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BACKGROUND: The present study aimed to validate the accuracy of a tumor-specific antibody to target liver metastases of colorectal cancer. METHODS: A humanized anti-CEA antibody conjugated to a fluorescent dye (M5A-IR800) was tested for targeting human colorectal cancer liver metastases (CRLMs) expressing luciferase in an orthotopic mouse model. Orthotopic mouse models of CRLMs were established by implanting fragments of a luciferase-expressing human colorectal cancer cell line, LS174T, in the liver of nude mice. Mice received 50 µg M5A-IR800 72 h prior to imaging. To test co-localization, bioluminescence imaging was performed using D-luciferin, which was given via intraperitoneal injection just prior to imaging. RESULTS: Tumors were able to be visualized non-invasively through the skin with the luciferase-luciferin signal. Intra-abdominal imaging showed accurate labeling of CRLMs with M5A-IR800, which co-localized with the luciferase-luciferin signal. CONCLUSIONS: The present results validate the accuracy of a tumor-specific anti-CEA antibody in targeting liver metastases of colorectal cancer.

Objective biomarkers are crucial for early diagnosis to promote treatment and raise survival rates for diseases. With the smallest non-coding RNAs-piwi-RNAs (piRNAs)-and their transcripts, we sought to identify if these piRNAs could be used as biomarkers for colorectal cancer (CRC). Using previously published data from serum samples of patients with CRC, 13 differently expressed piRNAs were selected as potential biomarkers. With this data, we developed a machine learning (ML) algorithm and created 1020 different piRNA sequence descriptors. With the Naïve Bayes Multinomial classifier, we were able to isolate the 27 most influential sequence descriptors and achieve an accuracy of 96.4%. To test the validity of our model, we used data from piRBase with known associations with CRC that we did not use to train the ML model. We were able to achieve an accuracy of 85.7% with these new independent data. To further validate our model, we also tested data from unrelated diseases, including piRNAs with a correlation to breast cancer and no proven correlation to CRC. The model scored 44.4% on these piRNAs, showing that it can identify a difference between biomarkers of CRC and biomarkers of other diseases. The final results show that our model is an effective tool for diagnosing colorectal cancer. We believe that in the future, this model will prove useful for colorectal cancer and other diseases diagnostics.

Despite ethical and historical arguments for removing race from clinical algorithms, the consequences of removal remain unclear. Here, we highlight a largely undiscussed consideration in this debate: varying data quality of input features across race groups. For example, family history of cancer is an essential predictor in cancer risk prediction algorithms but is less reliably documented for Black participants and may therefore be less predictive of cancer outcomes. Using data from the Southern Community Cohort Study, we assessed whether race adjustments could allow risk prediction models to capture varying data quality by race, focusing on colorectal cancer risk prediction. We analyzed 77,836 adults with no history of colorectal cancer at baseline. The predictive value of self-reported family history was greater for White participants than for Black participants. We compared two cancer risk prediction algorithms-a race-blind algorithm which included standard colorectal cancer risk factors but not race, and a race-adjusted algorithm which additionally included race. Relative to the race-blind algorithm, the race-adjusted algorithm improved predictive performance, as measured by goodness of fit in a likelihood ratio test (P-value:

BackgroundThe Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.MethodsMedicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences (DID) approach was used to compare changes in TTI (within 60 days) and 3-year OS between patients in ME states versus nonexpansion (NE) states before (2010-2013) and after (2015-2018) ME. Adjusted DID estimates for TTI and 3-year OS were calculated using multivariable linear regression and Cox proportional hazards regression models, respectively.ResultsME was associated with a relative increase in TTI within 60 days for breast (DID = 4.6; p

PURPOSE: To examine the association of a traditional Mexican diet score with risk of total, breast, and colorectal cancer among women of Mexican ethnic descent in the Womens Health Initiative (WHI). METHODS: Participants were WHI enrollees who self-identified as being of Mexican descent. Data from food frequency questionnaires self-administered at study baseline were used to calculate the MexD score, with higher scores indicating greater adherence to an a priori-defined traditional Mexican diet (high in dietary fiber, vegetables, and legumes). Incident cancers were self-reported by participants from 1993 to 2020 and adjudicated by trained physicians. We used multivariable-adjusted Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 2,343 Mexican descent women (median baseline age: 59 years), a total of 270 cancers (88 breast, 37 colorectal) occurred during a mean follow-up of 14.4 years. The highest tertile of MexD score was associated with a lower risk of all-cancer incidence (HR: 0.67; 95% CI 0.49-0.91; p-trend: 0.01) and colorectal cancer (HR: 0.38; 95% CI 0.14-0.998; p-trend

BACKGROUND: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. METHODS: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. FINDINGS: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. INTERPRETATION: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. FUNDING: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).

Today, colorectal cancer (CRC) diagnosis is performed using colonoscopy, which is the current, most effective screening method. However, colonoscopy poses risks of harm to the patient and is an invasive process. Recent research has proven metabolomics as a potential, non-invasive detection method, which can use identified biomarkers to detect potential cancer in a patients body. The aim of this study is to develop a machine-learning (ML) model based on chemical descriptors that will recognize CRC-associated metabolites. We selected a set of metabolites found as the biomarkers of CRC, confirmed that they participate in cancer-related pathways, and used them for training a machine-learning model for the diagnostics of CRC. Using a set of selective metabolites and random compounds, we developed a range of ML models. The best performing ML model trained on Stage 0-2 CRC metabolite data predicted a metabolite class with 89.55% accuracy. The best performing ML model trained on Stage 3-4 CRC metabolite data predicted a metabolite class with 95.21% accuracy. Lastly, the best-performing ML model trained on Stage 0-4 CRC metabolite data predicted a metabolite class with 93.04% accuracy. These models were then tested on independent datasets, including random and unrelated-disease metabolites. In addition, six pathways related to these CRC metabolites were also distinguished: aminoacyl-tRNA biosynthesis; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine biosynthesis; and alanine, aspartate, and glutamate metabolism. Thus, in this research study, we created machine-learning models based on metabolite-related descriptors that may be helpful in developing a non-invasive diagnosis method for CRC.

BACKGROUND: Rural residents have a higher prevalence of colorectal cancer (CRC) mortality compared to urban individuals. Policies have been aimed at improving access to CRC screening to reduce these outcomes. However, little attention has been paid to other determinants of CRC-related outcomes, such as stage at diagnosis, treatment, or survivorship care. The main objective of this analysis was to evaluate literature describing differences in CRC screening, stage at diagnosis, treatment, and survivorship care between rural and urban individuals. MATERIALS AND METHODS: We conducted a systematic review of electronic databases using a combination of MeSH and free-text search terms related to CRC screening, stage at diagnosis, treatment, survivorship care, and rurality. We identified 921 studies, of which 39 were included. We assessed methodological quality using the ROBINS-E tool and summarized findings descriptively. A meta-analysis was performed of studies evaluating CRC screening using a random-effects model. RESULTS: Seventeen studies reported disparities between urban and rural populations in CRC screening, 12 on treatment disparities, and 8 on staging disparities. We found that rural individuals were significantly less likely to report any type of screening at any time period (pooled odds ratio = 0.81, 95% CI, 0.76-0.86). Results were inconclusive for disparities in staging at diagnosis and treatment. One study reported a lower likelihood of use of CRC survivorship care for rural individuals compared to urban individuals. CONCLUSION: There remains an urgent need to evaluate and address CRC disparities in rural areas. Investigators should focus future work on assessing the quality of staging at diagnosis, treatment, and survivorship care in rural areas.

Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPHs potential role in CRC prevention.

Claudins (CLDN1-CLDN24) are a family of tight junction proteins whose dysregulation has been implicated in tumorigeneses of many cancer types. In colorectal cancer (CRC), CLDN1, CLDN2, CLDN4, and CLDN18 have been shown to either be upregulated or aberrantly expressed. In the normal colon, CLDN1 and CLDN3-7 are expressed. Although a few claudins, such as CLDN6 and CLDN7, are expressed in CRC their levels are reduced compared to the normal colon. The present review outlines the expression profiles of claudin proteins in CRC and those that are potential biomarkers for prognostication.

Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs' profile in a mouse CAC model. Further, gut macrophage-intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines' secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages' recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

As the Editor-in-Chief of World Journal of Gastroenterology, every week prior to a new issues online publication, I perform a careful review of all encompassed articles, including the title, clinical and/or research importance, originality, novelty, and ratings by the peer reviewers. Based on this review, I select the papers of choice and suggest pertinent changes (e.g., in the title) to the Company Editors responsible for publication. This process, while time-consuming, is very important for assuring the quality of publications and highlighting important articles that Readers may revisit.

INTRODUCTION: Non-Hispanic Black (NHB) Americans have a higher incidence of colorectal cancer (CRC) and worse survival than non-Hispanic white (NHW) Americans, but the relative contributions of biological versus access to care remain poorly characterized. This study used two nationwide cohorts in different healthcare contexts to study health system effects on this disparity. METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER) registry as well as the United States Veterans Health Administration (VA) to identify adults diagnosed with colorectal cancer between 2010 and 2020 who identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW). Stratified survival analyses were performed using a primary endpoint of overall survival, and sensitivity analyses were performed using cancer-specific survival. RESULTS: We identified 263,893 CRC patients in the SEER registry (36,662 (14%) NHB; 226,271 (86%) NHW) and 24,375 VA patients (4,860 (20%) NHB; 19,515 (80%) NHW). In the SEER registry, NHB patients had worse OS than NHW patients: median OS of 57 months (95% confidence interval (CI) 55-58) versus 72 months (95% CI 71-73) (hazard ratio (HR) 1.14, 95% CI 1.12-1.15, p = 0.001). In contrast, VA NHB median OS was 65 months (95% CI 62-69) versus NHW 69 months (95% CI 97-71) (HR 1.02, 95% CI 0.98-1.07, p = 0.375). There was significant interaction in the SEER registry between race and Medicare age eligibility (p

BACKGROUND: Primary care physicians (PCP) play a key role in offering colorectal cancer (CRC) screenings, particularly amongst underserved populations. Given potential delays in or omission of CRC screening in the absence of a PCP, we aimed to determine stage of CRC at diagnosis in an underserved population. METHODS: A retrospective chart review was conducted at two Los Angeles County safety-net hospitals. Inclusion criteria were a CRC diagnosis between 2018 and 2021 and age between 50 and 75 years at diagnosis time. The primary outcome was the cancer stage at diagnosis. RESULTS: A total of 373 patients were included, of those, 52.5 % had a PCP. Compared to others, PCP was similar in age, racial composition, and primary spoken language (Table 1). Of patients with a PCP, 52.0% were diagnosed by screening. After screening, the most common indication for colonoscopy were blood per rectum (24.9 %) and imaging findings (18.0 %). Patients with a PCP had a significantly lower rate of late stage CRC than those without a PCP (42.4 % vs. 68.0 %, p

Trivariate joint modeling for longitudinal count data, recurrent events, and a terminal event for family data has increased interest in medical studies. For example, families with Lynch syndrome (LS) are at high risk of developing colorectal cancer (CRC), where the number of polyps and the frequency of colonoscopy screening visits are highly associated with the risk of CRC among individuals and families. To assess how screening visits influence polyp detection, which in turn influences time to CRC, we propose a clustered trivariate joint model. The proposed model facilitates longitudinal count data that are zero‐inflated and over‐dispersed and invokes individual‐specific and family‐specific random effects to account for dependence among individuals and families. We formulate our proposed model as a latent Gaussian model to use the Bayesian estimation approach with the integrated nested Laplace approximation algorithm and evaluate its performance using simulation studies. Our trivariate joint model is applied to a series of 18 families from Newfoundland, with the occurrence of CRC taken as the terminal event, the colonoscopy screening visits as recurrent events, and the number of polyps detected at each visit as zero‐inflated count data with overdispersion. We showed that our trivariate model fits better than alternative bivariate models and that the cluster effects should not be ignored when analyzing family data. Finally, the proposed model enables us to quantify heterogeneity across families and individuals in polyp detection and CRC risk, thus helping to identify individuals and families who would benefit from more intensive screening visits. [ABSTRACT FROM AUTHOR]

AbstractThe current study aimed to determine the roles of pivotal and novel lncRNAs associated with the cell cycle in the occurrence and development of Colorectal cancer (CRC). To achieve this, the TCGA-COAD project related to CRC was downloaded, and differential expression analysis was performed to identify differentially expressed lncRNAs, miRNAs, and mRNAs. A cell cycle-associated lncRNA-miRNA-mRNA regulatory network was constructed, and two novel lncRNAs were selected. Two subnetworks were constructed for selected lncRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were illustrated for the genes in each sub-network. qPCR analysis was used to validate the expression levels of the selected lncRNAs in CRC tissues compared with in those adjacent normal tissues. The differential expression analysis identified 416 lncRNAs, 317 miRNAs, and 117 mRNAs. The ceRNA subnetwork genes were associated with different pathways, including cellular senescence, DNA replication, human T-cell leukemia virus 1 infection, and oocyte meiosis. The bioinformatic results based on TCGA project indicated the dysregulation of two novel lncRNAs, MIR29B2CHG and HELLPAR, in CRC tissues compared to adjacent normal tissues. Moreover, qPCR confirmed the dysregulation of lncRNAs in the CRC tissues. ROCs curves revealed that both selected lncRNAs had acceptable specificity and sensitivity as biomarkers. In conclusion, novel cell cycle-associated lncRNAs have the potential to be understood as the underlying molecular mechanisms that influence CRC. Therefore, these lncRNAs can be considered as promising biomarkers for the diagnosis and treatment of CRC. [ABSTRACT FROM AUTHOR]

Polyphenols are natural biomolecules known for circumventing several diseases including cancer with little adverse effects. This study aimed to investigate the polyphenol enriched fractions from the leaf extract of Asystasia gangetica for their composition, biological activities such as antioxidant activity, haemolytic effects, and in vitro cytotoxicity against cancer cell lines. LC–MS/MS analysis of the enriched fractions identified a total of 35 distinct polyphenols with caffeic acid, luteolin, apigenin, and protocatechuic acid at higher concentrations. Fractions AG-3 and AG-4 exhibited the highest total antioxidant activity with higher concentration of phenolics and flavonoids. The AG-4 fraction had the highest levels of DPPH radical scavenging (IC50 = 32.74 µg mL-1) and ABTS radical scavenging (IC50 = 29.45 µg mL–1) activity, in addition to a modest iron chelating activity and reducing power. The fractions exhibited the least haemolytic activity. The cytotoxic potential of enriched fractions against the HCT-116, HeLa, PC-3, and HDF cell lines was further examined. While the extract showed no inhibitory effect on normal HDF cells, the cytotoxic activity of fractions on cell lines varied, with HCT-116 cells having the strongest anticancer activity with an IC50 of 43.82 µg mL–1. Additionally, fractions induced apoptotic activity in HCT-116 cells, resulting in cell cycle arrest at the G2M phase and an increase in sub-G0/G1 cells, with an IC50 of 13.54 µg mL–1 after 48 h of incubation. The in silico molecular docking of the active compounds against the TNIK receptor protein and ADMET (Absorption–Distribution–Metabolism–Excretion–Toxicity) characteristics are described. Overall, the study highlights the enhanced biological and antiproliferative activities of polyphenols in Asystasia gangetica leaf extract, which could be further utilized as a potential cancer treatment strategy. [ABSTRACT FROM AUTHOR]

Fluorouracil-based chemotherapy responses in colorectal cancer (CRC) patients vary widely, highlighting the role of pharmacogenomics in developing better predictive models. We analyzed 379 CRC patients receiving fluorouracil-based chemotherapy, collecting data on fluorouracil metabolism-related SNPs (TYMS, MTHFR, DPYD, RRM1), blood inflammatory markers, and clinical status. Six machine learning models—K-nearest neighbors, support vector machine, gradient boosting decision trees (GBDT), eXtreme Gradient Boosting (XGBoost), LightGBM, and random forest—were compared against multivariate logistic regression and a deep learning model (i.e., multilayer perceptron, MLP). Feature importance analysis highlighted seven predictors: histological grade, N and M staging, monocyte count, platelet-to-lymphocyte ratio, MTHFR rs1801131, and RRM1 rs11030918. In a five-fold cross-validation, XGBoost and GBDT exhibited superior performance, with Area Under Curve (AUC) of 0.88 ± 0.02. XGBoost excelled in identifying favorable prognosis (recall = 0.939). GBDT demonstrated balance in recognizing both categories, with a recall for favorable prognosis of 0.908 and a precision for unfavorable prognosis of 0.863. MLP had a similar AUC (0.87) with high precision for favorable prognosis (recall = 0.946). In external validation, XGBoost model achieved an accuracy of 0.79. An online prognostic tool based on XGBoost was developed, integrating metabolism-related SNPs and inflammatory markers, enhancing CRC treatment precision and supporting tailored chemotherapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignant tumors. Identification of new effective drug targets for CRC and exploration of bioactive small‐molecules are clinically urgent. The human dCTP pyrophosphatase 1 (DCTPP1) is a newly identified pyrophosphatase regulating the cellular nucleotide pool but remains unexplored as potential target for CRC treatment. Here, twelve unprecedented chemical architectures terpene‐nonadride heterodimers (1–12) and their monomers (13–20) were isolated from endophyte Bipolaris victoriae S27. Compounds 1–12 represented the first example of terpene‐nonadride heterodimers, in which nonadride monomers of 1 and 2 were also first example of 5/6 bicyclic nonadrides. A series of assays showed that 2 could repress proliferation and induce cell cycle arrest, apoptotic and autophagic CRC cell death in vitro and in vivo. Clinical cancer samples data revealed that DCTPP1 was a novel target associated with poor survival in CRC. DCTPP1 was also identified as a new target protein of 2. Mechanically, compound 2 bound to DCTPP1, inhibited its enzymatic activity, intervened with amino acid metabolic reprogramming, and exerted anti‐CRC activity. Our study demonstrates that DCTPP1 was a novel potential biomarker and therapeutic target for CRC, and 2 was the first natural anti‐CRC drug candidate targeting DCTPP1. [ABSTRACT FROM AUTHOR]

PIK3CA gene encodes the p110α catalytic subunit of PI3K, which regulates the PI3K/AKT/mTOR signaling pathway. PIK3CA gene mutation is one of the most common mutations in colorectal cancer (CRC), affecting about 15%–20% of CRC patients. PIK3CA gene mutation leads to the persistent activation of the PI3K/AKT/mTOR signaling pathway, which promotes the proliferation, invasion, metastasis, and drug resistance of CRC. This article provides a summary of the key detection methods for PIK3CA gene mutation, and provides an introduction to the existing colorectal cancer treatments and their practical applications in the clinic. Besides, this article summarizes the role and mechanism of PIK3CA gene mutation in the occurrence and development of CRC. It also explores the relationship between PIK3CA gene mutation and the clinical features and prognosis of CRC. This article focuses on the influence and mechanism of PIK3CA gene mutation on the targeted therapy and immunotherapy of CRC, and discusses the potential value and future direction of PIK3CA gene mutation in the personalized therapy of CRC. We aim to provide new perspectives and ideas for the precise diagnosis and treatment of CRC. [ABSTRACT FROM AUTHOR]

Background: A complex inheritance has been suggested in families with colorectal-, gastric- and prostate cancer. Therefore, we conducted a genome-wide association study (GWAS) in colorectal cancer patients, who's relatives had prostate-, and/or gastric cancer. Methods: The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model. Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case–control study. Results: Candidate loci/genes on ten chromosomal regions were suggested with odds ratios between 1.71–3.62 and p-values < 5 × 10–8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of DNA from 122 colorectal cancer patients with gastric- and/or prostate cancer in their families was performed to search for candidate variants in the haplotype regions. The identified candidate variants were tested in a nested case–control study of similar colorectal cancer cases and controls. There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested. Conclusions: This study demonstrated a proof of principle strategy to identify risk variants found by GWAS, and identified ten candidate loci that could be associated with colorectal, gastric- and prostate cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer in Brazil is among the main public health concern. The burden of disease can be related to unhealthy lifestyle behavior and inequality in access to health services. The aim of this study was to identify the main factors associated with colorectal cancer mortality in Brazil. This is an ecological study that had the Brazilian Federal Units as the primary units of analysis. Colorectal cancer mortality data (ICD C18-C21) were obtained from Brazilian national mortality system to the year 2020. Prevalence of overweight, food consumption (fiber, whole grains and red meat), physical inactivity, smoke, alcohol consumption, the median of household income, years of study, rates of cancer treatment units and oncologist by Brazilian Federal Units were considered as factor associated to the colorectal cancer mortality. Quasipoisson Generalized Linear Models were used to associate CRC mortality and variables related to dietary intake, risk behavior, and access to health services. In 2020, there were 21,501 deaths by colorectal cancer (51% among women). Prevalence of overweight (men: IRR 1.03; CI: 1.01–1.04; women IRR 1.05; CI 1.02–1.08) and the density of oncologist (men: IRR 1.02; CI: 1.01–1.03; women IRR 1.02; CI 1.01–1.03) were the main factors associated with colorectal cancer mortality. Sociodemographic and food consumption characteristics were not statistically associated with CRC. Prevalence of overweight was the strongest factor associated with mortality from colorectal cancer in Brazil in 2020. Therefore, current public policies to reduce overweight and obesity should be prioritized and strengthened in Brazil. [ABSTRACT FROM AUTHOR]

Background: Tumor Mutational Burden (TMB) have emerged as pivotal predictive biomarkers in determining prognosis and response to immunotherapy in colorectal cancer (CRC) patients. While Whole Exome Sequencing (WES) stands as the gold standard for TMB assessment, carry substantial costs and demand considerable time commitments. Additionally, the heterogeneity among high-TMB patients remains poorly characterized. Methods: We employed eight advanced machine learning algorithms to develop gene-panel-based models for TMB estimation. To rigorously compare and validate these TMB estimation models, four external cohorts, involving 1,956 patients, were used. Furthermore, we computed the Pearson correlation coefficient between the estimated TMB and tumor neoantigen levels to elucidate their association. CD8+ tumor-infiltrating lymphocyte (TIL) density was assessed via immunohistochemistry. Results: The TMB estimation model based on the Lasso algorithm, incorporating 20 genes, exhibiting satisfactory performance across multiple independent cohorts (R2 ≥ 0.859). This 20-gene TMB model proved to be an independent prognostic indicator for the progression-free survival (PFS) of CRC patients (p = 0.001). DNAH5 mutations were associated with a more favorable prognosis in high-TMB CRC patients, and correlated strongly with tumor neoantigen levels and CD8+ TIL density. Conclusions: The 20-gene model offers a cost-efficient approach to precisely estimating TMB, providing prognosis in patients with CRC. Incorporating DNAH5 within this model further refines the categorization of patients with elevated TMB. Utilizing the 20-gene model facilitates the stratification of patients with CRC, enabling more precise treatment planning. [ABSTRACT FROM AUTHOR]

Standard-of-care (SoC) imaging for assessing colorectal polyps during colonoscopy, based on white-light colonoscopy (WLC) and narrow-band imaging (NBI), does not have sufficient accuracy to assess the invasion depth of complex polyps non-invasively during colonoscopy. We aimed to evaluate the feasibility of a custom endoscopic optical coherence tomography (OCT) probe for assessing colorectal polyps during routine colonoscopy. Patients referred for endoscopic treatment of large colorectal polyps were enrolled in this pilot clinical study, which used a side-viewing OCT catheter developed for use with an adult colonoscope. OCT images of polyps were captured during colonoscopy immediately before SoC treatment. A deep learning model was trained to differentiate benign from deeply invasive lesions for real-time diagnosis. 35 polyps from 32 patients were included. OCT imaging added on average 3:40 min (range 1:54–8:20) to the total procedure time. No complications due to OCT were observed. OCT revealed distinct subsurface tissue structures that correlated with histological findings, including tubular adenoma (n = 20), tubulovillous adenoma (n = 10), sessile serrated polyps (n = 3), and invasive cancer (n = 2). The deep learning model achieved an area under the receiver operating characteristic curve (AUROC) of 0.984 (95%CI 0.972–0.996) and Cohen's kappa of 0.845 (95%CI 0.774–0.915) when compared to gold standard histopathology. OCT is feasible and safe for polyp assessment during routine colonoscopy. When combined with deep learning, OCT offers clinicians increase confidence in identifying deeply invasive cancers, potentially improving clinical decision-making. Compared to previous studies, ours offers a nuanced comparison between not just benign and malignant lesions, but across multiple histological subtypes of polyps. [ABSTRACT FROM AUTHOR]

There is a growing interest in using fecal mRNA transcripts as biomarkers for non-invasive detection of colorectal cancer (CRC). The following study compares different RNA extraction and reverse transcription PCR (RT-PCR) methods for mRNA detection in stool and identifies a robust and sensitive protocol. A combination of the Stool total RNA purification kit (Norgen) and the Superscript III one-step RT-PCR kit (Invitrogen) provided high RNA purity and sensitive and consistent mRNA detection, making them well-suited candidates for large-scale studies. We tested the protocol by detecting the mRNA of several immune genes (CXCL1, IL8, IL1B, IL6, PTGS2, and SPP1) in 22 CRCs, 24 adenomatous polyps, and 22 control stool samples. All these inflammatory markers, except for CXCL1, showed a strong association with CRC. Cancer stool samples showed increased levels of IL1B, IL8, and PTGS2 transcripts compared to polyp and control groups. Thus, this work supports the potential use of fecal mRNA as biomarkers for CRC detection. [ABSTRACT FROM AUTHOR]

An improved DeepSurv model is proposed for predicting the prognosis of colorectal cancer patients at stage IV. Our model, called as PseudoDeepSurv, is optimized by a novel loss function, which is the combination of the average negative log partial likelihood and the mean-squared error derived from the pseudo-observations approach. The public BioStudies dataset including 999 patients was utilized for performance evaluation. Our PseudoDeepSurv model produced a C-index of 0.684 and 0.633 on the training and testing dataset, respectively. While for the original DeepSurv model, the corresponding values are 0.671 and 0.618, respectively. [ABSTRACT FROM AUTHOR]

Background: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways. Methods: The authors analyzed whole genome sequencing data from the Trans‐Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers. Results: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03–1.64; p =.02) but not colorectal (p =.77) or lung cancer (p =.32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced‐stage (p =.01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41–6.62; p <.001) and without adjustment (HR, 2.50; 95% CI, 1.32–4.72; p =.004) for advanced‐stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98–2.41; p =.06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06–1.83; p =.01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11–4.3; p =.02) with mCA >5%. Conclusions: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification. In the Women's Health Initiative Trans‐Omics for Precision Medicine study, participants with clonal hematopoiesis of indeterminate potential (CHIP) had higher breast cancer incidence and a higher colorectal cancer mortality than women without CHIP. The presence of autosomal mosaic chromosomal alterations with >5% cell fraction was associated with higher incidence of breast cancer but no other cancers. [ABSTRACT FROM AUTHOR]

Patients with locally advanced rectal cancer often require neoadjuvant chemoradiation therapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiation therapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target. Immunohistochemical analysis of a tissue microarray (TMA) for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using small interfering RNA, a small molecular inhibitor (wj460), and a CRISPR-Cas9 knockout cell line. Radiosensitization after treatment was assessed using 2-dimensional clonogenic assays, 3-dimensional spheroid models, and patient-derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence, and immunoblotting. Analysis of both the diagnostic biopsy and tumor resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant long-course chemoradiation therapy. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (P =.01; hazard ratio, 3.5; 95% CI, 1.27-10.04). This was externally validated using the Stratification in Colorectal Cancer database. Quantification of myoferlin using immunoblotting in immortalized colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacologic manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2-dimensional and 3-dimensional models. After irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double-strand breaks. This appeared to be mediated via nonhomologous end-joining. We have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of patients with rectal cancer to radiation therapy, and further work is required. [ABSTRACT FROM AUTHOR]

Though several anti-PD-1/PD-L1 antibodies approved for monotherapy in microsatellite instability-high or mismatch repair-deficient unresectable/metastatic solid tumors, novel immunotherapy with better anti-tumor activity is needed in clinic. In this single-arm, multicenter, pivotal, phase II study, patients received iparomlimab (a novel humanized anti-PD-1 mAb, 200 mg or 3 mg/kg for patients with body weight < 40 kg, IV, Q3W) until disease progression, intolerable toxicities, withdrawal of consent, death, or up to 2 years. The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC). Totally, 120 patients were enrolled, of whom 60 patients failed from prior standard therapy, were enrolled in the full analysis set (FAS). As of Jan 20, 2024, the confirmed ORR per IRRC in FAS were 50.0% (30/60; 95% CI 36.8–63.2%) patients, including 4 (6.7%) complete response (CR) and 26 (43.3%) partial response (PR). In colorectal cancer (CRC) patients in FAS, the ORR reached 57.9% (22/38; 95% CI 40.8–73.7%) per IRRC, with 3 (7.9%) CR and 19 (50.0%) PR. Furtherly, the ORRs in liver metastatic or non-liver metastatic CRC patients were 52.9% (9/17, 95% CI 27.8–77.0%) vs 61.9% (13/21, 95% CI 38.4%–81.9%). The incidence of TRAE was 90.8% (any grade) and 20.8% (grade ≥ 3). Immune-related adverse events occurred in 33.3% (any grade) and 5.0% (grade ≥ 3) of patients. No iparomlimab-related death occurred. Iparomlimab presented encouraging antitumor activity with durable response and tolerable safety profile. Trial registration ClinicalTrials.gov Identifier: NCT04326829. [ABSTRACT FROM AUTHOR]

PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a malignant tumor with poor prognosis and adverse therapeutic effect. The study aims to elucidate the contribution of OGT-mediated glycosylation of ADAR to chemoresistance in CRC through its role and regulatory mechanisms. Variations in OGT expression levels and their impact on CRC cell chemoresistance were investigated using gain-of-function and loss-of-function assays. Through a series of molecular biology experiments, we confirmed that ADAR is the downstream target of OGT regulation, emphasizing the role of OGT-mediated glycosylation in stabilizing ADAR. Furthermore, RNA immunoprecipitation (RIP) assays were conducted to examine the effects of ADAR-mediated A-to-I editing on the mRNA stability and translation of genes associated with DNA damage repair. Elevated OGT expression was found to enhance CRC's malignancy and resistance to chemotherapy. OGT's influence leads to the glycosylation of ADAR, thereby increasing its protein levels. ADAR, through its role in A-to-I editing, modulates the mRNA editing of genes implicated in DNA damage repair. This regulation enhances the expression of these genes, improves DNA repair capabilities, and ultimately, fosters chemoresistance in CRC cells. In conclusion, ADAR promotes PARP1 expression under the positive regulation of OGT-mediated O-glycosylation modification to enhance drug resistance in COAD cells. It provides the research basis for overcoming the drug resistance of CRC. [ABSTRACT FROM AUTHOR]

In consideration of the important influence of gut microbiota on colorectal cancer (CRC) development and host immune system, regulating microbiota and intestinal environment can be an assisting approach to CRC treatment. To remodel tumor microenvironment, the anti‐CRC molecular targeting drug regorafenib (REG)‐encapsulating nanoparticle (UIRN) is constructed with the amphiphilic inulin‐ursodeoxycholic acid conjugate. UIRN increases the intra‐tumoral concentration and accumulation time of REG. In the CT26 tumor‐bearing mouse model, the relative abundance of probiotics and short‐chain fatty acid concentrations in colon are upregulated after treatment with UIRN, with decreased proportion of pro‐tumoral bacteria. Combining gut microbiota modulation and the function of REG to induce polarization of tumor‐associated macrophages toward the M1‐type, UIRN conquers immunosuppression and enhances anti‐tumor immunity. UIRN not only efficiently controls tumor progression alone but also exhibits adjuvant effects to chemotherapy and immunotherapy agents. The microbiota‐regulating and tumor‐suppressing functions of UIRN also work in the colitis‐associated CRC model. With good biosafety, UIRN displays hopeful application prospects in CRC therapy. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions The study aimed to describe the incidence of pregnancy‐associated colorectal cancer (PACRC) in New South Wales (NSW), Australia, and to examine the perinatal outcomes of women with PACRC and their babies.A population‐based cohort study was conducted using linked data from NSW. The study group comprised all women diagnosed with colorectal cancer during pregnancy (gestational CRC) or postpartum (postpartum CRC). Women who gave birth without cancer during pregnancy or postpartum formed the comparison group (no‐cancer group).A total of 123 women were diagnosed with PACRC (22 gestational, 101 postpartum), and 1 786 078 women were in the no‐cancer group. The incidence of PACRC was 6.9/100 000 women giving birth. From 1994 to 2013, the incidence significantly increased even when adjusting for maternal age (adjusted increase of 5.8% per year). Women with gestational CRC had significantly higher odds of severe maternal complications (AOR 29.27, 95% CI: 11.18–76.63) and were more likely to give birth by labor induction or no‐labor caesarean section (AOR 4.39, 95% CI: 1.50–12.84) than women in the no‐cancer group. Although babies born to women with gestational CRC did not experience congenital anomalies, they had higher odds of planned preterm birth (AOR 9.91, 95% CI: 1.99–49.21) and severe neonatal adverse outcomes (AOR 8.65, CI: 3.65–20.5) than babies of women without cancer.The study found a significant increase in PACRC incidence in NSW over the study period, independent of maternal age. Increased interventions during gestational CRC births reflect management challenges with higher maternal and neonatal morbidities. [ABSTRACT FROM AUTHOR]

Keratin 17 (K17) is frequently overexpressed, associated with poor prognosis in various cancers, and contributes to p27 degradation during cancer progression. Using immunohistochemistry, we evaluated K17 and p27 expression and assessed their biological behavior and prognostic significance in 326 colorectal cancers. High K17 expression was associated with poorly differentiated tumors, high pT classification, and lymph node metastases. Low p27 expression was associated with large tumors, high pT classification, lymphovascular invasion, and lymph node metastases. The overall survival of patients with high K17 expression was significantly worse than that of patients with low K17 expression [hazard ratio (HR) = 1.805, 95% confidence interval (CI) 1.169–2.787; p = 0.007]. Patients with low p27 expression showed significantly worse overall survival than those with high p27 expression (HR = 3.082, 95% CI 1.722–5.517; p < 0.001). When combining the results of K17 and p27 expression, the K17highp27low expression group showed the worst overall survival. On the contrary, the K17high/lowp27high group showed the best overall survival (p < 0.001). Therefore, K17highp27low expression is an independent poor prognostic factor in colorectal cancer. Thus, high K17 and low p27 expression correlate with aggressive clinicopathologic behavior and can be used as poor prognostic markers in colorectal cancer. [ABSTRACT FROM AUTHOR]

To ascertain the involvement of insulin receptors (IRs) in colorectal carcinogenesis, we investigated the association of height, body mass index (BMI), and physical activity with colorectal cancer (CRC) and two subtypes of CRC according to the expression level of IR. We utilized data from a large‐scale, population‐based prospective cohort study of 18,158 middle‐aged and elderly subjects in Akita and Okinawa, Japan. In the statistical analysis, we used the Cox proportional hazards model and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CRC and its subtypes as defined by immunohistochemistry of IRβ, a transmembrane subunit of IR. In the IRβ‐defined subtypes, height showed no apparent association with the risk of IRβ‐positive CRC. In contrast, a multivariable HR of IRβ‐positive CRC was 1.77 (95% CI = 1.04–3.03) with a BMI of ≥30.0 kg/m2 (i.e., obesity), compared to a BMI of <25.0 kg/m2. Further, an increase in physical activity was significantly associated with decreased risk of IRβ‐positive CRC (multivariable HR per 5 METs‐hour/day = 0.93, 95% CI = 0.88–0.99). Meanwhile, we found no significant association between any exposure and IRβ‐negative CRC. Likewise, heterogeneity between the two subtypes of CRC was not statistically significant. These findings imply that obesity and physical activity exert promoting and suppressing effects on the development of CRC expressing IRs, respectively. What's new? The involvement of insulin receptors in colorectal carcinogenesis remains unclear. Here, the authors investigated the association of height, body mass index, and physical activity with colorectal cancer according to insulin receptor expression. In this large‐scale, population‐based study, risk of insulin receptor β‐positive colorectal cancer was elevated in individuals with obesity, whereas physical activity was associated with reduced risk. No significant association between any exposure and insulin receptor β‐negative colorectal cancer was found. The findings suggest that changes in insulin status related to obesity and physical activity may influence colorectal carcinogenesis via the insulin receptor. [ABSTRACT FROM AUTHOR]

Purpose: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRSH) or liver resection have led to increased survival in patients with peritoneal or liver metastases of colorectal cancer. Selected patients undergo concomitant CRSH and liver resection. Differences in survival and morbidity between patients who underwent concomitant surgery, CRSH or liver resection for peritoneal and/or liver metastases were compared. Methods: Patients who underwent liver resection and/or CRSH for colorectal liver and/or peritoneal metastases, 2006–2016, were included. Regression analysis was used to evaluate the associations between baseline characteristics and survival. Results: Overall, 634 patients were studied. Twenty-eight patients had peritoneal and liver metastases, 121 patients had peritoneal metastases only, and 485 patients had isolated liver metastases. Median survival after concomitant treatment was 23.8 months (95% CI 12.8–43.8), after CRSH 34.5 months (95% CI 27.1–41.9), and after liver resection 54.2 months (95% CI 47.4–61.0) (p < 0.001). Increased hepatic tumor burden (HR 3.2, 95% CI 1.8–5.8) and high-volume peritoneal disease (HR 6.0, 95% CI 3.7–9.8) were associated with decreased survival in multivariate analysis. Postoperative complications according to a Clavien–Dindo score > 3a were observed in 11% in the liver resection group, 15% in the CRSH group, and 11% in the concomitant treatment group (p = 0.945). Conclusions: Patients treated with concomitant surgery for liver and peritoneal metastases experienced a shorter median overall survival than patients treated for metastases at an isolated site but had a similar rate of severe postoperative complications. The extent of peritoneal spread seemed to impact survival more than the tumor burden in the liver. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) stands as the third most widespread cancer globally with poor prognosis. Berberine (Ber), as one herbal phytochemical, showed promise in CRC therapy, but its exact mechanism is unclear. Small molecule traditional drugs face challenges in quick metabolism and low bio-availability after systemic administration. Nanodrug deliver system, with their unique properties, has the advantages of protecting drugs, improving drug bio-availability, and reducing toxic and side effects, which exhibited huge drug delivery potential. Herein, the PEG-PLGA nanocarrier was used for encapsulated Ber according to nanoprecipitation and obtained nanomedicine, denoted as NPBer. In vitro , the flow cytometry test and CCK8 assays indicated that NPBer was more easily taken up by HCT116 CRC cells, and had stronger inhibition on cell proliferation with the increase of drug concentration. In addition, RNA-Seq was employed to explore the alterations in the transcriptomes of cancer cells subsequent to treatment with Free Ber or NPBer.The sequencing results indicate that Free Ber could activate cellular aging mechanisms, intensified the iron death pathway, optimized oxidative phosphorylation efficiency, exacerbated apoptosis, accelerated programmed cell death, and negatively modulated key signaling pathways in CRC cells including Wnt, TGF-beta, Hippo, and mTOR signaling pathways. Based on PEG-PLGA nanocarriers, NPBer can improve the in vivo delivery efficiency of Ber, thereby enhancing its antitumor efficacy in vivo , enhancing apoptosis by enhancing the mitochondrial autophagy and autophagy activities of CRC cells, negatively regulating the inflammatory mediator to regulate TRP channels, and inhibiting the activation of Notch signaling pathway. In vivo , NPBer can significantly improve its accumulation and durable drug targeting in tumor site, resulting in induce maximum cell apoptosis and effectively inhibit the proliferation of HCT116 tumor. This strategy provided a promising antitumor therapeutic strategy using Ber-based drugs. [ABSTRACT FROM AUTHOR]

Background: Additional surgery with lymph node (LN) dissection is recommended for pT1 colorectal carcinoma (CRC) resected by endoscopy, based on pathological risk factors for LN metastasis (LNM), according to guidelines by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO). Methods: We retrospectively analyzed 560 consecutive patients with T1 CRC who underwent endoscopic resection alone (n=190) or initial or additional surgery with LN dissection (n=370) between 1992 and 2017 at Hiroshima University Hospital. Patients were classified into LNM low- and high-risk groups according to guidelines by the JSCCR, NCCN, and ESMO as follows. Patients without any specified pathological LNM risk factor were included in the LNM low-risk group, while the high-risk group comprised all other patients. We analyzed the LNM predictive ability of each guideline. Results: The LNM high-risk rate, sensitivity, specificity, positive and negative predictive values, accuracy of LNM risk, and AUC for LNM predictive ability were 82%, 100%, 19%, 9%, 100%, 26% and 0.596 in the JSCCR guidelines; 52%, 98%, 52%, 15%, 99%, 56%, and 0.749 in the NCCN; and 54%, 98%, 50%, 15%, 99%, 54%, and 0.743 in the ESMO, respectively. Conclusions: The JSCCR guidelines could diagnose LNM in all cases but had the highest false-positive rate. It is important to reduce unnecessary additional surgeries for pT1 CRCs after ER. [ABSTRACT FROM AUTHOR]

Background: The efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors in the treatment of advanced colorectal cancer is controversial. This meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors for advanced colorectal cancer. Methods: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for relevant studies. Outcomes including median progression-free survival (mPFS), median overall survival (mOS), overall response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAEs) and ≥grade 3 TRAEs were extracted for further analysis. The risk of bias was assessed by subgroup analysis. Results: 12 articles with 566 patients were identified and subjected to meta-analysis. With regard to survival analysis, the pooled mOS and mPFS were 6.66 months (95%CI 4.85-9.16) and 2.92 months (95%CI 2.23-3.83), respectively. In terms of tumor response, the pooled ORR and DCR were 21% (95%CI 6%-41%) and 49% (95%CI 27%-71%), respectively. The pooled AEs rate and ≥ grade 3 AEs rate were 94% (95%CI 86%-99%) and 44% (95%CI 30%-58%). Conclusion: PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors have shown promising clinical responses in the treatment of colorectal cancer (CRC). Although the incidence of adverse reactions is high, they are generally tolerable. Systematic review registration: https://inplasy.com/ , identifier INPLASY202480030. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a malignant tumor that poses a significant threat to human health due to rising incidence and mortality rates. In recent years, immune checkpoint blockade (ICB) therapy, represented by Programmed death receptor 1 (PD-1), T-lymphocyte-associated protein 4 (CTLA-4), and others, has been widely applied in CRC and has achieved encouraging results in some patients and has become a hot topic in both clinical and basic research. Objective: This study undertakes a comprehensive bibliometric analysis of ICB research in CRC, aiming to evaluate the current status, identify future trends, and provide scientific insights for researchers and decision-makers. Methods: Utilizing the Web of Science Core Collection (WoSCC), articles focusing on ICB in CRC from 2000 to 2022 were retrieved. Knowledge mapping and bibliometric analysis were conducted using tools such as CiteSpace, VOSviewer, SCImago Graphicay, and the R package bibliometrix. Results: 6,718 publications were analyzed from 24,846 institutions across 639 regions. Temporally, ICB research in CRC is rapidly advancing, led by the USA and China with extensive global collaborations. Sun Yat-sen University from China stands out as the institution with the highest number of publications. Professor Thierry Andre from Sorbonne University in France is identified as a prolific author in this field, engaging in extensive collaboration for clinical trials on a global scale. Publications related to this research topic were published in 1,142 academic journals, demonstrating a positive co-citation relationship. Key clustering and burst terms analysis indicate that current research on ICB in CRC has shifted from basic experiments to clinical trials and from universal healthcare to precision medicine. Conclusion: ICB therapies have shown substantial progress in CRC, highlighting their therapeutic potential. Research trends emphasize deeper drug mechanisms, treatment efficacy prediction, managing immune-related adverse events, and exploring novel drug delivery methods. Collaboration across borders remains crucial for further advancements. [ABSTRACT FROM AUTHOR]

Background: This study aimed to predict metastasis risk and identify prognostic factors of gastrointestinal signet ring cell carcinoma (SRCC) using data from the SEER database, the largest cancer dataset in North America. Methods: Data were obtained from the SEER database, covering 17 cancer registries from 2004 to 2020. Demographic and clinical data included sex, age, race, tumor location, size, pathological grade, stage, overall survival time, and treatment modalities. Statistical analyses were conducted using SPSS and R software. Propensity Score Matching (PSM) ensured comparable baseline characteristics between gastric cancer (GC) and colorectal cancer (CRC) groups. LASSO regression analysis identified predictors of metastasis, leading to the construction of predictive models using the lrm function in R. Nomograms were visualized with the "rms" package and assessed via ROC curves, calibration curves, and decision curve analysis (DCA). Cox regression analyses identified prognostic indicators for overall survival (OS), and Kaplan–Meier curves compared OS between high-risk and low-risk groups. Results: From 2004 to 2020, 7680 SRCC patients were identified, including 4980 GC and 2700 CRC patients. CRC patients were older and had larger tumors, higher staging, and worse differentiation. Nomograms demonstrated good discriminative ability, with AUCs of 0.704 and 0.694 for GC, and 0.694 and 0.701 for CRC in training and validation cohorts, respectively. The DCA curve indicates that this predictive model has a high gain in predicting metastasis and OS. Conclusions: The nomograms effectively predicted metastasis risk and OS in metastatic SRCC patients, offering clinical utility in stratifying patients and guiding treatment decisions, thereby enhancing personalized treatment approaches. [ABSTRACT FROM AUTHOR]

This review delves into the pivotal role of circulating tumor cells (CTCs) in colorectal cancer (CRC) metastasis, focusing on their biological properties, interactions with the immune system, advanced detection techniques, and clinical implications. We explored how metastasis-competent CTCs evade immune surveillance and proliferate, utilizing cutting-edge detection and isolation technologies, such as microfluidic devices and immunological assays, to enhance sensitivity and specificity. The review highlights the significant impact of CTC interactions with immune cells on tumor progression and patient outcomes. It discusses the application of these findings in clinical settings, including non-invasive liquid biopsies for early diagnosis, prognosis, and treatment monitoring. Despite advancements, challenges remain, such as the need for standardized methods to consistently capture and analyze CTCs. Addressing these challenges through further molecular and cellular research on CTCs could lead to improved interventions and outcomes for CRC patients, underscoring the importance of unraveling the complex dynamics of CTCs in cancer progression. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety and efficacy of partial splenic embolization (PSE) in treating chemotherapy-induced thrombocytopenia (CIT) in patients with colorectal cancer who failed to respond to platelet growth factor therapy. Methods: 56 patients who underwent PSE were retrospectively analyzed. Based on the inclusion and the exclusion criteria, 29 patients were eligible for the study, of whom one underwent twice PSE procedures due to recurrent thrombocytopenia. The clinical characteristics were retrospectively analyzed with respect to efficacy, safety and outcome. Results: 60.0% of patients restarted antineoplastic therapy after PSE. There was a positive correlation between difference value of platelet count and embolization material size (Eta Squared = 0.252, p < 0.05). The correlation between the absolute volume of spleen embolized and postoperative complications was analyzed, with a statistically significant result (p < 0.001). The mean preoperative spleen volume, the preoperative platelet count, postoperative platelet count and difference value of platelet count in the non-cirrhotic group were larger than those in the cirrhotic group (p < 0.001). The mean overall survival was 47.7 ± 7.7 months. Conclusion: PSE is safe and effective in the treatment of CIT patients with colorectal cancer. The larger the embolized particle, the more platelets grew. The severity of complication was also positively correlated with the absolute volume of spleen embolized. Therefore, large particle embolization materials can be used to improve the efficacy of PSE and reduce complications. For CIT patients with cirrhosis, PSE was less effective in improving platelet count than those without cirrhosis. [ABSTRACT FROM AUTHOR]

Current knowledge of tumor biology offers many "targets" for therapeutic intervention. The molecular basis of many processes that play a role in the pathogenesis of colorectal cancer has been identified. One part of colorectal cancer clinical trials is focused on testing substances in a group of patients with tumors in which the TGF-β signalling pathway is hyperactivated. The TGF-β/SMAD signalling pathway members are considered important markers; however, genetic, proteomic, or metabolomic analyses still yield controversial results. According to our results, TGF-βRII, and SMAD4 can be used in monitoring CRC progression. With increasing CRC stage, TGF-βRII expression decreases and SMAD4 expression increases. The patients with TGF-βRII expression lower than 700 pg/ml had a slightly lower survival time (28.103 months) than patients with higher TGF-βRII expression (31.620 months). Conversely, patients with SMAD4 expression lower than 200 pg/ml had a higher survival rate (30.979 months) than patients with higher expression (26.316 months). Regarding TGF-β1 expression, the patient´s survival assessment determined no significant difference between patients with high or low tissue TGF-β1 expression. A personalized approach and consideration of a wide range of factors are important when using these markers in treatment assessment. [ABSTRACT FROM AUTHOR]

Liquid biopsy has an underexplored diagnostic potential in colorectal cancer (CRC). Sufficient quantity and quality of its elements (circulating cell-free DNA (ccfDNA), exosomes and exosomal RNA) are essential for accurate results. The present study aims to establish the optimal protocol for handling liquid biopsy samples. Samples were obtained by collecting peripheral blood from colorectal adenoma patients in CellSave tubes. Plasma was separated within six hours using differential centrifugation and aliquots stored at – 20/– 80 °C until further processing. Three methods for isolation of ccfDNA, and two combinations of kits for isolation of exosomes and exosomal RNA were tested. The quality and quantity of ccfDNA isolates were evaluated. Exosomes were characterised by determining size, concentration, and total and specific protein content. Expression of chosen microRNAs, miR-19a-3p and miR-92-3p, which have been implicated in CRC progression, were determined. The vacuum-column-based kit showed the highest quantities of isolated ccfDNA (P-value < 0.001). Kits for exosome isolation significantly differed in size (P-value = 0.016), concentration (P-value = 0.016) and protein content (P-value = 0.016). There was no significant difference in expressions of miR-19a-3p (P-value = 0.219) and miR-92a-3p (P-value = 0.094) between the two isolation kits. The new, adapted protocol described, enables simultaneous analysis of multiple elements when investigating potential biomarkers of CRC. [ABSTRACT FROM AUTHOR]

The incidence of Early-Onset Colorectal Cancer (EOCRC) is increasing. However, the prognosis of EOCRC compared to Late-Onset Colorectal Cancer (LOCRC), and the ideal age for initial colorectal cancer (CRC) screening are not clear. In this study, we identified the pathological differences between the groups and determined the optimal screening age for CRC patients. We included 10,172 patients diagnosed with CRC from January 2011 to December 2021 in this study. Survival differences were compared by plotting Kaplan–Meier survival curves and conducting landmark analysis. Additionally, the diagnostic age of CRC patients was analyzed using age cumulative curves. Compared to LOCRC patients, EOCRC patients had a higher proportion of deficient mismatch repair (dMMR) and more advanced TNM staging (P < 0.05). The five-year survival of EOCRC patients was significantly better than that of LOCRC patients (P < 0.05). Laparoscopic surgery improved the long-term survival of EOCRC patients. Proficient mismatch repair (pMMR) favored the long-term survival of EOCRC patients. The survival rate of EOCRC patients at TNM stages I and II was higher than that of LOCRC patients at the same stages (P < 0.05). The age cumulative curve showed a substantial increase in the number of CRC patients at 40 years. The long-term prognosis of EOCRC patients is better than that of LOCRC patients, especially among those with pMMR, stages I–II, and who undergo laparoscopic surgery. For people with a high risk of cancer, such as a family history of cancer and poor lifestyle habits, the starting age for CRC screening should be 40 years. [ABSTRACT FROM AUTHOR]

Aim: The faecal immunochemical test (FIT) is now widely used in English primary care to triage people who exhibit signs or symptoms of colorectal cancer (CRC). National guidelines for FIT implementation were based on data that acknowledged limitations. This study examines FIT accuracy in primary care patients with low‐ and high‐risk symptoms of CRC. Methods: This study describes a retrospective cohort study in South Yorkshire, UK (n = 2029). Consecutive symptomatic adult patients in primary care undergoing a FIT between 01/04/2021 and 30/04/2021 were assessed. A threshold > 10 μg Hb/g was defined as a positive FIT result. Lower gastrointestinal tract (LGI) investigations were the reference standard. Follow‐up over 24 months was used to identify serious colorectal diseases (CRC, high‐risk polyps and inflammatory bowel disease [IBD]). Results: Five hundred and fifteen (25.4%) patients had a positive FIT. The CRC prevalence was 1.2% (24/2029). Nineteen (79.1%) of the 24 CRC cases had NG12 symptoms, with two (8.3%) having a negative FIT. For CRC detection, FIT showed 91.7% sensitivity (95% CI: 71.5%–98.5%), 75.4% specificity (95% CI: 73.4%–77.2%), 4.3% positive predictive value (PPV) (95% CI: 2.8%–6.5%) and 99.9% negative predictive value (NPV) (95% CI: 99.5%–99.97%). Combining CRC, high‐risk polyps and IBD increased PPV and specificity but decreased sensitivity and NPV. Conclusions: In primary care, FIT safely triages patients having at‐risk CRC risk symptoms. Negative FIT results indicate a low likelihood of CRC and supports safety‐netting interventions. [ABSTRACT FROM AUTHOR]

Aim Method Results Conclusion While modern treatment has improved rectal cancer (RC) survival, it can cause late side effects that impact health‐related quality of life (HRQoL). The aim of this study was to evaluate HRQoL and late effects 1 year after diagnosis in patients who underwent major resection for Stage I–III RC.All patients with RC registered in the Cancer Registry of Norway between 1 January 2019 and 31 December 2020, aged ≥ 18 years, and a control group without colorectal cancer were invited to participate in the study by answering a questionnaire on HRQoL and late effects. Functional domains and symptoms were compared in different patient groups and between patients and controls.There were 558 patients and 1693 controls eligible for analysis. Response rates were 41% for patients and 23% for controls. Some differences in HRQoL were observed between treatment modalities. Major low anterior resection syndrome (LARS) was prevalent in 60.8% of patients, and was associated with lower functional and higher symptom scores compared with patients with no/minor LARS. Patients with major chronic pain [n = 86 (15.4%)] had significantly lower scores for most of the functional items and higher symptom scores than patients with no/minor chronic pain. Patients had some lower functional scores and several higher symptoms score compared with controls.Patients who suffered from major LARS or major chronic pain had significantly impaired functions and more symptoms beyond change in bowel function and pain, respectively. Identification and treatment of these patient may hopefully be beneficial for their HRQoL. [ABSTRACT FROM AUTHOR]

Mitophagy, the process by which cells eliminate damaged mitochondria, is mediated by PINK1 (PTEN induced kinase 1). Our recent research indicates that PINK1 functions as a tumor suppressor in colorectal cancer by regulating cellular metabolism. Interestingly, PINK1 ablation activated the NLRP3 (NLR family pyrin domain containing 3) inflammasome, releasing IL1B (interleukin 1 beta). However, inhibiting the NLRP3-IL1B signaling pathway with an IL1R (interleukin 1 receptor) antagonist or NLRP3 inhibitor did not hinder colon tumor growth after PINK1 loss. To identify druggable targets in PINK1-deficient tumors, ribonucleic acid sequencing analysis was performed on colon tumors from pink1 knockout and wild-type mice. Gene Set Enrichment Analysis highlighted the enrichment of iron ion transmembrane transporter activity. Subsequent qualitative polymerase chain reaction and western blot analysis revealed an increase in mitochondrial iron transporters, including mitochondrial calcium uniporter, in PINK1-deficient colon tumor cells and tissues. Live-cell iron staining demonstrated elevated cellular and mitochondrial iron levels in PINK1-deficient cells. Clinically used drugs deferiprone and minocycline reduced mitochondrial iron and superoxide levels, resulting in decreased colon tumor cell growth in vitro and in vivo. Manipulating the mitochondrial iron uptake protein MCU (mitochondrial calcium uniporter) also affected cell and xenograft tumor growth. This study suggests that therapies aimed at reducing mitochondrial iron levels may effectively inhibit colon tumor growth, particularly in patients with low PINK1 expression.Abbreviation: ANOVA: analysis of variance; APC: adenomatous polyposis coli; cAMP: cyclic adenosine monophosphate; CDX2: caudal type homeobox 2; CGAS: cyclic GMP-AMP synthase; CRC: colorectal cancer; DNA: deoxyribonucleic acid; DFP: deferiprone; DMEM: Dulbecco’s modified Eagle medium; DSS: dextran sodium sulfate; ERT2-Cre: Cre recombinase fused to a triple mutant form of the human estrogen receptor; EV: empty vector; GLB: glybenclamide/glyburide; H&E: hematoxylin and eosin; ICP-MS: inductively coupled plasma mass spectrometer; IL1B: interleukin 1 beta; kDa: kilodalton; MCU: mitochondrial calcium uniporter; MKI67: marker of proliferation Ki-67; mRNA: messenger ribonucleic acid; MTT: 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide; NLRP3: NLR family pyrin domain containing 3; OE: overexpression; PBS: phosphate-buffered saline; p-CREB: phosphorylated cAMP responsive element binding protein; PINK1: PTEN induced kinase 1; p-PRKAA/AMPK: phosphorylated protein kinase AMP-activated catalytic subunit alpha; qPCR: qualitative polymerase chain reaction; RNA-seq: ribonucleic acid sequencing; ROS: reactive oxygen species; sg: single guide; sh: short hairpin; SLC25A28: solute carrier family 25 member 28; SLC25A37/MFRN: solute carrier family 25 member 37; STING1: stimulator of interferon response cGAMP interactor 1; TP53/p53: tumor protein p53; TUBA: tubulin alpha; µL: microliter; µm: micrometer; µM: micromolar; mm: millimeter. [ABSTRACT FROM AUTHOR]