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.

Effect of optical diagnosis training on recognition and treatment of submucosal invasive colorectal cancer in community hospitals: a prospective multicenter intervention study.

BACKGROUND: Recognition of submucosal invasive colorectal cancer (T1 CRC) is difficult, with sensitivities of 35 %-60 % in Western countries. We evaluated the real-life effects of training in the OPTICAL model, a recently developed structured and validated prediction model, in Dutch community hospitals. METHODS: In this prospective multicenter study (OPTICAL II), 383 endoscopists from 40 hospitals were invited to follow an e-learning program on the OPTICAL model, to increase sensitivity in detecting T1 CRC in nonpedunculated polyps. Real-life recognition of T1 CRC was then evaluated in 25 hospitals. Endoscopic and pathologic reports of T1 CRCs detected during the next year were collected retrospectively, with endoscopists unaware of this evaluation. Sensitivity for T1 CRC recognition, R0 resection rate, and treatment modality were compared for trained vs. untrained endoscopists. RESULTS: 1 year after e-learning, 528 nonpedunculated T1 CRCs were recorded for endoscopies performed by 251 endoscopists (118 [47 %] trained). Median T1 CRC size was 20 mm. Lesions were mainly located in the distal colorectum (66 %). Trained endoscopists recognized T1 CRCs more frequently than untrained endoscopists (sensitivity 74 % vs. 62 %; mixed model analysis odds ratio [OR] 2.90, 95 %CI 1.54-5.45). R0 resection rate was higher for T1 CRCs detected by trained endoscopists (69 % vs. 56 %; OR 1.73, 95 %CI 1.03-2.91). CONCLUSION: Training in optical recognition of T1 CRCs in community hospitals was associated with increased recognition of T1 CRCs, leading to higher en bloc and R0 resection rates. This may be an important step toward more organ-preserving strategies.

Effects of Community-based Exercise Prehabilitation for Patients Scheduled for Colorectal Surgery With High Risk for Postoperative Complications: Results of a Randomized Clinical Trial.

OBJECTIVE: To assess the effects of a 3-week community-based exercise program on 30-day postoperative complications in high-risk patients scheduled for elective colorectal resection for (pre)malignancy. SUMMARY BACKGROUND DATA: Patients with a low preoperative aerobic fitness undergoing colorectal surgery have an increased risk of postoperative complications. It remains, however, to be demonstrated whether prehabilitation in these patients reduces postoperative complications. METHODS: This 2-center, prospective, single-blinded randomized clinical trial was carried out in 2 large teaching hospitals in the Netherlands. Patients (≥60 years) with colorectal (pre)malignancy scheduled for elective colorectal resection and with a score ≤7 metabolic equivalents on the veterans-specific activity questionnaire were randomly assigned to the prehabilitation group or the usual care group by using block-stratified randomization. An oxygen uptake at the ventilatory anaerobic threshold <11 mL/kg/min at the baseline cardiopulmonary exercise test was the final inclusion criterion. Inclusion was based on a power analysis. Patients in the prehabilitation group participated in a personalized 3-week (3 sessions per week, nine sessions in total) supervised exercise program given in community physical therapy practices before colorectal resection. Patients in the reference group received usual care. The primary outcome was the number of patients with one or more complications within 30 days of surgery, graded according to the Clavien-Dindo classification. Data were analyzed on an intention-to-treat basis. RESULTS: Between February 2014 and December 2018, 57 patients [30 males and 27 females; mean age 73.6 years (standard deviation 6.1), range 61-88 years] were randomized to either prehabilitation (n = 28) or usual care (n = 29). The rate of postoperative complications was lower in the prehabilitation group (n = 12, 42.9%) than in the usual care group (n = 21, 72.4%, relative risk 0.59, 95% confidence interval 0.37-0.96, P = 0.024). CONCLUSIONS: Exercise prehabilitation reduced postoperative complications in high-risk patients scheduled to undergo elective colon resection for (pre)malignancy. Prehabilitation should be considered as usual care in high-risk patients scheduled for elective colon, and probably also rectal, surgery.

Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome.

BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.

Substantial and sustained improvement of serrated polyp detection after a simple educational intervention: results from a prospective controlled trial.

OBJECTIVE: Serrated polyps (SPs) are an important cause of postcolonoscopy colorectal cancers (PCCRCs), which is likely the result of suboptimal SP detection during colonoscopy. We assessed the long-term effect of a simple educational intervention focusing on optimising SP detection. DESIGN: An educational intervention, consisting of two 45 min training sessions (held 3 years apart) on serrated polyp detection, was given to endoscopists from 9 Dutch hospitals. Hundred randomly selected and untrained endoscopists from other hospitals were selected as control group. Our primary outcome measure was the proximal SP detection rate (PSPDR) in trained versus untrained endoscopists who participated in our faecal immunochemical test (FIT)-based population screening programme. RESULTS: Seventeen trained and 100 untrained endoscopists were included, who performed 11 305 and 51 039 colonoscopies, respectively. At baseline, PSPDR was equal between the groups (9.3% vs 9.3%). After training, the PSPDR of trained endoscopists gradually increased to 15.6% in 2018. This was significantly higher than the PSPDR of untrained endoscopists, which remained stable around 10% (p=0.018). All below-average (ie, PSPDR ≤6%) endoscopists at baseline improved their PSPDR after training session 1, as did 57% of endoscopists with average PSPDR (6%-12%) at baseline. The second training session further improved the PSPDR in 44% of endoscopists with average PSPDR after the first training. CONCLUSION: A simple educational intervention was associated with substantial long-term improvement of PSPDR in a prospective controlled trial within FIT-based population screening. Widespread implementation of such interventions might be an easy way to improve SP detection, which may ultimately result in fewer PCCRCs. TRIAL REGISTRATION NUMBER: NCT03902899.

No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies.

BACKGROUND & AIMS: Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1-2-year intervals), and Finland (patients evaluated at 2-3-year intervals). METHODS: We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy). RESULTS: The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low- and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and time since last colonoscopy. CONCLUSIONS: We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1-2-year intervals, and Finland, with 2-3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.

Development and validation of the WASP classification system for optical diagnosis of adenomas, hyperplastic polyps and sessile serrated adenomas/polyps.

OBJECTIVE: Accurate endoscopic differentiation would enable to resect and discard small and diminutive colonic lesions, thereby increasing cost-efficiency. Current classification systems based on narrow band imaging (NBI), however, do not include neoplastic sessile serrated adenomas/polyps (SSA/Ps). We aimed to develop and validate a new classification system for endoscopic differentiation of adenomas, hyperplastic polyps and SSA/Ps <10 mm. DESIGN: We developed the Workgroup serrAted polypS and Polyposis (WASP) classification, combining the NBI International Colorectal Endoscopic classification and criteria for differentiation of SSA/Ps in a stepwise approach. Ten consultant gastroenterologists predicted polyp histology, including levels of confidence, based on the endoscopic aspect of 45 polyps, before and after participation in training in the WASP classification. After 6 months, the same endoscopists predicted polyp histology of a new set of 50 polyps, with a ratio of lesions comparable to daily practice. RESULTS: The accuracy of optical diagnosis was 0.63 (95% CI 0.54 to 0.71) at baseline, which improved to 0.79 (95% CI 0.72 to 0.86, p<0.001) after training. For polyps diagnosed with high confidence the accuracy was 0.73 (95% CI 0.64 to 0.82), which improved to 0.87 (95% CI 0.80 to 0.95, p<0.01). The accuracy of optical diagnosis after 6 months was 0.76 (95% CI 0.72 to 0.80), increasing to 0.84 (95% CI 0.81 to 0.88) considering high confidence diagnosis. The combined negative predictive value with high confidence of diminutive neoplastic lesions (adenomas and SSA/Ps together) was 0.91 (95% CI 0.83 to 0.96). CONCLUSIONS: We developed and validated the first integrative classification method for endoscopic differentiation of small and diminutive adenomas, hyperplastic polyps and SSA/Ps. In a still image evaluation setting, introduction of the WASP classification significantly improved the accuracy of optical diagnosis overall as well as SSA/P in particular, which proved to be sustainable after 6 months.

Equivalent Helicobacter pylori infection rates in Lynch syndrome mutation carriers with and without a first-degree relative with gastric cancer.

BACKGROUND: Patients with Lynch syndrome (LS) are at an increased risk of developing gastric cancer. In 2010, a guideline that recommended to screen all patients for Helicobacter pylori was implemented in the Netherlands. H. pylori is an important risk factor in the development of gastric cancer in the general population, and eradication of the bacterium reduces this risk. We aimed to assess the proportion of LS patients being tested and the yield and also addressed the question whether H. pylori infection is more prevalent in LS families with known cases of gastric cancer. METHODS: Proven mutation carriers from five different Dutch hospitals were included. The implementation of H. pylori screening and its outcome was examined. The observation period was 2008-2013. The presence of first-degree family members with gastric cancer was noted, and it was observed if H. pylori infection was more prevalent in Lynch families with known cases of gastric cancer. Obtainable endoscopy reports were reviewed. RESULTS: Four hundred forty-three (male, 184) proven mutation carriers were included. The proportion of patients screened increased after 2010, from 37 to 68%. Twenty percent of the patients were infected. The 25 patients who had a first-degree family member with gastric cancer did not have a higher infection rate. In 30% of cases, an endoscopy was performed; in four patients, intestinal metaplasia and in eight patients, gastric cancer was found. CONCLUSION: The recommendation to screen for H. pylori is increasingly followed. The prevalence of infection in this patient group does not differ from the general population. Patients who had a first-degree family member with gastric cancer did not have a higher infection rate.

Diagnosis and management of splanchnic ischemia.

Splanchnic or gastrointestinal ischemia is rare and randomized studies are absent. This review focuses on new developments in clinical presentation, diagnostic approaches, and treatments. Splanchnic ischemia can be caused by occlusions of arteries or veins and by physiological vasoconstriction during low-flow states. The prevalence of significant splanchnic arterial stenoses is high, but it remains mostly asymptomatic due to abundant collateral circulation. This is known as chronic splanchnic disease (CSD). Chronic splanchnic syndrome (CSS) occurs when ischemic symptoms develop. Ischemic symptoms are characterized by postprandial pain, fear of eating and weight loss. CSS is diagnosed by a test for actual ischemia. Recently, gastro-intestinal tonometry has been validated as a diagnostic test to detect splanchnic ischemia and to guide treatment. In single-vessel CSD, the complication rate is very low, but some patients have ischemic complaints, and can be treated successfully. In multi-vessel stenoses, the complication rate is considerable, while most have CSS and treatment should be strongly considered. CT and MR-based angiographic reconstruction techniques have emerged as alternatives for digital subtraction angiography for imaging of splanchnic vessels. Duplex ultrasound is still the first choice for screening purposes. The strengths and weaknesses of each modality will be discussed. CSS may be treated by minimally invasive endoscopic treatment of the celiac axis compression syndrome, endovascular antegrade stenting, or laparotomy-assisted retrograde endovascular recanalization and stenting. The treatment plan is highly individualized and is mainly based on precise vessel anatomy, body weight, co-morbidity and severity of ischemia.