patients underwent a second examination using WL, as the reference standard. The primary end point was the difference in the neoplasm miss rate, and secondary outcome was the neoplasm detection rate. In 276 tandem colonoscopy patients, there was no significant difference of miss or detection rates between NBI or WL colonoscopy techniques. Of the 135 patients in the NBI group, 17 patients (12.6%; 95% confidence interval (CI) 7.5 to 19.4%) had a missed neoplasm, as compared with 17 of the 141 patients (12.1%; 95% CI 7.2 to 18.6%) in the WL group, with a miss rate risk difference of 0.5% (95% CI -7.2 to 8.3). 130 patients (47%) had at least one neoplasm. Missed lesions with NBI showed similar characteristics to those missed with WL. All missed neoplasms were tubular adenomas, the majority (78%) was < or = 5 mm and none were larger than 1 cm (one-sided 95% CI up to 1%). Nonpolypoid lesions represented 35% (13/37) of missed neoplasms. NBI did not improve the colorectal neoplasm miss rate compared to WL; the miss rate for advanced adenomas was less than 1% and for all adenomas was 12%. The neoplasm detection rates were similar high using NBI or WL; almost a half the study patients had at least one adenoma. Clinicaltrials.gov identifier: NCT00628147.

Improved adenoma detection with Endocuff Vision: the ADENOMA randomised controlled trial.

PubMed

Ngu, Wee Sing; Bevan, Roisin; Tsiamoulos, Zacharias P; Bassett, Paul; Hoare, Zoë; Rutter, Matthew D; Clifford, Gayle; Totton, Nicola; Lee, Thomas J; Ramadas, Arvind; Silcock, John G; Painter, John; Neilson, Laura J; Saunders, Brian P; Rees, Colin J

2018-01-23

Low adenoma detection rates (ADR) are linked to increased postcolonoscopy colorectal cancer rates and reduced cancer survival. Devices to enhance mucosal visualisation such as Endocuff Vision (EV) may improve ADR. This multicentre randomised controlled trial compared ADR between EV-assisted colonoscopy (EAC) and standard colonoscopy (SC). Patients referred because of symptoms, surveillance or following a positive faecal occult blood test (FOBt) as part of the Bowel Cancer Screening Programme were recruited from seven hospitals. ADR, mean adenomas per procedure, size and location of adenomas, sessile serrated polyps, EV removal rate, caecal intubation rate, procedural time, patient experience, effect of EV on workload and adverse events were measured. 1772 patients (57% male, mean age 62 years) were recruited over 16 months with 45% recruited through screening. EAC increased ADR globally from 36.2% to 40.9% (P=0.02). The increase was driven by a 10.8% increase in FOBt-positive screening patients (50.9% SC vs 61.7% EAC, P<0.001). EV patients had higher detection of mean adenomas per procedure, sessile serrated polyps, left-sided, diminutive, small adenomas and cancers (cancer 4.1% vs 2.3%, P=0.02). EV removal rate was 4.1%. Median intubation was a minute quicker with EAC (P=0.001), with no difference in caecal intubation rate or withdrawal time. EAC was well tolerated but caused a minor increase in discomfort on anal intubation in patients undergoing colonoscopy with no or minimal sedation. There were no significant EV adverse events. EV significantly improved ADR in bowel cancer screening patients and should be used to improve colonoscopic detection. NCT 02552017, Results; ISRCTN 11821044, Results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Quality of colonoscopy in Lynch syndrome

PubMed Central

Niv, Yaron; Moeslein, Gabriela; Vasen, Hans F.A.; Karner-Hanusch, Judith; Lubinsky, Jan; Gasche, Christoph

2014-01-01

Lynch syndrome (LS) accounts for 2 – 4 % of all colorectal cancers. Affected family members have a germline mutation in one of the DNA mismatch repair genes MLH1, PMS2, MSH2, or MSH6, and a lifetime risk for development of colorectal cancer of 25 – 75 %. Current guidelines recommend annual to biannual surveillance colonoscopy in mutation carriers. Several factors may predict failure to prevent interval cancer in LS: more lesions in the right colon; more flat (“non polypoid”) and lateral growing polyps; small adenomas may already harbor high grade dysplasia or a high percentage of villous component and become advanced adenomas; there is a short duration of the adenoma – carcinoma sequence; synchronous lesions have high prevalence; patients are younger and less tolerant to colonoscopy (need more sedation); and repeated colonoscopies are needed for lifelong surveillance (patient experience is important for compliance). In order to prevent cancer in LS patients, surveillance colonoscopy should be performed in an endoscopic unit experienced with LS, every 1 – 2 years, starting at age 20 – 25 years, or 10 years younger than the age of first diagnosis in the family (whichever is first), and yearly after the age of 40 years. Colonoscopy in LS patients should be a very meticulous and precise procedure (i. e. taking sufficient withdrawal time, documentation of such warranted), with removal of all of the polyps, special attention to the right colon and alertness to flat lesions. Following quality indicators such as successful cleansing of the colon and removal of every polyp will probably improve prevention of interval cancers. At this moment, none of the new endoscopic techniques have shown convincing superiority over conventional high resolution white light colonoscopy. PMID:26135102

An updated Asia Pacific Consensus Recommendations on colorectal cancer screening.

PubMed

Sung, J J Y; Ng, S C; Chan, F K L; Chiu, H M; Kim, H S; Matsuda, T; Ng, S S M; Lau, J Y W; Zheng, S; Adler, S; Reddy, N; Yeoh, K G; Tsoi, K K F; Ching, J Y L; Kuipers, E J; Rabeneck, L; Young, G P; Steele, R J; Lieberman, D; Goh, K L

2015-01-01

Since the publication of the first Asia Pacific Consensus on Colorectal Cancer (CRC) in 2008, there are substantial advancements in the science and experience of implementing CRC screening. The Asia Pacific Working Group aimed to provide an updated set of consensus recommendations. Members from 14 Asian regions gathered to seek consensus using other national and international guidelines, and recent relevant literature published from 2008 to 2013. A modified Delphi process was adopted to develop the statements. Age range for CRC screening is defined as 50-75 years. Advancing age, male, family history of CRC, smoking and obesity are confirmed risk factors for CRC and advanced neoplasia. A risk-stratified scoring system is recommended for selecting high-risk patients for colonoscopy. Quantitative faecal immunochemical test (FIT) instead of guaiac-based faecal occult blood test (gFOBT) is preferred for average-risk subjects. Ancillary methods in colonoscopy, with the exception of chromoendoscopy, have not proven to be superior to high-definition white light endoscopy in identifying adenoma. Quality of colonoscopy should be upheld and quality assurance programme should be in place to audit every aspects of CRC screening. Serrated adenoma is recognised as a risk for interval cancer. There is no consensus on the recruitment of trained endoscopy nurses for CRC screening. Based on recent data on CRC screening, an updated list of recommendations on CRC screening is prepared. These consensus statements will further enhance the implementation of CRC screening in the Asia Pacific region. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

COLORECTAL CANCER PREVENTION BY AN OPTIMIZED COLONOSCOPY PROTOCOL IN ROUTINE PRACTICE

PubMed Central

Xirasagar, Sudha; Li, Yi-Jhen; Hurley, Thomas G.; Tsai, Meng Han; Hardin, James W.; Hurley, Deborah M.; Hebert, James R.; de Groen, Piet C.

2014-01-01

We conducted a retrospective cohort study to investigate the colorectal cancer (CRC) incidence and mortality prevention achievable in clinical practice with an optimized colonoscopy protocol targeting near-complete polyp clearance. The protocol consisted of: a) telephonic reinforcement of bowel preparation instructions; b) active inspection for polyps throughout insertion and circumferential withdrawal; and, c) timely updating of the protocol and documentation to incorporate the latest guidelines. Of 17,312 patients provided screening colonoscopies by 59 endoscopists in South Carolina, USA from 09/2001 through 12/2008, 997 were excluded using accepted exclusion criteria. Data on 16,315 patients were merged with the South Carolina Central Cancer Registry and Vital Records Registry data from 01/1996 – 12/2009 to identify incident CRC cases and deaths, incident lung cancers and brain cancer deaths (comparison control cancers). The standardized incidence ratios (SIR) and standardized mortality ratios (SMR) relative to South Carolina and US SEER-18 population rates were calculated. Over 78,375 person-years of observation, 18 patients developed CRC vs. 104.11 expected for an SIR of 0.17, or 83% CRC protection, the rates being 68% and 91%, respectively among the adenoma- and adenoma-free subgroups (all p<0.001). Restricting the cohort to ensure minimum 5-year follow-up (mean follow-up 6.58 years) did not change the results. The CRC mortality reduction was 89% (p<0.001; 4 CRC deaths vs. 35.95 expected). The lung cancer SIR was 0.96 (p=0.67), and brain cancer SMR was 0.92 (p=0.35). Over 80% reduction in CRC incidence and mortality is achievable in routine practice by implementing key colonoscopy principles targeting near-complete polyp clearance. PMID:25242510

Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: a meta-analysis.

PubMed

Wanders, Linda K; Dekker, Evelien; Pullens, Bo; Bassett, Paul; Travis, Simon P L; East, James E

2014-05-01

American and European guidelines propose complete endoscopic resection of polypoid dysplasia (adenomas or adenoma-like masses) in patients with longstanding colitis, with close endoscopic follow-up. The incidence of cancer after detection of flat low-grade dysplasia or dysplasia-associated lesion or mass is estimated at 14 cases/1000 years of patient follow-up. However, the risk for polypoid dysplasia has not been determined with precision. We investigated the risk of cancer after endoscopic resection of polypoid dysplasia in patients with ulcerative colitis. MEDLINE, EMBASE, PubMed, and the Cochrane library were searched for studies of patients with colitis and resected polypoid dysplasia, with reports of colonoscopic follow-up and data on cancers detected. Outcomes from included articles were pooled to provide a single combined estimate of outcomes by using Poisson regression. Of 425 articles retrieved, we analyzed data from 10 studies, comprising 376 patients with colitis and polypoid dysplasia with a combined 1704 years of follow-up. A mean of 2.8 colonoscopies were performed for each patient after the index procedure (range, 0-15 colonoscopies). The pooled incidence of cancer was 5.3 cases (95% confidence interval, 2.7-10.1 cases)/1000 years of patient follow-up. There was no evidence of heterogeneity or publication bias. The pooled rate of any dysplasia was 65 cases (95% confidence interval, 54-78 cases)/1000 patient years. Patients with colitis have a low risk of colorectal cancer after resection of polypoid dysplasia; these findings support the current strategy of resection and surveillance. However, these patients have a 10-fold greater risk of developing any dysplasia than colorectal cancer and should undergo close endoscopic follow-up. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Screening colonoscopy for the detection of neoplastic lesions in asymptomatic HIV-infected subjects.

PubMed

Bini, E J; Green, B; Poles, M A

2009-08-01

Although non-AIDS defining malignancies are rapidly increasing as HIV-infected subjects live longer, little is know about the results of screening for colonic neoplasms (adenomatous polyps and adenocarcinomas) in this population. We conducted a screening colonoscopy study to determine the prevalence of colonic neoplasms in 136 asymptomatic HIV-infected subjects >or=50 years of age and 272 asymptomatic uninfected control subjects matched for age, sex, and family history of colorectal cancer. Advanced neoplasms were defined as adenomas >or=10 mm or any adenoma, regardless of size, with villous histology, high-grade dysplasia, or adenocarcinoma. The prevalence of neoplastic lesions was significantly higher in HIV-infected subjects than in control subjects (62.5% vs 41.2%, p<0.001), and remained highly significant after adjustment for potential confounding variables (odds ratio = 3.00; 95% confidence interval, 1.83 to 4.93). Among patients with colorectal adenocarcinoma, HIV-infected subjects were significantly younger (52.4 (SD 1.3) vs 60.3 (SD 4.0) years, p = 0.002) and were more likely to have advanced cancers (stage III or IV) than control subjects (60.0% vs 16.7%, p = 0.24). Of HIV-infected subjects with advanced neoplasms proximal to the splenic flexure, distal neoplastic lesions were absent in 88.9% of individuals and these would have been missed by flexible sigmoidoscopy. HIV-infected subjects have a higher prevalence of colonic neoplasms, and adenocarcinomas develop at a younger age and are more advanced than in uninfected subjects. Our findings suggest that screening colonoscopy should be offered to HIV-infected subjects, but the age of initiation and the optimal frequency of screening require further study.

Advanced proximal neoplasia of the colon in average-risk adults.

PubMed

Rabeneck, Linda; Paszat, Lawrence F; Hilsden, Robert J; McGregor, S Elizabeth; Hsieh, Eugene; M Tinmouth, Jill; Baxter, Nancy N; Saskin, Refik; Ruco, Arlinda; Stock, David

2014-10-01

Estimating risk for advanced proximal neoplasia (APN) based on distal colon findings can help identify asymptomatic persons who should undergo examination of the proximal colon after flexible sigmoidoscopy (FS) screening. We aimed to determine the risk of APN by most advanced distal finding among an average-risk screening population. Prospective, cross-sectional study. Teaching hospital and colorectal cancer screening center. A total of 4651 asymptomatic persons at average risk for colorectal cancer aged 50 to 74 years (54.4% women [n = 2529] with a mean [± standard deviation] age of 58.4 ± 6.2 years). All participants underwent a complete colonoscopy, including endoscopic removal of all polyps. We explored associations between several risk factors and APN. Logistic regression was used to identify independent predictors of APN. A total of 142 persons (3.1%) had APN, of whom 85 (1.8%) had isolated APN (with no distal findings). APN was associated with older age, a BMI >27 kg/m(2), smoking, distal advanced adenoma and/or cancer, and distal non-advanced tubular adenoma. Those with a distal advanced neoplasm were more than twice as likely to have APN compared with those without distal lesions. Distal findings used to estimate risk of APN were derived from colonoscopy rather than FS itself. In persons at average risk for colorectal cancer, the prevalence of isolated APN was low (1.8%). Use of distal findings to predict APN may not be the most effective strategy. However, incorporating factors such as age (>65 years), sex, BMI (>27 kg/m(2)), and smoking status, in addition to distal findings, should be considered for tailoring colonoscopy recommendations. Further evaluation of risk stratification approaches in other asymptomatic screening populations is warranted. Copyright © 2014 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Association Between Consumption of Fruits and Vegetables and Risk of Colorectal Adenoma

PubMed Central

Ben, Qiwen; Zhong, Jie; Liu, Jun; Wang, Lifu; Sun, Yunwei; Yv, Lifen; Yuan, Yaozong

2015-01-01

Abstract There have been contradictory results about the association of fruits and vegetables intake with colorectal adenoma (CRA) risk, the precursor lesion of colorectal cancer. Herein, we have conducted a meta-analysis of the published observational studies to have a clear understanding about this association. Eligible studies up to November 30, 2014, were identified and retrieved by searching MEDLINE and EMBASE databases along with the manual review of the reference list of the retrieved studies. The quality of the included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale, and random-effects model was used to calculate summary relative risk (SRR) and corresponding 95% confidence interval (CI). A total of 22 studies involving 11,696 CRA subjects were part of this meta-analysis. The SRR for the highest versus the lowest intake of vegetables alone was 0.91 (95% CI: 0.80–1.02, Pheterogeneity = 0.025), whereas for vegetables and fruits combined, it was 0.82 (95% CI: 0.75–0.91, Pheterogeneity = 0.369), and for fruits alone, it was 0.79 (95% CI: 0.71–0.88, Pheterogeneity = 0.111). In addition, linear dose–response analysis also showed similar results, for example, for per 100 g/d increment of fruits, the SRR was 0.94 (95% CI: 0.92–0.97) and for vegetables it was 0.98 (95% CI: 0.96–1.01). Nonlinear association was only observed for vegetables (Pnonlinearity = 0.024), but not for fruits (Pnonlinearity = 0.583). Thus, this meta-analysis suggested that fruits consumption have a significant protective effect on CRA risk, but not vegetables. Moreover, we recommend additional studies with prospective designs that use validated questionnaires and control for important confounders to further validate the overall results. PMID:26496264

Association Between Consumption of Fruits and Vegetables and Risk of Colorectal Adenoma: A PRISMA-Compliant Meta-Analysis of Observational Studies.

PubMed

Ben, Qiwen; Zhong, Jie; Liu, Jun; Wang, Lifu; Sun, Yunwei; Yv, Lifen; Yuan, Yaozong

2015-10-01

There have been contradictory results about the association of fruits and vegetables intake with colorectal adenoma (CRA) risk, the precursor lesion of colorectal cancer. Herein, we have conducted a meta-analysis of the published observational studies to have a clear understanding about this association.Eligible studies up to November 30, 2014, were identified and retrieved by searching MEDLINE and EMBASE databases along with the manual review of the reference list of the retrieved studies. The quality of the included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale, and random-effects model was used to calculate summary relative risk (SRR) and corresponding 95% confidence interval (CI).A total of 22 studies involving 11,696 CRA subjects were part of this meta-analysis. The SRR for the highest versus the lowest intake of vegetables alone was 0.91 (95% CI: 0.80-1.02, Pheterogeneity = 0.025), whereas for vegetables and fruits combined, it was 0.82 (95% CI: 0.75-0.91, Pheterogeneity = 0.369), and for fruits alone, it was 0.79 (95% CI: 0.71-0.88, Pheterogeneity = 0.111). In addition, linear dose-response analysis also showed similar results, for example, for per 100 g/d increment of fruits, the SRR was 0.94 (95% CI: 0.92-0.97) and for vegetables it was 0.98 (95% CI: 0.96-1.01). Nonlinear association was only observed for vegetables (Pnonlinearity = 0.024), but not for fruits (Pnonlinearity = 0.583).Thus, this meta-analysis suggested that fruits consumption have a significant protective effect on CRA risk, but not vegetables. Moreover, we recommend additional studies with prospective designs that use validated questionnaires and control for important confounders to further validate the overall results.

Implementation of an optical diagnosis strategy saves costs and does not impair clinical outcomes of a fecal immunochemical test-based colorectal cancer screening program.

PubMed

Vleugels, Jasper L A; Greuter, Marjolein J E; Hazewinkel, Yark; Coupé, Veerle M H; Dekker, Evelien

2017-12-01

 In an optical diagnosis strategy, diminutive polyps that are endoscopically characterized with high confidence are removed without histopathological analysis and distal hyperplastic polyps are left in situ. We evaluated the effectiveness and costs of optical diagnosis.  Using the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model, we simulated biennial fecal immunochemical test (FIT) screening in individuals aged 55 - 75 years. In this program, we compared an optical diagnosis strategy with current histopathology assessment of all diminutive polyps. Base-case assumptions included 76 % high-confidence predictions and sensitivities of 88 %, 91 %, and 88 % for endoscopically characterizing adenomas, sessile serrated polyps, and hyperplastic polyps, respectively. Outcomes were colorectal cancer burden, number of colonoscopies, life-years, and costs.  Both the histopathology strategy and the optical diagnosis strategy resulted in 21 life-days gained per simulated individual compared with no screening. For optical diagnosis, €6 per individual was saved compared with the current histopathology strategy. These cost savings were related to a 31 % reduction in colonoscopies in which histopathology was needed for diminutive polyps. Projecting these results onto the Netherlands (17 million inhabitants), assuming a fully implemented FIT-based screening program, resulted in an annual undiscounted cost saving of € 1.7 - 2.2 million for optical diagnosis.  Implementation of optical diagnosis in a FIT-based screening program saves costs without decreasing program effectiveness when compared with current histopathology analysis of all diminutive polyps. Further work is required to evaluate how endoscopists participating in a screening program should be trained, audited, and monitored to achieve adequate competence in optical diagnosis.

DNA Methylation and Mutation of Small Colonic Neoplasms in Ulcerative Colitis and Crohn's Colitis: Implications for Surveillance.

PubMed

Johnson, David H; Taylor, William R; Aboelsoud, Mohammed M; Foote, Patrick H; Yab, Tracy C; Cao, Xiaoming; Smyrk, Thomas C; Loftus, Edward V; Mahoney, Douglas W; Ahlquist, David A; Kisiel, John B

2016-07-01

Stool DNA testing in patients with inflammatory bowel disease (IBD) may detect colorectal cancer and advanced precancers with high sensitivity; less is known about the presence of DNA markers in small IBD lesions, their association with metachronous neoplasia, or contribution to stool test positivity. At a single center in 2 blinded phases, we assayed methylated bone morphogenic protein 3, methylated N-Myc downstream-regulated gene 4, and mutant KRAS in DNA extracted from paraffin-embedded benign lesions, and matched control tissues of patients with IBD, who were followed for subsequent colorectal dysplasia. Stool samples from independent cases and controls with lesions <1 cm or advanced neoplasms were assayed for the same markers. Among IBD lesions (29 low-grade dysplasia, 19 serrated epithelial change, and 10 sessile serrated adenoma/polyps), the prevalence of methylation was significantly higher than in mucosae from 44 matched IBD controls (P < 0.0001 for methylated bone morphogenic protein 3 or methylated N-Myc downstream-regulated gene 4). KRAS mutations were more abundant in serrated epithelial change than all other groups (P < 0.001). Subsequent dysplasia was not associated with DNA marker levels. In stools, the sensitivity of methylated bone morphogenic protein 3 as a single marker was 60% for all lesions <1 cm, 63% for low-grade dysplasia ≥1 cm and 81% for high-grade dysplasia/colorectal cancer, all at 91% specificity (P < 0.0001). Selected DNA markers known to be present in advanced IBD neoplasia can also be detected in both tissues and stools from IBD patients with small adenomas and serrated lesions. Mutant KRAS exfoliated from serrated epithelial change lesions might raise false-positive rates. These findings have relevance to potential future applications of stool DNA testing for IBD surveillance.

Altered JS-2 expression in colorectal cancers and its clinical pathological relevance.

PubMed

Lam, Alfred King-Yin; Gopalan, Vinod; Nassiri, Mohammad Reza; Kasim, Kais; Dissanayake, Jayampathy; Tang, Johnny Chuek-On; Smith, Robert Anthony

2011-10-01

JS-2 is a novel gene located at 5p15.2 and originally detected in primary oesophageal cancer. There is no study on the role of JS-2 in colorectal cancer. The aim of this study is to determine the gene copy number and expression of JS-2 in a large cohort of patients with colorectal tumours and correlate these to the clinicopathological features of the cancer patients. We evaluated the DNA copy number and mRNA expression of JS-2 in 176 colorectal tissues (116 adenocarcinomas, 30 adenomas and 30 non-neoplastic tissues) using real-time polymerase chain reaction. JS-2 expression was also evaluated in two colorectal cancer cell lines and a benign colorectal cell line. JS-2 amplification was noted in 35% of the colorectal adenocarcinomas. Significant differences in relative expression levels for JS-2 mRNA between different colorectal tissues were noted (p = 0.05). Distal colorectal adenocarcinoma had significantly higher copy number than proximal adenocarcinoma (p = 0.005). The relative expression level of JS-2 was different between colonic and rectal adenocarcinoma (p = 0.007). Mucinous adenocarcinoma showed higher JS-2 expression than non-mucinous adenocarcinoma (p = 0.02). Early T-stage cancers appear to have higher JS-2 copy number and lower expression of JS-2 mRNA than later stage cancers (p = 0.001 and 0.03 respectively). Colorectal cancer cell lines showed lower expression of JS-2 than the benign colorectal cell line. JS-2 copy number change and expression were shown for the first time to be altered in the carcinogenesis of colorectal cancer. In addition, genetic alteration of JS-2 was found to be related to location, pathological subtypes and staging of colorectal cancer. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Study on image feature extraction and classification for human colorectal cancer using optical coherence tomography

NASA Astrophysics Data System (ADS)

Huang, Shu-Wei; Yang, Shan-Yi; Huang, Wei-Cheng; Chiu, Han-Mo; Lu, Chih-Wei

2011-06-01

Most of the colorectal cancer has grown from the adenomatous polyp. Adenomatous lesions have a well-documented relationship to colorectal cancer in previous studies. Thus, to detect the morphological changes between polyp and tumor can allow early diagnosis of colorectal cancer and simultaneous removal of lesions. OCT (Optical coherence tomography) has been several advantages including high resolution and non-invasive cross-sectional image in vivo. In this study, we investigated the relationship between the B-scan OCT image features and histology of malignant human colorectal tissues, also en-face OCT image and the endoscopic image pattern. The in-vitro experiments were performed by a swept-source optical coherence tomography (SS-OCT) system; the swept source has a center wavelength at 1310 nm and 160nm in wavelength scanning range which produced 6 um axial resolution. In the study, the en-face images were reconstructed by integrating the axial values in 3D OCT images. The reconstructed en-face images show the same roundish or gyrus-like pattern with endoscopy images. The pattern of en-face images relate to the stages of colon cancer. Endoscopic OCT technique would provide three-dimensional imaging and rapidly reconstruct en-face images which can increase the speed of colon cancer diagnosis. Our results indicate a great potential for early detection of colorectal adenomas by using the OCT imaging.

Prevalence of colorectal neoplasia among young African Americans and Hispanic Americans.

PubMed

Ashktorab, Hassan; Paydar, Mansour; Namin, Hassan Hassanzadeh; Sanderson, Andrew; Begum, Rehana; Brim, Hassan; Panchal, Heena; Lee, Edward; Kibreab, Angesom; Nouraie, Mehdi; Laiyemo, Adeyinka O

2014-02-01

The disproportionately higher incidence of and mortality from colorectal cancer (CRC) among African Americans (AA) led the American College of Gastroenterology to recommend screening starting at age 45 in 2005. The purpose of this study was to determine the prevalence of colorectal neoplasia among 40-49-year-old inner city AA and Hispanic Americans (HA). We reviewed the medical records of 2,435 inner city AA and HA who underwent colonoscopy regardless of indication and compared the prevalence of colorectal neoplasia between AA and HA patients. We used logistic regression models to calculate odds ratios (OR) and 95 % confidence intervals (CI). There were 2,163 AAs and 272 HA. There were 57 % women in both groups. A total of 158 (7 %) AA and 9 (3 %) HA (P = 0.014) underwent the procedures for CRC screening. When compared to HAs, AAs had higher prevalence of any polyp (35 vs. 18 %, OR = 2.53; 95 % CI 1.82-3.52). Overall, AA had higher prevalence of colorectal neoplasia (adenoma and cancer) when compared to HAs (16 vs. 10 %; OR = 1.68; 95 % CI 1.10-2.56). We observed a higher frequency of colorectal neoplasia among 40-49-year-old AAs as compared to HAs suggesting an increased susceptibility to CRC risk in this population.

Inhibition of intestinal tumors by curcumin is associated with changes in the intestinal immune cell profile.

PubMed

Churchill, M; Chadburn, A; Bilinski, R T; Bertagnolli, M M

2000-04-01

The C57BL/6J-Min/+ (Min/+) mouse bears a germline mutation in Apc and is therefore a model for familial adenomatous polyposis and sporadic colorectal cancer. Min/+ intestinal mucosa exhibits a marked tendency for spontaneous adenoma formation. Curcumin is a phenolic antioxidant known for its antitumor and immune modulatory functions in vitro. Curcumin prevents adenoma formation in Min/+ mice, through a mechanism that may be related to its immunomodulatory properties. To study the relationship between intestinal immunity and curcumin-induced antitumor response, we used immunohistochemistry to characterize the effect of curcumin treatment on resident intestinal immune effector cells in Min/+ mice. These results show that mucosal CD4(+) T cells and B cells increase in animals treated with curcumin, suggesting that curcumin modulates lymphocyte-mediated immune functions. Copyright 2000 Academic Press.

DNA methylome profiling identifies novel methylated genes in African American patients with colorectal neoplasia.

PubMed

Ashktorab, Hassan; Daremipouran, M; Goel, Ajay; Varma, Sudhir; Leavitt, R; Sun, Xueguang; Brim, Hassan

2014-04-01

The identification of genes that are differentially methylated in colorectal cancer (CRC) has potential value for both diagnostic and therapeutic interventions specifically in high-risk populations such as African Americans (AAs). However, DNA methylation patterns in CRC, especially in AAs, have not been systematically explored and remain poorly understood. Here, we performed DNA methylome profiling to identify the methylation status of CpG islands within candidate genes involved in critical pathways important in the initiation and development of CRC. We used reduced representation bisulfite sequencing (RRBS) in colorectal cancer and adenoma tissues that were compared with DNA methylome from a healthy AA subject's colon tissue and peripheral blood DNA. The identified methylation markers were validated in fresh frozen CRC tissues and corresponding normal tissues from AA patients diagnosed with CRC at Howard University Hospital. We identified and validated the methylation status of 355 CpG sites located within 16 gene promoter regions associated with CpG islands. Fifty CpG sites located within CpG islands-in genes ATXN7L1 (2), BMP3 (7), EID3 (15), GAS7 (1), GPR75 (24), and TNFAIP2 (1)-were significantly hypermethylated in tumor vs. normal tissues (P<0.05). The methylation status of BMP3, EID3, GAS7, and GPR75 was confirmed in an independent, validation cohort. Ingenuity pathway analysis mapped three of these markers (GAS7, BMP3 and GPR) in the insulin and TGF-β1 network-the two key pathways in CRC. In addition to hypermethylated genes, our analysis also revealed that LINE-1 repeat elements were progressively hypomethylated in the normal-adenoma-cancer sequence. We conclude that DNA methylome profiling based on RRBS is an effective method for screening aberrantly methylated genes in CRC. While previous studies focused on the limited identification of hypermethylated genes, ours is the first study to systematically and comprehensively identify novel hypermethylated genes, as well as hypomethylated LINE-1 sequences, which may serve as potential biomarkers for CRC in African Americans. Our discovered biomarkers were intimately linked to the insulin/TGF-B1 pathway, further strengthening the association of diabetic disorders with colon oncogenic transformation.

An x-ray-based capsule for colorectal cancer screening incorporating single photon counting technology

NASA Astrophysics Data System (ADS)

Lifshitz, Ronen; Kimchy, Yoav; Gelbard, Nir; Leibushor, Avi; Golan, Oleg; Elgali, Avner; Hassoon, Salah; Kaplan, Max; Smirnov, Michael; Shpigelman, Boaz; Bar-Ilan, Omer; Rubin, Daniel; Ovadia, Alex

2017-03-01

An ingestible capsule for colorectal cancer screening, based on ionizing-radiation imaging, has been developed and is in advanced stages of system stabilization and clinical evaluation. The imaging principle allows future patients using this technology to avoid bowel cleansing, and to continue the normal life routine during procedure. The Check-Cap capsule, or C-Scan ® Cap, imaging principle is essentially based on reconstructing scattered radiation, while both radiation source and radiation detectors reside within the capsule. The radiation source is a custom-made radioisotope encased in a small canister, collimated into rotating beams. While traveling along the human colon, irradiation occurs from within the capsule towards the colon wall. Scattering of radiation occurs both inside and outside the colon segment; some of this radiation is scattered back and detected by sensors onboard the capsule. During procedure, the patient receives small amounts of contrast agent as an addition to his/her normal diet. The presence of contrast agent inside the colon dictates the dominant physical processes to become Compton Scattering and X-Ray Fluorescence (XRF), which differ mainly by the energy of scattered photons. The detector readout electronics incorporates low-noise Single Photon Counting channels, allowing separation between the products of these different physical processes. Separating between radiation energies essentially allows estimation of the distance from the capsule to the colon wall, hence structural imaging of the intraluminal surface. This allows imaging of structural protrusions into the colon volume, especially focusing on adenomas that may develop into colorectal cancer.

Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial.

PubMed

Fedirko, Veronika; Bostick, Roberd M; Long, Qi; Flanders, W Dana; McCullough, Marjorie L; Sidelnikov, Eduard; Daniel, Carrie R; Rutherford, Robin E; Shaukat, Aasma

2010-01-01

The exact antineoplastic effects of calcium and vitamin D(3) in the human colon are unclear. Animal and in vitro studies show that these two agents reduce oxidative stress; however, these findings have never been investigated in humans. To address this, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D(3) on a marker of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine (8-OH-dG), in the normal colorectal mucosa. Patients (N = 92) with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d calcium and/or 800 IU/d vitamin D(3) versus placebo over 6 months. Overall labeling and colorectal crypt distribution of 8-OH-dG in biopsies of normal-appearing rectal mucosa were detected by standardized automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, 8-OH-dG labeling along the full lengths of colorectal crypts decreased by 22% (P = 0.15) and 25% (P = 0.10) in the calcium and vitamin D(3) groups, respectively, but not in the calcium plus vitamin D(3) group. The estimated treatment effects were strongest among participants with higher baseline colon crypt vitamin D receptor expression (P = 0.05). Overall, these preliminary results indicate that calcium and vitamin D(3) may decrease oxidative DNA damage in the normal human colorectal mucosa, support the hypothesis that 8-OH-dG labeling in colorectal crypts is a treatable oxidative DNA damage biomarker of risk for colorectal neoplasms, and provide support for further investigation of calcium and vitamin D(3) as chemopreventive agents against colorectal neoplasms.

Analytical validation of a novel multiplex test for detection of advanced adenoma and colorectal cancer in symptomatic patients.

PubMed

Dillon, Roslyn; Croner, Lisa J; Bucci, John; Kairs, Stefanie N; You, Jia; Beasley, Sharon; Blimline, Mark; Carino, Rochele B; Chan, Vicky C; Cuevas, Danissa; Diggs, Jeff; Jennings, Megan; Levy, Jacob; Mina, Ginger; Yee, Alvin; Wilcox, Bruce

2018-05-30

Early detection of colorectal cancer (CRC) is key to reducing associated mortality. Despite the importance of early detection, approximately 40% of individuals in the United States between the ages of 50-75 have never been screened for CRC. The low compliance with colonoscopy and fecal-based screening may be addressed with a non-invasive alternative such as a blood-based test. We describe here the analytical validation of a multiplexed blood-based assay that measures the plasma concentrations of 15 proteins to assess advanced adenoma (AA) and CRC risk in symptomatic patients. The test was developed on an electrochemiluminescent immunoassay platform employing four multi-marker panels, to be implemented in the clinic as a laboratory developed test (LDT). Under the Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathologists (CAP) regulations, a United States-based clinical laboratory utilizing an LDT must establish performance characteristics relating to analytical validity prior to releasing patient test results. This report describes a series of studies demonstrating the precision, accuracy, analytical sensitivity, and analytical specificity for each of the 15 assays, as required by CLIA/CAP. In addition, the report describes studies characterizing each of the assays' dynamic range, parallelism, tolerance to common interfering substances, spike recovery, and stability to sample freeze-thaw cycles. Upon completion of the analytical characterization, a clinical accuracy study was performed to evaluate concordance of AA and CRC classifier model calls using the analytical method intended for use in the clinic. Of 434 symptomatic patient samples tested, the percent agreement with original CRC and AA calls was 87% and 92% respectively. All studies followed CLSI guidelines and met the regulatory requirements for implementation of a new LDT. The results provide the analytical evidence to support the implementation of the novel multi-marker test as a clinical test for evaluating CRC and AA risk in symptomatic individuals. Copyright © 2018 Elsevier B.V. All rights reserved.

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside of the crypt base stem cell niche

PubMed Central

Bansal, Mukesh; Rafferty, Hannah; Boitsova, Tatjana; Bardella, Chiara; Jaeger, Emma; Lewis, Annabelle; Freeman-Mills, Luke; Giner, Francesc Castro; Rodenas-Cuadrado, Pedro; Mallappa, Sreelakshmi; Clark, Susan; Thomas, Huw; Jeffery, Rosemary; Poulsom, Richard; Rodriguez-Justo, Manuel; Novelli, Marco; Chetty, Runjan; Silver, Andrew; Sansom, Owen James; Greten, Florian R; Wang, Lai Mun; East, James Edward; Tomlinson, Ian; Leedham, Simon John

2015-01-01

Hereditary mixed polyposis syndrome (HMPS) is characterised by the development of mixed morphology colorectal tumours and is caused by a 40 kb duplication that results in aberrant epithelial expression of the mesenchymal Bone Morphogenetic Protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell-fate, that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem-cell properties in Lgr5 negative (non-expressing) progenitor cells that have exited the stem-cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem-cell is not the sole cell-of-origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic pre-malignant lesions with a hitherto unknown pathogenesis and these lesions can be considered the sporadic equivalents of HMPS polyps. PMID:25419707

Prom1 Function in Development, Intestinal Inflammation, and Intestinal Tumorigenesis

PubMed Central

Karim, Baktiar O.; Rhee, Ki-Jong; Liu, Guosheng; Yun, Kyuson; Brant, Steven R.

2014-01-01

Prom1/CD133 has been identified in colorectal, hepatocellular, and pancreatic cancer as a cancer stem cell marker and has been used as such to predict colon cancer recurrence in humans. Its potential molecular function as well as its role as a marker of intestinal regeneration is still not fully known. We evaluated the role of Prom1 in intestinal regeneration in inflammatory bowel disease (IBD), determined the function of Prom1, and characterized the effect of a lack of Prom1 on intestinal tumor formation in animal models. Our results suggest that Apc mutations lead to an increase in Prom1 expressing cells in the intestinal crypt stem cell compartment and in early intestinal adenomas. Also, Prom1 knockout mice are more susceptible to intestinal tumor formation. We conclude that Prom1 likely plays a role in regulating intestinal homeostasis and that these results clearly illustrate the role of Prom1 in intestinal regeneration. We further conclude that Prom1 may provide a novel therapeutic target for patients with gastrointestinal conditions such as IBD, short bowel syndrome, and colorectal cancer. PMID:25452936

Deep Learning Localizes and Identifies Polyps in Real Time with 96% Accuracy in Screening Colonoscopy.

PubMed

Urban, Gregor; Tripathi, Priyam; Alkayali, Talal; Mittal, Mohit; Jalali, Farid; Karnes, William; Baldi, Pierre

2018-06-18

The benefit of colonoscopy for colorectal cancer prevention depends on the adenoma detection rate (ADR). The ADR should reflect adenoma prevalence rate, estimated to be greater than 50% among the screening-age population. Yet the rate of adenoma detection by colonoscopists varies from 7% to 53%. It is estimated that every 1% increase in ADR reduces the risk of interval colorectal cancers by 3-6%. New strategies are needed to increase the ADR during colonoscopy. We tested the ability of computer-assisted image analysis, with convolutional neural networks (a deep learning model for image analysis), to improve polyp detection, a surrogate of ADR. We designed and trained deep convolutional neural networks (CNN) to detect polyps using a diverse and representative set of 8641 hand labeled images from screening colonoscopies collected from over 2000 patients. We tested the models on 20 colonoscopy videos with a total duration of 5 hours. Expert colonoscopists were asked to identify all polyps in 9 de-identified colonoscopy videos, selected from archived video studies, either with or without benefit of the CNN overlay. Their findings were compared with those of the CNN, using CNN-assisted expert review as the reference. When tested on manually labeled images, the CNN identified polyps with an area under the receiver operating characteristic curve (ROC-AUC) of 0.991 and an accuracy of 96.4%. In the analysis of colonoscopy videos in which 28 polyps were removed, 4 expert reviewers identified 8 additional polyps without CNN assistance that had not been removed and identified an additional 17 polyps with CNN assistance (45 in total). All polyps removed and identified by expert review were detected by the CNN. The CNN had a false-positive rate of 7%. In a set of 8641 colonoscopy images containing 4088 unique polyps the CNN identified polyps with a cross-validation accuracy of 96.4% and ROC-AUC value of 0.991. The CNN system can detect and localize polyps well within real-time constraints using an ordinary desktop machine with a contemporary graphics processing unit. This system could increase ADR and reduce interval colorectal cancers but requires validation in large multicenter trials. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Colorectal cancer screening programme by faecal occult blood test in Tuscany: first round results.

PubMed

Grazzini, G; Castiglione, G; Ciabattoni, C; Franceschini, F; Giorgi, D; Gozzi, S; Mantellini, P; Lopane, P; Perco, M; Rubeca, T; Salvadori, P; Visioli, C B; Zappa, M

2004-02-01

Screening with faecal occult blood test (FOBT) has been shown to be effective in reducing mortality from colorectal cancer. Tuscany was the first region in Italy in which a screening programme for colorectal cancer by FOBT was initiated region-wide. The aim of the paper was to describe organizational aspects, a quality control model and the results of this experience. From June 2000 to December 2001, 192583 subjects aged 50-70 were invited to undergo a 1-day immunochemical test without any dietary restriction. A total of 78505 subjects (41%) performed the screening test, of whom 4537 responders had a positive test result (5.8%). Among them, 1122 refused any form of assessment or underwent a colonoscopy outside the screening referral centres, with an overall assessment compliance of 75.3%. Malignancies were found in 193 patients and at least a high-risk adenomatous polyp in 692 patients. In about a quarter of the positive subjects who underwent assessment, cancer or high-risk adenoma was detected. In conclusion, data from this experience supported the feasibility of biennial colorectal screening programme by FOBT, particularly regarding invitation compliance and positivity rate. Further efforts are necessary to implement screening extension and to improve data collection.

Devising an endoluminal bimodal probe which combines autofluorescence and reflectance spectroscopy with high resolution MRI for early stage colorectal cancer diagnosis: technique, feasibility and preliminary in-vivo (rabbit) results

NASA Astrophysics Data System (ADS)

Ramgolam, A.; Sablong, R.; Bou-Saïd, B.; Bouvard, S.; Saint-Jalmes, H.; Beuf, O.

2011-07-01

Conventional white light endoscopy (WLE) is the most widespread technique used today for colorectal cancer diagnosis and is considered as the gold standard when coupled to biopsy and histology. However for early stage colorectal cancer diagnosis, which is very often characterised by flat adenomas, the use of WLE is quite difficult due to subtle or quasiinvisible morphological changes of the colonic lining. Figures worldwide point out that diagnosing colorectal cancer in its early stages would significantly reduce the death toll all while increasing the 5-year survival rate. Several techniques are currently being investigated in the scope of providing new tools that would allow such a diagnostic or assist actual techniques in so doing. We hereby present a novel technique where High spatial Resolution MRI (HR-MRI) is coupled to optical spectroscopy (autofluorescence and reflectance) in a bimodal endoluminal probe to extract morphological data and biochemical information respectively. The design and conception of the endoluminal probe along with the preliminary results obtained with an organic phantom and in-vivo (rabbit) are presented and discussed.

Serrated adenocarcinoma morphology in colorectal mucinous adenocarcinoma is associated with improved patient survival

PubMed Central

Lee, Chung-Ta; Chow, Nan-Haw; Su, Pei-Fang; Ho, Chung-Liang; Tsai, Hung-Wen; Chen, Yi-Lin; Lin, Shao-Chieh; Lin, Bo-Wen; Lin, Peng-Chan; Lee, Jenq-Chang

2017-01-01

Colorectal mucinous adenocarcinoma (MAC) and serrated adenocarcinoma (SAC) share many characteristics, including right-side colon location, frequent mucin production, and various molecular features. This study examined the frequency of SAC morphology in MACs. We assessed the correlation of SAC morphology with clinicopathological parameters, molecular characteristics, and patient prognosis. Eighty-eight colorectal MACs were collected and reviewed for SAC morphology according to Makinen's criteria. We sequenced KRAS and BRAF, assessed CpG island methylator phenotype (CIMP) frequency, and analyzed DNA mismatch repair enzyme levels using immunohistochemistry in tumor samples. SAC morphology was observed in 38% of MACs, and was associated with proximal location (P=0.001), BRAF mutation (P=0.042), CIMP-positive status (P=0.023), and contiguous traditional serrated adenoma (P=0.019). Multivariate analysis revealed that MACs without both SAC morphology and CIMP-positive status exhibited 3.955 times greater risk of cancer relapse than MACs having both characteristics or either one (P=0.035). Our results show that two MAC groups with distinct features can be identified using Makinen's criteria, and suggest a favorable prognostic role for the serrated neoplastic pathway in colorectal MAC. PMID:28422723

The Smad4/PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma

PubMed Central

Chung, Yumin; Wi, Young Chan; Kim, Yeseul; Bang, Seong Sik; Yang, Jung-Ho; Jang, Kiseok; Min, Kyueng-Whan; Paik, Seung Sam

2018-01-01

Background Smad4 and PTEN are prognostic indicators for various tumor types. Smad4 regulates tumor suppression, whereas PTEN inhibits cell proliferation. We analyzed and compared the performance of Smad4 and PTEN for predicting the prognosis of patients with colorectal adenocarcinoma. Methods Combined expression patterns based on Smad4+/– and PTEN+/– status were evaluated by immunostaining using a tissue microarray of colorectal adenocarcinoma. The relationships between the protein expression and clinicopathological variables were analyzed. Results Smad4–/PTEN– status was most frequently observed in metastatic adenocarcinoma, followed by primary adenocarcinoma and tubular adenoma (p<.001). When Smad4–/PTEN– and Smad4+/PTEN+ groups were compared, Smad4–/PTEN– status was associated with high N stage (p=.018) and defective mismatch repair proteins (p=.006). Significant differences in diseasefree survival and overall survival were observed among the three groups (Smad4+/PTEN+, Smad4–/PTEN+ or Smad4+/PTEN–, and Smad4–/PTEN–) (all p<.05). Conclusions Concurrent loss of Smad4 and PTEN may lead to more aggressive disease and poor prognosis in patients with colorectal adenocarcinoma compared to the loss of Smad4 or PTEN alone. PMID:29056035

Quantitative profiling of CpG island methylation in human stool for colorectal cancer detection.

PubMed

Elliott, Giles O; Johnson, Ian T; Scarll, Jane; Dainty, Jack; Williams, Elizabeth A; Garg, D; Coupe, Amanda; Bradburn, David M; Mathers, John C; Belshaw, Nigel J

2013-01-01

The aims of this study were to investigate the use of quantitative CGI methylation data from stool DNA to classify colon cancer patients and to relate stool CGI methylation levels to those found in corresponding tissue samples. We applied a quantitative methylation-specific PCR assay to determine CGI methylation levels of six genes, previously shown to be aberrantly methylated during colorectal carcinogenesis. Assays were performed on DNA from biopsies of "normal" mucosa and stool samples from 57 patients classified as disease-free, adenoma, or cancer by endoscopy, and in tumour tissue from cancer patients. Additionally, CGI methylation was analysed in stool DNA from an asymptomatic population of individuals covering a broad age range (mean = 47 ± 24 years) CGI methylation levels in stool DNA were significantly higher than in DNA from macroscopically normal mucosa, and a significant correlation between stool and mucosa was observed for ESR1 only. Multivariate statistical analyses using the methylation levels of each CGI in stool DNA as a continuous variable revealed a highly significant (p = 0.003) classification of cancer vs. non-cancer (adenoma + disease-free) patients (sensitivity = 65 %, specificity = 81 %). CGI methylation profiling of stool DNA successfully identified patients with cancer despite the methylation status of CGIs in stool DNA not generally reflecting those in DNA from the colonic mucosa.

Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression.

PubMed

Ibrahim, Ashraf E K; Arends, Mark J; Silva, Ana-Luisa; Wyllie, Andrew H; Greger, Liliana; Ito, Yoko; Vowler, Sarah L; Huang, Tim H-M; Tavaré, Simon; Murrell, Adele; Brenton, James D

2011-04-01

Although aberrant methylation of key genes in the progression of colorectal neoplasia has been reported, no model-based analysis of the incremental changes through the intermediate adenoma stage has been described. In addition, the biological drivers for these methylation changes have yet to be defined. Linear mixed-effects modelling was used in this study to understand the onset and patterns of the methylation changes of SFRP2, IGF2 DMR0, H19, LINE-1 and a CpG island methylator phenotype (CIMP) marker panel, and they were correlated with DNA methyltransferase 3B (DNMT3B) levels of expression in a sample set representative of colorectal neoplastic progression. Methylation of the above CpG islands was measured using quantitative pyrosequencing assays in 261 tissue samples. This included a prospective collection of 44 colectomy specimens with concurrent normal mucosa, adenoma and invasive cancer tissues. Tissue microarrays from a subset of 64 cases were used for immunohistochemical analysis of DNMT3B expression. It is shown that the onset and pattern of methylation changes during colorectal neoplastic progression are locus dependent. The CIMP marker RUNX3 was the earliest CpG island showing significant change, followed by the CIMP markers NEUROG1 and CACNA1G at the hyperplastic polyp stage. SFRP2 and IGF2 DMR0 showed significant methylation changes at the adenomatous polyp stage, followed by the CIMP markers CDKN2A and hMLH1 at the adenocarcinoma stage. DNMT3B levels of immunohistochemical expression increased significantly (p < 0.001) from normal to hyperplastic and from adenomatous polyps to carcinoma samples. DNMT3B expression correlated positively with SFRP2 methylation (r = 0.42, p < 0.001, 95% CI 0.25 to 0.56), but correlated negatively with IGF2 DMR0 methylation (r = 0.26, p = 0.01, 95% CI -0.45 to -0.05). A subset of the CIMP panel (NEUROG1, CACNA1G and CDKN2A) positively correlated with DNMT3B levels of expression (p < 0.05). Hierarchical epigenetic alterations occur at transition points during colorectal neoplastic progression. These cumulative changes are closely correlated with a gain of DNMT3B expression, suggesting a causal relationship.

Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement.

PubMed

Bibbins-Domingo, Kirsten; Grossman, David C; Curry, Susan J; Davidson, Karina W; Epling, John W; García, Francisco A R; Gillman, Matthew W; Harper, Diane M; Kemper, Alex R; Krist, Alex H; Kurth, Ann E; Landefeld, C Seth; Mangione, Carol M; Owens, Douglas K; Phillips, William R; Phipps, Maureen G; Pignone, Michael P; Siu, Albert L

2016-06-21

Colorectal cancer is the second leading cause of cancer death in the United States. In 2016, an estimated 134,000 persons will be diagnosed with the disease, and about 49,000 will die from it. Colorectal cancer is most frequently diagnosed among adults aged 65 to 74 years; the median age at death from colorectal cancer is 68 years. To update the 2008 US Preventive Services Task Force (USPSTF) recommendation on screening for colorectal cancer. The USPSTF reviewed the evidence on the effectiveness of screening with colonoscopy, flexible sigmoidoscopy, computed tomography colonography, the guaiac-based fecal occult blood test, the fecal immunochemical test, the multitargeted stool DNA test, and the methylated SEPT9 DNA test in reducing the incidence of and mortality from colorectal cancer or all-cause mortality; the harms of these screening tests; and the test performance characteristics of these tests for detecting adenomatous polyps, advanced adenomas based on size, or both, as well as colorectal cancer. The USPSTF also commissioned a comparative modeling study to provide information on optimal starting and stopping ages and screening intervals across the different available screening methods. The USPSTF concludes with high certainty that screening for colorectal cancer in average-risk, asymptomatic adults aged 50 to 75 years is of substantial net benefit. Multiple screening strategies are available to choose from, with different levels of evidence to support their effectiveness, as well as unique advantages and limitations, although there are no empirical data to demonstrate that any of the reviewed strategies provide a greater net benefit. Screening for colorectal cancer is a substantially underused preventive health strategy in the United States. The USPSTF recommends screening for colorectal cancer starting at age 50 years and continuing until age 75 years (A recommendation). The decision to screen for colorectal cancer in adults aged 76 to 85 years should be an individual one, taking into account the patient's overall health and prior screening history (C recommendation).

Use of a nitinol stent to palliate a colorectal neoplastic obstruction in a dog

PubMed Central

Culp, William T. N.; MacPhail, Catriona M.; Perry, James A.; Jensen, Tracey D.

2015-01-01

Case Description A 12-year-old castrated male Labrador Retriever was evaluated for clinical signs associated with colorectal obstruction. Clinical Findings The dog had a 2-week history of tenesmus and hematochezia. On rectal examination, an annular colorectal mass was palpable extending orad into the pelvic canal. The original diagnosis of the colorectal mass was a mucosal adenoma. The dog was maintained on a low-residue diet and fecal softeners for a period of 13 months after initial diagnosis. At that time, medical management was no longer effective. Treatment and Outcome Placement of a colonic stent was chosen to palliate the clinical signs associated with colorectal obstruction. By use of fluoroscopic and colonoscopic guidance, a nitinol stent was placed intraluminally to open the obstructed region. Placement of the stent resulted in improvement of clinical signs, although tenesmus and obstipation occurred periodically after stent placement. At 212 days after stent placement, the patient had extensive improvement in clinical signs with minimal complications; however, clinical signs became severe at 238 days after stent placement, and the dog was euthanized. Histologic evaluation of the rectal tumor from samples obtained during necropsy revealed that the tumor had undergone malignant transformation to a carcinoma in situ. Clinical Relevance A stent was successfully placed in the colon and rectum to relieve obstruction associated with a tumor originally diagnosed as a benign neoplasm. Placement of colorectal stents may be an option for the palliation of colorectal obstruction secondary to neoplastic disease; however, clinical signs may persist, and continuation of medical management may be necessary. PMID:21756178