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Background and Aims Almost all patients with familial adenomatous polyposis (FAP) develop duodenal adenomas, with a 4% to 18% risk of progression into duodenal cancer. Prophylactic endoscopic resection of duodenal adenomas may prevent cancer and is considered safer than surgical alternatives; however, data are limited. Therefore, the aim of this study was to assess safety and effectiveness of endoscopic duodenal interventions in patients with FAP. Methods We performed a historical cohort study including patients with FAP who underwent an endoscopic duodenal intervention between 2002 and 2018. Safety was defined as adverse event rate per intervention and effectiveness as duodenal surgery–free and duodenal cancer–free survival. Change in Spigelman stage was assessed as a secondary outcome. Results In 68 endoscopy sessions, 139 duodenal polypectomies were performed in 49 patients (20 men; median age, 43). Twenty-nine patients (14 men; median age, 49) underwent a papillectomy. After polypectomy, 9 (13%) bleedings and 1 (2%) perforation occurred, all managed endoscopically. Six (21%) bleedings (endoscopically managed), 4 (14%) cases of pancreatitis, and 1 (3%) perforation (conservatively treated) occurred after papillectomy. Duodenal surgery–free survival was 74% at 89 months after polypectomy and 71% at 71 months after papillectomy; no duodenal cancers were observed. After a median of 18 months (interquartile range, 10-40; range, 3-121) after polypectomy, Spigelman stages were significantly lower (P Conclusions In our FAP patients, prophylactic duodenal polypectomies were relatively safe. Papillectomies showed substantial adverse events, suggesting its benefits and risk should be carefully weighted. Both were effective, however, because surgical interventions were limited and none developed duodenal cancer.

Background Faecal immunochemical testing (FIT) is suboptimal in detecting advanced neoplasia (AN). To increase the sensitivity and yield of a FIT-based screening programme, FIT could be combined with risk factors for AN. We evaluated the incremental yield of adding a family history questionnaire (FHQ) on colorectal cancer (CRC) and Lynch syndrome-associated tumours to the Dutch FIT-based screening programme. Methods Six thousand screen-naive individuals, aged 59–75 years, were invited to complete a FIT (FOB-Gold, cut-off 47 µg Hb/g faeces) and a validated online FHQ. Participants with a positive FIT and/or positive FHQ, confirmed after genetic counselling, were referred for colonoscopy. Yield of detecting AN per 1000 invitees for the combined strategy was compared with the FIT-only strategy. Results Of the 5979 invitees, 1952 (32.6%) completed the FIT only, 2379 (39.8%) completed both the FIT and FHQ and 95 (1.6%) completed the FHQ only. Addition of the FHQ to FIT-based screening resulted in one extra case of AN detected after 16 additional colonoscopies, resulting in a yield of 19.6 (95% CI, 16.4–23.5) for the combined strategy versus 19.5 (95% CI, 16.3–23.3) for the FIT-only strategy (p = 1.0). Conclusions The addition of an FHQ to one round of FIT screening did not increase the detection of AN compared with FIT only (ClinicalTrials.gov NCT02698462).

BACKGROUND & AIMS: Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS. METHODS: We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model. RESULTS: The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%-65.2%) and 7.9% (95% CI, 5.2%-10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06-4.3), complete colonoscopies (20% vs 0%; P = .01), and panchromoendoscopy use (OR, 2.14; 95% CI, 1.15-3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14-0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03-1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17-3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02-2.33). CONCLUSIONS: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.

Background and Aims: Patients with familial adenomatous polyposis (FAP) undergo (procto)colectomy to prevent colorectal cancer from developing. Interestingly, after proctocolectomy with ileal pouch-anal anastomosis (IPAA), most patients develop adenomas in the pouch. This is not well described for patients with end ileostomy. We aimed to compare ileal adenoma development in patients with IPAA with those with end ileostomy. Methods: This historical cohort study included FAP patients with IPAA or end ileostomy who underwent surveillance endoscopies between 2001 and 2021. Primary outcomes were the proportion of patients with ileal adenomas, location of adenomas, and proportion of patients undergoing surgical excision of pouch/end ileostomy. Results: Overall, 144 patients with IPAA (n = 111) and end ileostomy (n = 33) were included. Five years after surgery, 15% of patients with IPAA had ileal adenomas versus 4% after ileostomy. At 10 years, these estimates were 48% versus 9% and at 20 years were 85% versus 43% (log-rank P

Background Patients with familial adenomatous polyposis (FAP) are at increased risk of developing gastric adenomas. There is limited understanding of their clinical course and no consensus on management. We reviewed the management of gastric adenomas in patients with FAP from two centers. Methods Patients with FAP and histologically confirmed gastric adenomas were identified between 1997 and 2018. Patient demographics, adenoma characteristics, and management/surveillance outcomes were collected. Results Of 726 patients with FAP, 104 (14 %; 49 female) were diagnosed with gastric adenomas at a median age of 47 years (range 19 – 80). The median size of gastric adenomas was 6 mm (range 1.5 – 50); 64 (62 %) patients had adenomas located distally to the incisura. Five patients (5 %) had gastric adenomas demonstrating high-grade dysplasia (HGD) on initial diagnosis, distributed equally within the stomach. The risk of HGD was associated with adenoma size (P = 0.04). Of adenomas > 20 mm, 33 % contained HGD. Two patients had gastric cancer at initial gastric adenoma diagnosis. A total of 63 patients (61 %) underwent endoscopic therapy for gastric adenomas. Complications occurred in three patients (5 %) and two (3 %) had recurrence, all following piecemeal resection of large (30 – 50 mm) lesions. Three patients were diagnosed with gastric cancer at median follow-up of 66 months (range 66 – 115) after initial diagnosis. Conclusions We observed gastric adenomas in 14 % of patients with FAP. Of these, 5 % contained HGD; risk of HGD correlated with adenoma size. Endoscopic resection was feasible, with few complications and low recurrence rates, but did not completely eliminate the cancer risk.

Main RecommendationsESGE recommends that individuals with hereditary gastrointestinal polyposis syndromes should be surveilled in dedicated units that provide monitoring of compliance and endoscopic performance measures. Strong recommendation, moderate quality of evidence, level of agreement 90 %.ESGE recommends performing esophagogastroduodenoscopy, small-bowel examination, and/or colonoscopy earlier than the planned surveillance procedure if a patient is symptomatic. Strong recommendation, low quality of evidence, level of agreement 100 %.

Background Colorectal cancer (CRC) associated with Lynch syndrome is characterized by an abundance of infiltrating lymphocytes. To study whether tumor-specific antibodies with therapeutic potential can be isolated from these patients, the B-cell repertoire from a patient with Lynch syndrome who recovered from a stage IV colon carcinoma was screened. Here we describe an antibody, AT1636 that recognizes a previously unidentified O-mannosylated 70kDa form of E-cadherin. The intercellular interactions by E-cadherin on tumor cells have for long been recognized as protective in cancer metastasis, and deregulation of E-cadherin is a hallmark for epithelial-mesenchymal transition (EMT). Methods The study protocol was approved by the Medical Ethical Committee of the Academic Medical Centre, Amsterdam, The Netherlands (NL42718.018.12). AIMM’s BCL6 and Bcl-xL immortalization method1 was used to interrogate the human antibody repertoire. From a carrier of a pathogenic gene variant in the MSH6 gene diagnosed with stage IV CRC and liver metastasis that had been treated with avastin, capecitabine and oxaliplatin, peripheral-blood memory B cells were obtained 9 years after last treatment. Antibodies-containing supernatant of cultured B-cells were screened for binding to 3 different CRC cell lines (DLD1, LS174T and COLO205) and absence of binding to fibroblast by flow cytometry. A high-affinity variant of AT1636 (AT1636IYN) was sorted from the original AT1636, AID-expressing B-cell clone.2 Results Antibodies that demonstrated differential binding to CRC cells were characterized and targets recognized by such antibodies were identified using immunoprecipitation and mass-spectrometry. One of the antibodies, AT1636, recognized a previously unidentified O-mannosylated 70kDa E-cadherin variant (ECV). Although the 70kDa ECV is found in all full-length E-cadherin expressing cells, tumor-specific binding of AT1636 is dependent on the O-mannosylation pattern in the antibody epitope on ECV. Using shRNA knock-down AT1636 binding was shown to depend on the transmembrane O-mannosyltransferase targeting cadherins 3 (TMTC3). 3 In accordance, coexpression of TMTC3 and E-cadherin in tumor cells is predictive for AT1636 binding. In addition, we observed that (over)expression of ECV results in a strong de-adhesive, EMT-like phenotype. Although AT1636 by itself is not able to induce ADCC, the CD3-bispecific antibody (single-chain UCHT1) AT1636 format specifically killed CRC cell lines. Conclusions The AT1636 antibody retrieved from a patient with Lynch syndrome binds a previous unidentified cancer-specific O-mannosylated 70kDa form of E-cadherin. This variant might play a role in tumor-cell invasion and metastasis. More importantly, we provide a rationale to advance AT1636 based therapeutics for treatment of CRC. Ethics Approval The study protocol was approved by the Medical Ethical Committee of the Academic Medical Centre, Amsterdam, The Netherlands (NL42718.018.12) References M.J. Kwakkenbos, et al. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nature Medicine 2010;16:123–128. K. Wagner, et al. Bispecific antibody generated with sortase and click chemistry has broad antiinfluenza virus activity. Proc Natl Acad Sci USA 2014; 111: 16820–16825. I.S.B. Larsen, et al. Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins. Proc Natl Acad Sci USA 2017;114:11163–11168.

BACKGROUND: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown. METHODS: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease. RESULTS: A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups. CONCLUSIONS: In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).

Main RecommendationsESGE recommends that individuals with Lynch syndrome should be followed in dedicated units that practice monitoring of compliance and endoscopic performance measures.Strong recommendation, low quality evidence, level of agreement 100 %.ESGE recommends starting colonoscopy surveillance at the age of 25 years for MLH1 and MSH2 mutation carriers and at the age of 35 years for MSH6 and PMS2 mutation carriers.Strong recommendation, moderate quality evidence, level of agreement 100 %. ESGE recommends the routine use of high-definition endoscopy systems in individuals with Lynch syndrome. Strong recommendation, high quality evidence, level of agreement 100 %. ESGE suggests the use of chromoendoscopy may be of benefit in individuals with Lynch syndrome undergoing colonoscopy; however routine use must be balanced against costs, training, and practical considerations.Weak recommendation, moderate quality evidence, level of agreement 89 %.ESGE recommends definition of familial risk of colorectal cancer as the presence of at least two first-degree relatives with colorectal cancer or at least one first-degree relative with colorectal cancer before the age of 50 years.Strong recommendation, moderate quality evidence, level of agreement 92 %.ESGE recommends colonoscopy surveillance in first-degree relatives of colorectal cancer patients in families that fulfill the definition of familial risk of colorectal cancer.Strong recommendation, moderate quality evidence, level of agreement 100 %.

ObjectiveAfter prophylactic colectomy, adenomas continue to develop in the remaining intestine of patients with familial adenomatous polyposis (FAP). There is a lack of standard clinical recommendation for chemoprevention in patients with FAP. Because of promising in vivo studies, the aim of this pilot study was to investigate the safety of sirolimus and its effect on progression of intestinal adenomas.DesignPatients with FAP with InSiGHT Polyposis Staging System 3 of the retained rectum or pouch received sirolimus for 6 months, dosed at plasma concentration levels of 5–8 µg/L. Primary outcomes were safety and change in marked polyp size. Secondary outcomes were change in number of polyps and effect on proliferation and apoptosis assessed by immunohistochemistry.ResultsEach of the included four patients reported 4 to 18 adverse events (toxicity grades 1–3). One patient prematurely terminated the study because of adverse events. Marked polyp size decreased in 16 (80%)/20 and remained the same in 4 (20%)/20 patients. The number of polyps decreased in all patients (MD −25.75, p=0.13). Three out of four patients showed substantial induction of apoptosis or inhibition of proliferation.ConclusionSix months of sirolimus treatment in four patients with FAP showed promising effects especially on the number of polyps in the rectal remnant and ileal pouch, although at the cost of numerous adverse events.Trial registration numberClinicalTrials.gov ID NCT03095703.

INTRODUCTION Colorectal cancer (CRC) associated with Lynch syndrome is characterized by an abundance of infiltrating lymphocytes. To study whether tumor-specific antibodies with therapeutic potential can be isolated from these patients, the B-cell repertoire from a patient with Lynch syndrome who recovered from a stage IV colon carcinoma was screened. Here we describe a novel human antibody, AT1636 that recognizes a previously unidentified O-mannosylated 70kDa form of E-cadherin. The intercellular interactions by E-cadherin on tumor cells have for long been recognized as protective in cancer metastasis, and deregulation of E-cadherin is a hallmark for epithelial-mesenchymal transition (EMT). METHODS AIMM's BCL6 and Bcl-xL immortalization method[1] was used to interrogate the human antibody repertoire against targets on colon cancer cells. From a carrier of a pathogenic gene variant in the MSH6 gene diagnosed with stage IV CRC and liver metastasis that had been treated with avastin, capecitabine and oxaliplatin, peripheral-blood memory B cells were obtained 9 years after last treatment. Antibodies-containing supernatant of cultured B-cells were screened for binding to 3 different CRC cell lines (DLD1, LS174T and COLO205) and absence of binding to fibroblast by flow cytometry. High-affinity variants of AT1636 (AT1636IYN) were sorted from the AID-expressing immortalized B-cells clone[2]. RESULTS Patient derived antibodies that demonstrated differential binding to CRC cells were further characterized. Targets recognized by such antibodies were identified using immunoprecipitation and mass-spectrometry. AT1636 binds to a previously unidentified single O-mannosylated 70kDa E-cadherin variant (ECV). Although the 70 kDa ECV is found in all cells that express full length E-cadherin, tumor-specific binding of AT1636 is dependent on the single O-mannosylation pattern in the antibody epitope on ECV. Using shRNA knock-down AT1636 binding was shown to depend on the transmembrane O-mannosyltransferase targeting cadherins 3 (TMTC3)[3]. In accordance, coexpression of TMTC3 and E-cadherin in tumor cells is predictive for AT1636 binding. In addition, we observed that (over)expression of ECV results in a strong de-adhesive, EMT-like phenotype. Although AT1636 by itself is not able to induce ADCC, the CD3-bispecific antibody (single-chain UCHT1) AT1636 format specifically killed CRC cell lines. CONCLUSION The AT1636 antibody retrieved from a patient with Lynch syndrome binds a previous unidentified cancer-specific O-mannosylated 70kDa form of E-cadherin. This variant might play a role in tumor-cell invasion and metastasis. More importantly, we provide a rationale to advance AT1636 based therapeutics for treatment of CRC. references 1) Kwakkenbos et al. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nature Medicine 2010 2) Wagner et al. Bispecific antibody generated with sortase and click chemistry has broad antiinfluenza virus activity. PNAS 2014 3) Larsen et al. Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins. PNAS 2017 Citation Format: Martijn Kedde, Tim Beaumont, Sabrina J. Merat, Mark J. Kwakkenbos, Lina Bartels, Dorien van de Berg, Koen Wagner, Arjen Q. Bakker, Kelly Maijoor, Martino Böhne, Camille Bru, Veronika Kattler, Hans van Eenennaam, Victorine H. Roos, Frank G.J. Kallenberg, Jan Paul Medema, Paul J. Hensbergen, Pauline van Helden, Evelien Dekker, Hergen Spits. A colon cancer survivor-derived antibody recognizes a previously unidentified truncated, O-mannosylated 70kDa variant of E-cadherin [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5163.

Background & Aims: Guidelines recommend that individuals with familial colorectal cancer undergo colonoscopy surveillance instead of average-risk screening. However, these recommendations vary widely. To substantiate appropriate surveillance strategies, precise and valid evidence-based risk estimates are needed for individuals with a family history of colorectal cancer (CRC). Methods: We systematically searched MEDLINE, EMBASE, and Cochrane from inception to July 2018 for case–control and cohort studies investigating the effect of family history on CRC risk. We calculated summary estimates of pooled relative risks (RRs) using a random-effects model. Life tables were created to convert RR estimates into absolute risk estimates. Results: We screened 4417 articles and identified 42 eligible case–control and 20 cohort studies. In case–control studies, the RR for CRC in patients with 1 first-degree relative (FDR with CRC) was 1.92 (95% CI, 1.53–2.41) and 1.37 (95% CI, 0.76–2.46) for cohort studies. For individuals with 2 or more FDRs with CRC, the RR was 2.81 in case–control studies (95% CI, 1.73–4.55) and 2.40 in cohort studies (95% CI, 1.76–3.28). For individuals having a FDR diagnosed with CRC at an age younger than 50 years, the RR for CRC in their FDRs was 3.57 in case–control studies (95% CI, 1.07–11.85) and 3.26 in cohort studies (95% CI, 2.82–3.77). The cumulative absolute risks for CRC at 85 years in Western Europe were 4.8% for persons with 1 FDR with CRC (95% CI, 2.7%–8.3%), 8.2% for individuals with 2 or more FDRs (95% CI, 6.1%–10.9%), and 11% for persons with a FDR diagnosed with CRC at an age younger than 50 years (95% CI, 9.5%–12.4%). Conclusions: In this systematic review and meta-analysis, we found that the RR of CRC among FDRs is lower than previously expected, especially based on cohort studies. Risk estimates are affected by the number of relatives with CRC and their age at diagnosis. Intensified colonoscopy surveillance strategies could be considered for high-risk groups. PROSPERO trial identification no: CRD42018103058.