Development of desmoid tumours after ileorectal anastomosis versus ileal pouch-anal anastomosis in familial adenomatous polyposis.

BACKGROUND & AIMS: Desmoid tumours (DT) are an important cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP). DT development might be related to the type and approach of colectomy. We aimed to compare DT development after colectomy with ileorectal anastomosis (IRA) and proctocolectomy with ileal pouch-anal anastomosis (IPAA). METHODS: We performed an international historical cohort study in FAP patients who underwent IRA or IPAA between 1961 and 2020. The primary outcome was the incidence of abdominal DT (either mesenteric, retroperitoneal or abdominal wall). Patients with a DT diagnosis before or at colectomy were excluded. Time to DT was considered censored at an eventual secondary proctectomy after IRA. We used multivariable Cox regression modelling to adjust for potential confounders. RESULTS: We analysed data from 852 patients: 514 after IRA and 338 after IPAA (median follow-up 21 and 16 years, respectively). DTs were diagnosed in 64 IRA patients (12%) and 66 IPAA patients (20%). The cumulative DT incidence at 5 and 10 years was 7.5% and 9.3% after open IRA and 4.7% and 10.9% after laparoscopic IRA. These estimates were 13.6% and 15.4% after open IPAA and 8.4% and 10.0% after laparoscopic IPAA. The post-operative risk was significantly higher after IPAA (p < 0.01) in multivariable analysis, while approach did not significantly influence the risk. CONCLUSIONS: The risk of developing an abdominal DT was found to be significantly higher after IPAA than after IRA. Postoperative DT risk should be taken into account when choosing between IRA and IPAA in FAP.

Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited. METHODS: We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses. RESULTS: Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease. CONCLUSIONS: In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.).

Germline NPAT inactivating variants as cause of hereditary colorectal cancer.

Two independent exome sequencing initiatives aimed to identify new genes involved in the predisposition to nonpolyposis colorectal cancer led to the identification of heterozygous loss-of-function variants in NPAT, a gene that encodes a cyclin E/CDK2 effector required for S phase entry and a coactivator of histone transcription, in two families with multiple members affected with colorectal cancer. Enrichment of loss-of-function and predicted deleterious NPAT variants was identified in familial/early-onset colorectal cancer patients compared to non-cancer gnomAD individuals, further supporting the association with the disease. Previous studies in Drosophila models showed that NPAT abrogation results in chromosomal instability, increase of double strand breaks, and induction of tumour formation. In line with these results, colorectal cancers with NPAT somatic variants and no DNA repair defects have significantly higher aneuploidy levels than NPAT-wildtype colorectal cancers. In conclusion, our findings suggest that constitutional inactivating NPAT variants predispose to mismatch repair-proficient nonpolyposis colorectal cancer.

Temporal Trends in Body Composition and Metabolic Markers Prior to Diagnosis of Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: Changes in body composition and metabolic factors may serve as biomarkers for the early detection of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to capture the longitudinal changes in body composition and metabolic factors before diagnosis of PDAC. METHODS: We performed a retrospective cohort study in which all patients (≥18 years) diagnosed with PDAC from 2002 to 2021 were identified. We collected all abdominal computed tomography scans and 10 different blood-based biomarkers up to 36 months before diagnosis. We applied a fully automated abdominal segmentation algorithm previously developed by our group for 3-dimensional quantification of body composition on computed tomography scans. Longitudinal trends of body composition and blood-based biomarkers before PDAC diagnosis were estimated using linear mixed models, compared across different time windows, and visualized using spline regression. RESULTS: We included 1690 patients in body composition analysis, of whom 516 (30.5%) had ≥2 prediagnostic computed tomography scans. For analysis of longitudinal trends of blood-based biomarkers, 3332 individuals were included. As an early manifestation of PDAC, we observed a significant decrease in visceral and subcutaneous adipose tissue (ß = -1.94 [95% confidence interval (CI), -2.39 to -1.48] and ß = -2.59 [95% CI, -3.17 to -2.02]) in area (cm2)/height (m2) per 6 months closer to diagnosis, accompanied by a decrease in serum lipids (eg, low-density lipoprotein [ß = -2.83; 95% CI, -3.31 to -2.34], total cholesterol [ß = -2.69; 95% CI, -3.18 to -2.20], and triglycerides [ß = -1.86; 95% CI, -2.61 to -1.11]), and an increase in blood glucose levels. Loss of muscle tissue and bone volume was predominantly observed in the last 6 months before diagnosis. CONCLUSIONS: This study identified significant alterations in a variety of soft tissue and metabolic markers that occur in the development of PDAC. Early recognition of these metabolic changes may provide an opportunity for early detection.

Screening for pancreatic cancer in high-risk individuals using MRI: optimization of scan techniques to detect small lesions.

Pancreatic cancer has a dismal prognosis in the general population. However, early detection and treatment of disease in high-risk individuals can improve survival, as patients with localized disease and especially patients with lesions smaller than 10 mm show greatly improved 5-year survival rates. To achieve early detection through MRI surveillance programs, optimization of imaging is required. Advances in MRI technologies in both hardware and software over the years have enabled reliable detection of pancreatic cancer at a small size and early stage. Standardization of dedicated imaging protocols for the pancreas are still lacking. In this review we discuss state of the art scan techniques, sequences, reduction of artifacts and imaging strategies that enable early detection of lesions. Furthermore, we present the imaging features of small pancreatic cancers from a large cohort of high-risk individuals. Refinement of MRI techniques, increased scan quality and the use of artificial intelligence may further improve early detection and the prognosis of pancreatic cancer in a screening setting.

The Added Value of Blood Glucose Monitoring in High-Risk Individuals Undergoing Pancreatic Cancer Surveillance.

OBJECTIVES: The study aimed to investigate the added value of blood glucose monitoring in high-risk individuals (HRIs) participating in pancreatic cancer surveillance. MATERIALS AND METHODS: High-risk individuals with a CDKN2A/p16 germline pathogenic variant participating in pancreatic cancer surveillance were included in this study. Multivariable logistic regression was performed to assess the relationship between new-onset diabetes (NOD) and pancreatic ductal adenocarcinoma (PDAC). To quantify the diagnostic performance of NOD as a marker for PDAC, receiver operating characteristic curve with area under the curve was computed. RESULTS: In total, 220 HRIs were included between 2000 and 2019. Median age was 61 (interquartile range. 53-71) years and 62.7% of participants were female. During the study period, 26 (11.8%) HRIs developed NOD, of whom 5 (19.2%) later developed PDAC. The other 23 (82.1%) PDAC cases remained NOD-free. Multivariable analysis showed no statistically significant relationship between NOD and PDAC (odds ratio, 1.21; 95% confidence interval, 0.39-3.78) and 4 of 5 PDAC cases seemed to have NOD within 3 months before diagnosis. Furthermore, NOD did not differentiate between HRIs with and without PDAC (area under the curve, 0.54; 95% confidence interval, 0.46-0.61). CONCLUSIONS: In this study, we found no added value for longitudinal glucose monitoring in CDKN2A pathogenic variant carriers participating in an imaging-based pancreatic cancer surveillance program.

Aspects and outcomes of surveillance for individuals at high-risk of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths and is associated with a poor prognosis. The majority of these cancers are detected at a late stage, contributing to the bad prognosis. This underscores the need for novel, enhanced early detection strategies to improve the outcomes. While population-based screening is not recommended due to the relatively low incidence of PDAC, surveillance is recommended for individuals at high risk for PDAC due to their increased incidence of the disease. However, the outcomes of pancreatic cancer surveillance in high-risk individuals are not sorted out yet. In this review, we will address the identification of individuals at high risk for PDAC, discuss the objectives and targets of surveillance, outline how surveillance programs are organized, summarize the outcomes of high-risk individuals undergoing pancreatic cancer surveillance, and conclude with a future perspective on pancreatic cancer surveillance and novel developments.

Utilization and Outcomes of Multigene Panel Testing in Patients With Pancreatic Ductal Adenocarcinoma.

PURPOSE: Guidelines recommend germline genetic testing (GT) for patients with pancreatic ductal adenocarcinoma (PDAC). This study aims to evaluate the utilization and outcomes of multigene panel GT in patients with PDAC. METHODS: This retrospective, multisite study included patients with PDAC diagnosed between May 2018 and August 2020 at Mayo Clinic Arizona, Florida, and Minnesota. Discussion, uptake, and outcomes of GT were compared before (May 1, 2018-May 1, 2019) and after (August 1, 2019-August 1, 2020) the guideline update, accounting for a transition period. RESULTS: The study identified 533 patients with PDAC, with 321 (60.2%) preguideline and 212 (39.8%) postguideline. Patient characteristics did not differ between the preguideline and postguideline periods. GT was discussed in 34.3% (110 of 321) of preguideline and 39.6% (84 of 212) of postguideline patients (odds ratio [OR], 1.26 [95% CI, 0.88 to 1.80]) and subsequently performed in 80.9% (89 of 110) of preguideline and 75.0% (63 of 84) of postguideline patients (OR, 1.10 [95% CI, 0.75 to 1.61]). Of 152 tested patients, 26 (17.1%) had a pathogenic variant (PV), of whom 17 (11.2%; 17 of 152) were PDAC-associated. Over the entire study period, GT was more likely in younger patients (65 v 70 years; P < .001), those seen by a medical oncologist (82.9% v 69.0%; P < .001), and those surviving more than 12 months from diagnosis (70.4% v 43.4%; P < .001). Demographics and personal/family cancer history were comparable between patients with and without a PDAC PV. CONCLUSION: GT remains underutilized despite National Comprehensive Cancer Network guideline recommendations. Given the poor prognosis of PDAC and potential implications of GT, efforts to increase utilization are needed to provide surveillance and support to both patients with PDAC and at-risk family members.

Polyketide synthase positive Escherichia coli one-time measurement in stool is not informative of colorectal cancer risk in a screening setting.

Environmental factors like the pathogenicity island polyketide synthase positive (pks+) Escherichia coli (E. coli) could have potential for risk stratification in colorectal cancer (CRC) screening. The association between pks+ E. coli measured in fecal immunochemical test (FIT) samples and the detection of advanced neoplasia (AN) at colonoscopy was investigated. Biobanked FIT samples were analyzed for both presence of E. coli and pks+ E. coli and correlated with colonoscopy findings; 5020 CRC screening participants were included. Controls were participants in which no relevant lesion was detected because of FIT-negative results (cut-off ≥15 µg Hb/g feces), a negative colonoscopy, or a colonoscopy during which only a nonadvanced polyp was detected. Cases were participants with AN [CRC, advanced adenoma (AA), or advanced serrated polyp (ASP)]. Existing DNA isolation and quantitative polymerase chain reaction (qPCR) procedures were used for the detection of E. coli and pks+ E. coli in stool. A total of 4542 (90.2%) individuals were E. coli positive, and 1322 (26.2%) were pks+ E. coli positive. The prevalence of E. coli in FIT samples from individuals with AN was 92.9% compared to 89.7% in FIT samples of controls (p = 0.010). The prevalence of pks+ E. coli in FIT samples from individuals with AN (28.6%) and controls (25.9%) was not significantly different (p = 0.13). The prevalences of pks+ E. coli in FIT samples from individuals with CRC, AA, or ASP were 29.6%, 28.3%, and 32.1%, respectively. In conclusion, the prevalence of pks+ E. coli in a screening population was 26.2% and did not differ significantly between individuals with AN and controls. These findings disqualify the straightforward option of using a snapshot measurement of pks+ E. coli in FIT samples as a stratification biomarker for CRC risk. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Management after non-curative endoscopic resection of T1 rectal cancer.

Since the introduction of population-based screening, increasing numbers of T1 rectal cancers are detected and removed by local endoscopic resection. Patients can be cured with endoscopic resection alone, but there is a possibility of residual tumor cells remaining after the initial resection. These can be located intraluminally at the resection site or extraluminally in the form of (lymph node) metastases. To decrease the risk of residual cells progressing towards more advanced disease, additional treatment is usually needed. However, with the currently available risk stratification models, it remains challenging to determine who should and should not be further treated after non-curative endoscopic resection. In this review, the different management strategies for patients with non-curatively treated T1 rectal cancers are discussed, along with the available evidence for each strategy and relevant considerations for clinical decision making. Furthermore, we provide practical guidance on the management and surveillance following non-curative endoscopic resection of T1 rectal cancer.

Emerge of colorectal cancer in Lynch syndrome despite colonoscopy surveillance: A challenge of hide and seek.

Even with colonoscopy surveillance, Lynch syndromes (LS) carriers still develop colorectal cancer (CRC). The cumulative incidence of CRCs under colonoscopy surveillance varies depending on the affected mismatch repair (MMR) gene. However, the precise mechanisms driving these epidemiological patterns remain incompletely understood. In recent years, several potential mechanisms explaining the occurrence of CRCs during colonoscopy surveillance have been proposed in individuals with and without LS. These encompass biological factors like concealed/accelerated carcinogenesis through a bypassed adenoma stage and accelerated progression from adenomas. Alongside these, various colonoscopy-related factors may contribute to formation of CRCs under colonoscopy surveillance, like missed yet detectable (pre)cancerous lesions, detected yet incompletely removed (pre)cancerous lesions, and colonoscopy-induced carcinogenesis due to tumor cell reimplantation. In this comprehensive literature update, we reviewed these potential factors and evaluated their relevance to each MMR group in an attempt to raise further awareness and stimulate research regarding this conflicting phenomenon.

Oncologic outcomes of screen-detected and non-screen-detected T1 colorectal cancers.

BACKGROUND: The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program. METHODS: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups. RESULTS: 1803 patients were included (1114 [62%] screen-detected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38-0.68). CONCLUSIONS: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival.

The multitarget faecal immunochemical test for improving stool-based colorectal cancer screening programmes: a Dutch population-based, paired-design, intervention study.

BACKGROUND: The faecal immunochemical test (FIT) is widely employed for colorectal cancer screening. However, its sensitivity for advanced precursor lesions remains suboptimal. The multitarget FIT (mtFIT), measuring haemoglobin, calprotectin, and serpin family F member 2, has demonstrated enhanced sensitivity for advanced neoplasia, especially advanced adenomas, at equal specificity to FIT. This study aimed to prospectively validate and investigate the clinical utlitity of mtFIT versus FIT in a setting of population-based colorectal cancer screening. METHODS: Individuals aged 55-75 years and who were eligible for the Dutch national FIT-based colorectal cancer screening programme were invited to submit both a FIT and mtFIT sample collected from the same bowel movement. Positive FIT (47 µg/g haemoglobin cutoff) or mtFIT (based on decision-tree algorithm) led to a colonoscopy referral. The primary outcome was the relative detection rate of mtFIT versus FIT for all advanced neoplasia. Secondary outcomes were the relative detection rates of colorectal cancer, advanced adenoma, and advanced serrated polyps individually and the long-term effect of mtFIT-based versus FIT-based programmatic screening on colorectal cancer incidence, mortality, and cost, determined with microsimulation modelling. The study has been registered in ClinicalTrials.gov, NCT05314309, and is complete. FINDINGS: Between March 25 and Dec 7, 2022, 35 786 individuals were invited to participate in the study, of whom 15 283 (42·7%) consented, and 13 187 (86·3%) of 15 283 provided both mtFIT and FIT samples with valid results. Of the 13 187 participants, 6637 (50·3%) were male and 6550 (49·7%) were female. mtFIT showed a 9·11% (95% CI 8·62-9·61) positivity rate and 2·27% (95% CI 2·02-2·54) detection rate for advanced neoplasia, compared with a positivity rate of 4·08% (3·75-4·43) and a detection rate of 1·21% (1·03-1·41) for FIT. Detection rates of mtFIT versus FIT were 0·20% (95% CI 0·13-0·29) versus 0·17% (0·11-0·27) for colorectal cancer; 1·64% (1·43-1·87) versus 0·86% (0·72-1·04) for advanced adenoma, and 0·43% (0·33-0·56) versus 0·17% (0·11-0·26) for advanced serrated polyps. Modelling demonstrated that mtFIT-based screening could reduce colorectal cancer incidence by 21% and associated mortality by 18% compared with the current Dutch colorectal cancer screening programme, at feasible costs. Furthermore, at equal positivity rates, mtFIT outperformed FIT in terms of diagnostic yield. At an equally low positivity rate, mtFIT-based screening was predicted to further decrease colorectal cancer incidence by 5% and associated mortality by 4% compared with FIT-based screening. INTERPRETATION: The higher detection rate of mtFIT for advanced adenoma compared with FIT holds the potential to translate into additional and clinically meaningful long-term colorectal cancer incidence and associated mortality reductions in programmatic colorectal cancer screening. FUNDING: Stand Up to Cancer, Dutch Cancer Society, Dutch Digestive Foundation, and Health~Holland.

Gastric and duodenal cancer in individuals with Lynch syndrome: a nationwide cohort study.

Background: Lynch syndrome increases the risk of gastric cancer (GC) and duodenal cancer (DC), particularly in individuals with MLH1 and MSH2 pathogenic variants (PVs). To provide further insight into whether, and from what age, esophagogastroduodenoscopy (EGD) surveillance may be beneficial, we evaluated the cumulative incidence and tumour characteristics of GC and DC in a large nationwide cohort of Dutch individuals with LS. Methods: For this retrospective nationwide cohort study, clinical data of individuals with LS registered at the Dutch Hereditary Cancer Registry were matched with pathology reports filed by the Dutch Pathology registry. All individuals registered between Jan 1, 1989 and Dec 31, 2021 with proven or putative PVs in one of the mismatch repair genes were included. Cumulative incidences of GC and DC were estimated for high-risk (MLH1, MSH2 and EpCAM) and low-risk (MSH6 and PMS2) PVs using competing risk methodology (Fine and Gray method) with death due to other causes as competing risk. Findings: Among 1002 individuals with high-risk and 765 individuals with low-risk PVs, 29 GCs (1.6%) and 39 DCs (2.2%) were diagnosed. Cumulative incidence of GC and DC under the age of 50 was very low (≤1%) for all individuals. At age 70 and 75, cumulative incidence of GC was 3% [95% CI 1%-5%] and 5% [3%-8%] for high-risk PVs and 1% [0%-2%] and 1% [0%-2%] for low-risk PVs (p = 0.006). For DC, cumulative incidence at age 70 and 75 was 5% [3%-7%] and 6% [3%-8%] in high-risk, 1% [0%-1%] and 2% [0%-4%] in low-risk PVs, respectively (p = 0.01). Primary tumour resection was performed in 62% (18/29) of GCs and 77% (30/39) of DC cases. Early-stage GC, defined as TNM stage I, was found in 32% (9/28) of GCs. Early-stage DC, defined as TNM stage I-IIa, was found in 39% (14/36) of DCs. Interpretation: Individuals with MLH1, MSH2, and EpCAM PVs have an increased risk of developing GC and DC at the age of 70 years, but this risk is very low before the age of 50 years. The age of onset of surveillance, the yield of GC and DC during EGD surveillance, and its cost-effectiveness should be subject of future studies. Funding: None.

The global leadership into malnutrition criteria reveals a high percentage of malnutrition which influences overall survival in patients with gastroenteropancreatic neuroendocrine tumours.

Patients with neuroendocrine tumours located in the gastroenteropancreatic tract (GEP-NETs) and treatment with somatostatin analogues (SSA's) are at risk of malnutrition which has been reported previously evaluating weight loss or body mass index (BMI) only. The global leadership into malnutrition (GLIM) criteria include weight loss, BMI, and sarcopenia, for diagnosing malnutrition. These GLIM criteria have not been assessed in patients with GEP-NETs on SSA. The effect of malnutrition on overall survival has not been explored before. The aim of this study is to describe the presence of malnutrition in patients with GEP-NET on SSA based on the GLIM criteria and associate this with overall survival. Cross-sectional study screening all patients with GEP-NETs on SSA's for malnutrition using the GLIM criteria. Body composition analysis for sarcopenia diagnosis were performed. Bloods including vitamins, minerals, and lipid profile were collected. Overall survival since the date of nutrition screening was calculated. Uni- and multivariate Cox regression analysis were performed to identify malnutrition as risk factor for overall survival. A total of 118 patients, 47% male, with median age 67 years (IQR 56.8-75.0) were included. Overall, malnutrition was present in 88 patients (75%); based on low BMI in 26 (22%) patients, based on weight loss in 35 (30%) patients, and based on sarcopenia in 83 (70%) patients. Vitamin deficiencies were present for vitamin D in 64 patients (54%), and vitamin A in 29 patients (25%). The presence of malnutrition demonstrated a significantly worse overall survival (p-value = .01). In multivariate analysis meeting 2 or 3 GLIM criteria was significantly associated with worse overall survival (HR 2.16 95% CI 1.34-3.48, p-value = .002). Weight loss was the most important risk factor out of the 3 GLIM criteria (HR 3.5 95% CI 1.14-10.85, p-value = .03) for worse overall survival. A high percentage (75%) of patients with GEP-NETs using a SSA meet the GLIM criteria for malnutrition. Meeting more than 1 GLIM criterium, especially if there is weight loss these are risk factors for worse overall survival.

Enrichment of colibactin-associated mutational signatures in unexplained colorectal polyposis patients.

BACKGROUND: Colibactin, a genotoxin produced by polyketide synthase harboring (pks+) bacteria, induces double-strand breaks and chromosome aberrations. Consequently, enrichment of pks+Escherichia coli in colorectal cancer and polyposis suggests a possible carcinogenic effect in the large intestine. Additionally, specific colibactin-associated mutational signatures; SBS88 and ID18 in the Catalogue of Somatic Mutations in Cancer database, are detected in colorectal carcinomas. Previous research showed that a recurrent APC splice variant perfectly fits SBS88. METHODS: In this study, we explore the presence of colibactin-associated signatures and fecal pks in an unexplained polyposis cohort. Somatic targeted Next-Generation Sequencing (NGS) was performed for 379 patients. Additionally, for a subset of 29 patients, metagenomics was performed on feces and mutational signature analyses using Whole-Genome Sequencing (WGS) on Formalin-Fixed Paraffin Embedded (FFPE) colorectal tissue blocks. RESULTS: NGS showed somatic APC variants fitting SBS88 or ID18 in at least one colorectal adenoma or carcinoma in 29% of patients. Fecal metagenomic analyses revealed enriched presence of pks genes in patients with somatic variants fitting colibactin-associated signatures compared to patients without variants fitting colibactin-associated signatures. Also, mutational signature analyses showed enrichment of SBS88 and ID18 in patients with variants fitting these signatures in NGS compared to patients without. CONCLUSIONS: These findings further support colibactins ability to mutagenize colorectal mucosa and contribute to the development of colorectal adenomas and carcinomas explaining a relevant part of patients with unexplained polyposis.

Standardised training for endoscopic mucosal resection of large non-pedunculated colorectal polyps to reduce recurrence (*STAR-LNPCP study): a multicentre cluster randomised trial.

OBJECTIVE: Endoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence rate of up to 30%. We evaluated whether standardised EMR training could reduce recurrence rates in Dutch community hospitals. DESIGN: In this multicentre cluster randomised trial, 59 endoscopists from 30 hospitals were randomly assigned to the intervention group (e-learning and 2-day training including hands-on session) or control group. From April 2019 to August 2021, all consecutive EMR-treated LNPCPs were included. Primary endpoint was recurrence rate after 6 months. RESULTS: A total of 1412 LNPCPs were included; 699 in the intervention group and 713 in the control group (median size 30 mm vs 30 mm, 45% vs 52% size, morphology, site and access (SMSA) score IV, 64% vs 64% proximal location). Recurrence rates were lower in the intervention group compared with controls (13% vs 25%, OR 0.43; 95% CI 0.23 to 0.78; p=0.005) with similar complication rates (8% vs 9%, OR 0.93; 95% CI 0.64 to 1.36; p=0.720). Recurrences were more often unifocal in the intervention group (92% vs 76%; p=0.006). In sensitivity analysis, the benefit of the intervention on recurrence rate was only observed in the 20-40 mm LNPCPs (5% vs 20% in 20-29 mm, p=0.001; 10% vs 21% in 30-39 mm, p=0.013) but less evident in ≥40 mm LNPCPs (24% vs 31%; p=0.151). In a post hoc analysis, the training effect was maintained in the study group, while in the control group the recurrence rate remained high. CONCLUSION: A compact standardised EMR training for LNPCPs significantly reduced recurrences in community hospitals. This strongly argues for a national dedicated training programme for endoscopists performing EMR of ≥20 mm LNPCPs. Interestingly, in sensitivity analysis, this benefit was limited for LNPCPs ≥40 mm. TRIAL REGISTRATION NUMBER: NTR7477.