Colonic Neoplasia Research Articles

Microbiological aspects of cancer progression: A systematic review conducted according to the PRISMA 2020 guidelines and the Cochrane Handbook for Systematic Reviews of Interventions.

The complex interplay between the gut microbiota, cancer treatments and patient characteristics has emerged as a significant area of research. This study sought to examine these relationships in the context of colorectal cancer (CRC).A comprehensive search of relevant studies was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The studies included a variety of treatment modalities and microbiological parameters. A data extraction form, designed specifically for this review, was used to assess a range of variables across all studies.The analysis revealed a multifaceted interaction between the gut microbiota, genetic factors and treatment outcomes. Elderly patients with CRC frequently received single-agent chemotherapy, with outcomes that were comparable to those of younger patients. The presence of tumorigenic bacteria, including Escherichia coli and Bacteroides fragilis, was associated with early colon neoplasia. Additionally, an abundance of Fusobacterium spp. was observed in colonic adenomas, contributing to a pro-inflammatory environment. Although the FcγRIIIa-158 V/V genotype was associated with higher cetuximab-mediated antibodydependent cellular cytotoxicity (ADCC), no direct influence of FcγR polymorphisms on treatment response was noted. Furthermore, the combination of programmed cell death protein-1 (PD-1), BRAF and MEK inhibition showed favorable response rates. The gut microbiome, especially the presence of Fusobacterium spp., had a notable influence on the therapeutic response in CRC.These findings underscore the role of the gut microbiota and genetic factors in cancer treatment outcomes, emphasizing the potential of a holistic approach to cancer management. Future research should exploit these findings in order to develop microbiota-modulating strategies and personalized medicine approaches for the purpose of improving the efficacy of cancer treatment.

Possibilities and features of endoscopic removal of epithelial colorectal neoplasms on an outpatient basis

In the fight against colorectal cancer, there is a growing demand for more endoscopic procedures to remove colonic epithelial neoplasia. It is relevant and possible to carry out such interventions without prolonged hospitalization. The results of 330 endoscopic operations performed in the endoscopic department at a level III institution of outpatient care for the adult population of the Moscow region are presented. The method removing neoplasia was determined by the available equipment and recommendations. 1500 colon neoplasia were removed, no intraoperative complications were noted, the frequency of postoperative complications as bleeding was 0.6%.

Guanine nucleotide exchange factors and colon neoplasia.

Despite many diagnostic and therapeutic advances, colorectal cancer (CRC) remains the second leading cause of cancer death for men and women in the United States. Alarmingly, for reasons currently unknown, the demographics of this disease have shifted towards a younger population. Hence, understanding the molecular mechanisms underlying CRC initiation and progression and leveraging these findings for therapeutic purposes remains a priority. Here, we review critically the evidence that canonical and noncanonical actions of guanine nucleotide exchange factors (GEFs) play important roles in CRC evolution. Rho GEF GTPases, which switch between inactive GDP-bound and active GTP-bound states, are commonly overexpressed and activated in a variety of cancers, including CRC, and may be tractable therapeutic targets. In addition to comprehensively reviewing this field, we focus on Rho/Rac GEFs that are involved in regulating key functions of normal and neoplastic cells like cell polarity, vesicle trafficking, cell cycle regulation, and transcriptional dynamics. Prime examples of such Rho/Rac GEFs include βPak-interacting exchange factor (βPix), a Rho family GEF for Cdc42/Rac1, Tiam1, GEF-H1, RGNEF, and other GEFs implicated in CRC development and progression. Throughout this analysis, we explore how these findings fill key gaps in knowledge regarding the molecular basis of colon carcinogenesis and how they may be leveraged to treat advanced CRC. Lastly, we address potential future directions for research into the role of GEFs as CRC biomarkers and therapeutic targets. In this regard, leveraging the noncanonical actions of GEFs appears to provide a relatively unexplored opportunity requiring further investigation.

Evaluation of the Danish Colorectal Cancer Screening Program Among People With Cystic Fibrosis.

We aimed to evaluate the Danish CRC screening program, estimate colonic neoplasia's prevalence, and assess the utilized BP regimens. People with cystic fibrosis (pwCF) have an increased risk of precancerous polyps and colorectal cancer (CRC), with occurrence at an earlier age compared with the general population. Consequently, colonoscopy screening is recommended. PwCF requires specific bowel preparation (BP) regimens to ensure an adequate colonoscopy. We conducted a national retrospective cohort study, which included all pwCF eligible for colonoscopy according to international recommendations in 26 months. Among 119 eligible pwCF, 58 completed colonoscopies during the screening period. The screening was omitted in 25% of pwCF. Among the pwCF undergoing colonoscopy screening, precancerous polyps were found in 24% and none with CRC. One patient developed CRC before being offered screening. Risk factors for neoplasia were old age and male sex. The quality of BP was high, even though most pwCF received standard BP. The best quality was found in nonorgan transplanted, pwCF who received modulator treatment and those with no laxatives use. We detected a high adherence to CRC screening, but also a substantial proportion of pwCF who were not informed about screening recommendations, calling for greater awareness among clinicians. Although lower than previously described, our study revealed high numbers of precancerous polyps and CRC compared with the general population, underlining the need for screening. BP quality remained high, despite frequent use of standard regimens, implicating the need for more individualized regimens before undergoing colonoscopy.

FP3.13 - Acute Complicated Diverticulitis: Colorectal Cancer in Disguise? Five Years of Follow-up Practice at a 600-bed Hospital

Abstract Aims Complicated diverticular disease is associated with colonic neoplasia rates of 7.8% to 10.9%. ACPGBI guidelines recommend optical or virtual colonoscopy six weeks following an attack of acute complicated diverticulitis unless performed within the preceding two years. It has been posited that flexible sigmoidoscopy may be sufficient to rule out malignancy given that diverticulitis predominantly affects the sigmoid colon. Five years of practice at a 600-bed hospital was audited to the ACPGBI standard and malignancy rates and locations investigated. Methods All emergency admissions coded for acute complicated diverticulitis from January 2017 to December 2022 were included. Patient electronic records were reviewed retrospectively for demographic data, operation notes, as well as radiology, endoscopy and histology reports. Results A total of 197 patients were included in the study period. 97 cases underwent emergency or semi-elective resection within one year. 8 patients had colonic visualisation in the two years prior to their attack, leaving 92 cases in whom colonic visualisation was indicated. 44 patients had colonoscopy, 22 had flexible sigmoidoscopy, 2 had CT colonography and 24 had no further imaging. 7 malignancies were identified, 5 from resection specimens and 2 from endoscopy. All tumours were in sigmoid colon. Conclusions The ACPGBI standard was met in 50% (46/92) of cases. If flexible sigmoidoscopy were deemed acceptable this would increase to 74% (68/92). Malignancy was identified in 4% (7/197) of cases. All malignancies were in the range of flexible sigmoidoscopy, suggesting full colonoscopy may be superfluous. Less extensive endoscopy may reduce procedure duration, bowel preparation and patient discomfort.

FP3.5 - Colonoscopy post diverticulitis – Compliance with ACPGBI guidance in a single centre audit

Abstract Introduction For decades the management of acute diverticulitis (AD) has included endoscopic evaluation to exclude malignancy. In complicated AD, the incidence of colonic neoplasia is between 7.8%-10.9% (1-5) so interval colonoscopy remains mandatory. However, in uncomplicated AD, the incidence is low, 1.6%-1.9% (1-5), therefore the routine colonoscopy may be unnecessary in this group. This audit aims to assess our single-centre compliance with the ACPGBI guidance of colonoscopy post-diverticulitis. Methods A retrospective single-centre audit enrolled 120 patients with CT-confirmed diverticulitis over 18 months. Patient identification involved on-call handover sheets or PACS reports containing "diverticulitis" or "complicated diverticular disease." Patient scans were reviewed, and their management was studied. Results Number Number Uncomplicated Surgery 0 (Hinchey 1A+1B) No surgery 90 (75%) Colonoscopy 71 (59%) No colonoscopy 19 (16%) Surgery 15 (12.5%) Complicated (Hinchey 2 or greater) No surgery 15 (12.5%) Colonoscopy 11 (9.2%) No colonoscopy 4 (3.3%) Total 120 3.3% of complicated diverticulitis did not undergo colonoscopy due to patient choice, comorbidities or frailty. Among the 82 patients who underwent colonoscopy, there was no detection of CRC, resulting in a 0% detection rate. Conclusion In this 120-patient cohort, the incidence of colorectal cancer was 0%, which is in keeping with the published data. 78.9% of patients with uncomplicated diverticulitis underwent colonoscopy, which may have been unnecessary. The use of faecal immunochemical testing may be beneficial as an adjunct to avoid endoscopy in this group, whilst taking into consideration individual risk factors such as age, clinical suspicion of malignancy or concerning features on imaging.

Diagnostic Accuracy of Artificial Intelligence in Endoscopy: Umbrella Review.

Some research has already reported the diagnostic value of artificial intelligence (AI) in different endoscopy outcomes. However, the evidence is confusing and of varying quality. This review aimed to comprehensively evaluate the credibility of the evidence of AI's diagnostic accuracy in endoscopy. Before the study began, the protocol was registered on PROSPERO (CRD42023483073). First, 2 researchers searched PubMed, Web of Science, Embase, and Cochrane Library using comprehensive search terms. Then, researchers screened the articles and extracted information. We used A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR2) to evaluate the quality of the articles. When there were multiple studies aiming at the same result, we chose the study with higher-quality evaluations for further analysis. To ensure the reliability of the conclusions, we recalculated each outcome. Finally, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to evaluate the credibility of the outcomes. A total of 21 studies were included for analysis. Through AMSTAR2, it was found that 8 research methodologies were of moderate quality, while other studies were regarded as having low or critically low quality. The sensitivity and specificity of 17 different outcomes were analyzed. There were 4 studies on esophagus, 4 studies on stomach, and 4 studies on colorectal regions. Two studies were associated with capsule endoscopy, two were related to laryngoscopy, and one was related to ultrasonic endoscopy. In terms of sensitivity, gastroesophageal reflux disease had the highest accuracy rate, reaching 97%, while the invasion depth of colon neoplasia, with 71%, had the lowest accuracy rate. On the other hand, the specificity of colorectal cancer was the highest, reaching 98%, while the gastrointestinal stromal tumor, with only 80%, had the lowest specificity. The GRADE evaluation suggested that the reliability of most outcomes was low or very low. AI proved valuabe in endoscopic diagnoses, especially in esophageal and colorectal diseases. These findings provide a theoretical basis for developing and evaluating AI-assisted systems, which are aimed at assisting endoscopists in carrying out examinations, leading to improved patient health outcomes. However, further high-quality research is needed in the future to fully validate AI's effectiveness.

Neoadjuvant Immunotherapy and Intestinal Microbiota: Unraveling their roles in Anastomotic Leakage and Fistula after Colorectal Cancer Surgery

This comprehensive review explores the multifaceted relationship between neoadjuvant immunotherapy, intestinal microbiota alterations, and anastomotic leakage risk in patients undergoing colectomy for colon neoplasia. With the advent of immunotherapy, remarkably immune checkpoint inhibitors, there has been a significant shift in the treatment paradigms for various cancers, including colon neoplasia. These treatments, while effective, have been associated with changes in the intestinal microbiome, which, in turn, may influence wound healing and the integrity of anastomotic sites. The review delves into the complex interactions between the immune system and the gut microbiota, examining how immunotherapy-induced dysbiosis could disrupt the delicate balance necessary for optimal anastomotic healing. It discusses the role of specific bacterial species in modulating the immune response to cancer and their impact on the efficacy of immunotherapeutic agents. Moreover, the review highlights the potential mechanisms through which the microbiota-immune system interaction could affect surgical outcomes, focusing on the development of anastomotic leaks. The implications of these findings for clinical practice are discussed, including the need for targeted strategies to modulate the gut microbiota in patients undergoing immunotherapy and colectomy. Through this discussion, the review aims to provide insights into improving patient outcomes by integrating microbiome management into colon neoplasia patients' treatment and perioperative care.

Novel method of image analysis that combines Radon and Fourier image transformations for the purpose of differentiating between malignant and benign colonic biopsies.

Colorectal cancer is the third most common type of cancer. It develops slowly as a polyp that can turn into a cancerous tumor. This study aimed to develop a decision-making algorithm of microscopic images using texture analysis that is orientation free, to be used for automated classification of normal and neoplastic (malignant or premalignant) colonic biopsies. Forty-nine colonic adenocarcinomas, 41 adenomas and a control group of adjacent normal colonic mucosa were included in the texture analysis. Radon transform followed by the Fast Fourier transform were applied to the images. Subsequently, the gray level co-occurrence matrix (GLCM) transform was applied allowing the extraction of four textural variables (homogeneity, contrast, correlation, and entropy). For classification and prediction of the diagnosis, a statistical multivariate regression model and a neural network (NNET) model were used and compared. The statistical model provided a sensitivity of 71.3% and a specificity of 50% (Area under the ROC curve: 0.67) for classifying the neoplastic and the normal images, respectively. The NNET model was superior to the statistical model and produced a sensitivity of 97.9% and specificity of 88% (Area under the ROC curve: 0.92). To our knowledge, this is the first study that used a combination of Radon, FFT, and GLCM transformations in order to overcome the tissue orientation problem in texture analysis of microscopic images of colonic biopsies. The NNET classifier trained by the extracted textural features proved to be superior to the statistical classifier, thus predicting colonic neoplasia with high accuracy. RESEARCH HIGHLIGHTS: We propose a novel decision-making algorithm of orientation invariant image texture analysis, fast and easily implemented for automated differentiation between benign and neoplastic epithelial tumors of the colon. This method can reduce the turnaround time allowing to prioritize the biopsies during their examination and diagnosis by the pathologist.

Early Discharge after Enhanced Recovery Colectomy does Not Increase ED Visits and Readmissions: A Single Institution Analysis

Background: With continued advancements in Enhanced Recovery Pathway (ERP) protocols, we have noticed a significant decrease in colorectal surgery emergency department (ED) visits and readmissions. When considering same-day discharge after colorectal surgery in ERP patients, it would be important to know if early discharge is associated with increased ED visits and readmissions. This study is to determine if discharge on postoperative days (POD) one or two is associated with increased rates of ED visits and hospital readmissions after left and right colectomy. Methods: This is a single institution analysis of a prospectively maintained institutional colorectal surgery database between 07/01/2018 and 07/15/2022. The primary outcomes were ED visit and readmission rates for enhanced recovery open and minimally invasive right and left colectomy using logistic regressions models. Results: 820 patients met inclusion criteria; mean age 62.8 years; 47.4% ASA-3, and 83.2% had a minimally invasive surgical approach. Hospital length-of-stay decreased over the study period. There were significant differences in discharge-day by diagnosis - 58.5% of patients with Crohn’s disease were discharged on POD≥4 and 21.6% of those with benign colon neoplasia were discharged on POD 0-1 (p < 0.001). ED visits occurred in 12.9% of the study population and were not significantly different between discharge-day groups (p=0.096). Overall readmission rate was 8.5% and significantly different between discharge-day groups (0% POD-0 vs 8.3% POD-1 vs 5.8% POD-2 vs 6.9% POD-3 vs 12.9% POD≥4, p=0.041). Logistic regression showed that ED visits and readmissions for longer discharge-days (POD-2, POD-3, POD≥4) were not significantly different than POD-0-1. Readmission diagnoses for the study population were higher for ileus (17.1%) and SSI III (22.9%) than for AKI (1.4%) and SSI I/II (1.4%). Readmissions were not related to discharge day of the week (p=0.494). Conclusions: Early discharge after left and right colectomy is not associated with increased rates of ED visits and readmissions. Same-day discharge may be feasible in selected enhanced recovery patients. Risks and benefits associated with same-day discharge require further investigation.

Neoadjuvant Immunotherapy and Intestinal Microbiota: Unraveling Their Roles in Anastomotic Leakage and Fistula After Colorectal Cancer Surgery

This comprehensive review explores the multifaceted relationship between neoadjuvant immunotherapy, intestinal microbiota alterations, and anastomotic leakage risk in patients undergoing colectomy for colon neoplasia. With the advent of immunotherapy, remarkably immune checkpoint inhibitors, there has been a significant shift in the treatment paradigms for various cancers, including colon neoplasia. These treatments, while effective, have been associated with changes in the intestinal microbiome, which, in turn, may influence wound healing and the integrity of anastomotic sites. The review delves into the complex interactions between the immune system and the gut microbiota, examining how immunotherapy-induced dysbiosis could disrupt the delicate balance necessary for optimal anastomotic healing. It discusses the role of specific bacterial species in modulating the immune response to cancer and their impact on the efficacy of immunotherapeutic agents. Moreover, the review highlights the potential mechanisms through which the microbiota-immune system interaction could affect surgical outcomes, focusing on the development of anastomotic leaks. The implications of these findings for clinical practice are discussed, including the need for targeted strategies to modulate the gut microbiota in patients undergoing immunotherapy and colectomy. Through this discussion, the review aims to provide insights into improving patient outcomes by integrating microbiome management into colon neoplasia patients' treatment and perioperative care.

Early-Onset Colorectal Cancer-A Retrospective Study from a Tertiary Referral Hospital in Romania.

Early-onset colorectal cancer emerges as a distinctive clinical and biological entity and is generally defined as the onset of colon or rectal neoplasia before the age of 50. Several reports describe an increasing incidence worldwide of colorectal cancers occurring in individuals younger than 50 years, along with particular histologic and molecular features. Although heredity may be an explanation in some cases with young-onset colorectal cancer, other driving factors remain partially unknown. The present study explores demographic, clinical, and pathological features within a group of patients diagnosed with colorectal cancer before the age of 50. It is a retrospective survey based on data collected between 2017 and 2023 within three surgical departments from a tertiary Romanian hospital. The clinical and pathological features we identified (later-stage disease, distal colon tumor localization, mucinous histology) are mainly superimposed with the existing data in the literature regarding this pathology. In order to lower the burden that colorectal neoplasia diagnosed in the young implies, a change of paradigm should be made in terms of establishing effective and targeted screening programs but also in the direction of enhancing complex clinical, pathological, and molecular diagnosis.

Serum ferritin and risk of colonic neoplasia: Implications for the workup and treatment of iron deficiency.

Iron deficiency is the most common extraintestinal sign of colonic neoplasia, including colorectal cancer (CRC) and other lower gastrointestinal pathology. Both upper endoscopy and colonoscopy is usually recommended in the work-up of patients with unexplained iron deficiency, particularly in men and postmenopausal women. As the incidence of early-onset CRC (age <50 years) rises in the United States, there is an increasing need to identify risk predictors to aid in the early detection of CRC. It remains unknown if serum ferritin (SF), and what specific threshold, can be used as a marker to stratify those at risk for CRC and other lower gastrointestinal pathology. In this current review of the literature, we aimed to review guidelines for diagnostic workup of colonic neoplasia in the setting of iron deficiency and examine the association and specific thresholds of SF and risk of CRC by age. Some of the published findings are conflicting, and conclusions specific to younger patients are limited. Though further investigation is warranted, the cumulative findings suggest that SF, in addition to considering the clinical context and screening guidelines, may have potential utility in the assessment of colonic neoplasia.

Early Discharge after Enhanced Recovery Colectomy Does Not Increase Emergency Department Visits and Readmissions: A Single Institution Analysis.

Same-day discharge after colorectal surgery in enhanced recovery pathways is increasing. This study aimed to determine if discharge on postoperative days (POD) one or two is associated with increased rates of emergency department (ED) visits and hospital readmissions after left and right colectomy. Single institution retrospective analysis of prospective institutional colorectal surgery database between 07/01/2018 and 07/15/2022. Primary outcomes were ED visit and readmission rates for enhanced recovery open and minimally invasive right and left colectomy using logistic regressions models. 820 patients met inclusion criteria. There were significant differences in discharge-day by diagnosis-58.5% of patients with Crohn's disease were discharged on POD ≥4 and 21.6% with benign colon neoplasia were discharged on POD-0-1 (P < .001). ED visits occurred in 12.9% of the study population and were not significantly different between discharge-day groups (P = .096). Overall readmission rate was 8.5% and significantly different between discharge-day groups (0% POD-0 vs 8.3% POD-1 vs 5.8% POD-2 vs 6.9% POD-3 vs 12.9% POD ≥4, P = .041). Logistic regression showed that ED visits and readmissions for longer discharge-days (POD-2, POD-3, POD ≥4) were not significantly different than POD-0-1. Readmission diagnoses for the study population were higher for ileus (17.1%) and surgical site infection (SSI) type-III (22.9%) than for acute kidney injury (1.4%) and SSI type-I/II (1.4%). Early discharge after left and right colectomy is not associated with increased rates of ED visits and readmissions. Same-day discharge may be feasible in selected enhanced recovery patients. Standardized post-discharge resources that safely allow same-day discharge require further investigation.

Abstract 260: Depletion of Ezh2 in the intestinal adenoma induced by JAK2V617F mutation leads to the malignant neoplasm

Abstract Background The increased JAK2 and EZH2 plays a critical role in the colorectal or colon cancer (CRC) progression. Targeting aberrant JAK2 expression caused by JAK2 gain-of-function (GOF) mutation, JAK2V617F and deregulated EZH2 kinase activity, JAK2 and/or EZH2 inhibitors have been used to treat the advanced CRCs. However, it is unclear whether the aberrant JAK2 can directly induce CRC or intestinal epithelial (IEC) malignancy. We hypothesize that the overexpressed JAK2 driven by JAK2V617F GOF mutation increases IEC neoplasia in which depletion of EZH2 can lead to IEC malignant neoplasm. Materials and Methods Colorectal samples were collected from 20 cases of CRC patients. Immunohistochemistry staining (IH), confocal immunofluorescence staining (IF) and bulk RNAseq were used to determine LGR5, Ki67, JAK2, EZH2, mutant β-catenin and JAK2V617F GOF mutation. Crypt-derived organoids or tumoroids were used to determine the JAK2 and EZH2 in the proliferative LGR5 cells (Ki67hiLGR5+) and were treated with JAK2 and/or EZH2 inhibitors. The mice with JAK2 and/or EZH2 deficiency in IECs were generated by crossing VilCreER mice, floxed-Jak2 and/or floxed-Ezh2 mice to determine the intestinal and colonic neoplasia. Lgr5, Ki67, Cdx2 Jak2, Ezh2, and mutant β-catenin IH or IF, organoids culture and peritoneal xenograft were used to determine the malignant neoplasm. The JAK2V617F-transfected HT29 or Caco-2 cells were used to determine the migration induced by JAK2V617F GOF mutation, then treated with EZH2 inhibitors to determine the effects of EZH2 inhibition on JAK2V617F GOF mutation-induced migration. The spheres were formed with Caco-cells with JAK2V617F GOF mutation and were used to observe the effects of JAK2V617F GOF mutation on IEC neoplasia formation. Results JAK2 and/or EZH2 overexpression are positively correlated with the probability of CRC initiation. JAK2 and EZH2 are highly expressed in the CRC tumoroids. Inhibition of EZH2 increases the CRC tumoroids growth and spheroid formation, and reduces budding numbers while reducing the proliferation of organoids from healthy crypts. Jak2 over-expression in IECs increases intestinal microadenoma, and depletion of EZH2 in the adenoma increases mutant β-catenin and severity of intestinal adenoma, suggesting that depletion of EZH2 enhances the malignancy of overexpressed Jak2-derived IEC neoplasia. Consistently, JAK2V617F GOF mutation increases HT29 or Caco-2 cell migration. Conclusion JAK2V617F GOF mutation can drive IEC neoplastic proliferation and adenoma, depletion of EZH2 in the adenoma leads to IEC malignant neoplasm. Our research suggests that loss of Ezh2 may synergistically cooperate with the Jak2V617F mutation in the pathogenesis of IEC malignant neoplasm. Citation Format: Nardana Esmaeili, Ahmed Bakheet, Wen Gao, Haifeng Li, Dan Cai, Xiaonan Han. Depletion of Ezh2 in the intestinal adenoma induced by JAK2V617F mutation leads to the malignant neoplasm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 260.

Abstract 2820: The effect of Pten haploinsufficiency on genomic and transcriptomic profiles in combined genetically-engineered mouse models for colonic neoplasia based on Apc inactivation

Abstract Background and Aim: We have reported genetically-engineered mouse models for colonic neoplasia by using our novel CDX2P-Cre mice, in which Cre is restrictedly expressed in colonic epithelial cells. Although colonic tumors are generated in CDX2P-Cre;Apcflox/+ (CPC;Apc) mice with highly penetrant rate, greater number and deeper invasion of colonic tumors were observed in CDX2P-Cre;Apcflox/+;Ptenflox/+ (CPC;Apc+Pten), possibly resulting from haploinsufficiency of Pten gene. We have also confirmed shorter lifespan in CPC;Apc+Pten than that in CPC;Apc (AACR Annual Meeting 2018). Here, we test if these phenotypes come from one copy loss of Pten itself or secondary genetic and/or transcriptomic alterations induced by Pten loss by using whole genome sequence (WGS) and RNA sequence from macroscopically-dissected colonic tumors (bulk RNA-seq). Methods: WGS for five tumors and five livers as counterpart controls in each mouse model was performed by DNBSEQ platforms. Bulk RNA-seq was performed for three tumors in each model. Results: In the analysis using B-allele frequency, copy-neutral LOH occurred in chromosome 18 including Apc loci specifically in colonic neoplasia in both CPC;Apc and CPC;Apc+Pten mice. In contrast, LOH was not observed in chromosome 19 including Pten loci in CPC;Apc+Pten mice. We also confirmed remarkably decreased coverage of reads in reference mapping in Apc locus, and there was a slight decrease of coverage in Pten locus. There were no additional driver gene mutations in CPC;Apc or CPC;Apc+Pten in WGS. All these results suggested just one copy loss of Pten resulting in aggressive tumor phenotype in CPC;Apc+Pten mice. In RNA-seq and subsequent GSEA comparing colonic tumors in CPC;Apc+Pten with those in CPC;Apc revealed upregulation of some signal pathways including mTORC1. Supporting this observation, number of colon tumors, especially adenocarcinomas, were decreased by rapamycin administration to CPC;Apc+Pten. Similarly, rapamycin was more effective in tumorids from CPC;Apc+Pten those from CPC;Apc. Conclusion: WGS reveals one copy loss of Pten locus is the only genetic alteration in CPC;Apc+Pten when compared with CPC;Apc. One copy loss of Pten is sufficient to upregulate mTORC1 pathway in a CPC;Apc+Pten mouse model, resulting in promotion of tumor formation and invasion. Citation Format: Haruki Sada, Hiroaki Niitsu, Hikaru Nakahara, Naoya Sakamoto, Hirotaka Tashiro, Hideki Ohdan, Takao Hinoi. The effect of Pten haploinsufficiency on genomic and transcriptomic profiles in combined genetically-engineered mouse models for colonic neoplasia based on Apc inactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2820.

Adenoma characteristics in the English Bowel Cancer Screening Programme.

The English Bowel Cancer Screening Programme detects colorectal cancers and premalignant polyps in a faecal occult blood test-positive population. The aim of this work is to describe the detection rates and characteristics of adenomas within the programme, identify predictive factors influencing the presence or absence of carcinoma within adenomas and identify the factors predicting the presence of advanced colonic neoplasia in different colon segments. The Bowel Cancer Screening System was retrospectively searched for polyps detected during colonoscopies between June 2006 and June 2012, at which time a guaiac test was being used. Data on size, location and histological features were collected, and described. Univariate and multivariate analyses were used to determine the significant factors influencing the development of carcinoma within an adenoma. A total of 229 419 polyps were identified; after exclusions 136 973 adenomas from 58 334 patients were evaluated. Over half were in the rectum or sigmoid colon. Subcentimetre adenomas accounted for 69.8% of the total. The proportion of adenomas containing advanced histological features increased with increasing adenoma size up to 35 mm, then plateaued. A focus of carcinoma was found in 2282 (1.7%) adenomas, of which 95.6% were located distally. Carcinoma was identified even in diminutive adenomas (0.1%). The proportion of adenomas containing cancer was significantly higher in women than men (2.0% vs. 1.5%, p < 0.001). This national, prospectively captured dataset adds robust information about histological features of adenomas that convey an increased risk for colorectal cancer, and identifies caecal adenomas, high-grade dysplasia, increasing adenoma size, distal location and female sex as independent risk factors associated with carcinoma.

The Efficacy of Real-time Computer-aided Detection of Colonic Neoplasia in Community Practice: A Pragmatic Randomized Controlled Trial

BackgroundThe use of computer-aided detection (CADe) has increased the adenoma detection rates (ADR) during colorectal cancer (CRC) screening/surveillance in randomized controlled trials (RCT) but has not shown benefit in real-world implementation studies. We performed a single-center pragmatic RCT to evaluate the impact of real-time CADe on ADR in colonoscopy performed by community gastroenterologists. MethodsWe enrolled 1100 patients undergoing colonoscopy for CRC screening, surveillance, positive fecal-immunohistochemical tests, and diagnostic indications at one community-based center from 09/2022 to 03/2023. Patients were randomly assigned (1:1) to traditional-colonoscopy or real-time CADe Blinded pathologists analyzed histopathologic findings. The primary outcome was adenoma detection rate (ADR, the percentage of patients with at least 1 histologically proven adenoma or carcinoma). Secondary outcomes were adenomas detected per colonoscopy (APC), sessile-serrated lesion detection rate (SSLDR), and non-neoplastic resection rate. ResultsThe median age was 55.5 (IQR 50-62), 61% were female, 72.7% were Hispanic ethnicity, and 9.1% had inadequate bowel preparation. The ADR for the CADe group was significantly higher than the traditional-colonoscopy group (42.5% vs. 34.4%, p=0.005). The mean APC was significantly higher in the CADe group compared to the traditional-colonoscopy group (0.89±1.46 vs. 0.60±1.12, p<0.001). The improvement in adenoma detection was driven by increased detection of <5 mm adenomas. CADe had a higher SSLDR than traditional-colonoscopy (4.7% vs. 2.0%, p=0.01) The improvement in ADR with CADe was significantly higher in the first half of the study (47.2% vs. 33.7%, p=0.002) compared to the second half (38.7% vs. 34.9%, p=0.33). ConclusionsIn a single-center pragmatic randomized controlled trial, real-time CADe modestly improved ADR and APC in average-detector community endoscopists. (ClinicalTrials.gov number, NCT05963724).

Impact of the SARS-CoV-2 on the journey of high-risk colon cancer patients within the scope of the Unified Health System in Brazil

BackgroundColon cancer is an important cause of mortality related to cancer. During the COVID-19 pandemic, an important reallotment of assistance resources was necessary to tackle the crisis, directly impacting medical practice all over the globe.ObjectiveTo assess the impact of the Sars-Cov-2 pandemic on the time between diagnosis and the beginning of systemic treatment in patients diagnosed with high-risk colon neoplasia.MethodsThis is a retrospective study based on the analysis of medical records of patients diagnosed with colon neoplasia who required systemic treatment and were treated between March 2019 and March 2022, in a reference Oncology unit of the Brazilian Unified Health System. The study’s population was divided into two groups: (I) Pre-COVID-19: diagnoses made between March 2019 and February 2020, (II) COVID-19: diagnoses made between March 2020 and March 2022.ResultsThe sample consisted of 228 patients, 108 (47.97%) of whom were diagnosed during pre-COVID-19 and 118 (52.21%) diagnosed during the two years-period of COVID-19. Regarding the time between colonoscopy and surgery, the time between surgery and first consultation in clinical oncology, and the time between requesting and beginning of systemic treatment, a statistically significant reduction was observed during the COVID-19 period.ConclusionA decrease in time between diagnosis and systemic treatment of patients with colorectal cancer during the COVID-19 pandemic was observed. Yet, even with this improvement, the time to begin treatment remains greater than the recommended by the current guidelines, regardless of the time of diagnosis (before or after the pandemic), which negatively impacts the disease outcome.

Muscarinic receptor agonist-induced βPix binding to β-catenin promotes colon neoplasia

M3 muscarinic receptors (M3R) modulate β-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, βPix, binds to β-catenin in colon cancer cells, augmenting β-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M3R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of βPix and β-catenin in stem cells overexpressing M3R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M3R agonist-induced cytoplasmic and nuclear association of βPix with β-catenin. βPix knockdown attenuated M3R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing βPix dose-dependently augmented β-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of βPix. Expression levels of β-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from βPix-deficient conditional knockout mice. Targeting the M3R/βPix/β-catenin axis may have therapeutic potential.