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.

Autistic traits in youth with familial adenomatous polyposis: A Dutch-Canadian case-control study.

This study investigated the neurodevelopmental impact of pathogenic adenomatous polyposis coli (APC) gene variants in patients with familial adenomatous polyposis (FAP), a cancer predisposition syndrome. We hypothesized that certain pathogenic APC variants result in behavioral-cognitive challenges. We compared 66 FAP patients (cases) and 34 unaffected siblings (controls) to explore associations between APC variants and behavioral and cognitive challenges. Our findings indicate that FAP patients exhibited higher Social Responsiveness Scale (SRS) scores, suggesting a greater prevalence of autistic traits when compared to unaffected siblings (mean 53.8 vs. 47.4, Wilcoxon p = 0.018). The distribution of SRS scores in cases suggested a bimodal pattern, potentially linked to the location of the APC variant, with scores increasing from the 5' to 3' end of the gene (Pearson's r = 0.33, p = 0.022). While we observed a trend toward lower educational attainment in cases, this difference was not statistically significant. This study is the first to explore the connection between APC variant location and neurodevelopmental traits in FAP, expanding our understanding of the genotype-phenotype correlation. Our results emphasize the importance of clinical assessment for autistic traits in FAP patients, shedding light on the potential role of APC gene variants in these behavioral and cognitive challenges.

Outcomes following duodenectomy in patients with familial adenomatous polyposis.

Background and study aims Some patients with familial adenomatous polyposis (FAP) and extensive duodenal polyposis or cancer require total duodenectomy. Regular postoperative endoscopic surveillance of the remaining jejunum and stomach is recommended, but little is known about the outcomes after this surgery. Patients and methods Patients with FAP who underwent either pancreatoduodenectomy (PD) or pancreas-preserving total duodenectomy (PPTD) were identified at two expert centers. Data about postoperative endoscopic surveillance outcomes were collected, as well as survival outcomes. Results Overall, 119 patients (50% female) underwent duodenectomy (86 PD and 33 PPTD); 100 for benign duodenal polyposis and 19 for duodenal or ampullary cancer. Details of postoperative endoscopic surveillance were available for 88 patients (74%). During a median follow-up of 106 months, 36 patients (41%) were diagnosed with jejunal adenomas after duodenectomy, with a significantly higher proportion in patients who underwent PPTD compared with patients who underwent PD (log-rank, P < 0.01). Two patients developed jejunal cancer (2%). Twenty-six patients (30%) were diagnosed with a total of 66 gastric adenomas, of which 61% were located in the fundus/body and 39% in the antrum. Five patients (6%) developed gastric cancer after a median of 15 years (range 6-23 years), all but one within carpeting fundic gland polyposis. Patients who underwent surgery for cancer had worse survival than patients with benign disease and all but one patient with postoperative gastric/jejunal cancer died. Conclusions After duodenectomy in FAP, a considerable risk of developing adenomas and cancer in the stomach and jejunum exists with poor cancer prognosis, highlighting the need for close postoperative endoscopic surveillance.

Cold snare polypectomy for duodenal adenomas in familial adenomatous polyposis: a prospective international cohort study.

Background and study aims In patients with familial adenomatous polyposis (FAP), endoscopic resection of duodenal adenomas is commonly performed to prevent cancer and prevent or defer duodenal surgery. However, based on studies using different resection techniques, adverse events (AEs) of polypectomy in the duodenum can be significant. We hypothesized that cold snare polypectomy (CSP) is a safe technique for duodenal adenomas in FAP and evaluated its outcomes in our centers. Patients and methods We performed a prospective international cohort study including FAP patients who underwent CSP for one or more superficial non-ampullary duodenal adenomas of any size between 2020 and 2022. At that time, this technique was common practice in our centers for superficial duodenal adenomas. The primary outcome was the occurrence of intraprocedural and post-procedural AEs. Results In total, 133 CSPs were performed in 39 patients with FAP (1-18 per session). Median adenoma size was 10 mm (interquartile range 8-15 mm), ranging from 5 to 40 mm; 27 adenomas were ≥20 mm (20%). Of the 133 polypectomies, 109 (82%) were performed after submucosal injection. Sixty-one adenomas (46%) were resected en bloc and 72 (54%) piecemeal. Macroscopic radical resection was achieved for 129 polypectomies (97%). Deep mural injury type II occurred in three polyps (2%) with no delayed perforation after prophylactic clipping. There were no clinically significant bleeds, perforations or other post-procedural AEs. Histopathology showed low-grade dysplasia in all 133 adenomas. Conclusions CSP for (multiple) superficial non-ampullary duodenal adenomas in FAP seems feasible and safe. Long-term prospective research is needed to evaluate whether protocolized duodenal polypectomies prevent cancer and surgery.

Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the European FAP Consortium strategy.

Background and study aims Patients with familial adenomatous polyposis (FAP) undergo colectomy and lifelong endoscopic surveillance to prevent colorectal, duodenal and gastric cancer. Endoscopy has advanced significantly in recent years, including both detection technology as well as treatment options. For the lower gastrointestinal tract, current guidelines do not provide clear recommendations for surveillance intervals. Furthermore, the Spigelman staging system for duodenal polyposis has its limitations. We present a newly developed personalized endoscopic surveillance strategy for the lower and upper gastrointestinal tract, aiming to improve the care for patients with FAP. We aim to inform centers caring for FAP patients and encourage the discussion on optimizing endoscopic surveillance and treatment in this high-risk population. Methods The European FAP Consortium, consisting of endoscopists with expertise in FAP, collaboratively developed new surveillance protocols. The proposed strategy was consensus-based and a result of several consortium meetings, discussing current evidence and limitations of existing systems. This strategy provides clear indications for endoscopic polypectomy in the rectum, pouch, duodenum and stomach and defines new criteria for surveillance intervals. This strategy will be evaluated in a 5-year prospective study in nine FAP expert centers in Europe. Results We present a newly developed personalized endoscopic surveillance and endoscopic treatment strategy for patients with FAP aiming to prevent cancer, optimize endoscopic resources and limit the number of surgical interventions. Following this new strategy, prospectively collected data in a large cohort of patients will inform us on the efficacy and safety of the proposed approaches.

A large family with MSH3-related polyposis.

Biallelic MSH3 germline variants are a rare cause of adenomatous polyposis as yet reported in two small families only. We describe the phenotype of a third family, the largest thus far, with adenomatous polyposis related to compound heterozygous MSH3 pathogenic variants. The index patient was a 55-years old male diagnosed with rectal cancer and adenomatous polyposis (cumulatively 52 polyps), with a family history of colorectal polyposis with unknown cause. Next-generation sequencing and copy number variation analysis of a panel of genes associated with colorectal cancer and polyposis revealed compound heterozygous germline pathogenic variants in the MSH3 gene. Nine out of 11 siblings were genotyped. Three siblings carried the same compound heterozygous MSH3 variants. Colonoscopy screening showed predominantly right-sided adenomatous polyposis in all compound heterozygous siblings, with a cumulative number of adenomas ranging from 18 to 54 in an average of four colonoscopies, and age at first adenoma detection ranging from 46 to 59. Microsatellite analysis demonstrated alterations at selected tetranucleotide repeats (EMAST) in DNA retrieved from the rectal adenocarcinoma, colorectal adenomas as well as of normal colonic mucosa. Gastro-duodenoscopy did not reveal adenomas in any of the four patients. Extra-intestinal findings included a ductal adenocarcinoma in ectopic breast tissue in one female sibling at the age of 46, and liver cysts in three affected siblings. None of the three heterozygous or wild type siblings who previously underwent colonoscopy had adenomatous polyposis. We conclude that biallelic variants in MSH3 are a rare cause of attenuated adenomatous polyposis with an onset in middle age.

Development of ileal adenomas after ileal pouch-anal anastomosis versus end ileostomy in patients with familial adenomatous polyposis.

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 < .001). Adenomas developed more often in the pouch body (95%) in the IPAA group and more often at the everted site of the ileostomy (77%) in the ileostomy group. Numbers for surgical excision of the pouch (n = 9) or ileostomy (n = 3) for polyposis or cancer were comparable. Taking into account potential confounders in a multivariable Cox regression analysis, having an IPAA was significantly associated with ileal adenoma development. CONCLUSIONS: After proctocolectomy, FAP patients with IPAA more often developed ileal adenomas than patients with end ileostomy. This could potentially affect long-term management, and patients with end ileostomy might benefit from less-frequent endoscopic surveillance.

The CHAMP-study: the CHemopreventive effect of lithium in familial AdenoMatous Polyposis; study protocol of a phase II trial.

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare autosomal dominant disease characterized by germline mutations in the Adenomatous Polyposis Coli (APC) gene, resulting in the development of numerous colorectal adenomas. As these patients have a high risk of developing colorectal cancer (CRC), guidelines suggest prophylactic colectomy during early adulthood, however, adenoma development is still observed in the remaining intestinal tract. Therefore, FAP patients would benefit from chemoprevention strategies reducing the development of adenomas. Recent work in mice reveals a chemopreventive effect of lithium on the development of adenomas by inhibiting the expansion of Apc mutated intestinal stem cells (ISCs) within the crypts of normal intestinal mucosa. Here, we aim to investigate the effect of lithium on the spread of APC mutant cells within the human intestinal epithelium. METHODS: This prospective phase II single arm trial has a duration of 18 months. FAP patients (18-35 years) with a genetically confirmed APC mutation who did not undergo colectomy will be treated with lithium carbonate orally achieving a serum level of 0.2-0.4 mmol/l between month 6 and 12. Colonoscopy with biopsies of normal intestinal mucosa will be performed at baseline and every six months. The primary endpoint is the effect of lithium on the spread of APC mutant cells within intestinal crypts over time by using APC specific marker NOTUM in situ hybridization. Secondary endpoints include change in adenoma burden, patient reported side effects and safety-outcomes. Total sample size is 12 patients and recruitment will take place in the Amsterdam UMC, location AMC in the Netherlands. DISCUSSION: The outcome of this study will function as a proof-of-concept for the development of novel chemoprevention approaches that interfere with the competition between normal and mutant ISCs. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT05402891 (June 1, 2022) and the EU Clinical Trials Register: EuraCT 2022-000240-30 (January 1, 2022).

Management of familial adenomatous polyposis and MUTYH-associated polyposis; new insights.

Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are rare inherited polyposis syndromes with a high colorectal cancer (CRC) risk. Therefore, frequent endoscopic surveillance including polypectomy of relevant premalignant lesions from a young age is warranted in patients. In FAP and less often in MAP, prophylactic colectomy is indicated followed by lifelong endoscopic surveillance of the retained rectum after (sub)total colectomy and ileal pouch after proctocolectomy to prevent CRC. No consensus is reached on the right type and timing of colectomy. As patients with FAP and MAP nowadays have an almost normal life-expectancy due to adequate treatment of colorectal polyposis, challenges in the management of FAP and MAP have shifted towards the treatment of duodenal and gastric adenomas as well as desmoid treatment in FAP. Whereas up until recently upper gastrointestinal surveillance was mostly diagnostic and patients were referred for surgery once duodenal or gastric polyposis was advanced, nowadays endoscopic treatment of premalignant lesions is widely performed. Aiming to reduce polyp burden in the colorectum as well as in the upper gastrointestinal tract, several chemopreventive agents are currently being studied.

Pancreas-preserving total duodenectomy for advanced duodenal polyposis in patients with familial adenomatous polyposis: short and long-term outcomes.

BACKGROUND: In patients with familial adenomatous polyposis (FAP), extensive nonmalignant duodenal polyposis not amenable to endoscopic management demands surgical resection for which pancreas-preserving total duodenectomy (PPTD) offers a pancreatic parenchyma sparing approach. METHODS: This is a retrospective cohort study including consecutive patients who underwent PPTD for FAP. Reconstruction involved a Billroth II anastomosis with a short isolated jejunal limb to facilitate future endoscopic surveillance. Short and long-term outcomes were evaluated. RESULTS: Overall, 30 patients underwent PPTD for Spigelman stage III (n = 6) or IV (n = 24). Sixteen patients experienced a severe complication (Clavien-Dindo grade III/IV) including postoperative pancreatic fistula (ISGPS grade B/C) in twelve. There was no all cause in-hospital and 90-day mortality. During follow-up (median 125 months), five patients developed acute pancreatitis, one new-onset diabetes and one exocrine pancreatic insufficiency. During endoscopic surveillance in 27 patients, jejunal adenomas were detected in 22 and advanced adenomas in 11. An additional surgical resection was required in four patients with extensive jejunal polyposis. None developed jejunal cancer. The 10-year overall survival rate was 93.3%. CONCLUSION: Postoperative morbidity after PPTD is substantial but on the long-term, rates of pancreatic insufficiencies are low. Most patients develop jejunal adenomas at follow-up, highlighting the need for endoscopic surveillance.

Colectomy and desmoid tumours in familial adenomatous polyposis: a systematic review and meta-analysis.

Desmoid tumours (DT) are one of the main causes of death in patients with familial adenomatous polyposis (FAP). Surgical trauma is a risk factor for DT, yet a colectomy is inevitable in FAP to prevent colorectal cancer. This systematic review and meta-analysis aimed to synthesize the available evidence on DT risk related to type, approach and timing of colectomy. A search was performed in MEDLINE, EMBASE and the Cochrane Library. Studies were considered eligible when DT incidence was reported after different types, approaches and timing of colectomy. Twenty studies including 6452 FAP patients were selected, all observational. No significant difference in DT incidence was observed after IRA versus IPAA (OR 0.99, 95% CI 0.69-1.42) and after open versus laparoscopic colectomy (OR 0.88, 95% CI 0.42-1.86). Conflicting DT incidences were seen after early versus late colectomy and when analysing open versus laparoscopic colectomy according to colectomy type. Three studies reported a (non-significantly) higher DT incidence after laparoscopic IPAA compared to laparoscopic IRA, with OR varying between 1.77 and 4.09. A significantly higher DT incidence was observed in patients with a history of abdominal surgery (OR 3.40, 95% CI 1.64-7.03, p = 0.001). Current literature does not allow to state firmly whether type, approach, or timing of colectomy affects DT risk in FAP patients. Fewer DT were observed after laparoscopic IRA compared to laparoscopic IPAA, suggesting laparoscopic IRA as the preferred choice if appropriate considering rectal polyp burden. PROSPERO REGISTRATION NUMBER: CRD42020161424.

Apc-mutant cells act as supercompetitors in intestinal tumour initiation.

A delicate equilibrium of WNT agonists and antagonists in the intestinal stem cell (ISC) niche is critical to maintaining the ISC compartment, as it accommodates the rapid renewal of the gut lining. Disruption of this balance by mutations in the tumour suppressor gene APC, which are found in approximately 80% of all human colon cancers, leads to unrestrained activation of the WNT pathway1,2. It has previously been established that Apc-mutant cells have a competitive advantage over wild-type ISCs3. Consequently, Apc-mutant ISCs frequently outcompete all wild-type stem cells within a crypt, thereby reaching clonal fixation in the tissue and initiating cancer formation. However, whether the increased relative fitness of Apc-mutant ISCs involves only cell-intrinsic features or whether Apc mutants are actively involved in the elimination of their wild-type neighbours remains unresolved. Here we show that Apc-mutant ISCs function as bona fide supercompetitors by secreting WNT antagonists, thereby inducing differentiation of neighbouring wild-type ISCs. Lithium chloride prevented the expansion of Apc-mutant clones and the formation of adenomas by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibition of GSK3ß. Our work suggests that boosting the fitness of healthy cells to limit the expansion of pre-malignant clones may be a powerful strategy to limit the formation of cancers in high-risk individuals.

Endoscopic management of duodenal adenomas in patients with familial adenomatous polyposis.

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 < .01). 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.

Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis Frequently Have Subclinical Inflammation in the Proximal Colon.

BACKGROUND & AIMS: Patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) have a high risk of colonic neoplasia. Neoplasia frequently develops in the proximal colon in patients with PSC. Histologic inflammation is an independent risk factor for the development of neoplasia; we investigated whether patients with UC and PSC have more subclinical disease activity than patients with UC alone. METHODS: We performed a retrospective analysis of data from 143 patients (205 examinations) with ulcerative pancolitis who were in clinical remission and treated at a tertiary medical center from May 2011 through May 2016. Endoscopic and histologic activity were compared between patients with PSC (from 36 examinations) and without PSC (from 169 examinations). Disease activity was scored per colonic segment using a modified Mayo endoscopic subscore and histologic assessment. In each colonic segment, differences in disease activity and the degree of discordance between endoscopic and histologic inflammation among UC patients with and without PSC were compared. RESULTS: Patients with UC-PSC had significantly more subclinical endoscopic (odds ratio [OR], 4.21; 95% CI, 1.67-10.63) and histologic activity (OR, 5.13; 95% CI, 2.25-11.68) in the right colon, as well as greater degree of histologic than endoscopic inflammation in the proximal colon (OR, 3.14, 95% CI, 1.24-7.97), compared with patients without PSC. Patients with UC-PSC had significantly less histologic activity in the rectum on multivariate analysis (OR, 0.24; 95% CI, 0.08-0.72). CONCLUSIONS: Patients with UC and PSC who are in clinical remission are significantly more likely to have endoscopic and histologic inflammation in the right colon than patients with UC without PSC. Our findings provide insight into cause of colorectal cancer in UC patients with PSC.

Risk of Postoperative Complications Among Inflammatory Bowel Disease Patients Treated Preoperatively With Vedolizumab.

OBJECTIVES: Vedolizumab is increasingly used to treat patients with ulcerative colitis (UC) and Crohn's disease (CD), however, its safety during the perioperative period remains unclear. We compared the 30-day postoperative complications among patients treated preoperatively with vedolizumab, anti-tumor necrosis factor (TNF)-α agents or non-biological therapy. METHODS: The retrospective study cohort was comprised of patients receiving vedolizumab, anti-TNF-α agents or non-biological therapy within 4 weeks of surgery. The rates of 30-day postoperative complications were compared between groups using univariate and multivariate analysis. Propensity score-matched analysis was performed to compare the outcome between groups. RESULTS: Among 443 patients (64 vedolizumab, 129 anti-TNF-α agents, and 250 non-biological therapy), a total of 144 patients experienced postoperative complications (32%). In multivariate analysis, age >65 (odds ratio (OR) 3.56, 95% confidence interval (CI) 1.30-9.76) and low-albumin (OR 2.26, 95% CI 1.28-4.00) were associated with increased risk of 30-day postoperative complications. For infectious complications, steroid use (OR 3.67, 95% CI 1.57-8.57, P=0.003) and low hemoglobin (OR 3.03, 95% CI 1.32-6.96, P=0.009) were associated with increased risk in multivariate analysis. Propensity score matched analysis demonstrated that the risks of postoperative complications were not different among patients preoperatively receiving vedolizumab, anti-TNF-α agents or non-biological therapy (UC, P=0.40; CD, P=0.35). CONCLUSIONS: In the present study, preoperative vedolizumab exposure did not affect the risk of 30-day postoperative complications in UC and CD. Further, larger studies are required to confirm our findings.