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Background: Biomarkers have revolutionized the management of colorectal cancer (CRC), facilitating early detection, prevention, personalized treatment, and minimal residual disease (MRD) monitoring. This review explores current CRC screening strategies and emerging biomarker applications. Main body. We summarize the landscape of non-invasive CRC screening and MRD detection strategies, discuss the limitations of the current approaches, and highlight the promising potential of novel biomarker solutions. The fecal immunochemical test remained the cornerstone of CRC screening, but its sensitivity has been improved by assays that combined its performance with other stool analytes. However, their sensitivity for advanced adenomas and the patient compliance both remain suboptimal. Blood-based tests promise to increase compliance but require further refinement to compete with stool-based biomarker tests. The ideal scenario involves leveraging blood tests to increase screening participation, and simultaneously promote stool- and endoscopy-based screening among those who are compliant. Once solely reliant on upfront surgery followed by stage and pathology-driven adjuvant chemotherapy, the treatment of stage II and III colon cancer has undergone a revolutionary transformation with the advent of MRD testing after surgery. A decade ago, the concept of using a post-surgical test instead of stage and pathology to determine the need for adjuvant chemotherapy was disruptive. Today, a blood test may be more informative of the need for chemotherapy than the stage at diagnosis. Conclusion: Biomarker research is not just improving, but bringing a transformative change to CRC clinical management. Early detection is not just getting better, but improving thanks to a multi-modality approach, and personalized treatment plans are not just becoming a reality, but a promising future with MRD testing. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Background: Colorectal adenomas (CRAs) are precancerous lesions of the large intestine presenting as colorectal polyps. At present, the conventional treatment methods for CRA mainly include high-frequency electrocoagulation and electroexcision, biopsy forceps polypectomy, cauterization by laser and microwave, and other endoscopic interventions. The principal advantages conferred by these treatment strategies include less trauma, quick postoperative recovery, and simplicity to perform. However, the higher recurrence rates and insignificant improvement of postoperative symptoms after endoscopic surgery are considerable drawbacks to this approach. Besides, there is currently no effective pharmacotherapy to prevent the recurrence of CRA. Jianpi Lishi Jiedu (JLJ) granules are a form of traditional Chinese medicine (TCM) used to manage postoperative patients with CRA, which has shown a certain degree of efficacy in clinical practice. However, its effectiveness and safety profile have not been convincingly evaluated. The purpose of this study is to evaluate the clinical efficacy and safety profile of JLJ granules in the management of postoperative patients with CRA and to observe the recurrence rate of adenoma in these patients.Methods: A randomized, double-blind, and placebo-controlled clinical trial is performed in this study. A total of 80 postoperative patients with CRA will be randomly classified into the Jianpi Lishi Jiedu granules group or the placebo control group. Patients in both groups shall receive 3 months of intervention, after which medical follow-up and safety evaluation will be performed for all of the patients. The primary outcome is the recurrence rate of adenomas within 12 months. The secondary outcomes are the cardinal TCM symptom scores, minor TCM symptom scores, Bristol Stool Scale, efficacy of TCM symptoms, safety indicators, and blinding assessment.Discussion: In this study, the impact on the recurrence of adenomas and the efficacy and safety of JLJ granules in terms of improving the clinical symptoms of postoperative patients with CRA will be evaluated.Trial Registration: Trial registration Chinese Clinical Trial Registry ChiCTR 2100044297. Registered on March 16, 2021. [ABSTRACT FROM AUTHOR]

Background and Aims: Colorectal cancer (CRC) is the third most common cancer, worldwide. Recently, much attention has been given to the association between Dietary Approaches to Stop Hypertension (DASH) and CRC, however, data on colorectal adenomas (CRAs) as its precursor are scarce. Thus, the purpose of this case-control study was to investigate the association of DASH score with the risk of CRC and CRA in Iranian adults.Method: A total of 499 participants, including 129 CRC and 130 CRA cases, along with 240 controls, were asked about their dietary intake via a validated questionnaire. The DASH score was then calculated based on a priori methods and categorized in quartiles. Multivariate logistic regression was performed to assess the association of DASH score and the risk of CRC and CRA.Results: After adjusting for confounding variables, adherence to the DASH diet was associated with a reduction in the risk of CRC and CRA, respectively (OR of 4th versus 1st quartile = 0.04, 95% CI: 0.01-0.11, OR = 0.10, 95% CI: 0.04-0.22). Also, subgroup analysis based on gender showed that women and men with a higher DASH score had a significantly lower risk of CRC and CRAs.Conclusion: The results of this study demonstrated that adherence to a DASH dietary pattern could reduce the risk of CRC and CRA in men and women. Promoting a DASH eating plan can be helpful in reducing the risk of CRC. [ABSTRACT FROM AUTHOR]

Background: Aberrant DNA hypomethylation of the long interspersed nuclear elements (LINE-1 or L1) has been recognized as an early event of colorectal transformation. Simultaneous genetic and epigenetic analysis of colorectal adenomas may be an effective and rapid strategy to identify key biological features leading to accelerated colorectal tumorigenesis. In particular, global and/or intragenic LINE-1 hypomethylation of adenomas may represent a helpful tool for improving colorectal cancer (CRC) risk stratification of patients after surgical removal of polyps. To verify this hypothesis, we analyzed a cohort of 102 adenomas derived from 40 high-risk patients (who developed CRC in a post-polypectomy of at least one year) and 43 low-risk patients (who did not develop CRC in a post-polypectomy of at least 5 years) for their main pathological features, the presence of hotspot variants in driver oncogenes (KRAS, NRAS, BRAF and PIK3CA), global (LINE-1) and intragenic (L1-MET) methylation status. Results: In addition to a significantly higher adenoma size and an older patients' age, adenomas from high-risk patients were more hypomethylated than those from low-risk patients for both global and intragenic LINE-1 assays. DNA hypomethylation, measured by pyrosequencing, was independent from other parameters, including the presence of oncogenic hotspot variants detected by mass spectrometry. Combining LINE-1 and L1-MET analyses and profiling the samples according to the presence of at least one hypomethylated assay improved the discrimination between high and low risk lesions (p = 0.005). Remarkably, adenomas with at least one hypomethylated assay identified the patients with a significantly (p < 0.001) higher risk of developing CRC. Multivariable analysis and logistic regression evaluated by the ROC curves proved that methylation status was an independent variable improving cancer risk prediction (p = 0.02). Conclusions: LINE-1 and L1-MET hypomethylation in colorectal adenomas are associated with a higher risk of developing CRC. DNA global and intragenic hypomethylation are independent markers that could be used in combination to successfully improve the stratification of patients who enter a colonoscopy surveillance program. [ABSTRACT FROM AUTHOR]

Background: Individuals with advanced colorectal adenomas (ACAs) are at high risk for colorectal cancer (CRC), and it is unclear which chemopreventive agent (CPA) is safe and cost-effective for secondary prevention. We aimed to determine, firstly, the most suitable CPA using network meta-analysis (NMA) and secondly, cost-effectiveness of CPA with or without surveillance colonoscopy (SC).Methods: Systematic review and NMA of randomised controlled trials were performed, and the most suitable CPA was chosen based on efficacy and the most favourable risk-benefit profile. The economic benefits of CPA alone, 3 yearly SC alone, and a combination of CPA and SC were determined using the cost-effectiveness analysis (CEA) in the Malaysian health-care perspective. Outcomes were reported as incremental cost-effectiveness ratios (ICERs) in 2018 US Dollars ($) per quality-adjusted life-year (QALY), and life-years (LYs) gained.Results: According to NMA, the risk-benefit profile favours the use of aspirin at very-low-dose (ASAVLD, ≤ 100 mg/day) for secondary prevention in individuals with previous ACAs. Celecoxib is the most effective CPA but the cardiovascular adverse events are of concern. According to CEA, the combination strategy (ASAVLD with 3-yearly SC) was cost-saving and dominates its competitors as the best buy option. The probability of being cost-effective for ASAVLD alone, 3-yearly SC alone, and combination strategy were 22%, 26%, and 53%, respectively. Extending the SC interval to five years in combination strategy was more cost-effective when compared to 3-yearly SC alone (ICER of $484/LY gain and $1875/QALY). However, extending to ten years in combination strategy was not cost-effective.Conclusion: ASAVLD combined with 3-yearly SC in individuals with ACAs may be a cost-effective strategy for CRC prevention. An extension of SC intervals to five years can be considered in resource-limited countries. [ABSTRACT FROM AUTHOR]

Background: A causal association has been suggested between certain bacteria and colorectal cancer (CRC). Only a few studies have, however, investigated the presence of these bacteria directly in colon tissue with conflicting results. It is thus uncertain which role they may have in prognosis and carcinogenesis of CRC.Methods: Formalin-fixed and paraffin-embedded (FFPE) colorectal tissue samples from patients diagnosed with colorectal cancer (CRC)(tumor and paired normal tissue, n = 99), adenomas (n = 96), or diverticular disease (n = 104) were tested for the presence and bacterial load of Streptococcus gallolyticus (S. gallolyticus), Fusobacterium nucleatum (F. nucleatum), and Bacteroides fragilis (B. fragilis) using quantitative PCR. A subsequent broader search was conducted on a subset of samples using 16S ribosomal RNA gene sequencing. Finally, to evaluate the prognostic value, the bacterial status was compared to patient outcome.Results: S. gallolyticus was not detected by qPCR in any of the investigated tissue samples and F. nucleatum and B. fragilis were found to be equally distributed in tumors, paired normal tissue, and diverticula, but significantly less present in adenomas compared to both tumors and diverticula. Neither, F. nucleatum nor B. fragilis status affected the five-year prognosis of the patients. The 16S rRNA gene sequencing data revealed that tumors were associated with the Prevotella genus while conversely adenomas and diverticula were associated with Acinetobacter genus.Conclusion: These findings do not support a role of F. nucleatum or B. fragilis during colorectal beginning, while S. gallolyticus was not implicated in the colorectal tissue of a Danish population. A potential role of the bacterial genera Prevotella and Acinetobacter was indicated, and requires further investigations. [ABSTRACT FROM AUTHOR]

Background: Genetic factors affect the risk of non-alcoholic fatty liver disease (NAFLD) and colorectal adenoma (CRA) importantly. Transmembrane protein 6 superfamily member 2 (TM6SF2) rs58542926 is a significant genetic susceptibility site for NAFLD. The relationships of TM6SF2 rs58542926 with the risk of NAFLD and CRA in Chinese Han population were unclear. The aim of this study was to investigate the association of TM6SF2 rs58542926 with the risk of NAFLD and CRA, and the effect of CRA on TM6SF2 rs58542926 carried NAFLD patients. Results: A total of 839 Chinese Han population were included in this retrospective study. TM6SF2 rs58542926 polymorphism was genotyped in B-type ultrasonography proven NAFLD patients with or without CRA, CRA patients and healthy controls, using polymerase chain reaction. Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS statistical software, version 16.0 for mac. There was a significant difference in the distribution of genotype and allele of TM6SF2 rs58542926 in NAFLD and NAFLD&CRA patients compared to controls. The CT + TT genotypes were tightly associated with the risk of NAFLD and NAFLD&CRA. TM6SF2 rs58542926 T allele promotes the abnormal regulation of lipids metabolism and liver injury in NAFLD patients and NAFLD&CRA patients. CRA aggravates the clinical performance of NAFLD in T allele carriers. Conclusions: We demonstrated the significant association between TM6SF2 rs58542926 polymorphism and the risk of NAFLD and NAFLD&CRA in a Chinese Han population. The TM6SF2 rs58542926 T allele promotes the abnormal regulation of lipid profiles and liver injury in NAFLD patients, NAFLD&CRA patients, and overall subjects. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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).Results: 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.Conclusion: 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. [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]