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Colorectal cancer (CRC) accounts for the third highest morbidity burden among malignant tumors worldwide. Previous studies investigated gut microbiome changes that occur during colorectal adenomas (CRA) progression to overt CRC, thus highlighting the importance of the gut microbiome in carcinogenesis. However, few studies have examined gut microbiome characteristics across the entire spectrum, from CRC development to treatment. The study used 16S ribosomal ribonucleic acid and internal transcribed spacer amplicon sequencing to compare the composition of gut bacteria and fungi in a Chinese cohort of healthy controls (HC), CRC patients, CRA patients, and CRC postoperative patients (PP). Our analysis showed that beta diversity was significantly different among the four groups based on the gut bacterial and fungal data. A total of 51 species of bacteria and 8 species of fungi were identified in the HC, CRA, CRC, and PP groups. Correlation networks for both the gut bacteria and fungi in HC vs. CRA, HC vs. CRC, and HC vs. PP indicated some hub bacterial and fungal genera in each model, and the correlation between bacterial and fungal data indicated that a highly significant negative correlation exists among groups. Quantitative polymerase chain reaction (qPCR) analysis in a large cohort of HC, CRC, CRA, and PP patients demonstrated a significantly increasing trend of Fusobacterium nucleatum, Bifidobacterium bifidum, Candida albicans , and Saccharomyces cerevisiae in the feces of CRC patients than that of HC patients ( p < 0.01). However, the abundance levels of CRA and PP were significantly lower in HC patients than those in CRC patients. Further studies are required to identify the functional consequences of the altered bacterial/fungal composition on metabolism and CRC tumorigenesis in the host., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Feng, Wang, Liu and Wang.)

OBJECTIVE: Thymosin beta 4 (Tβ4) is a ubiquitous peptide that plays pivotal roles in the cytoskeletal system and in cell differentiation. Recently, a role for Tβ4 has been proposed in experimental and human carcinogenesis, including gastrointestinal cancer. This study was aimed at evaluating the relationship between Tβ4 immunoreactivity and the initial steps of carcinogenesis. METHODS: In total, 60 intestinal biopsies, including 10 hyperplastic polyps, 10 sessile serrated adenomas/polyps, 15 colorectal adenomas with low-grade dysplasia, 15 adenomas with high-grade dysplasia, 15 adenocarcinomas and 10 samples of normal colon mucosa, were analyzed for Tβ4 expression by immunohistochemistry. RESULTS: Weak cytoplasmic reactivity for Tβ4 was detected in the normal colon mucosa. No reactivity for Tβ4 was found in hyperplastic and sessile serrated polyps/adenomas. Tβ4 expression was observed in 10/15 colorectal adenocarcinomas. In adenomas with low-grade dysplasia, Tβ4 immunoreactivity was mainly detected in dysplastic glands but was absent in hyperplastic glands. Tβ4 immunoreactivity was characterized by spot-like perinuclear staining. In high-grade dysplastic polyps, immunostaining for Tβ4 appeared diffuse throughout the entire cytoplasm of dysplastic cells. Spot-like perinuclear reactivity was detected in adenocarcinoma tumor cells. CONCLUSIONS: Our study shows for the first time that Tβ4 is expressed during different steps of colon carcinogenesis. The shift of Tβ4 immunolocalization from low-grade to high-grade dysplastic glands suggests a role for Tβ4 in colorectal carcinogenesis. However, the real meaning of Tβ4 reactivity in dysplastic intestinal epithelium remains unknown.

The morbidity and mortality of colorectal cancer (CRC) have been increasing in recent years, and early detection of CRC can improve the survival rate of patients. RNA methylation plays crucial roles in many biological processes and has been implicated in the initiation of various diseases, including cancer. Serum contains a variety of biomolecules and is an important clinical sample for biomarker discovery. In this study, we developed a targeted metabolomics method for the quantitative analysis of nucleosides in human serum samples by using liquid chromatography with tandem mass spectrometry (LC-MS/MS). We successfully quantified the concentrations of nucleosides in serum samples from 51 healthy controls, 37 patients with colorectal adenomas, and 55 patients with CRC. The results showed that the concentrations of N 6 -methyladenosine (m 6 A), N 1 -methyladenosine (m 1 A), and 3-methyluridine (m 3 U) were increased in patients with CRC, whereas the concentrations of N 2 ) were decreased in patients with CRC, compared with the healthy controls and patients with colorectal adenomas. Moreover, the levels of 2'-O-methyluridine and 2'-O-methylguanosine were lower in patients with colorectal adenomas than those in healthy controls. Interestingly, the levels of U 2 G), 2'-O-methyluridine (U m gradually decreased in the following order: healthy controls to colorectal adenoma patients to CRC patients. These results revealed that the aberrations of these nucleosides were tightly correlated to colorectal adenomas and CRC. In addition, the present work will stimulate future investigations about the regulatory roles of these nucleosides in the initiation and development of CRC.m ) were decreased in patients with CRC, compared with the healthy controls and patients with colorectal adenomas. Moreover, the levels of 2'-O-methyluridine and 2'-O-methylguanosine were lower in patients with colorectal adenomas than those in healthy controls. Interestingly, the levels of U m and G m gradually decreased in the following order: healthy controls to colorectal adenoma patients to CRC patients. These results revealed that the aberrations of these nucleosides were tightly correlated to colorectal adenomas and CRC. In addition, the present work will stimulate future investigations about the regulatory roles of these nucleosides in the initiation and development of CRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zheng, Wang, Chai, Pan, Xu, Wang, Lan, Hu, Zhang and Chen.)

Objective: Psen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer's disease. Little, if any, is known about its function in the gut. Here, we uncovered an unexpected functional role of Psen1 in gut epithelial cells during intestinal tumourigenesis., Design: Human colorectal cancer (CRC) and control samples were investigated for PSEN1 and proteins of theγ-secretase complex. Tumour formation was analysed in the AOM-DSS and Apc min/+ mouse models using newly generated epithelial-specific Psen1 deficient mice. Psen1 deficient human CRC cells were studied in a xenograft tumour model. Tumour-derived organoids were analysed for growth and RNA-Seq was performed to identify Psen1-regulated pathways. Tumouroids were generated to study EGFR activation and evaluation of the influence of prostanoids., Results: PSEN1 is expressed in the intestinal epithelium and its level is increased in human CRC. Psen1 -deficient mice developed only small tumours and human cancer cell lines deficient in Psen1 had a reduced tumourigenicity. Tumouroids derived from Psen1 -deficient Apc min/+ mice exhibited stunted growth and reduced cell proliferation. On a molecular level, PSEN1 potentiated tumour cell proliferation via enhanced EGFR signalling and COX-2 production. Exogenous administration of PGE 2 reversed the slow growth of PSEN1 deficient tumour cells via PGE 2 receptor 4 (EP4) receptor signalling., Conclusions: Psen1 drives tumour development by increasing EGFR signalling via NOTCH1 processing, and by activating the COX-2-PGE 2 pathway. PSEN1 inhibition could be a useful strategy in treatment of CRC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: High-quality colonoscopy is crucial to ensure complete mucosal visualisation and to maximise detection of pathology. Previous audits showing variable quality have prompted national and international colonoscopy improvement programmes, including the development of quality assurance standards and key performance indicators (KPIs). The most widely used marker of mucosal visualisation is the adenoma detection rate (ADR), however, histological confirmation is required to calculate this. We explored the relationship between core colonoscopy KPIs., Methods: Data were collected from colonoscopists in eight hospitals in North East England over a 6-month period, as part of a quality improvement study. Procedural information was collected including number of colonoscopies, caecal intubation rate (CIR), ADR and polyp detection rate (PDR). Associations between KPIs and colonoscopy performance were analysed., Results: 9265 colonoscopies performed by 118 endoscopists were included. Mean ADR and PDR per endoscopist were 16.6% (range 0-36.3, SD 7.4) and 27.2% (range 0-57.5, SD 9.3), respectively. Mean number of colonoscopies conducted in 6 months was 78.5 (range 4-334, SD 61). Mean CIR was 91.2% (range 55.5-100, SD 6.6). Total number of colonoscopies and ADR>15% were significantly associated (p=0.04). Undertaking fewer colonoscopies and using hyoscine butylbromide less frequently was significantly associated with ADR<15%. CIR, endoscopist grade, % male patients, mean patient age and CIR were not significantly related to ADR<15%. In adjusted analyses, factors which affected ADR were PDR and mean patient age., Conclusion: Colonoscopists who perform fewer than the nationally stipulated minimum of 100 procedures per year had significantly lower ADRs. This study demonstrates that PDR can be used as a marker of ADR; providing age is also considered., Competing Interests: Competing interests: CR has received grant funding from ARC medical, Norgine, 3-D Matrix, Medtronic and Olympus medical. He was an expert witness for ARC medical and for Olympus medical. LS is in receipt of project grants from 3-D Matrix and Medtronic. LJN is in receipt of a project grant from Medtronic. None of the remaining authors declare any conflicts of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Using data from former reports, this study reviews and analyzes the outcomes of tumor recurrence, tumor progression, and tumor-specific survival of patients with colorectal adenomas.Methods: Data were collected from 32 longitudinal studies of outcomes after the first diagnosis of colorectal adenoma and collected as individual patient results, that is, as failure times from the first tumor to the three outcomes. Altogether, there were 45,286 patients, including 22,148 for the outcome of additional adenomas, 23,796 for the outcome of progression to invasive carcinoma, and 2,602 for the outcome of disease-specific survival (some patients were available for more than one outcome).Results: In these data, the mean time to additional adenomas was 6 years, the mean time to invasive carcinoma was 15.9 years, and the mean tumor-specific survival time was 21.9 years.Conclusions: Although greater than 50% of those with colorectal adenomas will have additional adenomas, few progress to invasive tumor or die of colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: 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.Aims: 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.Methods: 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.Results: 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).Conclusions: 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. [ABSTRACT FROM AUTHOR]

Introduction: argon-plasma coagulation (APC) has been used safely and efficaciously in multiple settings including colon polyp treatment. The aim of this study was to evaluate APC efficacy and safety in the treatment of flat colorectal adenomas. Materials and methods: APC ablation was prospectively performed and evaluated in 22 consecutive patients with colorectal adenomas, 11 of which had large sessile adenomas that were treated with piecemeal polypectomy and APC ablation of residual adenomatous tissue, whereas the remaining eleven patients with flat or carpet-like adenomas were only treated with APC. The mean initial longitudinal extension of adenomas to be treated with APC was 22 mm (range, 20 to 40 mm). Results: the mean age of patients was 70 years. Adenomas were found most frequently in the rectum (50%) and cecum (23%). Complete ablation was achieved in 90.9% of adenomas. Recurrence was observed in 20% of patients, all of them in the rectum, after a mean follow-up period of 16.3 months (range, 8 to 35). All recurrences were managed satisfactorily. No major complications were seen. Conclusions: argon plasma coagulator ablation of flat colorectal adenomas is an efficacious and safe technique, specially in the right colon, but results must be confirmed in controlled trials with a higher number of patients.Introducción: el argón plasma (AP), como terapia endoscópica, ha sido utilizado en diferentes lesiones digestivas, incluyendo la ablación de tejido adenomatoso de pólipos colorrectales. El objetivo del presente estudio fue evaluar la seguridad y efectividad del tratamiento con AP de pólipos colorrectales. Material y métodos: se valoró de forma prospectiva la aplicación en la práctica clínica de AP en el tratamiento de 22 pacientes con pólipos colorrectales, de los cuales 11 pacientes con pólipos de gran tamaño fueron tratados con polipectomía endoscópica fragmentada más ablación del tejido adenomatoso con AP, y los otros 11 pacientes, con pólipos planos o en alfombra, solamente con AP. La extensión inicial de tejido adenomatoso a tratar tenía un diámetro medio de 22 (20-40) mm. Resultados: la edad media de los pacientes era de 70 años. Las localizaciones más frecuentes de los pólipos fueron recto (50%) y ciego (23%). Se observó respuesta completa al tratamiento endoscópico de pólipos colorrectales con AP en el 90,9% de los casos. Se produjo recurrencia en el 20%, en todos los casos pólipos rectales, tras un seguimiento medio de 16,3 (8-35) meses. Todas las recurrencias fueron tratadas satisfactoriamente. No se observaron complicaciones mayores derivadas del tratamiento con AP. Conclusiones: el tratamiento de pólipos colorrectales mediante ablación con AP es seguro y efectivo, principalmente en pólipos localizados en el colon derecho, aunque estos resultados debieran ser confirmados por estudios controlados con mayor número de pacientes.

Background: Several studies have shown that colorectal adenomas are the most important precancerous lesions. The colonoscopic identification of groups with the high risk of malignant colorectal adenomas remains a controversial issue for clinicians., Aims: To evaluate the basic characteristics of colorectal adenomas with malignancy risk using high-grade dysplasia (HGD) as an alternative marker for malignant transformation., Methods: Data from Shanghai General Hospital between January 2017 and December 2021 were retrospectively analyzed. The primary outcome was the incidence of HGD in adenomas, which was used as a surrogate marker for the risk of malignancy. Odds ratios (ORs) for the HGD rate in adenomas were analyzed in relation to adenoma-related factors., Results: A total of 9,646 patients identified with polyps during 57,445 screening colonoscopies were included in the study. Patients with flat polyps, sessile polyps, and pedunculated polyps represented 27.3% ( N = 2,638), 42.7% ( N = 4,114), and 30.0% ( N = 2,894) of the total number, respectively. HGD was found in 2.41% ( N = 97), 0.92% ( N = 24), and 3.51% ( N = 98) of sessile adenomas, flat adenomas, and pedunculated adenomas, respectively ( P < 0.001). Multivariable logistic regression showed that polyp size ( P < 0.001) but not shape ( P > 0.8), was an independent predictor of HGD. Contrast to the diameter ≤1 cm, the OR value for diameters 1-2, 2-3, and >3 cm was 13.9, 49.3, and 161.6, respectively. The HGD incidence also increased in multiple adenomas (>3 vs. >1, ORs 1.582) and distal adenomas (distal vs. proximal adenomas, OR 2.252). Adenoma morphology (pedunculated vs. flat) was statistically significant in univariate analysis but not when size was included in the multivariate analysis. Besides, the incidence of HGD was also significantly higher in older patients (>64 vs. <50 years old, OR = 2.129). Sex ( P = 0.681) was not statistically significant. All these associations were statistically significant ( P < 0.05)., Conclusion: The malignant potential of polyps is mostly affected by their size but not by their shape. In addition, distal location, multiple adenomas, and advanced age were also correlated with malignant transformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hu, Gong, Xu, Luo, Gao, Li and Jing.)

Purpose: Appropriate surveillance intervals for colorectal cancer (CRC) screening is one of the Centers for Medicare and Medicaid Services 2014 physician quality reporting system measures. Appropriateness of surveillance intervals will continue to be monitored closely, particularly as reimbursements become tied to quality measures.Aims: Quantify and identify predictors for guideline-concordant surveillance recommendations after adenoma polypectomy.Methods: We conducted a retrospective cohort study of patients who had colonoscopy with polypectomy at a safety-net health system between June 2011 and December 2013. Surveillance recommendations shorter and longer than guideline recommendations were defined as potential overuse and underuse. We used multivariate logistic regression to identify correlates of guideline-concordant surveillance recommendations, overuse, and underuse.Results: Among 1,822 patients with polypectomy, 1,329 had ≥1 adenoma. Surveillance interval recommendations were guideline-concordant in 1,410 (77.4%) patients, potential overuse in 263 (14.4%), potential underuse in 85 (4.7%), and missing in 64 (3.5%) patients. Predictors of guideline-concordant recommendations in multivariate analyses included age >65 years (OR 1.36, 95% CI 1.02-1.80), incomplete resection (OR 3.58, 95% CI 1.41-9.09), and good/excellent prep quality (OR 2.22, 95% CI 1.72-2.86). Underuse recommendations were more likely in patients with ≥3 adenomas; overuse recommendations were more likely in patients with high-grade dysplasia or fair prep quality and less likely in those with piecemeal resection, ≥3 adenomas, age >65, or Hispanic ethnicity.Conclusions: Surveillance recommendations are not concordant with guidelines in one of four cases. Interventions to improve prep quality and guideline concordance of surveillance recommendations can improve cost-effectiveness of CRC screening. [ABSTRACT FROM AUTHOR]

Background Insulin stimulates cell proliferation and inhibits apoptosis. While epidemiologic studies have investigated associations between markers of insulin resistance/hyperinsulinemia (i.e., circulating insulin, homeostasis model assessment-insulin resistance (HOMA-IR), C-peptide) and risk of colorectal adenoma (CRA), the effect size has not yet been quantified. Objective We aimed to summarize the association between hyperinsulinemia/insulin resistance and risk of CRA, including whether the association is independent of adiposity. Materials and Methods Pubmed and Embase were searched through April, 2015 to identify observational studies investigating the associations between insulin, C-peptide and HOMA-IR and CRA risk. Using the highest versus lowest category meta-analysis and dose–response meta-analysis based on a random-effects model, we estimated summary odds ratio (OR) and the corresponding 95% confidence interval (95% CI). Results A total of 27 studies (insulin: 16 studies including 14,007 cases; C-peptide: 11 studies including 8639 cases; HOMA-IR: 8 studies including 11,619 cases) were included in this meta-analysis. The summary ORs of CRA comparing the highest with the lowest quantile were 1.33 for insulin (95% CI = 1.12–1.58, I 2 = 73.9%, P heterogeneity < 0.001), 1.44 for C-peptide (95% CI = 1.13–1.83, I 2 = 63.5%, P heterogeneity = 0.003), and 1.33 for HOMA-IR (95% CI = 1.10–1.60, I 2 = 69.1%, P heterogeneity = 0.004). Upon stratification by ethnicity, higher levels of insulin and C-peptide were significantly associated with increased risk of CRA in non-Asian ethnicity (summary OR for insulin = 1.67 [95% CI = 1.28–2.17], I 2 = 34.9%, P heterogeneity = 0.16; summary OR for C-peptide = 1.59 [95% CI = 1.22–2.08], I 2 = 21.5%, P heterogeneity = 0.27) but not in Asians (summary OR for insulin = 1.10 [95% CI = 0.92–1.33], I 2 = 76.6%, P heterogeneity = 0.001; summary OR for C-peptide = 1.27 [95% CI = 0.84–1.91], I 2 = 72.6, P heterogeneity = 0.01). We observed evidence for the existence of publication bias for insulin (P = 0.01 by Egger test) and HOMA-IR (P = 0.05 by Egger test). The results were confirmed in linear dose–response meta-analysis. These significant positive associations generally persisted even after adjustment for adiposity, although the effect size was substantially attenuated. Conclusions Independent of adiposity, higher levels of insulin, C-peptide, and HOMA-IR were significantly associated with increased risk of CRA. The weaker associations and high heterogeneity in Asian studies warrant further research. These results indicate that insulin resistance and hyperinsulinemia may contribute in part to the association between obesity and CRA risk. [ABSTRACT FROM AUTHOR]

Background: Obesity-related hormonal and metabolic perturbations implicated in colorectal carcinogenesis are mainly driven by visceral adipose tissue (VAT) rather than subcutaneous adipose tissue (SAT). Yet, most epidemiologic studies have examined the relationship between excess adiposity and colorectal neoplasia using body mass index (BMI) and waist circumference (WC). Due to the inability of BMI and WC to distinguish VAT from SAT, they are likely to have underestimated the true association. Patients and methods: We conducted a dose-response meta-analysis to summarize the relationships between VAT and colorectal adenomas and to examine the value of VAT as an independent risk factor beyond BMI, WC, and SAT. PubMed and Embase were searched through September 2014 to identify relevant observational studies. The summary odds ratio (OR) 95% confidence interval (CI) were estimated using a random-effects model. Results: In linear dose-response meta-analysis, the summary OR for each 25 cm² increase in VAT area was 1.13 (95% CI 1.05-1.21; I² = 62%; 6 studies; 2776 cases; range of VAT area = 30-228 cm²). The dose-response curve suggested no evidence of nonlinearity (Pnon-linearity = 0.37). In meta-analysis comparing the highest versus lowest category of VAT based on 12 studies, a positive association between VAT and adenomas remained statistically significant even after adjustment for BMI, WC, and SAT. In contrast, adjustment for VAT substantially attenuated associations of BMI, WC, and SAT with adenomas. Across the studies, VAT was more strongly associated with advanced adenomas than nonadvanced adenomas. Conclusions: VAT may be the underlying mediator of the observed associations of BMI andWC with adenomas, increasing adenoma risk continuously over a wide range of VAT area. Considering that the joint use of BMI and WC better captures VAT than the use of either one, clinicians are recommended to use both BMI and WC to identify those at high risk for colorectal neoplasia. [ABSTRACT FROM AUTHOR]

Aims: 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. Methods: 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. Results: A total of 451 participants (mean age 61.1 ± 11.9 years, 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

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; I2 = 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; I2 = 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. [ABSTRACT FROM AUTHOR]

Incidence of colorectal cancer (CRC) is growing worldwide. Pathogenetic mechanisms responsible for its onset and progression need further clarification. Colorectal adenomatous polyps are precancerous lesions with malignant potential dependent on histological architecture and grade of nuclear dysplasia. One of the factors conditioning CRC development are abnormalities in sphingolipid metabolism. The aim of this study was to assess the levels of sphingolipids in human colorectal adenomas. The control group (C, n = 12) consisted of patients with no colonic polyps. The examined group consisted of patients with prior diagnosed colonic polyps, qualified to endoscopic polypectomy. This group was further divided due to histological architecture into tubular adenomas group (TA, n = 10), tubulovillous adenomas with low-grade dysplasia (LGD-TVA, n = 10), and tubulovillous adenomas group with high-grade dysplasia (HGD-TVA, n = 11). In tissue samples, sphingolipd metabolite contents were measured using high performance liquid chromatography (HPLC). In cases of polypoid lesions with low malignancy potential (tubular adenomas), concentration of ceramide, which is characterized by proapoptotic and anti-proliferative properties, increases compared with control group ( p < 0.05), whereas content of sphingosine-1-phosphate with anti-apoptotic and stimulating cellular proliferation properties is reduced in comparison with control group ( p < 0.05). On the contrary, in cases of more advanced form of adenomatous polyps (tubulovillous adenomas with high-grade dysplasia), the ceramide level decreases compared with control group ( p < 0.05) while sphingosine-1-phosphate concentration is elevated ( p < 0.05). We found that concentrations of pro-apoptotic ceramide are decreased and pro-proliferative S1P levels are increased in polypoid lesions with high malignancy potential, and it was the opposite in those with low malignancy potential. [ABSTRACT FROM AUTHOR]

Background: Colonoscopic removal of large colorectal polyps is challenging and requires advanced endoscopic technique. Successful endoscopic management not only avoids the morbidity of surgery but also risks perforation, hemorrhage, and recurrence. Methods: This study is a retrospective review of a prospectively maintained database of all patients undergoing cautery snare piecemeal polypectomy for large colorectal polyps by a single operator over 20 years with long-term followup. Results: 231 patients underwent 269 piecemeal polypectomies over a 20 year period. The complication rate was 4.3 %. Malignancy was identified in 25 (10.8 %) of patients. Local recurrences occurred in 24 % of patients with benign adenomas. The vast majority of these were managed with repeat endoscopy. Overall, benign large polyps were managed successfully endoscopically in 94.4 % of patients. Conclusions: Piecemeal polypectomy is effective and safe for the management of large colorectal polyps. With long-term followup, the recurrence rate is appreciable, but most recurrences can be successfully managed with further endoscopic intervention. More complex techniques such as endoscopic submucosal dissection are usually unnecessary. [ABSTRACT FROM AUTHOR]

Previous epidemiological studies have evaluated the association between common variations of cytochrome P450 ( CYP) 2C9 (430C>T and 1075A>C) and the risk of colorectal cancer (CRC) with conflicting results. To derive a more precise estimation of the relationship between these CYP2C9 polymorphisms and CRC, a meta-analysis was performed. PubMed, Embase, CNKI, and Web of Science databases were searched. A total of 16 studies including 9,463 cases and 11,416 controls were identified. Potential sources of heterogeneity including ethnicity, sample size of study, genotyping method, diagnostic criteria, and outcome were systematically assessed. Overall, the summary odds ratio of 430T variant for CRC was 0.92 (95 % confidence interval (CI) 0.86-0.98; P = 0.012) and 1.39 (95 % CI 1.07-1.81; P = 0.013) for colorectal adenomas (CRAs). As for CYP2C9 1075A>C polymorphism, no significant results were observed in overall and subgroup analysis. There was no evidence of publication bias. In conclusion, there is evidence to indicate a significant association between CYP2C9 430C>T polymorphism and CRC/CRA risk. [ABSTRACT FROM AUTHOR]

Background Biological processes are controlled by transcription networks. Expression changes of transcription factor (TF) genes in precancerous lesions are therefore crucial events in tumorigenesis. Our aim was to obtain a comprehensive picture of these changes in colorectal adenomas. Methods Using a 3-pronged selection procedure, we analyzed transcriptomic data on 34 human tissue samples (17 adenomas and paired samples of normal mucosa, all collected with ethics committee approval and written, informed patient consent) to identify TFs with highly significant tumor-associated gene expression changes whose potential roles in colorectal tumorigenesis have been under-researched. Microarray data were subjected to stringent statistical analysis of TF expression in tumor vs. normal tissues, MetaCore-mediated identification of TF networks displaying enrichment for genes that were differentially expressed in tumors, and a novel quantitative analysis of the publications examining the TF genes' roles in colorectal tumorigenesis. Results The 261 TF genes identified with this procedure included DACH1, which plays essential roles in the proper proliferation and differentiation of retinal and leg precursor cell populations in Drosophila melanogaster. Its possible roles in colorectal tumorigenesis are completely unknown, but it was found to be markedly overexpressed (mRNA and protein) in all colorectal adenomas and in most colorectal carcinomas. However, DACH1 expression was absent in some carcinomas, most of which were DNA mismatch-repair deficient. When networks were built using the set of TF genes identified by all three selection procedures, as well as the entire set of transcriptomic changes in adenomas, five hub genes (TGFB1, BIRC5, MYB, NR3C1, and TERT) where identified as putatively crucial components of the adenomatous transformation process. Conclusion The transcription-regulating network of colorectal adenomas (compared with that of normal colorectal mucosa) is characterized by significantly altered expression of over 250 TF genes, many of which have never been investigated in relation to colorectal tumorigenesis. [ABSTRACT FROM AUTHOR]

Background and aims: Subsite-specific incidence rates of colorectal cancer (CRC) and adenomas may vary considerably by race, sex and age as well as due to different screening strategies. We assessed variations in the anatomical distribution of adenomas according to age and sex in an average-risk screening cohort testing positive at immunological faecal occult blood test (i-FOBT) in northern Italy. Methods: Data from 2,281 consecutive asymptomatic i-FOBT-positive subjects ageing 50-70 years undergone colonoscopy were reviewed. Size, number, macroscopic and histological features of all adenomas found as well as their proximal or distal location in relation to the splenic flexure were examined. Odds ratios (OR) of proximal neoplasms, according to the presence of distal neoplasms and other selected covariates were assessed by multiple logistic regression analysis. Results: A total of 2,599 neoplasms were found in 1,396 patients. Of these, 116 (5 %) were colorectal cancers, diagnosed in 106 patients. Out of 2,483 adenomas found, 1,564 (63 %) were sessile, 795 (32 %) were peduncolated and 124 (5 %) were flat-type; 54 % of all adenomas were tubular, 36 % were tubulovillous or villous, and 10 % were serrated adenomas. The majority of neoplasms (66 %) were located in the distal colon. Tumour subsite distribution was consistent in both sexes, whereas significant proximal migration of neoplasms occurred in the older age cohort. Indeed, the rate of proximal neoplasms in patients aged ≥60 years was 37 % as compared with 29 % in those ageing 50-59 years. Male gender (OR 1.84), age of 60 years or older (OR 1.44), having a family history of colorectal neoplasms (OR 1.47) and presence of at least 1 distal advanced adenoma (OR 1.63) were all significant predictors of advanced proximal neoplasms. Conclusions: A left to right shift of colorectal adenomas with increasing age is evident in northern Italian asymptomatic i-FOBT-positive population. Advanced proximal neoplasms are not uncommon in subjects with or without distal adenomas, especially after 60 years of age. This should be carefully considered when implementing public screening strategies for CRC since the use of flexible sigmoidoscopy as a screening tool, particularly in older age groups, appears to be less effective. [ABSTRACT FROM AUTHOR]

Polymerases ϵ and δ are the main enzymes that replicate eukaryotic DNA. Accurate replication occurs through Watson-Crick base pairing and also through the action of the polymerases' exonuclease (proofreading) domains. We have recently shown that germline exonuclease domain mutations ( EDMs) of POLE and POLD1 confer a high risk of multiple colorectal adenomas and carcinoma ( CRC). POLD1 mutations also predispose to endometrial cancer ( EC). These mutations are associated with high penetrance and dominant inheritance, although the phenotype can be variable. We have named the condition polymerase proofreading-associated polyposis ( PPAP). Somatic POLE EDMs have also been found in sporadic CRCs and ECs, although very few somatic POLD1 EDMs have been detected. Both the germline and the somatic DNA polymerase EDMs cause an 'ultramutated', apparently microsatellite-stable, type of cancer, sometimes leading to over a million base substitutions per tumour. Here, we present the evidence for POLE and POLD1 as important contributors to the pathogenesis of CRC and EC, and highlight some of the key questions in this emerging field. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to have potentially useful anticancer effects against colorectal cancers in experimental studies, but clinical studies have shown inconsistent results on colorectal cancer incidence. Most colorectal cancers are believed to develop through the polyp-cancer sequence. We hypothesized that statins may protect against the development of adenomatous polyps, and this may contribute to the apparent cancer-protective effects. Objective: This study aims to compare previous statin use in patients with newly diagnosed adenomatous polyps against a control group without polyps. Method: A case-control study involving 264 patients attending for diagnostic colonoscopy at the Norfolk and Norwich University Hospital was used. Polyp cases were age and sex matched against controls with normal colonoscopies. Structured patient interviews and clinical notes were used to ascertain drug and risk factor. Logistic regression was used to compare statin exposure and correct for confounding factors. Results: There was a significant negative association between prior statin use and a diagnosis of adenomatous polyps [odds ratio (OR) = 0.40 (0.24-0.76)]. The association was significantly stronger with higher statin doses [≥40 mg simvastatin or equivalent; OR 0.33 (0.10-0.53)] or longer duration of use [>5 years; OR 0.36 (0.10-0.67)]. Statin use was negatively associated with both high- and low-risk polyps. Conclusions: Statins may have a protective effect against the development of adenomatous polyps. The negative association between statin use and polyp incidence showed a significant dose and duration relationship. [ABSTRACT FROM AUTHOR]

Abstract: Extracellular signal–regulated kinase (ERK) is a major downstream transducer of Ras and plays an important role in transducing extracellular signals to the nuclei of cells. It is located in both the cytoplasm and the nucleus of cells. The nuclear localization of phosphorylated or activated ERK is involved in the invasive behavior of tumor cells. We studied the association between Ras mutation/ERK activation and the prognosis of patients with colorectal cancer. We analyzed 126 surgically resected colorectal cancer specimens for K-Ras mutation using direct sequencing. Activation/phosphorylation of ERK was assayed by immunohistochemistry with tissue microarray, and the staining intensity was analyzed using a semiquantitative scoring system. K-Ras mutations were detected in 32.5% (41/126) of the colorectal tumors. Colorectal glands are important functional organs in colorectal tissue and form the origin of colorectal carcinomas. Tissue microarray immunohistochemistry tests showed that tumors in colorectal cancer specimens were significantly stained for phospho-ERK (100%; 126/126), whereas nonneoplastic colorectal glands mainly showed faint phosphorylated ERK staining. High nuclear phospho-ERK expression in tumors was associated with highly invasive cancer stage and T status of the disease. Kaplan-Meier analysis showed that nuclear but not cytoplasmic phosphorylated ERK expression correlated with the patients'' overall survival rate (P = .039). Colorectal adenomas including tubular adenomas and tubulovillous adenomas mainly showed weak cytoplasmic phospho-ERK expression. Our results suggest that immunohistologic analysis of phosphorylated ERK expression in colorectal glands may aid the diagnosis of colorectal cancer and that nuclear phosphorylated ERK might be a valuable prognostic marker for colorectal cancer. [Copyright &y& Elsevier]

Purpose: Carotenoids have been hypothesized to prevent carcinogenesis through their antioxidant and pro-vitamin A properties. We examined associations between intakes of specific carotenoids and risk of colorectal adenomas. Methods: Among 29,363 men who reported having a lower bowel endoscopy between 1986 and 2006, 3,997 cases of colorectal adenoma were identified in the Health Professionals Follow-up Study. Participants completed food frequency questionnaires every 4 years; dietary information was cumulatively updated. The associations between carotenoid intakes and risk of colorectal adenomas overall and by anatomic site, stage, smoking status and alcohol consumption were investigated using multivariate logistic regression models. Results: Total β-carotene and dietary β-carotene, lycopene and lutein/zeaxanthin intakes and the total carotenoid score were inversely associated with colorectal adenoma risk. The odds ratios (95 % confidence intervals) comparing the highest versus lowest quintile of intake were 0.78 (0.69-0.88) for total β-carotene, 0.72 (0.64-0.81) for dietary β-carotene, 0.83 (0.74-0.93) for lycopene, 0.86 (0.76-0.96) for lutein/zeaxanthin, and 0.87 (0.77-0.97) for the total carotenoid score. Associations for α-carotene and β-cryptoxanthin intakes were null. We did not find significant differences in the associations between intakes of each carotenoid and risk of colorectal adenoma by anatomic site or stage (all p values, test for common effects >0.10). The inverse associations we observed for total β-carotene and dietary β-carotene, lycopene, and lutein/zeaxanthin intakes and the total carotenoid score with adenoma risk also did not vary by smoking status and alcohol consumption. Conclusion: This study found that a diet high in carotenoids was associated with a reduced risk of colorectal adenomas. [ABSTRACT FROM AUTHOR]

Background: Current evidence indicates that red and processed meat intake increases the risk of colorectal cancer; however, the association with colorectal adenomas is unclear. Objective: To conduct a systematic review and meta-analysis of epidemiological studies of red and processed meat intake and risk of colorectal adenomas as part of the Continuous Update Project of the World Cancer Research Fund. Design: PubMed and several other databases were searched for relevant studies from their inception up to 31 December 2011. Summary relative risks (RRs) were estimated using a random effects model. Results: Nineteen case-control studies and seven prospective studies were included in the analyses. The summary RR per 100 g/day of red meat was 1.27 (95 % CI 1.16-1.40, I = 5 %, n = 16) for all studies combined, 1.20 (95 % CI 1.06-1.36, I = 0 %, n = 6) for prospective studies, and 1.34 (95 % CI 1.12-1.59, I = 31 %, n = 10) for case-control studies. The summary RR per 50 g/day of processed meat intake was 1.29 (95 % CI 1.10-1.53, I = 27 %, n = 10) for all studies combined, 1.45 (95 % CI 1.10-1.90, I = 0 %, n = 2) for prospective studies, and 1.23 (95 % CI 0.99-1.52, I = 37 %, n = 8) for case-control studies. There was evidence of a nonlinear association between red meat ( p < 0.001) and processed meat ( p = 0.01) intake and colorectal adenoma risk. Conclusion: These results indicate an elevated risk of colorectal adenomas with intake of red and processed meat, but further prospective studies are warranted. [ABSTRACT FROM AUTHOR]

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are thought to protect against colorectal adenoma (CRA) development. We aimed to further understand the underlying mechanisms by examining the relationships between ω-3 PUFAs and the gut microbiota on CRAs. We assessed the mucosal microbiota via bacterial 16S rRNA sequencing among 217 CRA cases and 218 controls who completed PUFA intake questionnaires. The overall microbial composition was assessed by α-diversity measurements (diversity, richness, and evenness). Global metabolomics was conducted using a random subset of case−control pairs (n = 50). We compared microbiota and metabolite signatures between cases and controls according to fold change (FC). Odds ratios (OR) and confidence intervals (CI) were estimated from logistic regression for associations of ω-3 PUFAs and the microbiota with CRAs. We observed an inverse association between overall ω-3 PUFA intake and CRAs, especially for short-chain ω -3 PUFAs (OR = 0.45, 95% CI: 0.21, 0.97). Such inverse associations were modified by bacterial evenness (p-interaction = 0.03). Participants with higher levels (FC > 2) of bile acid-relevant metabolites were more likely to have CRAs than the controls, and the correlation between bile acids and bacterial diversity differed by case−control status. Our findings suggest that ω-3 PUFAs are inversely associated with CRA development, and the association may be modified by gut microbiota profiles.

Background: Familial adenomatous polyposis (FAP) is a rare autosomal dominant disease characterized by germline mutations in the Adenomatous Polyposis Coli (APC) gene, resulting in the development of numerous colorectal adenomas. As these patients have a high risk of developing colorectal cancer (CRC), guidelines suggest prophylactic colectomy during early adulthood, however, adenoma development is still observed in the remaining intestinal tract. Therefore, FAP patients would benefit from chemoprevention strategies reducing the development of adenomas. Recent work in mice reveals a chemopreventive effect of lithium on the development of adenomas by inhibiting the expansion of Apc mutated intestinal stem cells (ISCs) within the crypts of normal intestinal mucosa. Here, we aim to investigate the effect of lithium on the spread of APC mutant cells within the human intestinal epithelium., Methods: This prospective phase II single arm trial has a duration of 18 months. FAP patients (18-35 years) with a genetically confirmed APC mutation who did not undergo colectomy will be treated with lithium carbonate orally achieving a serum level of 0.2-0.4 mmol/l between month 6 and 12. Colonoscopy with biopsies of normal intestinal mucosa will be performed at baseline and every six months. The primary endpoint is the effect of lithium on the spread of APC mutant cells within intestinal crypts over time by using APC specific marker NOTUM in situ hybridization. Secondary endpoints include change in adenoma burden, patient reported side effects and safety-outcomes. Total sample size is 12 patients and recruitment will take place in the Amsterdam UMC, location AMC in the Netherlands., Discussion: The outcome of this study will function as a proof-of-concept for the development of novel chemoprevention approaches that interfere with the competition between normal and mutant ISCs., Trial Registration: ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT05402891 (June 1, 2022) and the EU Clinical Trials Register: EuraCT 2022-000240-30 (January 1, 2022)., (© 2022. The Author(s).)

Introduction: Unlike colorectal cancer (CRC), few studies have explored the predictive value of genetic risk scores (GRS) in the development of colorectal adenomas (CRA), either alone or in combination with other demographic and clinical factors., Methods: In this study, genomic DNA from 613 Spanish Caucasian patients with CRA and 829 polyp-free individuals was genotyped for 88 single-nucleotide polymorphisms (SNPs) associated with CRC risk using the MassArray™ (Sequenom) platform. After applying a multivariate logistic regression model, five SNPs were selected to calculate the GRS. Regression models adjusted by sex, age, family history of CRC, chronic use of NSAIDs, low-dose ASA, and consumption of tobacco were built in order to study the association between GRS and CRA risk. We evaluated the discriminatory capacity using the area under the receiver operating characteristic curve (AUC). The interactions between demographic information and GRS were also analyzed., Results: Significant associations between high GRS values and risk of CRA for analyzed models were observed. In particular, patients with higher GRS values had 2.3-2.6-fold increase in risk of CRA compared to patients with middle values. Combining sex and age with the GRS significantly increased the discriminatory accuracy of the univariate model with GRS alone. The best model achieved an AUC value of 0.665 (95% CI: 0.63-0.69). The GRS showed a different behavior depending on sex and age., Conclusion: Our findings showed that, besides sex and age, GRS is an important risk factor for development of CRA and may be useful for CRC risk stratification and adaptation of screening programs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Texture and color enhancement imaging (TXI) has been developed as a novel image-enhancing endoscopy. However, the effectiveness of TXI detecting adenomas is inferior to narrow band imaging. Thus, future studies will need to focus on investigating the feasibility of such combination in clinical settings in order to provide patients with more accurate diagnoses., Competing Interests: Conflict-of-interest statement: All authors have no conflict(s) of interest to declare in relation to this manuscript., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)