Circulating small extracellular vesicle RNA profiling for the detection of T1a stage colorectal cancer and precancerous advanced adenoma.

It takes more than 20 years for normal colorectal mucosa to develop into metastatic carcinoma. The long time window provides a golden opportunity for early detection to terminate the malignant progression. Here, we aim to enable liquid biopsy of T1a stage colorectal cancer (CRC) and precancerous advanced adenoma (AA) by profiling circulating small extracellular vesicle (sEV)-derived RNAs. We exhibited a full RNA landscape for the circulating sEVs isolated from 60 participants. A total of 58,333 annotated RNAs were detected from plasma sEVs, among which 1,615 and 888 sEV-RNAs were found differentially expressed in plasma from T1a stage CRC and AA compared to normal controls (NC). Then we further categorized these sEV-RNAs into six modules by a weighted gene coexpression network analysis and constructed a 60-gene t-SNE model consisting of the top 10 RNAs of each module that could well distinguish T1a stage CRC/AA from NC samples. Some sEV-RNAs were also identified as indicators of specific endoscopic and morphological features of different colorectal lesions. The top-ranked biomarkers were further verified by RT-qPCR, proving that these candidate sEV-RNAs successfully identified T1a stage CRC/AA from NC in another cohort of 124 participants. Finally, we adopted different algorithms to improve the performance of RT-qPCR-based models and successfully constructed an optimized classifier with 79.3% specificity and 99.0% sensitivity. In conclusion, circulating sEVs of T1a stage CRC and AA patients have distinct RNA profiles, which successfully enable the detection of both T1a stage CRC and AA via liquid biopsy.

Comprehensive serum proteomics profiles and potential protein biomarkers for the early detection of advanced adenoma and colorectal cancer.

BACKGROUND: The majority of colorectal cancer (CRC) cases develop from precursor advanced adenoma (AA). With the development of proteomics technologies, blood protein biomarkers have potential applications in the early screening of AA and CRC in the general population. AIM: To identify serum protein biomarkers for the early screening of AA and CRC. METHODS: We collected 43 serum samples from 8 normal controls (NCs), 19 AA patients and 16 CRC patients at China-Japan Friendship Hospital. Quantitative proteomic analysis was performed using liquid chromatography-mass spectrometry/mass spectrometry and data independent acquisition, and differentially expressed proteins (DEPs) with P-values < 0.05 and absolute fold changes > 1.5 were screened out, followed by bioinformatics analysis. Prognosis was further analyzed based on public databases, and proteins expression in tissues were validated by immunohistochemistry. RESULTS: A total of 2132 proteins and 17365 peptides were identified in the serum samples. There were 459 upregulated proteins and 118 downregulated proteins in the NC vs AA group, 289 and 180 in the NC vs CRC group, and 52 and 248 in the AA vs CRC group, respectively. Bioinformatic analysis revealed that these DEPs had different functions and participated in extensive signaling pathways. We also identified DIAPH1, VASP, RAB11B, LBP, SAR1A, TUBGCP5, and DOK3 as important proteins for the progression of AA and CRC. Furthermore, VASP (P < 0.01), LBP (P = 0.01), TUBGCP5 (P < 0.01), and DOK3 (P < 0.01) were associated with a poor prognosis. In addition, we propose that LBP and VASP may be more promising protein biomarkers for the early screening of colorectal tumors. CONCLUSION: Our study elucidated the serum proteomic profiles of AA and CRC patients, and the identified proteins, such as LBP and VASP, may contribute to the early detection of AA and CRC.

Faecal immunochemical tests can improve colonoscopy triage in patients with iron deficiency: A systematic review and meta-analysis.

BACKGROUND: Use of the faecal immunochemical test (FIT) to triage patients with iron deficiency (ID) for colonoscopy due to suspected colorectal cancer (CRC) may improve distribution of colonoscopic resources. We reviewed the diagnostic performance of FIT for detecting advanced colorectal neoplasia, including CRC and advanced pre-cancerous neoplasia (APCN), in patients with ID, with or without anaemia. METHODS: We performed a systematic review of three databases for studies comprising of patients with ID, with or without anaemia, completing a quantitative FIT within six months prior to colonoscopy, where test performance was compared against the reference standard colonoscopy. Random effects meta-analyses determined the diagnostic performance of FIT for advanced colorectal neoplasia. RESULTS: Nine studies were included on a total of n=1761 patients with ID, reporting FIT positivity thresholds between 4-150 µg haemoglobin/g faeces. Only one study included a non-anaemic ID (NAID) cohort. FIT detected CRC and APCN in ID patients with 90.7 % and 49.3 % sensitivity, and 81.0 % and 82.4 % specificity, respectively. FIT was 88.0 % sensitive and 83.4 % specific for CRC in patients with ID anaemia at a FIT positivity threshold of 10 µg haemoglobin/g faeces. CONCLUSIONS: FIT shows high sensitivity for advanced colorectal neoplasia and may be used to triage those with ID anaemia where colonoscopic resources are limited, enabling those at higher risk of CRC to be prioritised for colonoscopy. There is a need for further research investigating the diagnostic performance of FIT in NAID patients.

Colorectal cancer and advanced adenoma characteristics according to causative mismatch repair gene variant in Japanese colorectal surveillance for Lynch syndrome.

BACKGROUND: The optimal interval of colonoscopy (CS) surveillance in cases with Lynch syndrome (LS), and stratification according to the causative mismatch repair gene mutation, has received much attention. To verify a feasible and effective CS surveillance strategy, we investigated the colorectal cancer (CRC) incidence at different intervals and the characteristics of precancerous colorectal lesions of LS cases. METHODS: This retrospective multicenter study was conducted in Japan. CRCs and advanced adenomas (AAs) in 316 LS cases with germline pathogenic variants (path_) were analyzed according to the data of 1,756 registered CS. RESULTS: The mean time interval for advanced CRCs (ACs) detected via CS surveillance was 28.7 months (95% confidence interval: 13.8-43.5). The rate of AC detection within (2.1%) and beyond 2 years (8.7%) differed significantly (p = 0.0003). AAs accounted for 43%, 46%, and 41% of lesions < 10 mm in size in the MLH1-, MSH2-, and MSH6-groups, respectively. The lifetime incidence of metachronous CRCs requiring intestinal resection for path_MLH1, path_MSH2, and path_MSH6 cases was 34%, 23%, and 14% in these cases, respectively. The cumulative CRC incidence showed a trend towards a 10-year delay for path_MSH6 cases as compared with that for path_MLH1 and path_MSH2 cases. CONCLUSIONS: In cases with path_MLH1, path_MSH2, and path_MSH6, maintaining an appropriate CS surveillance interval of within 2 years is advisable to detect of the colorectal lesion amenable to endoscopic treatment. path_MSH6 cases could be stratified with path_MLH1 and MSH2 cases in terms of risk of metachronous CRC and age of onset.

Effect of fecal immunochemical test cut-off levels on adenoma detection rate: a systematic review and meta-analysis.

BACKGROUND: Adenoma detection rate (ADR) is higher after a positive fecal immunochemical test (FIT) compared to direct screening colonoscopy. OBJECTIVE: This meta-analysis evaluated how ADR, the rates of advanced adenoma detection (AADR), colorectal cancer detection (CDR), and sessile serrated lesion detection (SSLDR) are affected by different FIT positivity thresholds. METHODS: We searched MEDLINE, EMBASE, CINAHL, and EBM Reviews databases for studies reporting ADR, AADR, CDR, and SSLDR according to different FIT cut-off values in asymptomatic average-risk individuals aged 50-74 years old. Data were stratified according to sex, age, time to colonoscopy, publication year, continent, and FIT kit type. Study quality, heterogeneity, and publication bias were assessed. RESULTS: Overall, 4280 articles were retrieved and fifty-eight studies were included (277,661 FIT-positive colonoscopies; mean cecal intubation 96.3%; mean age 60.8 years; male 52.1%). Mean ADR was 56.1% (95% CI 53.4 - 58.7%), while mean AADR, CDR, and SSLDR were 27.2% (95% CI 24.4 - 30.1%), 5.3% (95% CI 4.7 - 6.0%), and 3.0% (95% CI 1.7 - 4.6%), respectively. For each 20 µg Hb/g increase in FIT cut-off level, ADR increased by 1.54% (95% CI 0.52 - 2.56%, p < 0.01), AADR by 3.90% (95% CI 2.76 - 5.05%, p < 0.01) and CDR by 1.46% (95% CI 0.66 - 2.24%, p < 0.01). Many detection rates were greater amongst males and Europeans. CONCLUSIONS: ADRs in FIT-positive colonoscopies are influenced by the adopted FIT positivity threshold, and identified targets, importantly, proved to be higher than most current societal recommendations.

Exogenous Insulin Therapy Is Associated with the Risk of Advanced Colorectal Adenoma in Patients with Diabetes Mellitus.

BACKGROUND/AIMS: Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. METHODS: A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40-80 years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1-365 days and > 365 days). The outcome was time to incident advanced adenoma. RESULTS: Of the 975 eligible patients, 184 patients accumulated > 365 days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365 days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82-8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90-10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46-4.69) at the follow-up colonoscopy examination. CONCLUSION: Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs.

A population-based analysis on the incidence of metachronous colon cancer after endoscopic resection of advanced adenomas with high-grade dysplasia: does location matter?

BACKGROUND: Advanced adenomas (AAs) with high-grade dysplasia (HGD) represent a risk factor for metachronous neoplasia, with guidelines recommending short-interval surveillance. Although the worse prognosis of proximal (vs distal) colon cancers (CCs) is established, there is paucity of evidence on the impact of laterality on the risk of subsequent neoplasia for these AAs. METHODS: Adults with HGD adenomas undergoing polypectomy were identified in the Surveillance, Epidemiology, and End Results database (2000-2019). Cumulative incidence of malignancy was estimated using the Kaplan-Meier method. Fine-Gray models assessed the effect of patient and disease characteristics on CC incidence. RESULTS: Of 3199 patients, 26% had proximal AAs. A total of 65 cases of metachronous adenocarcinoma were identified after polypectomy of 35 proximal and 30 distal adenomas with HGD. The 10-year cumulative incidence of CC was 2.3%; when stratified by location, it was 4.8% for proximal vs 1.4% for distal adenomas. Proximal location was significantly associated with increased incidence of metachronous cancer (adjusted hazard ratio, 3.32; 95% CI, 2.05-5.38). CONCLUSION: Proximal location of AAs with HGD was associated with >3-fold increased incidence of metachronous CC and shorter time to diagnosis. These data suggest laterality should be considered in the treatment and follow-up of these patients.

Evaluating the clinical performance of SDC2/NDRG4 methylation for colorectal cancer detection.

Purpose: The performance and clinical accuracy of combined SDC2/NDRG4 methylation were evaluated in diagnosing colorectal cancer (CRC) and advanced adenoma. Methods: A total of 2333 participants were enrolled to assess the sensitivity and specificity of biomarkers in diagnosing CRC in a multicenter clinical trial through feces DNA methylation tests. Results: SDC2/NDRG4 methylation showed excellent performance for CRC detection in biomarker research and the real world. Its sensitivity for detecting CRC, early CRC and advanced adenoma were 92.06%, 91.45% and 62.61%, respectively. Its specificity was 94.29%, with a total coincidence rate of 88.28%. When interference samples were included, the specificity was still good (82.61%). Therefore, the SDC2/NDRG4 methylation test showed excellent performance in detecting CRC and advanced adenoma under clinical application.

Colorectal cancer (CRC) is one of the most malignant tumors of the digestive system and second only to breast cancer and lung cancer in terms of global incidence. Early CRCs are challenging to determine given their atypical nature. In contrast, late CRC symptoms are affected by the type, location and range of the lesion and complications. Therefore, CRC patients are generally diagnosed late, present with a high degree of malignancy, and have poor prognosis and 5-year survival rates. The current study therefore evaluated whether SDC2 and NDRG4 methylation could be used for diagnosis CRCs at an early stage and whether it has the potential to detect asymptomatic patients with adenomas. The findings presented herein will certainly help support the early diagnosis of CRC and precancerous lesions in clinical practice.

Features of colorectal adenomas among young patients with Lynch syndrome according to path_MMR: Results from the PRED-IdF registry.

BACKGROUND: Lynch syndrome (LS) is the most frequent inherited colorectal cancer syndrome. AIM: To assess the burden of adenoma in LS patients under 50 years-old followed in the PRED-IdF network. METHODS: From January 2010 to January 2019, all patients under 50 years of age with a confirmed LS germline mutation were included. The main objective was the description of adenomas characteristics according to path_MMR. RESULTS: We analyzed data from 708 patients (mean age 34.8 ± 8.6), of which 41.8 % were male. Among these patients, 37.6% had path_MLH1, 45.4% path_MSH2, 13.9% path_MSH6, 2.9% path_PMS2, and 1.2% path_EpCAM. The analysis included 1721 (70.9%) follow-up colonoscopies. A total of 682 adenomas were detected, including 140 (20.5%) advanced adenomas. The adenoma detection rates during the first and follow-up colonoscopies were 19.2% and 20.5%, respectively. Most adenomas were <10 mm (57.9%), located in the proximal colon (334, 48.9%), and presented as non-polypoid lesions (493, 72.3%). The median growth time for adenomas was 23 months (range 9-114) irrespective of the path_MMR mutation (p = 0.62). CONCLUSION: LS patients under 50 years of age have a high burden of adenomas, particularly small non-polypoid adenomas located in the proximal colon. These results highlight the need for intensive screening, with a particular focus on the proximal colon.

Estimate of Increase in Colorectal Cancer Diagnoses with Expansion of Fecal Immunochemical Testing in an Urban Safety-Net Population.

BACKGROUND: Fecal immunochemical test (FIT) is less effective in detecting advanced adenomas (AA) than colonoscopy. Increase in FIT for colorectal cancer (CRC) screening may lead to an increased number of undetected AAs which may develop into future CRCs. AIM: We determined the potential impact of FIT expansion on missed AAs and future CRC diagnoses in an urban, tertiary-care, safety-net hospital. METHODS: CRC and AA diagnoses were identified in patients undergoing colonoscopy for average-risk CRC screening or positive FIT between 2017 and 2019 at Boston Medical Center. Poisson regression modeling was used to estimate the frequency of AAs per year by age group using data from 2017 to 2019, assuming average outpatient volume and proportion of screening colonoscopies. Total number of patients who received FIT was extrapolated from those who underwent colonoscopy for positive FIT. We estimated AAs per year if 'one-time' FIT was used for screening in 75% and 100% of the population and subtracted this from the estimated AAs per year under the Poisson model to determine missed AAs. We used previously described, age and gender specific estimates of the annual progression of AA to CRC. RESULTS: The estimated number of CRCs detected per year is 4.6/1785 males and 4.6/2086 females screened. With 75% FIT expansion, we estimate an additional 3.5 (95% CI 1.3, 9.5) and 2.2 (95% CI 0.64, 7.6) CRCs; with 100% FIT expansion, we estimate an additional 7.4 (95% CI 3.7, 14.9) and 4.2 (95% CI 1.7, 10.5) CRCs, in 5 years, in males and females, respectively. CONCLUSION: Expansion of FIT may substantially increase CRC incidence.

Natural killer cell activity level in colorectal cancer screening in an average risk population.

Introduction: Increased natural killer cell activity (NKCA) is linked to reduced risk of colorectal cancer (CRC). Several prior studies have investigated the association of NKCA and the incidence of CRC in high-risk subjects. The aim of our study was to investigate NKCA sensitivity in diagnosing advanced neoplasia (AN) and CRC in an average risk population. Material and methods: NKCA was assessed by an enzyme-linked immunosorbent assay (ELISA) blood test in average risk subjects with a range of 25-2500 pg/ml set for ELISA. NKCA higher than 200 pg/ml was defined as negative. The performance of NKCA was evaluated using measures such as sensitivity, specificity, negative and positive predictive values (NPV, PPV), clinical utility index, etc. In addition, odds ratios for developing CRC using logistic regression models were calculated. Results: NKCA was evaluated in 354 average risk individuals (mean age: 58.5 years; 36.2% male). The diagnostic accuracy of NKCA for CRC and AN was 75.5% and 72.3% respectively, with 96.4% NPV. The NKCA test demonstrated a good negative clinical utility index for CRC and AN (0.664 and 0.741, respectively). Individuals with low NKCA had 6.84 times higher odds of having CRC (95% CI: 2.31-20.27; p < 0.001). NKCA was higher in men vs. women (548.5 pg/ml vs. 500.0 pg/ml) and lower in smokers (412 pg/ml vs. 544 pg/ml), non-exercisers (413 pg/ml vs. 653.5 pg/ml), alcohol users (389 pg/ml vs. 476 pg/ml), and native Kazakhs and other Asian ethnic groups (446 pg/ml vs. 514 pg/ml). Conclusions: A high NKCA level has potential ability to rule out CRC and AN in an average risk population.

Progress in the field of noninvasive diagnostics for colorectal cancer: a systematic review for the accuracy of blood-based biomarkers for detection of advanced pre-cancerous lesions.

BACKGROUND: Early detection of pre-cancerous adenomas through screening can reduce colorectal cancer (CRC) incidence. Fecal immunochemical tests are commonly used, but have limited sensitivity for pre-cancerous lesions. Blood-based screening may improve test sensitivity. This systematic review and meta-analysis was conducted to evaluate the accuracy of blood-based biomarkers for detection of advanced pre-cancerous lesions. RESEARCH DESIGN AND METHODS: We present the accuracy of blood-based biomarkers for the detection of advanced pre-cancerous lesions. EMBASE, Web of Science and PubMed databases were searched, with study populations limited to adults diagnosed with advanced pre-cancerous lesions at colonoscopy, who had a blood-based biomarker test analyzed with reports of sensitivity and specificity. RESULTS: 69 studies were identified, which assessed 133 unique biomarkers sets. The best performing test was a panel of 6 miRNAs, with a sensitivity of 95% and specificity of 90% for advanced pre-cancerous lesions. Only 6 biomarkers demonstrated sensitivity ≥ 50% and specificity ≥ 90% for the detection of advanced pre-cancerous lesions. CONCLUSION: Many different blood-based biomarkers have been assessed for detection of advanced pre-cancerous lesions, but few have progressed beyond the discovery stage. While some biomarkers have reported high sensitivity and specificity, larger prospective studies in unbiased intended-use screening populations are required for validation.

Increased detection rates of advanced colorectal adenoma in women with metabolic dysfunction-associated fatty liver disease.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new concept with its own diagnostic criteria. There are few studies on its relationship with colorectal adenoma. Objective: This study aimed to explore the relationship between MAFLD and colorectal adenoma and to compare the predictive value of MAFLD with other risk factors. Methods: A total of 4436 consecutive physical examination subjects were enrolled. They all underwent colonoscopy and abdominal ultrasound. MAFLD was diagnosed by both fatty liver disease and metabolic dysfunction. The correlation between colorectal adenoma and MAFLD was studied using a logistic regression model. Results: The prevalence of MAFLD was 31.72 % (1407/4436). The adenoma detection rate in MAFLD patients was higher than that in controls (13.50 %, 190/1407 vs. 10.70 %, 324/3029, p < 0.001). Univariate analysis indicated that MAFLD individuals were 1.303-fold as likely to have colonic adenoma as controls [odds ratio (OR) 1.303 and 95 % confidence interval (CI), 1.076-1.578, p = 0.007]. Multivariate analysis showed that age, male sex, BMI and smoking were positively associated with the risk of colorectal adenoma, with OR values of 1.044 (95 % CI, 1.031 to 1.058), 1.720 (95 % CI, 1.221 to 2.424), 1.046 (95 % CI, 1.009 to 1.085) and 1.342 (95 % CI, 1.072 to 1.680), respectively. MAFLD in women, but not in men, had an independent relationship with increased detection of advanced adenoma (OR 3.932, 95 % CI, 1.023-15.1117, p = 0.046). Conclusion: Individuals with MAFLD are more likely to develop colorectal adenoma than those without MAFLD. The influence of MAFLD on advanced colorectal adenoma was especially prominent in females.

Progression of duodenal neoplasia to advanced adenoma in patients with familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) have a lifetime risk of developing duodenal adenomas approaching 100%, and the relative risk for duodenal cancer compared with the general population is high. We conducted a retrospective study to investigate the progression of non-ampullary duodenal adenomas (NADAs) and risk factors for advanced lesions in patients with FAP. METHODS: Of 248 patients with 139 pedigrees at 2 institutes, we assessed 151 patients with 100 pedigrees with a pathogenic germline variant in the adenomatous polyposis coli gene, excluding mosaic variants. We evaluated the prevalence of NADAs in patients with FAP, the progression of these adenomas to advanced adenoma during the observation period, and the risk factors for the lifetime development of high-grade dysplasia (HGD), large (≥ 10 mm) duodenal adenomas, and Spiegelman stage IV. RESULTS: During the median observation period of 7 years, the incidences of patients with NADAs, with more than 20 polyps, with polyps ≥ 10 mm, with HGD, and with stage IV at the last esophagogastroduodenoscopy were increased 1.6-fold, 1.7-fold, 5-fold, 22-fold, and 9-fold, respectively. Intramucosal cancer occurred in three patients (2%), but no patients developed invasive cancer during the observation period because we performed endoscopic intervention for advanced adenomas. Stage progression was observed in 71% of 113 patients. Stage IV was more common in women, patients with a history of colectomy, and those with a 3' side mutation in their adenomatous polyposis coli gene. CONCLUSIONS: NADAs in patients with FAP frequently become exacerbated. Our findings suggest that patients with FAP who develop duodenal adenomas should be surveyed to prevent the development of duodenal cancer.

High accuracy of a blood ctDNA-based multimodal test to detect colorectal cancer.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer (CRC) screening. PATIENTS AND METHODS: A novel multimodal ctDNA-based blood assay that integrates genomics, epigenomics and fragmentomics, as well as proteomics in a refined version, was tested in blood samples from two cohorts: (i) consecutive fecal immunochemical test (FIT)-positive individuals from the CRC Barcelona stool-based screening program; (ii) patients diagnosed with CRC. Primary endpoint was the performance of the test to detect CRC at different tumor-node-metastasis (TNM) stages. Secondary endpoint was the ability of the test to detect advanced precancerous lesions (advanced adenoma or advanced serrated lesion). RESULTS: A total of 623 blood samples were analyzed in the primary analysis. Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection according to TNM stages was 84% for stage I, 94% for stage II and 96% for stage III (70/73) (P< 0.024). Sensitivity to detect advanced precancerous lesions was 23% with a refined version of the test (including protein and updating bioinformatic thresholding). CONCLUSION: A blood-based multimodal ctDNA assay detected CRC with high accuracy. This minimally invasive, accessible and convenient assay may help to increase the effectiveness of CRC screening.

Human immunodeficiency virus patients with low CD4 counts are more likely to have precancerous polyps identified during index colonoscopy.

BACKGROUND: Antiretroviral treatment (ART) has improved the life expectancy of patients living with human immunodeficiency virus (HIV). As these patients age, they are at increased risk for developing non-acquired immunodeficiency syndrome defining malignancies (NADMs) such as colon cancers. AIM: To determine which factors are associated with the development of precancerous polyps on screening colonoscopy in patients with HIV and to investigate whether HIV disease status, measured by viral load and CD4 count, might influence precancerous polyp development. METHODS: A retrospective review of records at two urban academic medical centers was performed for HIV patients who had a screening colonoscopy between 2005-2015. Patients with a history of colorectal cancer or polyps, poor bowel preparation, or inflammatory bowel disease were excluded. Demographic data such as sex, age, race, and body mass index (BMI) as well as information regarding the HIV disease status such as CD4 count, viral load, and medication regimen were collected. Well-controlled patients were defined as those that had viral load < 50 copies, and poorly-controlled patients were those with viral load ≥ 50. Patients were also stratified based on their CD4 count, comparing those with a low CD4 count to those with a high CD4 count. Using colonoscopy reports in the medical record, the size, histology, and number of polyps were recorded for each patient. Precancerous polyps included adenomas and proximal serrated polyps. Data was analyzed using Fisher's exact tests and logistic regression through SAS 3.8 software. RESULTS: Two hundred and seven patients met our inclusion criteria. The mean age was 56.13 years, and 58% were males. There were no significant differences in terms of age, race or ethnicity, insurance, and smoking status between patients with CD4 counts above or below 500. BMI was lower in patients with CD4 count < 500 as compared to those with count > 500 (P = 0.0276). In patients with CD4 > 500, 53.85% of patients were female, and 70.87% of patients with CD4 < 500 were male (P = 0.0004). Only 1.92% of patients with CD4 ≥ 500 had precancerous polyps vs 10.68% of patients with CD4 < 500 (P = 0.0102). When controlled for sex, BMI, and ART use, patients with CD4 < 500 were 9.01 times more likely to have precancerous polyps [95% confidence interval (CI): 1.69-47.97; P = 0.0100]. Patients taking non-nucleoside reverse transcriptase inhibitors were also found to be 10.23 times more likely to have precancerous polyps (95%CI: 1.08-97.15; P = 0.0428). There was not a significant difference noted in precancerous polyps between those that had viral loads greater or less than 50 copies. CONCLUSION: Patients with low CD4 counts were more likely to have precancerous polyps on their screening colonoscopy although the etiology for this association is unclear. We also found an increased risk of precancerous polyps in patients taking non-nucleoside reverse transcriptase inhibitors, which is contradictory to prior literature showing ART has decreased the risk of development of NADMs. However, there have not been studies looking at colorectal cancer and ART by drug class, to our knowledge. Further prospective studies are needed to determine the effect of HIV control and therapies on polyp development.

Liquid Biopsies for Colorectal Cancer and Advanced Adenoma Screening and Surveillance: What to Measure?

Colorectal cancer (CRC) colonoscopic surveillance is effective but burdensome. Circulating tumor DNA (ctDNA) analysis has emerged as a promising, minimally invasive tool for disease detection and management. Here, we assessed which ctDNA assay might be most suitable for a ctDNA-based CRC screening/surveillance blood test. In this prospective, proof-of-concept study, patients with colonoscopies for Lynch surveillance or the National Colorectal Cancer screening program were included between 7 July 2019 and 3 June 2022. Blood was drawn, and if advanced neoplasia (adenoma with villous component, high-grade dysplasia, ≥10 mm, or CRC) was detected, it was analyzed for chromosomal copy number variations, single nucleotide variants, and genome-wide methylation (MeD-seq). Outcomes were compared with corresponding patients' tissues and the MeD-seq results of healthy blood donors. Two Lynch carriers and eight screening program patients were included: five with CRC and five with advanced adenomas. cfDNA showed copy number variations and single nucleotide variants in one patient with CRC and liver metastases. Eight patients analyzed with MeD-seq showed clustering of Lynch-associated and sporadic microsatellite instable lesions separate from microsatellite stable lesions, as did healthy blood donors. In conclusion, whereas copy number changes and single nucleotide variants were only detected in one patient, cfDNA methylation profiles could discriminate all microsatellite instable advanced neoplasia, rendering this tool particularly promising for LS surveillance. Larger studies are warranted to validate these findings.

Risk of recurrent advanced colorectal neoplasia in individuals with baseline non-advanced neoplasia followed up at 5 vs 7-10 years.

BACKGROUND AND AIM: Colorectal cancer (CRC) is one of the commonest cancers, especially among the Asian populations. We compared the recurrence rate of advanced colorectal neoplasia (ACN) at 5 year vs 7-10 years among individuals with non-advanced adenoma (NAA) detected and polypectomized at baseline colonoscopy in a large Chinese population. METHODS: We extracted data of a large Chinese population with NAA polypectomized who received surveillance colonoscopy after 5 or 7-10 years from a large database (2008-2018). The outcome variable included recurrence of ACN at surveillance colonoscopy. We examined the association between length of surveillance and the outcome variable, whilst controlling for risk factors of colorectal cancer. RESULTS: We include 109 768 subjects who have received a baseline colonoscopy from our dataset. They were aged 67.35 (SD 9.84) years, and 60.9% of them were male subjects. The crude 5-year and 10-year recurrence rate of ACN was 1.50% and 2.42%, respectively (crude odds ratio = 1.629, 95% CI 1.362 to 1.949, P < 0.001). From the binary logistic regression model, individuals with surveillance colonoscopy performed at 10 years had a statistically higher recurrence rate of ACN than those followed-up at 5 year (adjusted odds ratio [aOR] = 1.544, 95% CI 1.266 to 1.877, P < 0.001), but the effect size of aOR is small. CONCLUSIONS: There is a small difference in recurrence of ACN between individuals who received colonoscopy workup at 5 years vs 7-10 years. These findings support a 7-10 years surveillance period after baseline NAA was polypectomized.

Adenoma Detection Rate in Average-Risk Population: An Observational Consecutive Retrospective Study.

BACKGROUND: Although colonoscopy is considered the most effective tool for reducing colorectal cancer-related morbidity, the age at which average-risk individuals begin colonoscopic screening is undetermined. This study aimed to compare the adenoma and advanced adenoma detection rates according to age and sex in a large average-risk population in the rural areas of Eastern China. METHODS: This observational, single-center, retrospective study included patients with average colorectal cancer risk and examined the adenoma and advanced adenoma detection rates using age intervals of 5 years. We also compared the size and age of patients with and without advanced adenoma. RESULTS: We included 18 928 patients with a median age of 54 years (range 15-90 years), including 10 143 men and 8785 women. The adenoma and advanced adenoma detection rates were 17.08% and 5.24%, respectively, and increased with age in the whole population. The adenoma detection rates increased from 8.97% (aged 40-44) to 14.98% (aged 45-49) and 6.24% (aged 45-49) to 11.00% (aged 50-54) in men and women (both P < .001), respectively. The advanced adenoma detection rates increased from 2.19% (aged 40-44) to 4.76% (aged 45-49) and 1.89% (aged 45-49) to 3.13% (aged 50-54) in men (P = .002) and women (P = .056), respectively. Patients with advanced adenomas were significantly older than those with non-advanced adenomas (P < .001). The tumors in the advanced adenoma group were significantly larger than those in the non-advanced adenoma group (P < .001). CONCLUSION: The adenoma and advanced adenoma detection rates increased significantly in average-risk population aged 45 years and older, especially in men.

UHPLC-HRMS-based serum untargeted lipidomics: Phosphatidylcholines and sphingomyelins are the main disturbed lipid markers to distinguish colorectal advanced adenoma from cancer.

Colorectal advanced adenoma (CAA) is a key precancerous lesion of colorectal cancer (CRC), and early diagnosis can lessen CRC morbidity and mortality. Although abnormal lipid metabolism is associated with the development of CRC, there are no studies on the biomarkers and mechanism of lipid metabolism linked to CAA carcinogenesis. Hence, we performed a lipidomics study of serum samples from 46 CAA, and 50 CRC patients by the ultra high-performance liquid chromatography tandem high resolution mass spectrometry (UHPLC-HRMS) in both electrospray ionization (ESI) modes. Differential lipids were selected by univariate and multivariate statistics analysis, and their diagnostic performance was evaluated using a receiver operating characteristic curve (ROC) analysis. Combining P < 0.05 and variable importance in projection (VIP) > 1, 59 differential lipids were obtained totally. Ten of them showed good discriminant ability for CAA and CRC (AUC > 0.900). Especially, the lipid panel consisting of PC 44:5, PC 35:6e, and SM d40:3 showed the highest selection frequency and outperformed (AUC = 0.952). Additionally, phosphatidylcholine (PC) and sphingomyelin (SM) were the main differential and high-performance lipids. In short, this is the first study to explore the biomarkers and mechanism for CAA-CRC sequence with large-scale serum lipidomics. The findings should provide valuable reference and new clues for the development of diagnostic and therapeutic strategies of CRC.