Advanced Polyps Research Articles

Extended delay in endoscopic mucosal resection is not associated with adverse outcomes: Findings from the COVID-19 pandemic.

Abstract Background and study aims The aim of this study was to investigate the impact of delayed endoscopic mucosal resection (EMR) of colorectal polyps on health outcomes. Patients and methods A bidirectional cohort study was completed. A baseline group consisting of all EMRs performed within a 15-month period before a province-wide, government-mandated cessation of EMR procedures due to the global pandemic was compared to EMRs impacted by the shutdown, defined as the COVID-19-delayed group. The primary outcome was the incidence of malignant polyps. Secondary outcomes included technical success, polyp recurrence at follow-up colonoscopy, advanced polyp histology, probability of meeting endoscopic criteria for adequate resection for malignant polyps, metastatic colorectal cancer, and complications. Results A total of 268 EMR procedures were included in the study cohort, of which 208 formed the baseline group and 60 were in the COVID-19-delayed group. The median (IQR) patient age was 72 (13.0) and 113 (41.2 %) were females. The median (IQR) wait time was 92 days (87.8) in the baseline group and 191 days (127.8) in the COVID-19-delayed group (P < 0.001). Overall, there were no significant differences in the incidence of malignant polyps, technical success, polyp recurrence on follow-up colonoscopy, advanced polyp histology, adequate endoscopic resection for malignant polyps, metastatic colorectal cancer, or complications between the two groups (P > 0.05 for all outcomes). Conclusions A longer wait time for EMR of colorectal polyps, increasing from a median of 92 to 191 days, was not associated with worse outcomes.

Deep polyp image enhancement using region of interest with paired supervision

Endoscopic medical imaging in complex curved intestinal structures are prone to uneven illumination, low contrast and lack of texture information. These problems may lead to diagnostic challenges. This paper described the first supervised deep learning based image fusion framework to enable the polyp region highlight through a global image enhancement and a local region of interest (ROI) with paired supervision. Firstly, we conducted a dual attention based network in global image enhancement. The Detail Attention Maps was used to preserve more image details and the Luminance Attention Maps was used to adjust the global illumination of the image. Secondly, we adopted the advanced polyp segmentation network ACSNet to obtain the accurate mask image of lesion region in local ROI acquisition. Finally, a new image fusion strategy was proposed to realize the local enhancement effect of polyp image. Experimental results show that our method can highlight the local details of the lesion area better and reach the optimal comprehensive performance with comparing with 16 traditional and state-of-the-art enhancement algorithms. And 8 doctors and 12 medical students were asked to evaluate our method for assisting clinical diagnosis and treatment effectively. Furthermore, the first paired image dataset LHI was constructed, which will be made available as an open source to research communities.

Long non‑coding RNA LINC00460 contributes as a potential prognostic biomarker through its oncogenic role with ANXA2 in colorectal polyps.

Long intergenic non-coding RNA 460 (LINC00460) as a potential oncogene and Annexin A2 (ANXA2) as a promoter in different cancer progression processes was considered. A significant relationship between the LINC00460 and ANXA2 has been recently discovered in colorectal cancer (CRC). Therefore, defining molecular biomarkers accompanied by lesion histopathologic features can be a suggestive prognostic biomarker in precancerous polyps. This study aimed to investigate the elusive expression pattern of ANXA2 and LINC00460 in polyps. The construction of the co-expression and correlation network of LINC00460 and ANXA2 was plotted. LINC00460 and ANXA2 expression in 40 colon polyps was quantified by reverse transcription-real-time polymerase chain reaction. The receiver operating characteristic (ROC) curve was designed for distinguishing the high-risk precancerous lesion from the low-risk. Further, bioinformatics analysis was applied to find the shared MicroRNA-Interaction-Targets (MITs) between ANXA2 and LINC00460, and the associated pathways. ANXA2 has a high co-expression rank with LINC00460 in the lncHUB database. Overexpression of ANXA2 and LINC00460 was distinguished in advanced adenoma polyps compared to the adjacent normal samples. The estimated AUC for ANXA2 and LINC00460 was 0.88 - 0.85 with 93%-90% sensitivity and 81%-70% specificity. In addition, eight MITs were shared between ANXA2 and LINC00460. Enrichment analysis detected several GO terms and pathways, including HIF-1α associated with cancer development. In conclusion, the expression of the ANXA2 and LINC00460 were significantly elevated in pre-cancerous polyps, especially in high-risk adenomas. Collectively, ANXA2 and LINC00460 may be administered as potential prognostic biomarkers in patients with a precancerous large intestine lesion as an alarming issue.

Abstract 644: Gut microbiota-derived metabolites as regulators of immunity in pre-cancer

Abstract Introduction: Tryptophan (Trp) as an essential amino acid that can only be obtained through diet and is a precursor of serotonin and melatonin and required for protein and niacin biosynthesis. In addition, Trp is appreciated for its influence on both host and microbial metabolism. Trp is shunted into the Kyn pathway (mostly) and indolic pathway (bacterial degradation), especially in the immune cells. Both Kyn and Indole/indole derivatives, in part by activating the ligand-dependent transcription factor aryl hydrocarbon receptor (AHR), can become dysfunctional in cancer. Most individuals with cancer such as colon cancer, exhibit increased L-kynurenine levels, which in part is explained by progression of immunosuppressive phenotype and excessive inflammatory signaling molecules. To date, studies in mice and humans have linked Kyn and AHR as potent modulators of host immunity to colon cancer (CRC). Nothing is yet known about their role in pre-cancer, during the development of adenomatous polyps. We hypothesized that increases in plasma Kyn and I3A and their receptor AHR on immune cells would be detected in patients with pre-malignant polyps, suggesting dysbiosis and increased colon cancer risk due to immune modulation. Methods: We measured with mass spectrometry Kyn and I3A in plasma samples of 88 polyp patients and compared to 22 colon cancer patients. We analyzed by flow cytometry PBMCs from 64 newly diagnosed advanced polyp patients (40-70 years old) and 9 age-matched colon cancer patients in order to evaluate AHR expression in different subsets of T cells, NKT cells and NK cells, and their possible association with exhaustion markers Tim-3, LAG-3 and PD-1, as well as Granzyme K, and the presence of immunosuppressive Treg and MDSC. Results: We showed high level of expression of gut microbiota-derived metabolites in plasma of colon pre-cancer compared to cancer patients. We identified CD8+ T effector memory cells (TEM) as primary T cell population expressing their receptor AHR in polyp patients, which had a statistically significant association with Granzyme K expression, which is a hallmark of inflammaging. Conclusions: Our results suggest gut microbiota-derived metabolites as potential mediators of immunosuppression in the setting of premalignancy, which could increase cancer risk and be targets of cancer-preventing strategies. Citation Format: Amir Hossein Mohseni, Sedigheh Taghinezhad-S, Pamela L. Beatty, Olivera J. Finn. Gut microbiota-derived metabolites as regulators of immunity in pre-cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 644.

Association of Life Expectancy With Surveillance Colonoscopy Findings and Follow-up Recommendations in Older Adults

Surveillance after prior colon polyps is the most frequent indication for colonoscopy in older adults. However, to our knowledge, the current use of surveillance colonoscopy, clinical outcomes, and follow-up recommendations in association with life expectancy, factoring in both age and comorbidities, have not been studied. To evaluate the association of estimated life expectancy with surveillance colonoscopy findings and follow-up recommendations among older adults. This registry-based cohort study used data from the New Hampshire Colonoscopy Registry (NHCR) linked with Medicare claims data and included adults in the NHCR who were older than 65 years, underwent colonoscopy for surveillance after prior polyps between April 1, 2009, and December 31, 2018, and had full Medicare Parts A and B coverage and no Medicare managed care plan enrollment in the year prior to colonoscopy. Data were analyzed from December 2019 to March 2021. Life expectancy (<5 years, 5 to <10 years, or ≥10 years), estimated using a validated prediction model. The main outcomes were clinical findings of colon polyps or colorectal cancer (CRC) and recommendations for future colonoscopy. Among 9831 adults included in the study, the mean (SD) age was 73.2 (5.0) years and 5285 (53.8%) were male. A total of 5649 patients (57.5%) had an estimated life expectancy of 10 or more years, 3443 (35.0%) of 5 to less than 10 years, and 739 (7.5%) of less than 5 years. Overall, 791 patients (8.0%) had advanced polyps (768 [7.8%]) or CRC (23 [0.2%]). Among the 5281 patients with available recommendations (53.7%), 4588 (86.9%) were recommended to return for future colonoscopy. Those with longer life expectancy or more advanced clinical findings were more likely to be told to return. For example, among patients with no polyps or only small hyperplastic polyps, 132 of 227 (58.1%) with life expectancy of less than 5 years were told to return for future surveillance colonoscopy vs 940 of 1257 (74.8%) with life expectancy of 5 to less than 10 years and 2163 of 2272 (95.2%) with life expectancy of 10 years or more (P < .001). In this cohort study, the likelihood of finding advanced polyps and CRC on surveillance colonoscopy was low regardless of life expectancy. Despite this observation, 58.1% of older adults with less than 5 years' life expectancy were recommended to return for future surveillance colonoscopy. These data may help refine decision-making about pursuing or stopping surveillance colonoscopy in older adults with a history of polyps.

The detection rate and yield of advanced relevant serrated polyps: one small step for the yield, one giant leap for the quality of colonoscopy.

Over the last two decades, it has been well clarified that the serrated/methylated pathway of colorectal carcinogenesis is responsible for about 20 %–30 % of all colorectal cancers (CRCs) and is distinct from the traditional adenoma–carcinoma sequence [1]. Three main subgroups of serrated polyps have been recognized, with different malignant potential [2]. Hyperplastic polyps (HPPs) are believed to have a benign course, unless larger than 10 mm, whereas sessile serrated lesions (SSLs), especially those with dysplasia, and traditional serrated adenomas (TSAs), regardless of their size, have the potential for malignant transformation. Therefore, there is no doubt that these precancerous lesions are clinically relevant and deserve all our attention, above all they are often flat in appearance with indistinct borders and difficult to detect.

Immunohistochemical assessment of COX2, P53, and beta-catenin expression to predict metachronous lesion development following polypectomy.

234 Background: Following colorectal polypectomy, 20-50% develop metachronous polyps, and some have increased colorectal cancer (CRC) risk. Surveillance colonoscopy is recommended to high-risk patients, based on index polyp number, histology and size. We aimed to assess if COX2, p53 and beta-catenin expression could predict metachronous polyp/ CRC risk. Methods: Tissue microarrays (TMA’s) were constructed for 339 patients from the INCISE study, a retrospective analysis of all patients undergoing screening polypectomy (Apr’09-Dec’16) followed by surveillance (6months-6years) in Glasgow, UK. Epithelial COX2, p53 and beta-catenin expression were assessed for each patient’s most advanced index polyp using immunohistochemistry, quantified by QuPath software. Kaplan-Meier analysis, log-rank tests and univariate/ multivariate cox regression assessed the association between marker expression and time to metachronous polyp/ CRC detection. Results: Low nuclear p53 expression was associated with shorter time to metachronous polyp/ CRC detection (p=0.024). Low nuclear (p=0.012) and membranous (p=0.046) beta-catenin expression was associated with shorter time to metachronous polyp/ CRC detection. There was no association between cytoplasmic COX2 expression and time to metachronous polyp/ CRC detection overall (p=0.309), but high cytoplasmic COX2 expression was associated with shorter time to detection of advanced metachronous lesions (advanced colorectal polyps/ CRC) (p=0.011). A combined score using the two most powerful biomarkers (nuclear p53 and nuclear beta-catenin – both high/ one low/ both low) was also associated with shorter time to metachronous polyp/ CRC detection (p=0.011). Univariate and multivariate cox regression are shown. Conclusions: Index polyp number and combined nuclear p53/beta-catenin expression independently predicted time to metachronous polyp/ CRC detection. [Table: see text]

Clinical features and long-term outcomes of patients with colonic oligopolyposis of unknown etiology.

Colonic adenomatous polyposis of unknown etiology (CPUE) is an adenomatous polyposis phenotype that resembles Familial Adenomatous Polyposis (FAP) even though no germline pathogenic variant is identified. We sought to better characterize the clinical features and outcomes in a cohort of CPUE patients. This is a retrospective case series of patients 18 years old or older with aden-omatous oligopolyposis (between 10-100 adenomas) and negative genetic testing, identified through the Hereditary Gastrointestinal Cancer Database at Massachusetts General Hospital, a tertiary academic referral center. A retrospective chart review was performed with a focus on demographics, alcohol and tobacco use, medication use, familial malignancy and polyp burden, genetic testing information, endoscopic surveillance data including the corresponding histopathology, colonic and extracolonic malignancies, mortality events, and their etiology. Spearman correlation and Pearson Chi-square test (or Fisher's exact test) were used for continuous and categorical variables respectively. CPUE patients were primarily male (69%) and presented for genetic counseling at 63.7 years. Only 2 patients (2.9%) reported a first-degree relative with polyposis. During an average surveillance period of 12.3 years, 0.5 colonoscopies per year were performed. Patients developed 2.3 new adenomas per year. 4 (5.7%) were diagnosed with colorectal cancer (CRC) at a mean age of 66 years, and 3 were diagnosed prior to the onset of oligopolyposis. 7 (10%) required colectomy due to advanced dysplasia or polyp burden. With respect to upper gastrointestinal manifestations, 1 patient had a gastric adenoma, but there were no cases of gastric or small bowel polyposis. During surveillance, 10 (14%) patients died at a mean age of 72, and none were due to CRC. CPUE is distinct from familial adenomatous polyposis (FAP) syndrome and the use of FAP surveillance guidelines may result in unnecessarily frequent upper and lower endoscopies.

The multitarget fecal immunochemical test versus the fecal immunochemical test for programmatic colorectal cancer screening: a cross-sectional intervention study with paired design

BackgroundMany screening programs for colorectal cancer (CRC) use the fecal immunochemical test (FIT) to triage individuals for colonoscopy. Although these programs reduce CRC incidence and CRC-related mortality, the detection of advanced precursor lesions (advanced adenomas and advanced serrated polyps) by FIT could be improved. As an alternative for FIT, the antibody-based multitargetFIT (mtFIT) has been proposed. The mtFIT measures three protein markers: hemoglobin, calprotectin, and serpin family F member 2. In a retrospective diagnostic accuracy study in a large colonoscopy-controlled series (n = 1284), mtFIT showed increased sensitivity for advanced neoplasia (AN), at equal specificity, compared to FIT (42.9% versus 37.3%; p = 0.025). This increase was mainly due to a higher sensitivity of mtFIT for advanced adenomas (37.8% versus 28.1% for FIT; p = 0.006). The present mtFIT study aims to prospectively validate these findings in the context of the Dutch national CRC screening program.MethodThe mtFIT study is a cross-sectional intervention study with a paired design. Eligible subjects for the Dutch FIT-based national CRC screening program are invited to perform mtFIT in addition to FIT. Samples are collected at home, from the same bowel movement, and are shipped to a central laboratory by postal mail. If either one or both tests are positive, participants are referred for colonoscopy. Detailed colonoscopy and pathology data are centrally stored in a national screening database (ScreenIT; Topicus, Deventer, the Netherlands) that is managed by the screening organization, and will be retrieved for this study. We aim to determine the relative sensitivity for AN, comprising of CRC, advanced adenomas and advanced serrated polyps, of mtFIT compared to FIT at an equal positivity rate. Additionally, we will use the Adenoma and Serrated Pathway to Colorectal CAncer model to predict lifetime health effects and costs for programmatic mtFIT- versus FIT-based screening. The target sample size is 13,131 participants.DiscussionThe outcome of this study will inform on the comparative clinical utility of mtFIT versus FIT in the Dutch national CRC screening program and is an important step forward in the development of a new non-invasive stool test for CRC screening.Trial registrationClinicaltrials.gov; NCT05314309, registered April 6th 2022, first inclusions March 25th 2022 https://clinicaltrials.gov/ct2/results?cond=&term=NCT05314309&cntry=&state=&city=&dist=.

Improving early detection of colorectal cancer in Aotearoa New Zealand; how do the direct access criteria perform?

Colorectal cancer (CRC) is a common malignancy in New Zealand, and there is increasing pressure on investigative resources for diagnosis. The national direct access referral guidelines from the Ministry of Health (MoH) guide who should be referred for investigation, but their performance in detecting CRC and other significant diseases has not been reported previously. This paper describes the yield, by direct access criterion, of all referrals through the direct access pathway to the Canterbury District Health Board (CDHB) during 2018. First referrals received through the direct access colonoscopy/computed tomography colonography (CTC) pathway for 2018 were audited. Patients were assigned to symptom groups corresponding to the MoH direct access criteria, and demographic data were captured. Diagnostic outcomes were collected through analysis of all endoscopy, CT colonography and histology reports in the 18 months following referral for primary analysis, with further follow-up through to May 2021 to detect missed pathology. Three thousand two hundred referrals were analysed, and 88.5% underwent colorectal investigation. 128 CRC were diagnosed, 176 advanced polyps, 49 cases of inflammatory bowel disease (IBD) and there were 56 other significant findings. The yield by category for the direct access criteria varied between 0-15.0%, and one urgent criterion had a CRC yield lower than two semi-urgent categories. For patients whose symptoms met at least one of the criteria, excluding those referred with suspected IBD, the combined CRC yield was 4.9%, compared with 1.8% in those who did not meet criteria. The sensitivity and specificity of the criteria for CRC (excluding IBD) was 90% and 23% respectively. There were no CRC detected during the extended follow-up period. In this referred population, the MoH direct access colonoscopy/CTC criteria varied significantly in their CRC yield, with an arbitrary distinction between urgent and semi-urgent categories. The low specificity of the criteria means the number needed to investigate to detect one CRC was one in 22. Improved diagnostic algorithms are urgently required to improve both the sensitivity and specificity, thereby more appropriately allocating finite resources to those patients who are most in need of investigation.

A Multi-Centre Study to Risk Stratify Colorectal Polyp Surveillance Patients Utilising Volatile Organic Compounds and Faecal Immunochemical Test.

Simple SummaryA total of 15% of the annual colonoscopies are undertaken for polyp surveillance, and this causes strain on already stretched endoscopy services in the U.K. Hence, there is an urgent need to triage and prioritise patients with high-risk findings. The performance of the faecal immunochemical test is not adequate to be used within polyp surveillance. In light of this, we investigated the usefulness of urinary volatile organic compounds for the detection of high-risk findings. We confirmed that urinary volatile organic compounds can be used to triage patients with high-risk findings. It can be used alone or in combination with faecal immunochemical tests.(1) Background: The service capacity for colonoscopy remains constrained, and while efforts are being made to recover elective services, polyp surveillance remains a challenge. (2) Methods: This is a multi-centre study recruiting patients already on polyp surveillance. Stool and urine samples were collected for the faecal immunochemical test (FIT) and volatile organic compounds (VOC) analysis, and all participants then underwent surveillance colonoscopy. (3) Results: The sensitivity and specificity of VOC for the detection of a high-risk finding ((≥2 premalignant polyps including ≥1 advanced polyp or ≥5 premalignant polyps) were 0.94 (95% CI, 0.88 to 0.98) and 0.69 (95% CI, 0.64 to 0.75) respectively. For FIT, the sensitivity was (≥10 µg of haemoglobin (Hb) / g faeces) 0.54 (95% CI, 0.43 to 0.65) and the specificity was 0.79 (95% CI, 0.73 to 0.84). The probability reduction for having a high-risk finding following both negative VOC and FIT will be 24% if both tests are applied sequentially. (4) Conclusion: The diagnostic performance of VOC is superior to FIT for the detection of a high-risk finding. The performance further improves when VOC is applied together with FIT sequentially (VOC first and then FIT). VOC alone or the combination of VOC and FIT can be used as a triage tool for patients awaiting colonoscopy within a polyp surveillance population, especially in resource-constrained healthcare systems.

Three-Year Interval for the Multi-Target Stool DNA Test for Colorectal Cancer Screening: A Longitudinal Study.

Understanding the 3-year yield of mt-sDNA for colorectal cancer and advanced precancerous polyps is required to ensure the clinical appropriateness of the 3-year interval and to optimize mt-sDNA's screening effectiveness.

A two-phase approach to re-calibrating expensive computer simulation for sex-specific colorectal neoplasia development modeling

BackgroundMedical evidence from more recent observational studies may significantly alter our understanding of disease incidence and progression, and would require recalibration of existing computational and predictive disease models. However, it is often challenging to perform recalibration when there are a large number of model parameters to be estimated. Moreover, comparing the fitting performances of candidate parameter designs can be difficult due to significant variation in simulated outcomes under limited computational budget and long runtime, even for one simulation replication.MethodsWe developed a two-phase recalibration procedure. As a proof-of-the-concept study, we verified the procedure in the context of sex-specific colorectal neoplasia development. We considered two individual-based state-transition stochastic simulation models, estimating model parameters that govern colorectal adenoma occurrence and its growth through three preclinical states: non-advanced precancerous polyp, advanced precancerous polyp, and cancerous polyp. For the calibration, we used a weighted-sum-squared error between three prevalence values reported in the literature and the corresponding simulation outcomes. In phase 1 of the calibration procedure, we first extracted the baseline parameter design from relevant studies on the same model. We then performed sampling-based searches within a proper range around the baseline design to identify the initial set of good candidate designs. In phase 2, we performed local search (e.g., the Nelder-Mead algorithm), starting from the candidate designs identified at the end of phase 1. Further, we investigated the efficiency of exploring dimensions of the parameter space sequentially based on our prior knowledge of the system dynamics.ResultsThe efficiency of our two-phase re-calibration procedure was first investigated with CMOST, a relatively inexpensive computational model. It was then further verified with the V/NCS model, which is much more expensive. Overall, our two-phase procedure showed a better goodness-of-fit than the straightforward employment of the Nelder-Mead algorithm, when only a limited number of simulation replications were allowed. In addition, in phase 2, performing local search along parameter space dimensions sequentially was more efficient than performing the search over all dimensions concurrently.ConclusionThe proposed two-phase re-calibration procedure is efficient at estimating parameters of computationally expensive stochastic dynamic disease models.

Adaptive Strategies for Outpatient Colonoscopies in Response to COVID-19

The coronavirus disease 2019 (COVID-19) pandemic caused a decline in outpatient colonoscopies that continues at varying levels.1 To prevent delay in colorectal cancer (CRC) diagnoses, centers strategized to expand fecal immunochemical tests (FITs) and triage symptomatic and FIT-positive colonoscopies.2,3 Although much has been written about missed CRC diagnoses,4 few studies have examined the impact of adaptive strategies on CRC and advanced polyp (AP) detection rates.5 It was hypothesized that these strategies would increase detection rates compared with prepandemic levels owing to the targeting of high-risk patients.

Artificial intelligence for diagnosing gastric lesions under white-light endoscopy.

The ability of endoscopists to identify gastric lesions is uneven. Even experienced endoscopists may miss or misdiagnose lesions due to heavy workload or fatigue or subtle changes in lesions under white-light endoscopy (WLE). This study aimed to develop an artificial intelligence (AI) system that could diagnose six common gastric lesions under WLE and to explore its role in assisting endoscopists in diagnosis. Images of early gastric cancer, advanced gastric cancer, submucosal tumor, polyp, peptic ulcer, erosion, and lesion-free gastric mucosa were retrospectively collected to train and test the system. The performance of the system was compared with that of 12 endoscopists. The performance of endoscopists with or without referring to the system was also evaluated. A total of 29,809 images from 8947 patients and 1579 images from 496 patients were used to train and test the system, respectively. For per-lesion analysis, the overall accuracy of the system was 85.7%, which was comparable to that of senior endoscopists (85.1%, P = 0.729) and significantly higher than that of junior endoscopists (78.8%, P < 0.001). With system assistance, the overall accuracies of senior and junior endoscopists increased to 89.3% (4.2%, P < 0.001) and 86.2% (7.4%, P < 0.001), respectively. Senior and junior endoscopists achieved varying degrees of improvement in the diagnostic performance of other types of lesions except for polyp. The diagnostic times of senior (3.8 vs 3.2s per image, P = 0.500) and junior endoscopists (6.2 vs 4.6s per image, P = 0.144) assisted by the system were both slightly shortened, despite no significant differences. The proposed AI system could be applied as an auxiliary tool to reduce the workload of endoscopists and improve the diagnostic accuracy of gastric lesions.

Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA

BackgroundCurrent noninvasive assays have limitations in the early detection of colorectal cancer. We evaluated the clinical utility of promoter methylation of the long noncoding RNA LINC00473 as a noninvasive biomarker to detect colorectal cancer and associated precancerous lesions.MethodsWe evaluated the epigenetic regulation of LINC00473 through promoter hypermethylation in colorectal cancer cell lines using bisulfite genomic sequencing and expression analyses. DNA methylation of LINC00473 was analyzed in primary colorectal tumors using 450K arrays and RNA-seq from The Cancer Genome Atlas (TCGA). Tissue-based findings were validated in several independent cohorts of colorectal cancer and advanced colorectal polyp patients by pyrosequencing. We explored the clinical utility of LINC00473 methylation for the early detection of colorectal cancer in plasma cell-free DNA by quantitative methylation-specific PCR and droplet digital PCR.ResultsLINC00473 showed transcriptionally silencing due to promoter hypermethylation in colorectal cancer cell lines and primary tumors. Methylation of the LINC00473 promoter accurately detected primary colorectal tumors in two independent clinical cohorts, with areas under the receiver operating characteristic curves (AUCs) of 0.94 and 0.89. This biomarker also identified advanced colorectal polyps from two other tissue-based clinical cohorts with high diagnostic accuracy (AUCs of 0.99 and 0.78). Finally, methylation analysis of the LINC00473 promoter in plasma cell-free DNA accurately identified patients with colorectal cancer and advanced colorectal polyps (AUCs of 0.88 and 0.84, respectively), which was confirmed in an independent cohort of patients.ConclusionsHypermethylation of the LINC00473 promoter is a new promising biomarker for noninvasive early detection of colorectal cancer and related precancerous lesions.

Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

Serum Chloride and Admission Status Are Potential Prognostic Markers of High-Risk Polyps: A Prospective Characterization of Colorectal Polyps in a Tertiary Hospital in Saudi Arabia.

Background: Colorectal cancer (CRC) is the most common cancer in men in Saudi Arabia. Other than age and family history, clinical and laboratory prognostic surrogates that may aid in streamlining and prioritization of screening colonoscopies are scarce. Through the examination of the local prevalence of advanced and malignant colorectal polyps, we hypothesized that the presence of certain clinical or laboratory parameters may signify an association with having high-risk polyps.Methods: A prospective study over a period of one year starting on January 21, 2018 and involving all adult patients undergoing colonoscopy at King Saud Medical City, Riyadh. Of the total 1,104 recruited patients, 717 were included. The patients were sub-grouped based on the presence or absence of polyps. Patients with polyps were further sub-grouped into high-risk or low-risk polyps. Comparisons between groups were performed using univariate, relative risks (RRs), and multivariate analyses.Results: Our polyp detection rate was 34.7% and our adenoma detection rate was 21.3%. The prevalence of advanced adenoma was 15.2% and the prevalence of malignant polyps was 6.7%. Several prognostic markers were associated with high-risk polyps such as advanced age (RR = 1.35, 95% confidence interval [CI]: 1.03 to 1.78), male gender (RR = 1.18, 95% CI: 1.06 to 1.31), inpatient status (RR = 1.46, 95% CI: 1.04 to 2.21), and low serum chloride (RR = 1.89, 95% CI: 1.05 to 2.37). With multivariate analysis, the hazard ratios for inpatient status and hypochloremia were 1.67 (95% CI: 1.034 to 2.612) and 1.12 (95% CI: 1.011 to 1.265), respectively.Conclusion: We report the prevalence of malignant colorectal polyps in Saudi Arabia which was not reported before. Two unique prognostic markers for high-risk polyps were identified, namely, inpatient status and hypochloremia.

Kudo's pit pattern classification for in vivo optical diagnosis and discrimination of advanced colorectal polyps.

Colonoscopy is currently the basic diagnostic tool for the large intestine. The size of lesions assessed during the investigation is one criterion for assessing the risk of polyps transforming into colorectal cancer. The techno-logical development of endoscopes and the possibility of direct assessment of lesion's surface during the endoscopic examination and to use appropriate treatment. The aim of this study is to analyze the consistency between the histopathological assessment of high-risk lesions in colonoscopy and the determination according to Kudo's pit pattern classification. The analysis included the results of colonoscopies performed over a 2-year period, in which polyps were diagnosed endoscopically and either polypectomies were performed, or sections were taken from these polyps and a pit pattern analysis was done according to Kudo's classification. A total of 1038 patients (age, 67.2 ± 12.7 years) were enrolled in the study. Of the 1981 samples taken in total, polyps larger than 1 cm were found in 96 cases, laterally spreading tumors (LSTs) were found in 48 cases, and macroscopic infiltration or tumors were found in 110 cases. The results of the histopathological examination were obtained in 248 cases. A value of 4 or higher in the Kudo classification turned out to be the best parameter to differentiate malignant lesions from benign ones for lesions larger than 1 cm and laterally spreading tumors, with a sensitivity of 91.2% and a specificity of 70.4%. The assessment of polyps according to Kudo's classification is a useful tool for assessing the malignancy of lesions as part of a routine colonoscopy.

Sessile serrated lesions: Clinicopathological characteristics, endoscopic diagnosis, and management.

The 2019 World Health Organization (WHO) Classification of Tumours of the Digestive System (5th edition) introduced the term "sessile serrated lesion" (SSL) to replace the term "sessile serrated adenoma/polyp" (SSA/P). SSLs are early precursor lesions in the serrated neoplasia pathway that result in colorectal carcinomas with BRAF mutations, methylation for DNA repair genes, a CpG island methylator phenotype, and high levels of microsatellite instability. Some of these lesions can rapidly become dysplastic or invasive carcinomas that exhibit high lymphatic invasion and lymph node metastasis potential. The 2019 WHO classification noted that dysplasia arising in an SSL most likely is an advanced polyp, regardless of the morphologic grade of the dysplasia. Detecting SSLs with or without dysplasia is critical; however, detection of SSLs is challenging, and theiridentification by endoscopists and pathologists is inconsistent. Furthermore, indications for their endoscopic treatment have not been established. Moreover, SSLs are considered to contribute to the development of post-colonoscopy colorectal cancers. Herein, the clinicopathological and endoscopic characteristics of SSLs, including features determined using white light and image-enhanced endoscopy, therapeutic indications, therapeutic methods, and surveillance are reviewed based on the literature. This information may lead to more intensive research to improve detection, diagnosis, and rates of complete resection of these lesions and reduce post-colonoscopy colorectal cancer rates.