Stage at diagnosis of colorectal cancer through diagnostic route: Who should be screened?

BACKGROUND: Colorectal cancer (CRC) is a global health concern, with advanced-stage diagnoses contributing to poor prognoses. The efficacy of CRC screening has been well-established; nevertheless, a significant proportion of patients remain unscreened, with > 70% of cases diagnosed outside screening. Although identifying specific subgroups for whom CRC screening should be particularly recommended is crucial owing to limited resources, the association between the diagnostic routes and identification of these subgroups has been less appreciated. In the Japanese cancer registry, the diagnostic routes for groups discovered outside of screening are primarily categorized into those with comorbidities found during hospital visits and those with CRC-related symptoms. AIM: To clarify the stage at CRC diagnosis based on diagnostic routes. METHODS: We conducted a retrospective observational study using a cancer registry of patients with CRC between January 2016 and December 2019 at two hospitals. The diagnostic routes were primarily classified into three groups: Cancer screening, follow-up, and symptomatic. The early-stage was defined as Stages 0 or I. Multivariate and univariate logistic regressions were exploited to determine the odds of early-stage diagnosis in the symptomatic and cancer screening groups, referencing the follow-up group. The adjusted covariates were age, sex, and tumor location. RESULTS: Of the 2083 patients, 715 (34.4%), 1064 (51.1%), and 304 (14.6%) belonged to the follow-up, symptomatic, and cancer screening groups, respectively. Among the 2083 patients, CRCs diagnosed at an early stage were 57.3% (410 of 715), 23.9% (254 of 1064), and 59.5% (181 of 304) in the follow-up, symptomatic, and cancer screening groups, respectively. The symptomatic group exhibited a lower likelihood of early-stage diagnosis than the follow-up group [P < 0.001, adjusted odds ratio (aOR), 0.23; 95% confidence interval (95%CI): 0.19-0.29]. The likelihood of diagnosis at an early stage was similar between the follow-up and cancer screening groups (P = 0.493, aOR for early-stage diagnosis in the cancer screening group vs follow-up group = 1.11; 95%CI = 0.82-1.49). CONCLUSION: CRCs detected during hospital visits for comorbidities were diagnosed earlier, similar to cancer screening. CRC screening should be recommended, particularly for patients without periodical hospital visits for comorbidities.

Association between Endoscopist Volume and Interval Cancers after Colonoscopy: Results from the National Colorectal Cancer Screening Program in Korea.

Purpose: The rate of interval colorectal cancer (iCRC) is now accepted as a key performance indicator of organized colorectal cancer (CRC) screening programs. We aimed to examine the association between endoscopist volumes and the rate of iCRC among individuals with a positive fecal immunochemical test (FIT) within a nationwide population-based CRC screening program. Materials and Methods: Individuals aged ≥50 years who underwent colonoscopy after a positive FIT from January 1, 2019 until December 31, 2020 in the Korean National Cancer Screening Program (KNCSP) were enrolled. We converted the data into per-endoscopist screening results, calculated the iCRC rates per endoscopist, and compared them to the previous year's annual volume that was divided into five groups (V1, 1-9; V2, 10-29; V3, 30-59; V4, 60-119; V5, ≥120). Results: A total of 10,412 endoscopists performed 216,907 colonoscopies. Overall, the average rate of iCRC per endoscopist was 8.46 per 1,000 examinations. Compared with the group with the highest volume (V5 group), the rate of iCRC was 2.21 times higher in the V1 group. Similar trends were observed in the other groups (V2: Relative risks [RR], 2.15; 95% Confidence Interval [CI], 1.57-2.94; V3: RR, 1.56, 95% CI, 1.15-2.13; V4: RR, 1.18; 95% CI, 0.83-1.67). Conclusion: The findings emphasize that endoscopists with lower procedure volumes have higher risks of interval cancer being missed or undetected. To maximize the preventative impact of colonoscopy for colorectal cancer, this issue should be addressed by monitoring endoscopist volumes and variations in performances.

Implementation of home 'finger-prick' carcino-embryonic antigen testing for colorectal cancer follow-up - A pilot study of user acceptability.

Aim: Routine carcino-embryonic antigen blood testing is required after colorectal cancer resection, requiring face-to-face appointments. This has workforce implications, and impacts patients' lives. We assessed feasibility and acceptability of self-taken blood tests. Methods: 50 colorectal cancer patients with experience of face-to-face phlebotomy surveillance agreed to self-testing finger-prick kits. Follow-up questionnaires assessed perspectives and preferences. Results: 68% (50/74) of patients agreed to participate. 76% (38/50) successfully completed samples. 62% (29/47) felt it was no worse than their previous experience. Regarding future testing, 47% (22/47) preferred finger-prick testing. 19% (9/47) expressed no preference. This was unaffected by patient age. Qualitative assessment showed difficulties with pain, discomfort, and sample collection, but was more convenient and saved time for patients. Conclusions: Many preferred finger-prick assessment, but some found it challenging, unnecessary or less preferable. This may reduce burden of follow-up blood tests but currently would only be acceptable to a limited patient cohort.

The role of fungi in the diagnosis of colorectal cancer.

Colorectal cancer (CRC) is a prevalent tumour with high morbidity rates worldwide, and its incidence among younger populations is rising. Early diagnosis of CRC can help control the associated mortality. Fungi are common microorganisms in nature. Recent studies have shown that fungi may have a similar association with tumours as bacteria do. As an increasing number of tumour-associated fungi are discovered, this provides new ideas for the diagnosis and prognosis of tumours. The relationship between fungi and colorectal tumours has also been recently identified by scientists. Therefore, this paper describes the limitations and prospects of the application of fungi in diagnosing CRC and predicting CRC prognosis.

Association of cancer diagnosis with disability status among older survivors of colorectal cancer: a population-based retrospective cohort study.

Background: Older cancer survivors likely experience physical function limitations due to cancer and its treatments, leading to disability and early mortality. Existing studies have focused on factors associated with surgical complications and mortality risk rather than factors associated with the development of poor disability status (DS), a proxy measure of poor performance status, in cancer survivors. We aimed to identify factors associated with the development of poor DS among older survivors of colorectal cancer (CRC) and compare poor DS rates to an age-sex-matched, non-cancer cohort. Methods: This retrospective cohort study utilized administrative data from the Texas Cancer Registry Medicare-linked database. The study cohort consisted of 13,229 survivors of CRC diagnosed between 2005 and 2013 and an age-sex-matched, non-cancer cohort of 13,225 beneficiaries. The primary outcome was poor DS, determined by Davidoff's method, using predictors from 12 months of Medicare claims after cancer diagnosis. Multivariable Cox proportional hazards regression was used to identify risk factors associated with the development of poor DS. Results: Among the survivors of CRC, 97% were 65 years or older. After a 9-year follow-up, 54% of survivors of CRC developed poor DS. Significant factors associated with future poor DS included: age at diagnosis (hazard ratio [HR] = 3.50 for >80 years old), female sex (HR = 1.50), race/ethnicity (HR = 1.34 for Hispanic and 1.21 for Black), stage at diagnosis (HR = 2.26 for distant metastasis), comorbidity index (HR = 2.18 for >1), and radiation therapy (HR = 1.21). Having cancer (HR = 1.07) was significantly associated with developing poor DS in the pooled cohorts; age and race/ethnicity were also significant factors. Conclusions: Our findings suggest that a CRC diagnosis is independently associated with a small increase in the risk of developing poor DS after accounting for other known factors. The study identified risk factors for developing poor DS in CRC survivors, including Hispanic and Black race/ethnicity, age, sex, histologic stage, and comorbidities. These findings underscore the importance of consistent physical function assessments, particularly among subsets of older survivors of CRC who are at higher risk of disability, to prevent developing poor DS.

Epidemiological insights into colorectal cancer in northwestern Algeria.

Objectives: The incidence of colorectal cancer (CRC) has exhibited regional variability in North Africa and the Middle East, with a steady increase in Algeria. Despite this trend, limited data exist on the epidemiology of CRC in northwestern Algeria. Our study aimed to investigate the epidemiological characteristics of CRC in this region. Methods: We conducted a retrospective study examining 255 confirmed CRC cases through medical records from patients at the Sidi Bel Abbes anti-cancer centre. Results: The mean age of the study participants was 59 ± 13 years. The results showed a higher incidence in males (57%) than in females, and colon (62%) than rectal cancer. Within this cohort, 47% had a pre-existing medical condition, while 39% had a family history of cancer. Adenocarcinomas were the prevailing histological subtype in 94% of CRC cases. Compared with colon cancer, rectal cancer was less often diagnosed at stage IV of the disease (OR = 0.75; 95% CI = 0.09, 4.86; p = 0.8) and more likely in early-onset patients (OR = 2.27; 95% CI = 1.25, 4.17; p = 0.007). Men were at a higher risk of being diagnosed with metastatic CRC primarily hepatic metastases (OR = 2.03; 95% CI = 1.07, 3.99; p = 0.033) and pulmonary metastases (OR = 2.50; 95% CI = 1.07, 6.59; p = 0.045). Conclusion: This study may provide a comprehensive glimpse into CRC epidemiology in northwest Algeria. Understanding regional differences is the key to implementing specific preventive and interventional strategies.

The Impact of potential 'confounders' on the diagnostic sensitivity of circulating free DNA in management of FIT+ patients: a pilot study.

Cell-free DNA (cfDNA) has long been established as a useful diagnostic and prognostic tool in a variety of clinical settings, ranging from infectious to cardiovascular and neoplastic diseases. However, non-neoplastic diseases can act as confounders impacting on the amount of cfDNA shed in bloodstream and on technical feasibility of tumour derived free circulating nucleic acids selecting patients with cancer. Here, we investigated the potential impact of other pathological processes in the clinical stratification of 637 FIT+ patients. A single and multiple logistic regression yielded similar results. Crude sensitivity was 75.9% versus adjusted sensitivity of 74.1%, relative risk 0.9761 (0.8516 to 1.1188), risk difference 0.0181 (-0.0835 to 0.1199) and OR 0.9079 (0.5264 to 1.5658). Potential confounding effect from other source of cfDNA plays a pivotal role in the clinical stratification of FIT+ patients.

Accuracy of surgeons for predicting radiological sarcopenia in colorectal cancer surgery.

BACKGROUND: This study explored the performance of surgeons for predicting radiological sarcopenia as accessed by psoas cross-sectional area in patients with colorectal cancer (CRC). METHODS: A cross-sectional study was carried out and a diagnostic accuracy strategy was applied using the radiologist team assessment as gold standard. RESULTS: Cohort analysis of 45 consecutive patients found that 31.1% had sarcopenia. Correlation of Total Psoas Index between radiologists and surgeons was very strong for the Junior and strong for the Senior surgeon, with a strong correlation between the surgeons. By the simplistic criterion, agreement between radiologists and surgeons was substantial for both the Junior and Senior surgeons, with a moderate level between the surgeons. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of Junior surgeon were 92.9%, 83.9%, 72.2%, 96.3%, and 86.7%, respectively. The corresponding results for the Senior surgeon were 78.6%, 90.3%, 78.6%, 90.3%, and 86.7%, respectively. We found no major differences on agreement levels and performance of surgeons using the composite criterion. CONCLUSIONS: Surgeons seem to be accurate for identifying radiological sarcopenia in patients with CRC. The simplistic criterion should be preferred since a composite criterion adds complexity without increasing accuracy or agreement levels.

Investigating the Effects of HMGB1 Overexpression on Colorectal Cancer Cell Migration via Oncolytic Herpes simplex Virus Type 1 (oHSV-1).

Background: Colorectal Cancer (CRC) represents a significant global health challenge, and its progression, resistance to therapy, and metastasis are strongly influenced by the tumor microenvironment, including factors like hypoxia. This study explores the impact of High Mobility Group Box 1 (HMGB1) overexpression on CRC cell migration, while identifying potential genes associated with this process. Methods: To explore this, we developed oncolytic virotherapy, resulting in HSVHMGB1, an oncolytic Herpes simplex virus that expresses HMGB1. HMGB1 is known its role in cancer progression, particularly in the context of cancer cell migration. Results: Contrary to expectations, our scratch assays indicated that HSV-HMGB1 did not significantly induce migration in CRC cells, suggesting that HMGB1 might not directly contribute to this process. Employing microarray analysis, we investigated gene expression changes linked to CRC cell migration, leading to construction of a Protein-Protein Interaction (PPI) network. This network revealed the presence of hub proteins, including as NDRG1, LGALS1, and ANGPTL4, which are recognized for their roles in cancer cell migration. The differential expression of these genes under hypoxic conditions was further validated using quantitative RT-PCR, aligning with the findings from our microarray data. Conclusion: Our findings emphasize the complex regulation of CRC cell migration, and provides valuable insights into potential molecular mechanisms and pathways. These findings have implications for further research into cancer progression and the development of therapeutic strategies.

Linked color imaging improves colorectal lesion detection especially for low performance endoscopists: An international trial in Asia.

BACKGROUND AND AIM: Linked color imaging (LCI) is an image-enhanced endoscopy technique that accentuates the color difference between red and white, potentially improving the adenoma detection rate (ADR). However, it remains unclear whether LCI performance in detecting colorectal lesions differs based on endoscopists' experience levels. We aimed to evaluate the differences in LCI efficacy based on the experience levels of endoscopists by conducting an exploratory analysis. METHODS: In this post hoc analysis of an international randomized controlled trial comparing the detection of adenoma and other lesions using colonoscopy with LCI and high-definition white light imaging (WLI), we included patients from 11 institutions across four countries/regions: Japan, Thailand, Taiwan, and Singapore. We retrospectively reviewed differences in the lesion detection of LCI according to endoscopists' colonoscopy history or ADR. RESULTS: We included 1692 and 1138 patients who underwent colonoscopies performed by 54 experts (experience of ≥ 5000 colonoscopies) and by 43 non-experts (experience of < 5000 colonoscopies), respectively. Both expert and non-expert groups showed a significant improvement in ADR with LCI compared to WLI (expert, 61.7% vs 46.4%; P < 0.001; non-expert, 56.6% vs 46.4%; P < 0.001). LCI had no effect on sessile serrated lesion detection rate in non-experts (3.1% vs 2.5%; P = 0.518). LCI significantly improved detection rates in endoscopists with relatively low detection performance, defined as an ADR < 50%. CONCLUSIONS: This exploratory study analyzed data from a previous trial and revealed that LCI is useful for both experts and non-experts and is even more beneficial for endoscopists with relatively low detection performance using WLI.

Perceived Economic Strain, Subjective Social Status, and Colorectal Cancer Screening Utilization in U.S. Men-A Cross-Sectional Analysis.

Although socioeconomic status (SES) is fundamentally related to underutilization of colorectal cancer (CRC) screening, the role of perceived economic strain and subjective social status with CRC screening is understudied. The aim of this study was to investigate whether greater perceived economic strain or lower subjective social status would decrease the odds of CRC screening uptake and being up-to-date with guideline-recommended CRC screening. We also explored interactions with household income and educational attainment. Cross-sectional survey-based data from men aged 45-75 years living in the United States (N = 499) were collected in February 2022. Study outcomes were ever completing a stool- or exam-based CRC screening test and being up-to-date with CRC screening. Perceived economic strain and subjective social status were the predictors. We conducted logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI). Greater perceptions of economic strain decreased odds of being up-to-date with CRC screening. Household income modified the association between perceived economic strain and completing a stool-based test; the association was stronger for men from lower-income households. In unadjusted models, higher subjective social status increased odds of completing an exam-based test and being up-to-date with CRC screening. Our findings suggest that experiencing economic strain may interfere with men's CRC screening decisions and may capture additional information about barriers to CRC screening utilization beyond those captured by income or education.

Emerging and under-recognised patterns of colorectal carcinoma morphologies: a comprehensive review.

While the overwhelming majority of colorectal carcinomas (CRC) are diagnosed as adenocarcinoma not otherwise specified, there are numerous under-recognised morphologic patterns of CRC. These patterns are recognised by the WHO, appear in reporting manuals for the American Joint Committee of Cancer, and/or are listed on synoptic reports, while many other variants have either fallen out of favour or are emerging as future bona fide patterns. Herein, we discuss 13 variants: serrated adenocarcinoma, micropapillary adenocarcinoma, medullary carcinoma, neuroendocrine carcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, adenosquamous carcinoma, adenoma-like adenocarcinoma, lymphoglandular complex-like CRC, carcinoma with sarcomatoid components, cribriform-comedo-type adenocarcinoma, undifferentiated carcinoma and low-grade tubuloglandular adenocarcinoma. The purpose of this review is to scrutinise these variants by assessing their clinical characteristics, morphologic cues, as well as pitfalls, and address their prognostic significance. Our analysis aims to bring clarity and updated understanding to these variants, offering valuable insights for pathologists. This contributes to more nuanced CRC diagnosis and treatment strategies, highlighting the importance of recognising a broad spectrum of morphologic patterns in CRC.

Incidence of incisional hernia following liver surgery for colorectal liver metastases. Does the laparoscopic approach reduce the risk? A comparative study.

Backgrounds/Aims: No reports to compare incisional hernia (IH) incidence between laparoscopic and open colorectal liver metastases (CRLM) resections have previously been made. This is the first comparative study. Methods: Single-center retrospective review of patients who underwent CRLM surgery between January 2011 and December 2018. IH relating to liver surgery was confirmed by computed tomography. Patients were divided into laparoscopic liver resection (LLR) and open liver resection (OLR) groups. Data collection included age, sex, presence of diabetes mellitus, steroid intake, history of previous hernia or liver resection, subcutaneous and peri-renal fat thickness, preoperative creatinine and albumin, American Society of Anesthesiologists (ASA) score, major liver resection, surgical site infection, synchronous presentation, and preoperative chemotherapy. Results: Two hundred and forty-seven patients were included with a mean follow-up period of 41 ± 29 months (mean ± standard deviation). Eighty seven (35%) patients had LLR and 160 patients had OLR. No significant difference in the incidence of IH between LLR and OLR was found at 1 and 3 years, respectively ([10%, 19%] vs. [10%, 19%], p = 0.95). On multivariate analysis, previous hernia history (hazard ratio [HR], 2.22; 95% confidence interval [CI], 1.56-4.86) and subcutaneous fat thickness (HR, 2.22; 95% CI, 1.19-4.13) were independent risk factors. Length of hospital stay was shorter in LLR (6 ± 4 days vs. 10 ± 8 days, p < 0.001), in comparison to OLR. Conclusions: In CRLM, no difference in the incidence of IH between LLR and OLR was found. Previous hernia and subcutaneous fat thickness were risk factors. Further studies are needed to assess modifiable risk factors to develop IH in LLR.

Anti-EGFR antibody monotherapy for colorectal cancer with severe hyperbilirubinemia: A case report.

BACKGROUND: Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer (CRC). Effective drainage is often impossible before initiating systemic chemotherapy, owing to the liver's diffuse metastatic involvement. Moreover, an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently unavailable. CASE SUMMARY: The patient, a man in his 50s, presented with progressive fatigue and severe jaundice. Computed tomography revealed multiple hepatic masses with thickened walls in the sigmoid colon, which was pathologically confirmed as a well-differentiated adenocarcinoma. No RAS or BRAF mutations were detected. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was 2. Biliary drainage was impossible due to the absence of a dilated bile duct, and panitumumab monotherapy was promptly initiated. Subsequently, the bilirubin level decreased and then normalized, and the patient's PS improved to zero ECOG score after four cycles of therapy without significant adverse events. CONCLUSION: Anti-EGFR antibody monotherapy is a safe and effective treatment for RAS wild-type CRC and hepatic metastases with severe hyperbilirubinemia.

Effect of Preoperative Lifestyle Management and Prehabilitation on Postoperative Capability of Colorectal Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: The surgical intervention serves as the paramount and prevalent remedy for individuals afflicted with colorectal malignancies, with the significance of perioperative stewardship and convalescence being indisputable. Prehabilitation coupled with preoperative lifestyle modulation has demonstrated efficacy in patients subjected to certain classifications of abdominal procedures. However, the evidence pertaining to its impact on those battling colorectal cancer remains equivocal. METHODS: A meta-analysis, grounded in pairwise contrast, of randomized controlled trials (RCTs) was orchestrated, coupled with a systematic review, to probe the efficacy of preoperative lifestyle modulation and prehabilitation on patients' postoperative functionality and recuperation. An exhaustive exploration of 8 electronic databases and trial registries was undertaken to encompass all pertinent RCTs disseminated in English or Chinese from January 2012 through December 2022. Employing a random-effects model, we evaluated parameters such as the 6-minute walk test (6 MWT), complications, quality of life (QoL), aggregate and postoperative duration of hospitalization (tLHS and postLHS), and healthcare expenditure (HExp) for postoperative patients. RESULTS: A total of 28 RCTs were incorporated into the systematic review and meta-analysis. Relative to conventional preoperative care, rehabilitation or preoperative lifestyle management was found to enhance postoperative 6MWT (SMD 1.30, 95% CI 0.30 to 2.29) and diminish the complication rate (OR 0.53, 95% CI 0.40 to 0.69). Nonetheless, no significant discrepancies were observed in QoL (SMD 1.81, 95% CI -0.26 to 3.87), tLHS (SMD -0.26, 95% CI -0.68 to 0.15), and postLHS (SMD -1.46, 95% CI -3.12 to 0.20) between the groups. HExp could not be evaluated due to a lack of sufficient data for synthesis. Most pooled outcomes exhibited significant heterogeneity, urging a cautious interpretation. Subgroup analysis revealed that nutritional interventions could mitigate the incidence of complications, and preoperative exercise could improve tLHS and postLHS. A combined approach of physical, nutritional, and psychological intervention or prehabilitation proved superior to any single intervention in enhancing postoperative capabilities. CONCLUSION: This meta-analysis delineated the efficacy of preoperative interventions on postoperative capabilities in patients with colorectal cancer, thereby offering evidence for clinical practice. It was concluded that preoperative interventions are unequivocally beneficial for postoperative functional recovery and the reduction of complication rates in patients with colorectal cancer. Nonetheless, the acquisition of more high-level evidence is still necessitated to further ascertain the effectiveness of this strategy for other patient groups and to establish its best practices. The heterogeneity in the pooled outcomes underlines the need for future studies to be more uniform in their design and reporting, which would facilitate more robust and reliable meta-analyses.

Temporal trends in colorectal cancer mortality rates (1999-2022) in the United States.

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths in the United States (U.S.). Our study aims to analyze CRC mortality patterns in the U.S., focusing on gender and age groups from 1999 to 2022. We analyzed Age-Adjusted Mortality Rates (AAMRs) for CRC-related deaths using the CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database and assessed differences between age and sex. CRC-related mortality decreased significantly from 1999 to 2011 (-2.81% APC) and from 2011 to 2020 (-1.95% APC) but a not significant uptrend from 2020 to 2022 (2% APC). Males experienced a more significant decrease. Among age groups, crude mortality decreased until 2020, except in age group 45-54, which showed an annual increase in mortality of 0.9% from 2004 to 2022. Furthermore, individuals aged 75-84 and 85+ saw a nonsignificant annual increase of 1.8% and 4.5% from 2020 to 2022, respectively. Our study highlights a significant decline in age and gender-specific CRC-related mortality from 1999 to 2020. However, the worrisome uptrend observed in the younger age group of 45-54 emphasizes the importance of implementing targeted public health measures and evidence-based interventions.

Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

Melittin as an Activator of the Autophagy and Unfolded Protein Response Pathways in Colorectal HCT116 Cell Line.

Background: The potential anticancer effect of melittin has motivated scientists to find its exact molecular mechanism of action. There are few data on the effect of melittin on the UPR and autophagy as two critical pathways involved in tumorigenesis of colorectal and drug resistance. This study aimed to investigate the effect of melittin on these pathways in the colorectal cancer (CRC) HCT116 cells. Methods: MTT method was carried out to assess the cytotoxicity of melittin on the HCT116 cell line for 24, 48, and 72 h. After selecting the optimal concentrations and treatment times, the gene expression of autophagy flux markers (LC3-ßII and P62) and UPR markers (CHOP and XBP-1s) were determined using qRT-PCR. The protein level of autophagy initiation marker (Beclin1) was also determined by Western blotting. Results: MTT assay showed a cytotoxic effect of melittin on the HCT116 cells. The increase in LC3-ßII and decrease in P62 mRNA expression levels, along with the elevation in the Beclin1 protein level, indicated the stimulatory role of melittin on the autophagy. Melittin also significantly enhanced the CHOP and XBP-1s expressions at mRNA level, suggesting the positive role of the melittin on the UPR activation. Conclusion: This study shows that UPR and autophagy can potentially be considered as two key signaling pathways in tumorigenesis, which can be targeted by the BV melittin in the HCT116 cells. Further in vivo evaluations are recommended to verify the obtained results.

Association of the rs1966265 and rs351855 FGFR4 Variants with Colorectal Cancer in a Mexican Population and Their Analysis In Silico.

The aim of this study was to associate FGFR4 rs1966265 and rs351855 variants with colorectal cancer (CRC) in a Mexican population and to perform in silico analysis. Genomic DNA from 412 healthy individuals and 475 CRC patients was analyzed. In silico analysis was performed using the PolyPhen-V2, GEPIA, GTEx, and Cytoscape platforms. The GA genotype dominant model (GAAA) of rs1966265 and the AA genotype dominant and recessive models of rs351855 were identified as CRC risk factors (p < 0.05). CRC patients aged ≥ 50 years at diagnosis who consumed alcohol had a higher incidence of the rs351855 GA genotype than the control group (p < 0.05). Associations were observed between the rs1966265 GA genotype and patients with rectal cancer and stage III-IV disease. The rs351855 AA genotype was a risk factor for partial chemotherapy response, and the GA + AA genotype for age ≥ 50 years at diagnosis and rectal cancer was associated with a partial response to chemotherapy (p < 0.05). The AA haplotype was associated with increased susceptibility to CRC. In silico analysis indicated that the rs351855 variant is likely pathogenic (score = 0.998). Genotypic expression analysis in blood samples showed statistically significant differences (p < 0.05). EFNA4, SLC3A2, and HNF1A share signaling pathways with FGFR4. Therefore, rs1966265 and rs351855 may be potential CRC risk factors.

Association between Surrogate Markers of Insulin Resistance and the Incidence of Colorectal Cancer in Korea: A Nationwide Population-Based Study.

Background: Insulin resistance (IR) is assessed using surrogate markers such as the triglyceride-glucose (TyG) index, the triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio, and the metabolic score for IR (METS-IR). Limited studies investigated their association with colorectal cancer (CRC) incidence, and no research has been conducted on their association with the METS-IR. Method: This study used claims data from the Korean National Health Insurance Service, analyzing a cohort of 314,141 Koreans aged over 40 who participated in the National Health Screening Program from 2009 to 2010. The follow-up period was extended until 31 December 2019. Participants were divided into four groups based on quartiles (Q1-Q4) of the markers. Results: All surrogate markers of IR had sequentially statistically lower disease-free probabilities from Q1 to Q4. The Cox proportional hazard model demonstrated statistically significant positive associations between CRC incidence and Q3 and Q4 of the TyG index, as well as Q3 and Q4 of the TG/HDL-C ratio and Q4 of the METS-IR. The constrained cubic spline method revealed a nonlinear, positive dose-response relationship between the TyG index and the METS-IR in relation to CRC incidence. Conclusions: In conclusion, the TyG index, TG/HDL-C ratio, and METS-IR were positively correlated with CRC incidence in Koreans.