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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]

Abstract 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.

(1) Colorectal cancer is a major cause of cancer-related death, with colorectal adenomas (CRAs) serving as precursors. Identifying risk factors such as vitamin D deficiency and the insulin-like growth factor (IGF) axis is crucial for prevention. (2) This case–control study included 85 participants (53 CRA patients and 32 controls) who underwent colonoscopy. We measured serum vitamin D3 (cholecalciferol), calcidiol (vitamin D metabolite), calcitriol (active vitamin D metabolite), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) to explore their associations with CRA risk. (3) Results: We found that lower cholecalciferol levels were a significant risk factor for CRA (OR = 4.63, p = 0.004). Although no significant differences in calcidiol and calcitriol levels were observed between CRA patients and controls, calcidiol deficiency was common in the study population. IGF-1 levels inversely correlated with age, calcitriol, and IGFBP-3 in CRA patients. (4) This study highlights the potential of lower cholecalciferol levels to detect patients at risk of CRA when calcidiol values cannot, suggesting the importance of evaluating different vitamin D metabolites in cancer prevention research. Our findings underscore the need to further investigate the interactions between calcitriol, the active form of vitamin D, and the IGF axis in colorectal cancer development. [ABSTRACT FROM AUTHOR]

The intestinal microbiome plays a crucial role in colorectal adenomas and the mucosa associated microbiota are thought to play a more critical role in interactions with the host immune system. Current omics approaches, offer a holistic assessment of the gut microbiome and the human host interaction. To enhance the value of data from these sequencing methods, appropriate sample collection is vital. We evaluated the potential use of endoscopic brush samples for mucosal microbiota analysis in colorectal adenomas and compared it with direct adenoma tissue sequencing in terms of microbial gene sequencing. The results showed a significant increase in microbial diversity in samples collected by the endoscopic brush, which did not interfere with pathological biopsy. This study found that utilizing endoscopic brush sampling for the microbiome analysis of colorectal adenomas offers several advantages over the direct examination of microbiomes within tumor tissues, including the capacity to accurately collect gut microbiome from different locations in the intestine, circumventing interference from tissue genes, providing more abundant microbial data and enabling inclusion of small adenomas without disrupting pathological biopsies.

Colorectal cancer (CRC) may develop from focal changes within benign or precancerous polyps. The immune system's failure to detect and eradicate tumor cells due to immune surveillance evasion, allows cancer to develop and spread. This study aims to analyze the differences in circulating lymphocyte subpopulations in patients with colorectal inflammatory polyps, colorectal adenomas and CRC. We retrospectively reviewed patients from September 2016 to December 2019 at the Shaoxing Second Hospital. Using flow cytometry, the subset distribution and immunophenotype of T cells, CD4+ T cells, CD8+ T cells, B cells and NK cells were investigated in peripheral blood mononuclear cell samples. The counts of lymphocytes were determined by white blood cell counts. In total, 518 patients were included in this study. The counts of lymphocytes, T cells and NK cells in patients with inflammatory polyps, colorectal adenomas and CRC were lower than controls. The counts and percentages of CD8+ T cells in patients with inflammatory polyps, colorectal adenomas and CRC were lower than controls. The counts of CD4+ T cells were lower in patients with CRC than inflammatory polyps. The percentages of CD4+ T cells in patients with inflammatory polyps, colorectal adenomas and CRC were higher than controls, but lower in the CRC than inflammatory polyps, colorectal adenomas. The counts and percentages of B cells were lower in CRC patients than colorectal adenomas patients. In addition, the percentages of B cells were higher in patients with inflammatory polyps and colorectal adenomas than in controls. The decrease in counts of lymphocyte, T cells, CD8+ T cells and NK cells in patients may be related to the dysplasia of epithelial cells. Furthermore, the B cells and CD4+ T cells may be related to the malignant growth of the dysplastic epithelial cells. [ABSTRACT FROM AUTHOR]

Abstract Background Colibactin, a genotoxin produced by polyketide synthase harboring (pks + ) bacteria, induces double-strand breaks and chromosome aberrations. Consequently, enrichment of pks + Escherichia coli in colorectal cancer and polyposis suggests a possible carcinogenic effect in the large intestine. Additionally, specific colibactin-associated mutational signatures; SBS88 and ID18 in the Catalogue of Somatic Mutations in Cancer database, are detected in colorectal carcinomas. Previous research showed that a recurrent APC splice variant perfectly fits SBS88. Methods In this study, we explore the presence of colibactin-associated signatures and fecal pks in an unexplained polyposis cohort. Somatic targeted Next-Generation Sequencing (NGS) was performed for 379 patients. Additionally, for a subset of 29 patients, metagenomics was performed on feces and mutational signature analyses using Whole-Genome Sequencing (WGS) on Formalin-Fixed Paraffin Embedded (FFPE) colorectal tissue blocks. Results NGS showed somatic APC variants fitting SBS88 or ID18 in at least one colorectal adenoma or carcinoma in 29% of patients. Fecal metagenomic analyses revealed enriched presence of pks genes in patients with somatic variants fitting colibactin-associated signatures compared to patients without variants fitting colibactin-associated signatures. Also, mutational signature analyses showed enrichment of SBS88 and ID18 in patients with variants fitting these signatures in NGS compared to patients without. Conclusions These findings further support colibactins ability to mutagenize colorectal mucosa and contribute to the development of colorectal adenomas and carcinomas explaining a relevant part of patients with unexplained polyposis.

Purpose: Recent studies suggested a protective role of metformin in the development of colorectal cancer (CRC) and its precursors. We aimed to investigate if metformin was associated with a lower prevalence and number of colorectal polyps in diabetic patients and also adenomas, high-risk adenomas, and CRC. Methods: Retrospective study on adult patients with diabetes mellitus followed in our hospital with a total colonoscopy between 2015 and 2019, treated with either metformin for > 5 years or other antidiabetic agent (control group). We assessed the number, size, and histopathology examination of proliferative lesions detected on colonoscopy. Results: We included 401 patients aged 69 ± 9 years, 57% males, divided into two groups: treated with metformin (n = 260) and without (n = 141). The number of polyps detected was significantly lower in patients under metformin (p = 0.014). There was a nonsignificant trend towards lower polyp detection rates in the metformin compared to the control group both in unadjusted analysis (50% vs 60%, p = 0.058) and multivariable adjusted analysis (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.43–1.09, p = 0.111). In the latter, we identified male gender (OR 2.24, 95%CI 1.44–3.49, p < 0.001), age (OR 1.35 for every 10 years, 95%CI 1.07–1.71, p = 0.012), glycated hemoglobin value (OR 1.20 for every 1% increase, 95%CI 1.06–1.37, p = 0.005), and hypertension (OR 1.76, 95%CI 1.01–3.08, p = 0.046) as factors associated with a higher prevalence of polyps. We saw no statistically significant differences regarding adenoma (p = 0.231), high-risk adenoma (p = 0.810), and CRC (p = 0.705) diagnoses between groups. Conclusion: In our study, metformin was associated with less colorectal polyps in diabetic patients compared to other treatment modalities. We observed a nonsignificant trend towards lower polyp detection rates in the metformin group both in unadjusted and adjusted analyses. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Colorectal adenomas are an important precancerous lesion of colorectal adenoma with a high incidence. This study aims to explore new prognostic targets for colorectal adenomas through bioinformatics techniques. MATERIALS AND METHODS: In this study, data from 29 colonic adenomas and 38 normal colonic mucosa in GSE37364 were analyzed to screen for differentially expressed genes (DEGs). Then, batch survival analysis, construction of risk model, mutation analysis, Cox regression analysis and expression analysis were performed on DEGs to determine the hub genes of this study. Finally, immune correlation analysis and cell experiments were carried out on the hub gene to explore its potential mechanism. RESULTS: In our study, a total of 431 up-regulated and 809 down-regulated differentially expressed genes (DEGs) were identified. Among these, Unc-5 Netrin Receptor D (UNC5D) emerged as a pivotal gene associated with colorectal adenoma. Notably, UNC5D expression levels were found to be significantly higher in normal tissues compared to colorectal adenoma tissues. Furthermore, our analysis demonstrated that UNC5D showed promising diagnostic potential for patients with colon adenocarcinoma. In vitro experiments revealed that the overexpression of UNC5D had a profound impact on the behavior of colorectal tumor cells. Specifically, it led to a substantial reduction in the proliferation, motility, and invasion of these tumor cells. Additionally, UNC5D was shown to exert control over STAT1/STAT3 phosphorylation, which in turn regulated the expression of PD-L1 in response to interferon (IFN) stimulation. These findings highlight the significant role of UNC5D in modulating immune responses and the development of colorectal adenoma. UNC5D emerges as a potential diagnostic biomarker and an attractive immunotherapeutic target in the context of colorectal malignancies. These results call for further exploration of UNC5D-based strategies for the diagnosis and treatment of colorectal adenoma and adenocarcinoma. CONCLUSIONS: In addition to having the potential to be used as a diagnostic biomarker and an immunotherapeutic target in colorectal malignancies, UNC5D is necessary for the growth of colorectal adenomas. Additionally, UNC5D controlled STAT1/STAT3 phosphorylation to suppress the growth of colorectal cancers by regulating IFN-induced PD-L1 expression. [ABSTRACT FROM AUTHOR]

(1) Colorectal cancer is a major cause of cancer-related death, with colorectal adenomas (CRAs) serving as precursors. Identifying risk factors such as vitamin D deficiency and the insulin-like growth factor (IGF) axis is crucial for prevention. (2) This case–control study included 85 participants (53 CRA patients and 32 controls) who underwent colonoscopy. We measured serum vitamin D3 (cholecalciferol), calcidiol (vitamin D metabolite), calcitriol (active vitamin D metabolite), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) to explore their associations with CRA risk. (3) Results: We found that lower cholecalciferol levels were a significant risk factor for CRA (OR = 4.63, p = 0.004). Although no significant differences in calcidiol and calcitriol levels were observed between CRA patients and controls, calcidiol deficiency was common in the study population. IGF-1 levels inversely correlated with age, calcitriol, and IGFBP-3 in CRA patients. (4) This study highlights the potential of lower cholecalciferol levels to detect patients at risk of CRA when calcidiol values cannot, suggesting the importance of evaluating different vitamin D metabolites in cancer prevention research. Our findings underscore the need to further investigate the interactions between calcitriol, the active form of vitamin D, and the IGF axis in colorectal cancer development.

Klara Cervena,1,2 Anna Siskova,1,2 Jiri Jungwirth,3,4 Marin Volari&cacute;,5 Jan Kral,6 Pavel Kohout,7 Miroslav Levy,8 Veronika Vymetalkova1,2,9 1Institute of Experimental Medicine, Czech Academy of Sciences, Prague, 142 00, Czech Republic; 2Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, 128 00, Czech Republic; 3Institute of Physiology, 1st Faculty of Medicine Charles University, Prague, 121 08, Czech Republic; 4Department of Surgery, Weiden Clinic, Weiden in der Oberpfalz, 92637, Germany; 5Laboratory for Non-Coding DNA, Ru&dstrok;er Boškovi&cacute; Institute, Zagreb, 10000, Croatia; 6Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, 140 21, Czech Republic; 7Department of Internal Medicine, 3rd Faculty of Medicine Charles University and Faculty Thomayer Hospital Prague, Prague, 140 00, Czech Republic; 8Department of Surgery, First Faculty of Medicine, Charles University and Thomayer Hospital Prague, Prague, 140 59, Czech Republic; 9Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, 323 00, Czech RepublicCorrespondence: Klara Cervena, Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, Prague, 142 00, Czech Republic, Email klara.cervena@iem.cas.czIntroduction: The development of colorectal cancer (CRC) is a multistep process accompanied by the accumulation of mutations that start from specific precancerous lesion – colorectal adenomas (CA). CRC incidence and mortality can be reduced by the early identification of these neoplasm. Colonoscopy is the most widely used screening method for CRC identification. Nowadays, clinical research interest is shifting to the use of liquid biopsy that may help with the early diagnosis of CA and CRC. In our previous study, we identified long non-coding RNA MALAT1 gene amplification associated with the development of CA.Methods: This study aimed to describe the potential of MALAT1 expression levels in the adenoma tissue of patients used in the previous study by real-time qPCR. Furthermore, we analysed the plasma samples of an independent group of patients with CA (n=97), CRC (n=101), and cancer-free individuals (CFI, n=48).Results: There was no difference in the MALAT1 expression level between CA patients with or without MALAT1 amplification. However, the plasma MALAT1 expression levels were significantly upregulated in patients with CRC and CA compared to CFI (for both p< 0.001). Moreover, a correlation between MALAT1 expression and histological types of adenomas was identified– high-CRC-risk adenomas also displayed the highest MALAT1 expression levels. Furthermore, in CRC patients, MALAT1 levels were associated with a response to therapy.Conclusion: MALAT1 expression levels could serve as a promising circulating biomarker for early CA and CRC diagnosis, and even as a predictor of therapy response in CRC patients.Keywords: MALAT1, colorectal adenomas, colorectal cancer, plasma, liquid biopsy

Objectives: We performed a clinical study comparing early-onset and late-onset conventional colorectal adenomas (CCRAs) since little is known about the differences in their characteristics. Methods: Pearson's chi-square test and the Kruskal‒Wallis test were used to compare basic information. MCAR tests and multiple imputation were performed to complete missing values. Multivariate logistic analysis and propensity score matching were used to identify the risk factors for recurrence. Results: We included 2793 patients (688 with early-onset CCRAs and 2105 with late-onset CCRAs) from January 2017 to December 2021. Patients with early-onset CCRAs had higher levels of Hb, ALB, and triglycerides but lower HDL levels and N/L ratios. Moreover, we found that more early-onset CCRAs were in the left colon than late-onset CCRAs, and the size of early-onset CCRAs was larger. Early-onset CCRAs tended to lack pedicles compared to late-onset CCRAs. Additionally, the ratio of EMR and APC in early-onset CCRAs was higher than that in late-onset CCRAs, and the ratio of ESD and surgery for late-onset CCRAs was higher. We found that age ≥ 50 years, abnormal vessels, drinking alcohol, and DB and ALB levels may be risk factors for recurrence, while the LDL level may be a protective factor. Finally, analysis of cumulative recurrence rates after PSM showed that patients with late-onset CCRAs exhibited higher recurrence rates (P < 0.05). Conclusion: Compared with late-onset CCRAs, early-onset CCRAs were associated with higher triglyceride levels, lower HDL levels, and larger tumor volumes. Age ≥ 50 years, abnormal vessels, alcohol consumption, and DB and ALB levels were independent risk factors for recurrence of CCRAs. [ABSTRACT FROM AUTHOR]

BackgroundThere are many studies on the association of tea and its extracts with colorectal adenomas, but the results have varied. The study aims to investigate the effect of tea and its extracts on colorectal adenomas using meta analysis and systematic review.MethodsLiterature was obtained through PubMed, Cochrane Library, Embase and Chinese BioMedical Literature Service System since the establishment of the database until April 31, 2023. Search terms include adenomas, polyps, colorectal, rectal, rectum, tea, epigallocatechin, drinking and beverages. Meta-regression analysis was used to infer the source of heterogeneity. Heterogeneity was assessed using I2 statistics and Q test. The effect measures were odds ratio (OR) and 95% confidence interval (95% CI). Stata17.0 software was used for data processing.ResultsThe findings indicated that study design (t = 0.78, P = 0.454), types of tea intake (t = 1.35, P = 0.205), occurrences (t = -0.19, P = 0.852), regions (t = 1.13, P = 0.281) and grades of adenomas (t = 0.06, P = 0.952) were statistical homogeneity. Tea and its extracts were negatively correlated with the risk of colorectal adenomas (OR = 0.81, 95% CI: 0.66–0.98). No publication bias was found in this study (t = -0.22, P = 0.828) and the results are robust.ConclusionThis study suggests that tea and its extracts have a certain protective effect on colorectal adenomas, which provides scientific evidence for preventive strategies for colorectal adenomas. As for the causal relationship between tea and its extracts on colorectal adenomas, further prospective studies are needed.

Background: In recent years, morbidity and mortality from colorectal cancer have increased. Colorectal adenoma is the main precancerous lesion. Understanding the pathogenesis of colorectal adenoma will help to improve the early diagnosis rate of colorectal cancer. Methods: In this case–control study, we focused on three single nucleotide polymorphisms (SNPs) in genes SLC8A1 (rs4952490), KCNJ1 (rs2855798), and SLC12A1 (rs1531916). We analyzed 207 colorectal adenoma patients (112 high-risk cases and 95 low-risk cases) and 212 control subjects by Sanger sequencing. A food frequency questionnaire (FFQ) was used to survey demographic characteristics and dietary nutrition. Results: In the overall analysis, the results suggested that the AA+AG and AG genotype carriers of rs4952490 had a 73.1% and 78% lower risk of colorectal adenoma compared to GG genotype carriers, respectively. However rs2855798 and rs1531916 were not associated with the incidence of colorectal adenoma. Additionally, stratified analysis showed that rs4952490 AA+AG and AG genotypes had a protective effect against low-risk colorectal adenoma in patients aged ≤ 60 years old who were non-smokers. We also observed that when calcium intake was higher than 616 mg/d and patients carried at least one gene with variant alleles there was a protective effect against low-risk colorectal adenoma. Conclusions: Interactions between dietary calcium intake and calcium reabsorption genes may affect the occurrence and development of colorectal adenoma. [ABSTRACT FROM AUTHOR]

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 dierent 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 [ABSTRACT FROM AUTHOR]

Background: There is an urgent need to identify biomarkers for advanced adenoma, an important precursor of colorectal cancer (CRC). We aimed to determine alterations in ileal juice bile acids associated with colorectal advanced adenoma. Methods: We quantified a comprehensive panel of primary and secondary bile acids and their conjugates using an ultraperformance liquid chromatography triple-quadrupole mass spectrometric assay in ileal juice collected at colonoscopy from 46 study subjects (i.e., 14 biopsy-confirmed advanced adenomas and 32 controls free of adenoma or cancer). Using analysis of covariance (ANCOVA), we examined the differences in bile acid concentrations by disease status, adjusting for age, sex, body mass index, smoking status and type 2 diabetes. Results: The concentrations of hyodeoxycholic acid (HCA) species in ileal juice of the advanced adenoma patients (geometric mean = 4501.9 nM) were significantly higher than those of controls (geometric mean = 1292.3 nM, p = 0.001). The relative abundance of ursodeoxycholic acid (UDCA) in total bile acids was significantly reduced in cases than controls (0.73% in cases vs. 1.33% in controls; p = 0.046). No significant difference between cases and controls was observed for concentrations of total or specific primary bile acids (i.e., cholic acid (CA), chenodeoxycholic acid (CDCA) and their glycine- and taurine-conjugates) and total and specific major secondary bile acids (i.e., deoxycholic acid and lithocholic acid). Conclusions: Colorectal advanced adenoma was associated with altered bile acids in ileal juice. The HCA species may promote the development of colorectal advanced adenoma, whereas gut microbiota responsible for the conversion of CDCA to UDCA may protect against it. Our findings have important implications for the use of bile acids as biomarkers in early detection of colorectal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Aspirin has been studied for a long time in familial adenomatous polyposis (FAP), but the data on the prevention of colorectal adenoma formation and recurrence remain controversial. We conducted a biomarker-based clinical study in eight FAP patients treated with low-dose Aspirin to clarify the drug's mechanism of action. Aspirin appropriately acetylated platelet cyclooxygenase (COX)-1 but left persistently high systemic thromboxane(TX)A2 and prostaglandin (PG)E2 biosynthesis (assessed by measuring their primary urinary metabolites, i.e., 11-dehydro-TXB2 and PGEM) associated with the incomplete acetylation of COX-1 in colorectal mucosa and adenomas. Proteomics of colorectal adenomas of FAP patients showed that the vimentin upregulation and hemoglobin subunit beta downregulation distinguished the FAP patients in two groups with high vs. low residual 11-dehydro-TXB2 levels, possibly identifying Aspirin nonresponders and responders, respectively. Novel chemotherapeutic strategies in FAP may involve drugs that affect TXA2 and PGE2 signaling in the colorectum with receptor antagonists, and clinical studies should be performed to verify the drugs' impact. Background: The results of Aspirin prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP) are controversial. Methods: We conducted a biomarker-based clinical study in eight FAP patients treated with enteric-coated low-dose Aspirin (100 mg daily for three months) to explore whether the drug targets mainly platelet cyclooxygenase (COX)-1 or affects extraplatelet cellular sources expressing COX-isozymes and/or off-target effects in colorectal adenomas. Results: In FAP patients, low-dose Aspirin-acetylated platelet COX-1 at Serine529 (>70%) was associated with an almost complete inhibition of platelet thromboxane (TX) B2 generation ex vivo (serum TXB2). However, enhanced residual urinary 11-dehydro-TXB2 and urinary PGEM, primary metabolites of TXA2 and prostaglandin (PG)E2, respectively, were detected in association with incomplete acetylation of COX-1 in normal colorectal biopsies and adenomas. Proteomics of adenomas showed that Aspirin significantly modulated only eight proteins. The upregulation of vimentin and downregulation of HBB (hemoglobin subunit beta) distinguished two groups with high vs. low residual 11-dehydro-TXB2 levels, possibly identifying the nonresponders and responders to Aspirin. Conclusions: Although low-dose Aspirin appropriately inhibited the platelet, persistently high systemic TXA2 and PGE2 biosynthesis were found, plausibly for a marginal inhibitory effect on prostanoid biosynthesis in the colorectum. Novel chemotherapeutic strategies in FAP can involve blocking the effects of TXA2 and PGE2 signaling with receptor antagonists. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) develops from pre-cancerous cellular lesions in the gut epithelium and mainly originates from specific types of colonic adenomas with dysplasia. However, gut microbiota signatures among sampling sites in patients with colorectal adenomas with low-grade dysplasia (ALGD) and normal control (NC) remain uncharacterized. To characterize gut microbial and fungal profiles in ALGD and normal colorectal mucosa tissues. We used 16S and ITS1-2 rRNA gene sequencing and bioinformatics analysis on the microbiota of ALGD and normal colorectal mucosa from 40 subjects. Bacterial sequences in the ALGD group showed an increase in Rhodobacterales, Thermales, Thermaceae, Rhodobacteraceae, and several genera, including Thermus, Paracoccus, Sphingobium, and Pseudomonas, compared to the NC group. Fungal sequences in the ALGD group showed an increase in Helotiales, Leotiomycetes, and Basidiomycota, while several orders, families, and genera, including Verrucariales, Russulales, and Trichosporonales, were decreased. The study found various interactions between intestinal bacteria and fungi. The bacterial functional analysis showed increased glycogen and vanillin degradation pathways in the ALGD group. Meanwhile, the fungal functional analysis showed a decrease in pathways related to the biosynthesis of gondoate and stearate, as well as degradation of glucose, starch, glycogen, sucrose, L-tryptophan, and pantothenate, and an increase in the octane oxidation pathway in the ALGD group. The mucosal microbiota in ALGD exhibits altered fungal and microbial composition compared to the NC mucosa, potentially contributing to the development of intestinal cancer by regulating specific metabolic pathways. Therefore, these changes in microbiota and metabolic pathways may be potential markers for diagnosing and treating colorectal adenoma and carcinoma. [ABSTRACT FROM AUTHOR]

Background: Colorectal endoscopic submucosal dissection (ESD) is still not widely used due to its technical difficulty and the risk of complications. Several techniques, such as traction techniques, pocket techniques and others, have been proposed to facilitate it. One modified pocket technique especially suitable for large lesions is endoscopic submucosal tunnel dissection (ESTD). The aim of this study was to evaluate the safety and efficacy of ESTD and compare ESTD to the conventional ESD (CESD) for treating large colorectal lesions. Methods: The charts of consecutive patients referred to the Arcispedale Santa Maria Nuova (Reggio Emilia, Italy) for colorectal ESD between January 2014 and February 2021 for colorectal neoplasms > 40 mm were retrospectively analysed. The primary outcome of the study was the en bloc resection rate. Secondary outcomes were complete and curative resection rates, procedure speed, the adverse events rate and the recurrence rate. Results: There were 59 patients (M:F ratio 29:30, median age 70 years [range 50–93 years]). Of 59 colorectal lesions > 40 mm, 25 were removed by ESTD and 34 by CESD. The en bloc resection rate was 100% in both groups and the complete resection rate was similar (ESTD 92% vs CESD 97.1%, p = 0.569), while the curative resection rate was higher in the CESD group, but not significantly (94.1% vs 76%, p = 0.061). Procedure speed was significantly faster with ESTD (22 vs 17 mm2/min, p = 0.045), and the overall incidence of adverse events was low (6.8%). Eight patients were referred to surgery due to non-curative resection. During follow-up, no recurrence was observed in either treatment group. Conclusion: ESTD achieves a very high en bloc resection rate and is faster than CESD. [ABSTRACT FROM AUTHOR]

Objective: We aimed to examine associations between the oral, fecal, and mucosal microbiome communities and adenoma formation. Summary Background Data: Data are limited regarding the relationships between microbiota and preneoplastic colorectal lesions. Methods: Individuals undergoing screening colonoscopy were prospectively enrolled and divided into adenoma and nonadenoma formers. Oral, fecal, nonadenoma and adenoma-adjacent mucosa were collected along with clinical and dietary information. 16S rRNA gene libraries were generated using V4 primers. DADA2 processed sequence reads and custom R-scripts quantified microbial diversity. Linear regression identified differential taxonomy and diversity in microbial communities and machine learning identified adenoma former microbial signatures. Results: One hundred four subjects were included, 46% with adenomas. Mucosal and fecal samples were dominated by Firmicutes and Bacteroidetes whereas Firmicutes and Proteobacteria were most abundant in oral communities. Mucosal communities harbored significant microbial diversity that was not observed in fecal or oral communities. Random forest classifiers predicted adenoma formation using fecal, oral, and mucosal amplicon sequence variant (ASV) abundances. The mucosal classifier reliably diagnosed adenoma formation with an area under the curve (AUC) = 0.993 and an out-of-bag (OOB) error of 3.2%. Mucosal classifier accuracy was strongly influenced by five taxa associated with the family Lachnospiraceae, genera Bacteroides and Marvinbryantia, and Blautia obeum. In contrast, classifiers built using fecal and oral samples manifested high OOB error rates (47.3% and 51.1%, respectively) and poor diagnostic abilities (fecal and oral AUC = 0.53). Conclusion: Normal mucosa microbial abundances of adenoma formers manifest unique patterns of microbial diversity that may be predictive of adenoma formation. [ABSTRACT FROM AUTHOR]

Abstract 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).

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 N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 3-methyluridine (m3U) were increased in patients with CRC, whereas the concentrations of N2-methylguanosine (m2G), 2′-O-methyluridine (Um), and 2′-O-methylguanosine (Gm) 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 Um and Gm 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.

Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.

Abstract 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

Preneoplastic lesions represent a useful target for early diagnosis and follow-up of gastrointestinal malignancies. hERG1 channel expression was tested by immunohistochemistry (IHC) in a cohort of colorectal adenoma samples belonging to Italian subjects. Overall, hERG1 was expressed in 56.5% of cases with both high staining intensity and a high percentage of positive cells. Moreover, hERG1 was expressed in a higher percentage of dysplastic adenomas with respect to hyperplastic lesions, and the proportion of positive samples further increased in patients with high-grade dysplasia. Comparing hERG1 expression in other preneoplastic lesions of the GI tract (gastric dysplasia and Barrett’s esophagus), it emerged that in all the conditions, hERG1 was expressed with a diffused pattern, throughout the cell, with variable staining intensity within the samples. The highest expression was detected in gastric dysplasia samples and the lowest in Barrett’s esophagus at similar levels observed in colorectal adenomas. Our results show that hERG1 is aberrantly expressed in human preneoplastic lesions of the gastrointestinal tract and has a different pattern of expression and role in the different sites. Overall, the detection of hERG1 expression in preneoplastic lesions could represent a novel diagnostic or prognostic marker of progression in the gastrointestinal tract.

BackgroundSeveral 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.AimsTo evaluate the basic characteristics of colorectal adenomas with malignancy risk using high-grade dysplasia (HGD) as an alternative marker for malignant transformation.MethodsData 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.ResultsA 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.

Colorectal adenomas (CRAs) represent precancerous lesions that precede the development of colorectal cancer (CRC). Regular monitoring of CRAs can hinder the progression into carcinoma. To explore the utility of tissue DNA and circulating cell-free DNA (cfDNA) in early diagnosis of CRC, we retrospectively sequenced paired tissue and plasma samples from 85 patients with conventional CRAs. The genetic alterations identified were compared with those from 78 stage-I CRC patients (CRC-I) in the ChangKang project. Within the CRA cohort, we pinpointed 12 genes, notably APC , KRAS , and SOX9 , that exhibited significant mutated rates in tissue. Patients harboring KMT2C and KMT2D mutations displayed persistent polyps. By comparing with the mutational profiles of metastatic CRC plasma samples, we found that ZNF717 was exclusively mutated in CRAs, while KMT2C and KMT2D mutations were detected in both CRA and CRC. The presence of cfDNA mutations in plasma was validated through polymerase chain reaction, enhancing the feasibility of using cfDNA mutations for early CRC screening. Compared with CRC-I, CRAs exhibited a reduced frequency of TP53 and PIK3CA somatic mutations and underwent non-neutral evolution more often. We established a random forest model based on 15 characteristic genes to distinguish CRA and CRC, achieving an area under the curve of 0.89. Through this endeavor, we identified two novel genes, CNTNAP5 and GATA6 , implicated in CRC carcinogenesis. Overall, our findings reveal convincing biomarkers markers for detecting CRAs with a propensity for CRC development, highlighting the importance of early genetic screening in CRC prevention., Competing Interests: Authors Yang Pan, Xiaoni Zhang and Jing Zhang are employees in HaploX Biotechnology but have no potential relevant financial or nonfinancial interests to disclose. The other authors have no conflicts of interest to declare., (© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

The intestinal microbiome plays a crucial role in colorectal adenomas and the mucosa associated microbiota are thought to play a more critical role in interactions with the host immune system. Current omics approaches, offer a holistic assessment of the gut microbiome and the human host interaction. To enhance the value of data from these sequencing methods, appropriate sample collection is vital. We evaluated the potential use of endoscopic brush samples for mucosal microbiota analysis in colorectal adenomas and compared it with direct adenoma tissue sequencing in terms of microbial gene sequencing. The results showed a significant increase in microbial diversity in samples collected by the endoscopic brush, which did not interfere with pathological biopsy. This study found that utilizing endoscopic brush sampling for the microbiome analysis of colorectal adenomas offers several advantages over the direct examination of microbiomes within tumor tissues, including the capacity to accurately collect gut microbiome from different locations in the intestine, circumventing interference from tissue genes, providing more abundant microbial data and enabling inclusion of small adenomas without disrupting pathological biopsies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

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]

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. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment. [ABSTRACT FROM AUTHOR]

Abstract 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.

Colorectal cancer (CRC) develops from pre-cancerous cellular lesions in the gut epithelium and mainly originates from specific types of colonic adenomas with dysplasia. However, gut microbiota signatures among sampling sites in patients with colorectal adenomas with low-grade dysplasia (ALGD) and normal control (NC) remain uncharacterized. To characterize gut microbial and fungal profiles in ALGD and normal colorectal mucosa tissues. We used 16S and ITS1-2 rRNA gene sequencing and bioinformatics analysis on the microbiota of ALGD and normal colorectal mucosa from 40 subjects. Bacterial sequences in the ALGD group showed an increase in Rhodobacterales, Thermales, Thermaceae, Rhodobacteraceae, and several genera, including Thermus, Paracoccus, Sphingobium, and Pseudomonas, compared to the NC group. Fungal sequences in the ALGD group showed an increase in Helotiales, Leotiomycetes, and Basidiomycota, while several orders, families, and genera, including Verrucariales, Russulales, and Trichosporonales, were decreased. The study found various interactions between intestinal bacteria and fungi. The bacterial functional analysis showed increased glycogen and vanillin degradation pathways in the ALGD group. Meanwhile, the fungal functional analysis showed a decrease in pathways related to the biosynthesis of gondoate and stearate, as well as degradation of glucose, starch, glycogen, sucrose, L-tryptophan, and pantothenate, and an increase in the octane oxidation pathway in the ALGD group. The mucosal microbiota in ALGD exhibits altered fungal and microbial composition compared to the NC mucosa, potentially contributing to the development of intestinal cancer by regulating specific metabolic pathways. Therefore, these changes in microbiota and metabolic pathways may be potential markers for diagnosing and treating colorectal adenoma and carcinoma.

Simple Summary: Identifying patients with an increased risk of early recurrence of colorectal lesions is still a problem. In our study, we focused on improving this identification by determining the mutation profile of index lesions. We found a statistically significant association between the mutation in exon 7 of the TP53 gene in the index lesion and the risk of early metachronous adenoma. (1) Background: this prospective study was focused on detailed analysis of the mutation heterogeneity in colorectal lesions removed during baseline (index) colonoscopy to identify patients at high risk of early occurrence of metachronous adenomas. (2) Methods: a total of 120 patients after endoscopic therapy of advanced colorectal neoplasia size ≥10 mm (index lesion) with subsequent surveillance colonoscopy after 10–18 months were included. In total, 143 index lesions and 84 synchronous lesions in paraffin blocks were divided into up to 30 samples. In each of them, the detection of somatic mutations in 11 hot spot gene loci was performed. Statistical analysis to correlate the mutation profiles and the degree of heterogeneity of the lesions with the risk of metachronous adenoma occurrence was undertaken. (3) Results: mutation in exon 7 of the TP53 gene found in the index lesion significantly correlated with the early occurrence of metachronous adenoma (log-rank test p = 0.003, hazard ratio 2.73, 95% confidence interval 1.14–6.56). We did not find an association between the risk of metachronous adenomas and other markers monitored. (4) Conclusions: the findings of this study could lead to an adjustment of existing recommendations for surveillance colonoscopies in a specific group of patients with mutations in exon 7 of the TP53 gene in an index lesion, where a shortening of surveillance interval may be warranted. [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]

How metabolome changes influence the early process of colorectal cancer (CRC) development remains unknown. We conducted a 1:2 matched nested case–control study to examine the associations of pre-diagnostic plasma metabolome (profiled using LC–MS) with risk of CRC precursors, including conventional adenomas (n = 586 vs. 1141) and serrated polyps (n = 509 vs. 993), in the Nurses' Health Study (NHS) and NHSII. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). We used the permutation-based Westfall and Young approach to account for multiple testing. Subgroup analyses were performed for advanced conventional adenomas (defined as at least one adenoma of ≥ 10 mm or with high-grade dysplasia, or tubulovillous or villous histology) and high-risk serrated polyps that were located in the proximal colon or with size of ≥ 10 mm. After multiple testing correction, among 207 metabolites, higher levels of C36:3 phosphatidylcholine (PC) plasmalogen were associated with lower risk of conventional adenomas, with the OR (95% CI) comparing the 90th to the 10th percentile of 0.62 (0.48–0.81); C54:8 triglyceride (TAG) was associated with higher risk of serrated polyps (OR = 1.79, 95% CI: 1.31–2.43), and phenylacetylglutamine (PAG) was associated with lower risk (OR = 0.57, 95% CI:0.43–0.77). PAG was also inversely associated with advanced adenomas (OR = 0.57, 95% CI: 0.36–0.89) and high-risk serrated polyps (OR = 0.54, 95% CI: 0.32–0.89), although the multiple testing-corrected p value was > 0.05. Our findings suggest potential roles of lipid metabolism and phenylacetylglutamine, a microbial metabolite, in the early stage of colorectal carcinogenesis, particularly for the serrated pathway. [ABSTRACT FROM AUTHOR]

Abstract 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.

Louise Rasmussen, Hans Jørgen Nielsen, Ib Jarle Christensen Department of Surgical Gastroenterology 360, Hvidovre Hospital, University of Copenhagen, Hvidovre 2650, DenmarkCorrespondence: Louise RasmussenDepartment of Surgical Gastroenterology 360, Hvidovre Hospital, University of Copenhagen, Hvidovre 2650, DenmarkEmail loui_rasmussen@hotmail.comIntroduction: Plasma levels of eight combined proteins have shown value as biomarkers for detection of colorectal cancer (CRC). However, their value in identifying colorectal adenoma needs further evaluation. The aim was to evaluate the eight proteins (AFP, CA19-9, CEA, CyFra21-1, Ferritin, Galectin-3, hs-CRP and TIMP-1) in detection of high-risk adenoma (HRA) and in prediction of recurrence of adenoma. Furthermore, the discrimination between HRA and low-risk adenoma (LRA) or CRC lesions was evaluated.Methods: The study included 4698 individuals undergoing diagnostic colonoscopy. Automated ELISA platforms were used in the determination of protein levels in samples collected just before colonoscopy.Results: Univariably, five proteins (AFP, CEA, CyFra21-1, hs-CRP and TIMP-1), respectively, significantly discriminated individuals with HRA from individuals with non-malignant findings. Multivariably, the combination of CEA and hs-CRP improved performance; AUC= 0.63 (sensitivity=0.19 at specificity=0.90). CyFra21-1, Ferritin and TIMP-1 demonstrated significant discrimination between individuals with HRA and LRA in univariable analyses, respectively. Performance was improved in multivariable analysis; AUC=0.61 (sensitivity=0.13 at specificity=0.90). Discrimination between individuals with colorectal adenomas and healthy individuals was significant for CA19-9, CEA, hs-CRP and TIMP-1, respectively, in univariable analyses. Multivariable analysis improved performance; AUC=0.63 (sensitivity=0.17 at specificity=0.90). All proteins except AFP demonstrated significant discrimination between individuals with HRA and CRC. Combination of CEA, CyFra21-1, Ferritin, hs-CRP and TIMP-1 in multivariable analysis improved discrimination; AUC=0.78 (sensitivity=0.34 at specificity=0.90). Association between plasma levels of any of the eight proteins and recurrence of colorectal adenomas after endoscopic removal could not be demonstrated.Discussion: The protein panel shows a promising potential in detection of colorectal adenomas in general, but specifically of HRA. However, improvements are needed for the panel to be valuable as a screening test. Finally, plasma levels of the eight proteins were not predictive of recurrence of colorectal adenomas.Keywords: biomarkers, tumor, neoplasm recurrence, local, colorectal adenomas, colorectal neoplasms, alpha-feto protein, cancer antigen 19-9, carcino embryogenic antigen, cytokeratin fragment 21-1, Ferritin, Galectin-3, high sensitivity C-reactive protein, tissue inhibitor of metalloproteinases-1

Objective: Colorectal cancer (CRC) is the fourth most common cancer in the UK. Patients with symptoms suggestive of CRC should be referred for urgent investigation. However, gastrointestinal symptoms are often non-specific and there is a need for suitable triage tools to enable prioritisation of investigations. In this study, the performance of the faecal immunochemical test (FIT), anaemia and the artificial intelligence algorithm ColonFlag were retrospectively examined and evaluated for their potential clinical benefits in patients who had been referred on an urgent lower gastrointestinal cancer pathway., Design: All patients aged over 40 years referred in a 12-month period were included. After 6 months, clinical outcomes were determined and the performance of the triage tests was evaluated., Results: A total of 3822 patients completed investigations and received a diagnosis. 143 had CRC, 126 high-risk adenomas (HRA). ColonFlag would have missed 27 CRC and 29 HRA. Faecal haemoglobin (f-Hb) at a cut-off of 10 µg/g would have missed 10 CRC and 26 HRA; f-Hb in combination with anaemia would have missed 2 CRC and 14 HRA. Using f-Hb in combination with ColonFlag would have missed only 1 CRC and 5 HRA and would have reduced the need for urgent referral by over 400 patients., Conclusion: ColonFlag has potential to assist detection of CRC and HRA, alone where no faecal sample is present and in combination with FIT and to reduce the need for urgent referral., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Whether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain., Design: Patients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic control at baseline was defined as mean haemoglobin A1c (HbA1c)<7%. Outcomes of interest included colorectal cancer (CRC) and colonic adenoma development. We used propensity score (PS) matching with competing risk models to estimate subdistribution HRs (SHRs). We further analysed the combined effect of baseline and postbaseline glycaemic control based on time-weighted mean HbA1c during follow-up., Results: Of 88 468 PS-matched patients with DM (mean (SD) age: 61.5 (±11.7) years; male: 47 127 (53.3%)), 1229 (1.4%) patients developed CRC during a median follow-up of 7.2 (IQR: 5.5-9.4) years. Optimal glycaemic control was associated with lower CRC risk (SHR 0.72; 95% CI 0.65 to 0.81). The beneficial effect was limited to left-sided colon (SHR 0.71; 95% CI 0.59 to 0.85) and rectum (SHR 0.71; 95% CI 0.57 to 0.89), but not right-sided colon (SHR 0.86; 95% CI 0.67 to 1.10). Setting suboptimal glycaemic control at baseline/postbaseline as a reference, a decreased CRC risk was found in optimal control at postbaseline (SHR 0.79), baseline (SHR 0.71) and both time periods (SHR 0.61). Similar associations were demonstrated using glycaemic control as a time-varying covariate (HR 0.75). A stepwise greater risk of CRC was found (P trend <0.001) with increasing HbA1c (SHRs 1.34, 1.30, 1.44, 1.58 for HbA1c 7.0% to <7.5%, 7.5% to <8.0%, 8.0% to <8.5% and ≥8.5%, respectively). Optimal glycaemic control was associated with a lower risk of any, non-advanced and advanced colonic adenoma (SHRs 0.73-0.87)., Conclusion: Glycaemic control in patients with DM was independently associated with the risk of colonic adenoma and CRC development with a biological gradient., Competing Interests: Competing interests: C-LC received research funding from AstraZeneca, Merck KGaA and Taiho. L-YM is an advisory board member of Gilead Sciences. WKL received speaker’s fees from AbbVie, Ferring Pharmaceuticals and Janssen. MFY received research funding from Assembly Biosciences, Arrowhead Pharmaceuticals, Bristol Myer Squibb, Fujirebio Incorporation, Gilead Sciences, Merck Sharp and Dohme, Springbank Pharmaceuticals, Sysmex, Roche and is an advisory board member and/or received research funding from AbbVie, Aligos therarpeutics, Arbutus Biopharma, Bristol Myer Squibb, Dicerna Pharmaceuticals, Finch Therapeutics, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals, Roche. W-KS received speaker’s fees from AstraZeneca, is an advisory board member and received speaker’s fees of Abbott, received research funding from Alexion Pharmaceuticals, Boehringer Ingelheim, Pfizer and Ribo Life Science, and is an advisory board member, received speaker’s fees and researching funding from Gilead Sciences. The other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Colorectal cancer is a leading cancer worldwide and in Vietnam. Adenomas (adenomatous polyps) is an important precursor of colorectal cancer. There is currently no study to determine the modifiable risk factors for colorectal adenomas, including body mass index (BMI) in Vietnam. We conducted an individually matched case‐control study of 1149 colorectal adenomas and 1145 controls in a large‐scale colorectal screening program involving 103 542 individuals aged 40‐75 years old in Hanoi, Vietnam. Conditional logistic regression was used to evaluate the association between BMI and colorectal adenomas prevalence, after controlling for potential confounders. Overall, comparing to normal weight (ie, 18.5‐22.9 kg/m2), underweight (ie, BMI < 18.5) was associated with a non‐statistically significant increased prevalence of colorectal adenomas (odd ratio [OR] = 1.29 and 95% confident interval [CI]: 0.88‐1.87). This association became significant among male (OR = 1.98, 95% CI: 1.20‐3.27), male who were ever smokers (OR = 2.59, 95% CI: 1.33‐5.03), nonregular exercise (OR = 2.44, 95% CI: 1.26‐4.73) and individuals with cardiometabolic disorders (OR = 3.46, 95% CI: 1.19‐10.00). The association between underweight and colorectal adenomas did not vary by smoking status, drinking status, family history of cancer, adenomas types or cardiometabolic disorders. No association was observed among obese individuals (BMI ≥ 25). In the population with low prevalence of obesity, we found that the association between BMI and colorectal adenomas followed a reversed J‐shape that underweight was associated with increased prevalence. Further studies are, therefore, warranted to replicate our results and to investigate the biologic mechanism the effect of underweight on colorectal adenomas prevalence. What's new? High body mass index (BMI) has been associated with an increased risk of colorectal adenomas in studies including Asian populations. To date, no study has identified modifiable risk factors for colorectal adenomas in Vietnam, a country with a rising colorectal cancer incidence and low obesity prevalence. This case‐control study based on a large‐scale colorectal cancer screening program in Vietnam reports a potential association between underweight and colorectal adenomas prevalence with an inverse J‐shape. The modification of specific factors such as maintaining a normal BMI range, quitting smoking and exercising regularly showed great potential for colorectal cancer prevention and control programs. [ABSTRACT FROM AUTHOR]

Objectives: Colorectal cancer (CRC) is the third and second most prevalent cancer in men and women, respectively. Various epidemiological studies indicated that dietary factors are implicated in the aetiology of CRC and its precursor, colorectal adenomas (CRA). Recently, much attention has been given to the role of acid-base balance in the development of chronic diseases including cancers. Therefore, the aim of the current study is to examine the association of diet-dependent acid load and the risk of CRC and CRA.Design: In this case-control study, potential renal acid load (PRAL) was computed based on dietary intake of participants assessed via a validated FFQ. Negative PRAL values indicated a base-forming potential, while positive values of PRAL implied acid-forming potential of diet. Logistic regression was used to derive OR and 95 % CI after adjusting for confounders.Setting: Tehran, Iran.Participants: A total of 499 participants aged 30-70 years were included in the study (240 hospital controls, 129 newly diagnosed CRC and 130 newly diagnosed CRA). The current study was conducted between December 2016 and September 2018.Results: After adjusting for potential confounders, a higher PRAL was associated with increased odds of CRC and CRA. The highest v. the lowest tertile of PRAL for CRC and CRA was OR 4·82 (95 % CI 2·51-9·25) and OR 2·47 (95 % CI 1·38-4·42), respectively.Conclusions: The findings of the current study suggested that higher diet-dependent acid load is associated with higher risk of CRC and CRA. [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 Underwater endoscopic mucosal resection (UEMR) without submucosal injection has been described as an alternative technique to the endoscopic resection of adenomas and colorectal serrated lesions. We aimed to assess the feasibility, safety, and efficacy of UEMR in a Brazilian setting. Methods This was a prospective observational study of consecutive patients who underwent UEMR between January and July 2019, in a single tertiary care center. Inclusion criteria were lesions without endoscopic stigmata of deep submucosal invasion in patients referred for endoscopic resection of colorectal adenomas, and serrated lesions detected in a previous colonoscopy. The following features were assessed: complete resection rate, en bloc resection rate, resection time, adverse events, and resection infeasibility. Results A total of 36 patients underwent UEMR for 51 colorectal lesions. The mean/median lesion size was 16.24/13 mm and the mean/median resection time was 16.97/9.19 min. Histopathology revealed the following: tubular adenoma (43.1%), tubulovillous adenoma (13.7%), serrated lesions (41.2%), and intramucosal adenocarcinoma (2%). Complete resection was achieved in 86.3% of cases; 52.9% of the lesions were removed en bloc, while 47.1% were resected in a piecemeal fashion. UEMR was feasible in 96.1% of cases and failed on 2 occasions, requiring conversion to standard endoscopic mucosal resection. Minor intraoperative bleeding occurred in 5 patients (9.8%) and only 1 presented with delayed bleeding (2%), all controlled endoscopically. Conclusion UEMR for removal of adenomas and colorectal serrated lesions was demonstrated to be feasible, safe and effective. [ABSTRACT FROM AUTHOR]

Abstract 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.

Sajesh K Veettil,1 Surakit Nathisuwan,2 Siew Mooi Ching,3–5 Peerawat Jinatongthai,6,7 Kean Ghee Lim,8 Siang Tong Kew,9 Nathorn Chaiyakunapruk7,10–12 1Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia; 2Clinical Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 3Department of Family Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia; 4Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia; 5Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Selangor, Malaysia; 6Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand; 7School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia; 8Department of Surgery, Clinical School, International Medical University, Seremban, Malaysia; 9Department of Internal Medicine, School of Medicine, International Medical University, Kuala Lumpur, Malaysia; 10Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Center of Pharmaceutical Outcomes Research, Naresuan University, Phitsanulok, Thailand; 11School of Pharmacy, University of Wisconsin, Madison, WI, USA; 12Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Selangor, Malaysia Background: Celecoxib has previously been shown to be effective in reducing recurrent colorectal adenomas, but its long-term effects are unknown. In addition, safety issues are of major concern. Therefore, we examined the efficacy and safety of celecoxib as a chemopreventive agent along with its posttreatment effect.Methods: We performed a meta-analysis based on a systematic review of randomized controlled trials (RCTs) comparing celecoxib at various doses (400 mg once daily, 200 mg twice daily, and 400 mg twice daily) vs placebo in persons with history of colorectal adenomas. Several databases were searched from inception up to April 2018. Long-term follow-ups of RCTs were also included to evaluate posttreatment effect. Primary outcome was the incidence of recurrent colorectal adenomas. Various safety outcomes were evaluated, especially cardiovascular (CV) events. Risk–benefit integrated analyses were also performed.Results: A total of three RCTs (4,420 patients) and three post-trial studies (2,159 patients) were included in the analysis. Use of celecoxib at any dose for 1–3 years significantly reduced the incidence of recurrent advanced adenomas (risk ratio, 0.42 [95% CI, 0.34–0.53]) and any adenomas (0.67 [95% CI, 0.62–0.72]) compared with placebo. Subgroup analysis on different dosing suggested a greater effect with 400 mg twice daily. However, celecoxib 400 mg twice daily significantly increased the risk of serious adverse (1.2 [95% CI, 1.0–1.5]) and CV events (3.42 [95% CI, 1.56–7.46]), while celecoxib at 400 mg/day, especially with once daily dosing, did not increase CV risk (1.01 [95% CI, 0.70–1.46]). Analysis of post-trial studies indicated that the treatment effect disappeared (1.15 [95% CI, 0.88–1.49]) after discontinuing celecoxib for >2 years.Conclusion: Celecoxib 400 mg once daily dosing could potentially be considered as a viable chemopreventive option in patients with high risk of adenomas but with low CV risk. Long-term trials on celecoxib at a dose of ≤400 mg either once or twice daily are warranted. Keywords: colorectal cancer, colorectal adenomas, chemoprevention, celecoxib, meta-analysis, randomized controlled trials, risk–benefit integrated analyses