Familial Adenomatous Polyposis Patients Research Articles

Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision.

Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers. A team of 38 experts convened to update the 2008 European recommendations for the clinical management of patients with adenomatous polyposis syndromes. Additionally, other rare monogenic adenomatous polyposis syndromes were reviewed and added. Eighty-nine clinically relevant questions were answered after a systematic review of the existing literature with grading of the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation methodology. Two levels of consensus were identified: consensus threshold (≥67% of voting guideline committee members voting either 'Strongly agree' or 'Agree' during the Delphi rounds) and high threshold (consensus ≥ 80%). One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes. These updated guidelines provide current, comprehensive, and evidence-based practical recommendations for the management of surveillance and treatment of familial adenomatous polyposis patients, encompassing additionally MUTYH-associated polyposis, gastric adenocarcinoma and proximal polyposis of the stomach and other recently identified polyposis syndromes based on pathogenic variants in other genes than APC or MUTYH. Due to the rarity of these diseases, patients should be managed at specialized centres.

Which Drugs are More Effective in Preventing Familial Adenomatous Polyposis Progression Based on Network Meta-Analysis?

Familial adenomatous polyposis (FAP) is an inherited disorder. At present, an increasing number of medications are being employed to treat FAP; however, only a few have been assessed for their efficacy and safety. Therefore, this study aimed to conduct a network meta-analysis to compare the therapeutic outcomes and adverse drug reactions of all FAP-associated medications. Six relevant databases were searched to identify pertinent randomized controlled trials (RCTs), and information on the dosage and frequency of various drugs was extracted. Additionally, data on changes in polyp counts and dimensions, as well as treatment-related adverse reactions for different medications were collected. The Bayesian method was employed to directly or indirectly compare the impact of different treatment regimens on changes in polyp numbers and diameters, and the safety of the drugs was investigated. CXB at 16 mg/kg/day significantly reduced polyp numbers. Celecoxib at 8 mg/kg/day and sulindac (150 mg twice daily) plus erlotinib (75 mg/day) were effective for tolerant FAP patients. Additionally, EPAFFA 2 g daily and sulindac (150 mg twice daily) plus erlotinib (75 mg/day) emerged as the most effective for reducing polyp size. The most effective treatment for reducing the number of colorectal polyps is celecoxib 16 mg/kg/day. On the other hand, a daily dosage of 2 g EPA-FFA demonstrates the best results in terms of decreasing colorectal polyp diameter.

Gut microbiota and serum metabolite signatures along the colorectal adenoma-carcinoma sequence: Implications for early detection and intervention

AimOur study focuses on the microbial and metabolomic profile changes during the adenoma stage, as adenomas can be considered potential precursors to colorectal cancer through the adenoma-carcinoma sequence. Identifying possible intervention targets at this stage may aid in preventing the progression of colorectal adenoma (CRA) to malignant lesions. Furthermore, we evaluate the efficacy of combined microbial and metabolite biomarkers in detecting CRA. MethodsFecal metagenomic and serum metabolomic analyses were performed for the discovery of alterations of gut microbiome and metabolites in CRA patients (n = 26), Colorectal cancer (CRC) patients (n = 19), Familial Adenomatous Polyposis (FAP) patients (n = 10), and healthy controls (n = 20). Finally, analyzing the associations between gut microbes and metabolites was performed by a Receiver Operating Characteristic (ROC) curve. ResultsOur analysis present that CRA patients differ significantly in gut microflora and serum metabolites compared with healthy controls, especially for Lachnospiraceae and Parasutterella. Its main metabolite, butyric acid, concentrations were raised in CRA patients compared with the healthy controls, indicating its role as a promoter of colorectal tumorigenesis. α-Linolenic acid and lysophosphatidylcholine represented the other healthy metabolite for CRA. Combining five microbial and five metabolite biomarkers, we differentiated CRA from CRC with an Area Under the Curve (AUC) of 0.85 out of this performance vastly superior to the specificity recorded by traditional markers CEA and CA199 in such differentiation of these conditions. ConclusionsThe study underlines significant microbial and metabolic alterations in CRA with a novel insight into screening and early intervention of its tumorigenesis.

Evaluation of EGFR and COX pathway inhibition in human colon organoids of serrated polyposis and other hereditary cancer syndromes.

Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study (MYC, FOSL1, EGR1, IL33, LGR5 and FOXQ1) may be used to identify other new molecular targets for chemoprevention of SSLs.

Abstract SY07-02: Cell competition vs cell cooperation: Unlocking oncogenic potential of mutant clones in the gut

Abstract The epithelial monolayer of the intestine is one of the fastest renewing tissues of the human body. Every week, the entire epithelium is replaced by intestinal stem cells (ISCs) that reside in crypt-like structures within the monolayer. Within these crypts, a small number of ISCs continuously divide to provide all specialized cell types necessary to maintain normal intestinal homeostasis, while simultaneously competing with each other for a position within the crypt bottom. This competition, characterized by neutral loss-and-replacement events, can be drastically disturbed when one of the ISCs acquires a mutation that confers a competitive advantage. As a result, mutant ISCs will replace all normal ISCs, colonize the intestinal crypt, and facilitate the initiation of colorectal cancer (CRC). CRC development is a stepwise process characterized by the accumulation of mutations in cancer driver genes over time. Almost 80% of all CRCs present with early mutations in the tumor suppressor gene APC, leading to constitutive activation of the Wnt pathway and the formation of pre-malignant adenomas. We have previously demonstrated that, within individual crypts, Apc-mutant ISCs have a competitive advantage over normal ISCs, although the mechanism underlying this unequal competition remained unclear. Recently, we revealed that Apc-mutant ISCs in fact act as "supercompetitors" by secreting Wnt antagonists such as NOTUM, WIF1 and DKK2, that actively disadvantage neighboring wild type ISCs by forcing them do differentiate. We demonstrated that boosting wild type fitness by downstream pharmacological activation of the Wnt signaling pathway by GSK3β-inhibitor lithium rendered wild type ISCs resistant to the Wnt antagonists, reduced the number of Apc-mutant crypts, and prevented adenoma formation. Together, this work highlights that modulating cell competition between normal and mutant cells within the crypt can provide a novel approach to prevent CRC development. Our findings are particularly relevant for familial adenomatous polyposis (FAP) patients, that carry germline mutations in APC and are predisposed to the development of CRC. Based on our fundamental discoveries, we are currently performing a clinical trial to assess the chemopreventive effect of lithium on the expansion of APC-mutant clones in FAP patients [ClinicalTrials.gov: NCT05402891]. Importantly, it is becoming increasingly evident that intestinal adenomas do not form from a single Apc-mutant crypt, but require fields of multiple mutant crypts to facilitate tumor initiation. Although field cancerization by enhanced crypt fission has been observed for several oncogenic mutants in the gut (e.g. KrasG12D, PIK3CAH1047R), Apc-mutant cells are often contained within individual crypts. This indicates that multiple independent mutant clones may act cooperatively to facilitate tumorigenesis, thereby pointing towards a polyclonal origin of intestinal adenomas. Our current work investigates how Apc-mutant clones interact by modifying their local environment through reciprocal signalling with stromal and epithelial cells to escape the anatomical constraints of the crypt, thereby unlocking their oncogenic potential in the gut. Ultimately, unravelling the molecular mechanisms underlying clonal cooperation will inform potential chemoprevention strategies for CRC. Citation Format: Sanne van Neerven. Cell competition vs cell cooperation: Unlocking oncogenic potential of mutant clones in the gut [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY07-02.

Downregulation of ABCC3 activates MAPK signaling through accumulation of deoxycholic acid in colorectal cancer cells.

ABCC3 (also known as MRP3) is an ATP binding cassette transporter for bile acids, whose expression is downregulated in colorectal cancer through the Wnt/β-catenin signaling pathway. However, it remained unclear how downregulation of ABCC3 expression contributes to colorectal carcinogenesis. We explored the role of ABCC3 in the progression of colorectal cancer-in particular, focusing on the regulation of bile acid export. Gene expression analysis of colorectal adenoma isolated from familial adenomatous polyposis patients revealed that genes related to bile acid secretion including ABCC3 were downregulated as early as at the stage of adenoma formation. Knockdown or overexpression of ABCC3 increased or decreased intracellular concentration of deoxycholic acid, a secondary bile acid, respectively, in colorectal cancer cells. Forced expression of ABCC3 suppressed deoxycholic acid-induced activation of MAPK signaling. Finally, we found that nonsteroidal anti-inflammatory drugs increased ABCC3 expression in colorectal cancer cells, suggesting that ABCC3 could be one of the targets for therapeutic intervention of familial adenomatous polyposis. Our data thus suggest that downregulation of ABCC3 expression contributes to colorectal carcinogenesis through the regulation of intracellular accumulation of bile acids and activity of MAPK signaling.

Perceived food intolerances and its impact on diet quality in patients with an ileoanal pouch

Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice for patients with medically-refractory ulcerative colitis (UC) and familial adenomatous polyposis (FAP). Whilst quality of life is generally good, as many as 83% of patients associate dietary factors with the onset of symptoms(1) and around two-thirds employ some form of dietary restriction post-pouch creation(2,3). There is growing interest to understand the role of diet (as a whole) on pouch function and how it can be used therapeutically. It is imperative that we know the dietary characteristics of pouch patients before attempting to introduce strategies altering their food choice. Since there is good rationale to assess overall diet quality to identify potential avenues for targeting dietary strategies, this study aimed to examine the frequency of perceived food intolerances and diet quality in patients with an ileoanal pouch and the relationship between these two indices. In this cross-sectional study, patients with an ileoanal pouch completed a food intolerance questionnaire and a validated 297-item semi-quantitative food frequency questionnaire (Monash Comprehensive Nutritional Assessment Questionnaire). Dietary data was used to score diet quality using the 2013 Dietary Guidelines Index (DGI), a scoring system which compares how closely an individual’s dietary intake aligns with the Australian Dietary Guidelines (ADG). The DGI also comprises of 11 subcomponents (scored out of 10 respectively) based on each of the ADG guidelines and provides a total score of 110, with higher scores reflecting greater compliance to the ADG. In order to determine if perceived dietary intolerances was negatively associated with the intake of specific dietary factors, univariable and multivariable linear regression analysis of the correlation of intolerance and diet quality was performed. Of the 58 (10 FAP and 48 UC) patients studied, 81% of UC and 80% of FAP patients reported dietary intolerances. Mean total DGI score was 78 (95% CI: 74-80) of 110 in the overall pouch cohort with no differences across pouch sub-groups. However, only 5% of patients achieved a full score for food variety. Both uni- [OR −0.94 (−1.7,-0.10); p = 0.02] and multivariable analysis (adjusting for age and sex) showed that only intolerances to dairy products were associated with reduced intake of lactose-containing dairy [OR −0.29 (−1.8,-0.08); p=0.03]. No other significant correlations were found for overall or subcomponents of DGI scores. High rates of perceived food intolerances were observed in patients with an ileoanal pouch. However, only those with perceived dairy intolerances restricted their intake of lactose-containing dairy products. Additionally, patients with ileoanal pouch scored highly for overall diet quality but specific gaps in achieving better diet quality, particularly for diet variety were observed. These results provide some starting points for targeted dietary counselling to optimise nutritional health and potentially to improve pouch function these patients.

Abstract 5276: Immunomodulatory activity of intermittent low-dose erlotinib plus sulindac: Implications for hereditary and sporadic colorectal cancer

Abstract A once-weekly optimized dosing regimen of erlotinib (ERL) in the polyposis in rat colon (Pirc) model [1] was a reliable predictor of antitumor efficacy in familial adenomatous polyposis (FAP) patients [2]. Pirc rats are increasingly used as a translational tool for FAP studies. Based on transcriptomic data from FAP patients receiving ERL plus sulindac (SUL) vs. placebo [3], we determined the timing of changes in interferon-γ signaling in Pirc adenomas, while performing additional dose titration. In rats that were given ERL administered at 5 mg per kilogram of body weight through oral gavage (two times a week) and that received a diet containing 125 parts per million of SUL, a regimen referred to as SUL125+ERL5x2, significant suppression of tumor growth was observed. This combination represented half of the standard of care SUL dose and about one-quarter of the ERL dose in FAP patients. In adenomas collected after one year of treatment from SUL125+ERL5x2 treated rats, the expression of genes related to the major histocompatibility complex (MHC) class I (β2m, Cnx, Psmb8 and Tap1) and MHC class II (RT1-A2, Cd74, RT-1Bb, Cd74, and Ciita) was increased, compared to vehicle controls, excluding a subset of adenomas that remained resistant. Through the use of multiplex mass cytometry (CyTOF), an increase in tumor-infiltrating CD4+ T cells was observed in adenomas from the SUL125+ERL5x2 treatment group. Administration of single or combined agents increased CD68+ cells and reduced the presence of Foxp3+ and Arg1+ cells in Pirc adenomas. The natural history of adenomatous colon polyps indicated an increase in MHC gene expression as tumors increased in size; however, this trend reversed markedly in fully occluding lesions. Additionally, expression of MHC-related factors increased in Pirc colon adenoma and murine colon carcinoma cells treated with ERL±SUL, resulting in enhanced CD8+ T-cell activation and IL-2 secretion. In conclusion, treatment with intermittent low doses of ERL±SUL increased MHC gene expression and induced changes in the immune cell component in the tumor microenvironment of Pirc rat adenomas. A subset of non-responsive adenomas could benefit from additional immunopreventive approaches, with implications for possible clinical applications in both hereditary and sporadic colorectal cancer.

Abstract 3872: Multi-ancestral origins of colorectal lesionsMulti-ancestral origins of colorectal lesions

Abstract The widely accepted paradigm that cancer initiation is a monoclonal event has not been definitively resolved. In sporadic cancers this is due to the requirement for longitudinal sampling to study this occult process, which occurs over years to decades. Individuals with familial adenomatous polyposis (FAP) possess a germline APC mutation, leading to hundreds of colonic polyps in adolescence and a 100% lifetime risk of colorectal cancer. Resected colons from FAP patients contain normal mucosa, benign and dysplastic polyps that embed the natural history of colorectal tumorigenesis at different points of malignant progression. Through genome sequencing of 127 independent polyps or mucosa samples from six FAP patients, we characterized the genomic landscape, relative timing of somatic alterations, and clonal dynamics in normal, dysplastic, and invasive colon tissue. Comparison with multi-region sequencing data from FAP patients and sporadic colorectal adenomas and carcinomas indicates similar molecular profiles, with canonical cancer driver genes present across benign and dysplastic premalignant lesions and shared mutational orders. Pairwise sample comparisons and phylogenetic reconstructions revealed extensive heterogeneity and subclonal sharing within a patient’s benign and dysplastic lesions, irrespective of location in the colon. These data imply that polyps were initiated from multiple cells from distinct lineages whose most recent common ancestor arose during development. We corroborate these findings using a mechanistic mathematical model, which infers polyclonality in 100% of benign and 83% of dysplastic samples. Based on these findings, we propose a conceptual model of the multi-ancestral origin of intestinal malignancies. Citation Format: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Debra Van Egeren, HTAN–FAP Consortium, William Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. Multi-ancestral origins of colorectal lesionsMulti-ancestral origins of colorectal lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3872.

Abstract 1479: ABCC3 (MRP3)-mediated export of deoxycholic acid regulates MAPK signaling in colorectal adenoma and adenocarcinoma

Abstract ABCC3 (also known as MRP3) is an ATP binding cassette transporter and it works as a bile acids transporter. We previously elucidated that ABCC3 expression is downregulated in colorectal cancer through the Wnt/β-catenin signaling pathway. However, it remained unclear how downregulation of ABCC3 expression contributes to colorectal carcinogenesis. We here explored the role of ABCC3 in the progression of colorectal cancer-in particular, focusing on the regulation of bile acid export. First, we performed experiments with clinical samples of familial adenomatous polyposis (FAP) patients to confirm whether ABCC3 expression is already downregulated in colorectal adenomas. Next, we investigated the effect of ABCC3 expression on intracellular bile acid concentrations using ABCC3 knockdown and overexpression colorectal cancer cell lines (HT-29, SW620). The intracellular concentration of deoxycholic acid, which is known to have carcinogenic effects, was verified with fluorescently labeled deoxycholic acid. Then, we tested whether activation of oncogenic signaling by deoxycholic acid is affected by ABCC3 expression changes. Finally, we examined the effect of nonsteroidal anti-inflammatory drugs (NSAIDs), which have been suggested to inhibit the carcinogenesis of FAP, on the expression of ABCC3 in experiments with colorectal cancer cell lines. Gene and protein expression analysis of colorectal adenomas isolated from FAP patients revealed that ABCC3 were downregulated as early as at the stage of adenoma formation, and many other genes related to bile acid efflux were also downregulated. Knockdown or overexpression of ABCC3 increased or decreased intracellular concentration of deoxycholic acid in colorectal cancer cells, respectively. Forced expression of ABCC3 suppressed deoxycholic acid-induced activation of MAPK signaling. Finally, we found that several NSAIDs increased ABCC3 expression in colorectal cancer cells, suggesting that ABCC3 could be one of the targets for therapeutic intervention of FAP. Our data thus suggest that downregulation of ABCC3 expression contributes to colorectal carcinogenesis through the regulation of intracellular accumulation of bile acids and activity of MAPK signaling. Citation Format: Yukihiro Sato, Minoru Kobayashi, Masahiro Ohira, Ryo Funayama, Masamitsu Maekawa, Hideaki Karasawa, Shinobu Ohnuma, Michiaki Unno, Keiko Nakayama. ABCC3 (MRP3)-mediated export of deoxycholic acid regulates MAPK signaling in colorectal adenoma and adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1479.

Microenvironmental changes in familial adenomatous polyposis during colorectal cancer carcinogenesis

Familial adenomatous polyposis (FAP) is a heritable disease that increases the risk of colorectal cancer (CRC) development because of heterozygous mutations in APC. Little is known about the microenvironment of FAP. Here, single-cell RNA sequencing was performed on matched normal tissues, adenomas, and carcinomas from four patients with FAP. We analyzed the transcriptomes of 56,225 unsorted single cells, revealing the heterogeneity of each cell type, and compared gene expression among tissues. Then we compared the gene expression with that of sporadic CRC. Furthermore, we analyzed specimens of 26 FAP patients and 40 sporadic CRC patients by immunohistochemistry. Immunosuppressiveness of myeloid cells, fibroblasts, and regulatory T cells was upregulated even in the early stages of carcinogenesis. CD8+ T cells became exhausted only in carcinoma, although the cytotoxicity of CD8+ T cells was gradually increased according to the carcinogenic step. When compared with those in the sporadic CRC microenvironment, the composition and function of each cell type in the FAP-derived CRC microenvironment had differences. Our findings indicate that an immunosuppressive microenvironment is constructed from a precancerous stage in FAP.

Long-term prognosis after stapled and hand-sewn ileal pouch–anal anastomoses for familial adenomatous polyposis: a multicenter retrospective study

PurposeThe long-term prognosis of stapled and hand-sewn ileal pouch–anal anastomoses in familial adenomatous polyposis patients in Japan remains unknown. This study aimed to compare the overall survival in familial adenomatous polyposis patients who underwent stapled or hand-sewn ileal pouch–anal anastomosis.MethodsThis multicenter retrospective study was conducted at 12 institutions in Shizuoka Prefecture, Japan. The clinical outcomes of 53 eligible familial adenomatous polyposis patients who underwent stapled (n = 24) and hand-sewn (n = 29) ileal pouch–anal anastomosis were compared.ResultsThe median follow-up duration was 171.5 months. The incidence of adenoma in the remnant rectum or anal transitional zone and metachronous rectal cancer was significantly more common in stapled ileal pouch–anal anastomosis (adenoma: stapled, 45.8%, vs. hand-sewn, 10.3%, p = 0.005; metachronous rectal cancer: 29.2%, vs. none, p = 0.002). The number of deaths was remarkably higher in stapled ileal pouch–anal anastomosis (p = 0.002). Metachronous rectal cancer was the most common cause of death. Overall survival was worse in stapled ileal pouch–anal anastomosis than in hand-sewn ileal pouch–anal anastomosis (120 months, 90.7% vs. 96.6%; 240 months, 63.7% vs. 96.6%; p = 0.044). Cox regression analysis revealed the independent effects of preoperative advanced colorectal cancer and stapled ileal pouch–anal anastomosis on overall survival.ConclusionStapled ileal pouch–anal anastomosis negatively affected the overall survival of familial adenomatous polyposis patients. Therefore, hand-sewn ileal pouch–anal anastomosis is recommended for better prognosis in these patients.

Histopathological Evaluation of Pouch Neoplasia in IBD and Familial Adenomatous Polyposis.

IPAA is often required for patients with ulcerative colitis or familial adenomatous polyposis after colectomy. This procedure reduces but does not completely eliminate the risk of neoplasia. This study focuses on the histopathology of neoplasia in the ileal pouch, rectal cuff, and anal transition zone. We performed a MEDLINE search for English-language studies published between 1981 and 2022 using the PubMed search engine. The terms "ileal pouch-anal anastomosis," "pouchitis," "pouch dysplasia," "pouch lymphoma," "pouch squamous cell carcinoma," "pouch adenocarcinoma," "pouch neoplasia," "dysplasia of rectal cuff," and "colitis-associated dysplasia" were used. Human studies of neoplasia occurring in the pouch and para-pouch were selected, and the full text was reviewed. Comparisons were made within and across studies, with key concepts selected for inclusion in this article. Neoplasia in the pouch is a rare complication in patients with IPAA. Annual endoscopic surveillance is recommended for familial adenomatous polyposis patients and ulcerative colitis patients with a history of prior dysplasia or carcinoma. In familial adenomatous polyposis, dysplastic polyps of the pouch are visible and readily amenable to endoscopic removal; however, glandular dysplasia in the setting of ulcerative colitis may be invisible on endoscopy. Therefore, random biopsies and adequate tissue sampling of the pouch and rectal cuff are recommended in this setting. The histological diagnosis of IBD-associated dysplasia can be challenging and should be confirmed by at least 1 expert GI pathologist. See video from the symposium.

Black raspberry-mediated metabolic changes in patients with familial adenomatous polyposis associated with rectal polyp regression.

Familial adenomatous polyposis (FAP) patients face an almost certain 100% risk of developing colorectal cancer, necessitating prophylactic colectomy to prevent disease progression. A crucial goal is to hinder this progression. In a recent clinical trial involving 14 FAP patients, half received 60 g of black raspberry (BRB) powder orally and BRB suppositories at bedtime, while the other half received only BRB suppositories at bedtime over 9 months. This intervention led to a notable reduction in rectal polyps for 11 patients, although 3 showed no response. In this study, we delved into the metabolic changes induced by BRBs in the same patient cohort. Employing mass spectrometry-based non-targeted metabolomics, we analyzed pre- and post-BRB urinary and plasma samples from the 11 responders. The results showed significant alterations in 23 urinary and 6 plasma metabolites, influencing various pathways including polyamine, glutathione metabolism, the tricarboxylic acid cycle, inositol metabolism, and benzoate production. BRBs notably elevated levels of several metabolites associated with these pathways, suggesting a potential mechanism through which BRBs facilitate rectal polyp regression in FAP patients by modulating multiple metabolic pathways. Notably, metabolites derived from BRB polyphenols were significantly increased post-BRB intervention, emphasizing the potential therapeutic value of BRBs in FAP management.

Incidence and risk factors for recurrence of ampullary adenomas after endoscopic papillectomy: Comparative analysis of familial adenomatous polyposis and sporadic ampullary adenomas in an international multicenter cohort.

Endoscopic papillectomy (EP) is a minimally invasive therapy for the management of ampullary adenomas (AA). We conducted this multicenter study to assess the incidence of and factors related to the recurrence of AA after EP in patients with familial adenomatous polyposis (FAP) compared to sporadic AA. We included patients who underwent EP for AA at 10 tertiary hospitals. Adenomatous tissue at the resection site at the time of surveillance endoscopies was considered recurrent disease. In all, 257 patients, 100 (38.9%) with FAP and 157 (61%) patients with sporadic AA, were included. Over a median of 31 (range, 11-61) months, recurrence occurred in 48/100 (48%) of patients with FAP and 58/157 (36.9%) with sporadic AA (P = 0.07). Two (2%) FAP patients and 10 (6.3%) patients with sporadic AA underwent surgery for recurrence. On multivariable regression analysis, the recurrence in FAP was higher than in sporadic patients after the first year of follow-up. AA size (hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.001, 1.056), periampullary extension (HR 2.5, 95% CI 1.5, 4.01), and biliary duct dilation (HR 2.04, 95% CI 1.2, 3.4) increased the risk, while en bloc resection (HR 0.6, 95% CI 0.41, 0.9) decreased the risk of recurrence. Recurrence rates are high after EP. Most recurrences in sporadic patients occur within the first year of follow-up, but after the first year of follow-up in patients with FAP. Recurrences are higher with larger adenomas, biliary duct dilation, and periampullary extensions, and may be mitigated by en bloc resection. These factors should be considered in decision-making with the patients.

Region-specific Wnt signaling responses promote gastric polyp formation in patients with familial adenomatous polyposis.

Germline adenomatous polyposis coli (APC) mutation in patients with familial adenomatous polyposis (FAP) promotes gastrointestinal polyposis, including the formation of frequent gastric fundic gland polyps (FGPs). In this study, we investigated how dysregulated Wnt signaling promotes FGPs and why they localize to the corpus region of the stomach. We developed a biobank of FGP and surrounding nonpolyp corpus biopsies and organoids from patients with FAP for comparative studies. Polyp biopsies and polyp-derived organoids exhibited enhanced Wnt target gene expression. Polyp-derived organoids with intrinsically upregulated Wnt signaling showed poor tolerance to further induction, suggesting that high Wnt restricts growth. Targeted genomic sequencing revealed that most gastric polyps did not arise via APC loss of heterozygosity. Studies in genetic mouse models demonstrated that heterozygous Apc loss increased epithelial cell proliferation in the corpus but not the antrum, while homozygous Apc loss was not maintained in the corpus yet induced hyperproliferation in the antrum. Our findings suggest that heterozygous APC mutation in patients with FAP may be sufficient to drive polyp formation in the corpus region while subsequent loss of heterozygosity to further enhance Wnt signaling is not tolerated. This finding contextualizes the abundant yet benign nature of gastric polyps in FAP patient corpus compared with the rare, yet adenomatous polyps in the antrum.

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

Abstract 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. ResultsIn 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.

Integrated genotype–phenotype analysis of familial adenomatous polyposis-associated hepatocellular adenomas

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene, characterized by numerous colorectal adenomas. In addition, FAP patients may develop extraintestinal manifestations. Several cases of hepatocellular adenomas (HCA) detected accidentally in FAP patients have raised the so-far unsolved question of whether they represent a specific manifestation of FAP or a mere coincidence. To investigate the incidence of liver tumors in FAP patients, we analyzed our diagnostic database from 1991 to 2021. Among the 58 hepatic mass lesions identified, five HCAs occurring in three patients with FAP were identified, and comprehensive morphological, immunohistological, and molecular analysis employing targeted next-generation sequencing was conducted for characterization. The HCAs in this study showed no cytological or histological atypia. They displayed a diffuse, strong positivity for glutamine synthetase but no nuclear beta-catenin immunostaining. In two patients, the adenomas showed moderate immunoreactivity against serum amyloid A. Consistent with the diagnosis of FAP, molecular profiling revealed a pathogenic germline mutation of the APC gene in all analyzed adenomas as well as deleterious somatic second hits. All somatic mutations were localized between codons 1345 and 1577. No mutations were found in the catenin beta 1 gene. HCA in FAP patients can be a specific, although rare, neoplastic manifestation of this inborn disease and represents a distinct subgroup of HCAs. These benign tumors represent an important differential diagnosis for hepatic metastases in FAP patients and require adequate clinical and molecular (diagnostic) assessments for optimal patient guidance.

Gastric Polyps in Familial Adenomatous Polyposis Portuguese Patients: The First Western Cohort with Asian Features

Introduction: Chronic atrophic gastritis may contribute to gastric polyps (GP) phenotype in familial adenomatous polyposis (FAP). Considering the high prevalence of Helicobacter pylori (HP) infection in Portugal, we aim to characterize GP in a series of Portuguese patients. Methods: In a retrospectively selected series of 53 FAP patients, clinical data and histopathological features of GP and background gastric mucosa were studied. SPSS (27.0) was used for statistical analysis. Results: Thirteen patients (24.5%) developed fundic gland polyps (FGP), seven (13.2%) gastric adenomas (GA), and ten (18.9%) both FGP and GA. Out of 100 GP, four were hyperplastic polyps, 58 FGP (24 with dysplasia), 35 intestinal-type GA (intGA), and three foveolar-type GA (fovGA). IntGA were larger (60% >7 mm, p = 0.03), occurred predominantly in the distal stomach (66.7%, p = 0.024), in patients harboring gastric intestinal metaplasia (IM) (86.7%, p p Conclusion: This is the first Western series showing high prevalence of intGA in FAP patients, comparable to Asian cohorts. HP infection and chronic atrophic gastritis/intestinal metaplasia are likely responsible for this difference, with risk of neoplastic transformation and management implications. Biopsy/excision of GP >7 mm in the distal stomach and in patients harboring gastric intestinal metaplasia/duodenal adenomas should be considered.

Genotype-phenotype correlation for extracolonic aggressive phenotypes in patients with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can be explained by the localization of the adenomatous polyposis coli (APC) variant, but few reports provide definitive findings about genotype-phenotype correlations. Therefore, we investigated FAP patients and the association between the severe phenotypes and APC variants. Of 247 FAP patients, 126 patients from 85 families identified to have APC germline variant sites were extracted. These sites were divided into six groups (Regions A to F), and the frequency of severe comorbidities was compared among the patient phenotypes. Of the 126 patients, the proportions of patients with desmoid tumor stage ≥III, number of FGPs ≥1000, multiple gastric neoplasms, gastric neoplasm with high-grade dysplasia, and Spigelman stage ≥III were 3%, 16%, 21%, 12%, and 41%, respectively, while the corresponding rates were 30%, 50%, 70%, 50%, and 80% in patients with Region E (codons 1398-1580) variants. These latter rates were significantly higher than those for patients with variants in other regions. Moreover, the proportion of patients with all three indicators (desmoid tumor stage ≥III, number of FGPs ≥1000, and Spigelman stage ≥III) was 20% for those with variants in Region E and 0% for those with variants in other regions. Variants in Region E indicate aggressive phenotypes, and more intensive management is required.