BACKGROUND & AIMS:Inflammatory bowel disease involves intractable intestinal inflammation often refractory to current pharmacotherapies. We investigated the therapeutic potential of a novel, orally available inhibitor targeting α-1,6-fucosyltransferase-the sole glycosyltransferase catalyzing core fucosylation of N-glycans in mammals-as an anti-inflammatory agent. METHODS:α-1,6-Fucosyltransferase inhibitor efficacy was evaluated in 2 murine models: a trinitrobenzene sulfonic acid-induced colitis model and a naive CD4+ T-cell adoptive transfer model using recombination activating gene 2 (Rag2)-deficient mice. Amelioration of trinitrobenzene sulfonic acid-induced colitis by the α-1,6-fucosyltransferase inhibitor was also evaluated in LckcreFut8fl/fl mice in which α-1,6-fucosyltransferase is conditionally abrogated in T cells. Splenic CD4+ T cells from wild-type mice were treated with the α-1,6-fucosyltransferase inhibitor to evaluate its effects on cell signaling, cytokine production, and T helper 1, 2, and 17 differentiation. In vivo safety was assessed in wild-type mice. RESULTS:Oral administration of the α-1,6-fucosyltransferase inhibitor effectively decreased T-cell core fucosylation and ameliorated trinitrobenzene sulfonic acid-induced colitis and colitis induced by adoptive T-cell transfer. These clinical effects were accompanied by decreased T helper 1 and 2 cytokine production from CD4+ T cells. Trinitrobenzene sulfonic acid-induced colitis was attenuated in LckcreFut8fl/fl mice, demonstrating that the ameliorative effect of α-1,6-fucosyltransferase inhibition is directly mediated by T cells. In vitro, the inhibitor suppressed T-cell signal transduction and T helper 1, 2, and 17 cell differentiation. No apparent hepatorenal toxicity or intestinal mucus layer disruption was observed. CONCLUSIONS:α-1,6-Fucosyltransferase inhibition modulated T-cell core fucosylation and reduced inflammation in murine colitis models without apparent toxicity, indicating that targeting α-1,6-fucosyltransferase may offer a novel therapeutic approach for inflammatory bowel disease by disrupting proinflammatory T-cell responses.

Background and Aims:Effective, minimally invasive biomarkers are needed to predict treatment outcomes in ulcerative colitis (UC). This multicenter observational study investigated predictive serum and genetic biomarkers for vedolizumab (VDZ) therapy in UC, including serum leucine-rich α-2-glycoprotein (LRG), cytokines, and differentially expressed genes (DEGs) in intestinal tissue. Methods:Eligible patients (18-80 years; moderately to severely active UC) received intravenous VDZ (300 mg; Weeks 0, 2, 6, then every 8 weeks through Week 54). Serum biomarkers were compared between those who did/did not achieve clinical remission (CR; full Mayo score ≤2, all subscores ≤1) or mucosal healing (MH; Mayo endoscopic subscore ≤1) at Week 14. Week 0 inflammatory tissue data were stratified by Week 14 VDZ effect (CR and complete-MH [Mayo endoscopic subscore = 0]) for DEGs. Results:Overall, 21 patients were included. Mean serum LRG was significantly lower in the CR (n = 11) versus non-CR (n = 10) group at Week 0 (19.0 vs 29.0 µg/mL; P = .0267) and Week 6 (13.4 vs 19.6 µg/mL; P = .0340), and in the MH (n = 14) versus non-MH (n = 7) group at Week 6 (13.7 vs 21.6 µg/mL; P = .0326). Mean monocyte chemoattractant protein-1 (MCP-1) was significantly different between CR and non-CR groups at Week 0 (609.0 vs 403.4 pg/mL; P = .0018) and MH versus non-MH at Week 0 (587.2 vs 358.9 pg/mL; P < .001) and Week 6 (606.9 vs 451.6 pg/mL; P = .037). No significant differences in C-reactive protein and fecal calprotectin levels were observed. DEGs included LRG1, LRG-related cytokines, and MCP1. Conclusions:Serum LRG and MCP-1 may be candidate biomarkers of VDZ treatment response in UC.

Small bowel (SB) lesions in Crohn’s disease (CD) are often asymptomatic despite being highly active. Fecal calprotectin (FC) is the most widely used biomarker of CD activity, but its drawbacks include a large intra-individual sample variability and the burden of collecting stool samples. Meanwhile, serum leucine-rich alpha-2 glycoprotein (LRG) has recently attracted attention as a biomarker that can address the limitations of FC. This study determined the diagnostic accuracy of LRG and its cut-off values for diagnosing CD activity in SB. This was a retrospective, multi-center study of CD patients undergoing retrograde balloon-assisted endoscopy. For ileal- and ileocolonic-type patients with a colon SES-CD score of 0, we estimated the receiver operating characteristic curve of LRG and determined the cut-off value to achieve a target sensitivity level of 80

Background:There are currently no standardized guidelines for optimizing 5-aminosalicylic acid (5-ASA) maintenance treatment, particularly in patients with ulcerative colitis (UC) who have achieved clinical remission (CR). Therefore, this study examined the perspectives of patients and physicians regarding 5-ASA dose reduction and medication adherence to optimize maintenance treatment. Methods:This cross-sectional study was conducted from February 2023 to May 2023 at 19 institutions and included patients with UC and physicians. The participants' perspectives were assessed using an anonymous questionnaire. Results:This study included 369 patients with UC (female, 43.1%; age, > 60 years, 29.3%; CR, 88.9%). Preference to reduce the 5-ASA dose and low medication adherence were observed in 46.1% and 16.0% of patients, respectively. Low medication adherence (odds ratio [OR]: 3.43, 95% confidence interval [CI]: 1.67-7.03) was associated with the preference to reduce the 5-ASA dose. Multivariate analysis for factors associated with low medication adherence revealed age < 60 years (OR: 10.25, 95% CI: 3.58-29.38), no intractable disease subsidy (OR: 2.63, 95% CI: 1.09-6.35), dosing frequency ≥ 2 times/day (OR: 9.04, 95% CI: 3.67-22.25), and preference to reduce the 5-ASA dose (OR: 2.57, 95% CI: 1.16-5.70) as significant. Among 153 physicians, 62.7% had > 10 years of experience, and 51.0% regularly verified adherence, with experience being a significant factor (OR: 2.01, 95% CI: 1.10-3.68). Conclusions:Factors influencing medication adherence with 5-ASA included patients' desire for dose reduction and physicians' lack of experience. Improving communication with patients and enhancing education for physicians could help optimize treatment with 5-ASA.

A boy in his late teens had undergone proctocolectomy for refractory ulcerative colitis eight months ago. Two months earlier, he had developed pouchitis and received intensive treatment with infliximab (IFX). Two days after the IFX injection, a fever and generalized rash appeared. Varicella zoster virus (VZV) antigen positivity in the blisters led to a diagnosis of varicella. Based on the history of VZV vaccination, environmental conditions, and VZV antibody titers in the early stages of the disease, VZV reactivation was suggested. The possibility of varicella should be considered when blisters occur in immunosuppressed patients, although this is rare.

The clinical usefulness of serum leucine-rich alpha-2 glycoprotein (LRG) levels as a surrogate marker of endoscopic activity including postoperative recurrence in patients with Crohn’s disease (CD) remains unclear, and LRG production in the small intestinal mucosa has not been explored. The present study investigated the usefulness of serum LRG to ascertain endoscopic activity, the secretion of LRG from the small intestinal mucosa, and the significance of LRG as a predictor of postoperative disease course. We included 364 patients who underwent transanal endoscopy at Osaka University Hospital. Serum LRG correlated highly with endoscopic severity (LRG, r = 0.65; CRP, r = 0.37) and reflected strictly moderate endoscopic activity better than serum CRP. Especially, serum LRG reflected mucosal healing even in patients whose inflammation was confined to the small intestine. In multivariate analyses, serum LRG was an independent factor influencing mucosal healing. LRG was more strongly expressed in the inflamed mucosa of the small intestine compared with that in uninflamed mucosa, and serum LRG was more strongly correlated with postoperative small intestinal recurrence severity than CRP (LRG, r = 0.62; CRP, r = 0.32). In conclusion, serum LRG is a useful surrogate marker of endoscopic CD severity and activity, with increased LRG expression in the small bowel predicting postoperative recurrence.

Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play an important role in tumor progression. Colon cancer cells deficient in p53 activate fibroblasts and enhance fibroblast-mediated tumor growth. Meflin is a CAF marker capable of inhibiting tumor growth. In this study, we investigated the role of Meflin in fibroblasts using human cell lines (colon cancer HCT116 and fibroblasts CCD-18Co) and clinical specimens. TP53-suppressed HCT116 (HCT116sh p53) cells cocultured with CCD-18Co cells showed significantly faster proliferation than HCT116sh control cells. In xenograft experiments, the volume of tumors induced by coinoculation with HCT116sh p53 and CCD-18Co cells was significantly larger than that induced by HCT116sh control cells co-inoculated with CCD-18Co cells. HCT116sh p53 cells increased the levels of CAF-like phenotypic markers in CCD-18Co cells. Moreover, Meflin expression was significantly reduced in CCD-18Co cells cocultured with HCT116sh p53 cells compared to that in CCD-18Co cells cocultured with HCT116sh control cells. si-RNA-mediated inhibition of Meflin activated CCD-18Co cells into tumor-promoting CAF-like cells, which significantly promoted xenograft tumor growth. Overexpression of Meflin in CCD-18Co cells using lentivirus suppressed fibroblast-mediated growth of HCT116sh p53 tumor xenografts. The expression of Meflin in CCD-18Co cells was suppressed by TGF-β and enhanced by vitamin D. These results indicate that colon cancer cells deficient in p53 suppress Meflin expression in fibroblasts, which affects tumor growth by altering the properties of tumor growth-promoting CAFs. Our results suggest that targeting Meflin in fibroblasts may be a novel therapeutic strategy for colorectal cancer.

ABSTRACT Aims The Japan COVID‐19 Survey and the Questionnaire for Inflammatory Bowel Disease (J‐DESIRE) identified multiple factors associated with anxiety regarding the novel coronavirus disease 2019 (COVID‐19). However, no regional differences in anxiety were observed. In this post hoc analysis of J‐DESIRE, we investigated the relationship between the municipal population size at the place of residence (MPSPR) and anxiety among patients with IBD in Japan during the COVID‐19 pandemic. Methods and Results We analyzed 2958 questionnaires collected from patients with IBD aged ≥ 16 years between March 2020 and June 2021. The primary endpoint was the association between the visual analogue scale (VAS) scores of anxiety and MPSPR during the COVID‐19 pandemic. The mean VAS score for anxiety was higher than the overall mean VAS score in municipalities with large and small populations, while it was lower in municipalities with medium populations. Therefore, we categorized the population into three groups based on MPSPR: ≤ 150 000, 150 001–1 000 000, and ≥ 1 000 001. The three groups had different background factors, contents of anxiety, and sources of information regarding therapeutic drugs. These differences may have led to differences in the degree and content of anxiety. Conclusions We investigated the association between anxiety in Japanese patients with IBD and MPSPR nationwide during the COVID‐19 pandemic in Japan. The results obtained in this analysis are useful not only in special situations such as the COVID‐19 pandemic but also for considering regional differences in medical care.

Abstract Background Close monitoring of disease activity is essential for the therapeutic management of inflammatory bowel disease. A minimally invasive and reliable serum biomarker is desirable, but its reliability and validity have not yet been fully evaluated. The purpose of this study (UMIN000043185) was to investigate the utility of leucine-rich α-2-glycoprotein (LRG) in the management of vedolizumab therapy in patients with ulcerative colitis (UC), and to identify mucosal signatures and surrogate biomarkers by using serum cytokine and mucosal transcriptome analysis. Methods Serum LRG, C-reactive protein (CRP), serum Mucosal Vascular Addressin Cell Adhesion Molecule 1(MadCAM1), serum vedolizumab levels, 19 serum cytokines, and fecal calprotectin (fCal) were measured over 54 weeks (week 0, 2, 6, 14, 30, and 54) (n=21). Clinical remission (Mayo score <= 2, all subscore < = 1) and mucosal healing (Mayo endoscopic subscore <= 1) at week 14 were compared between the clinical remission (CR) group (n=11) and non-clinical remission (non-CR) group (n=10), and between the mucosal healing (MH) group (n=14) and non-mucosal healing (non-MH) group (n=7). Differentially expressed gene (DEG) extraction was performed by stratifying data at week 0 and comparing two groups: CR (n=10) and non-CR (n=3), and complete MH (Mayo endoscopic subscore = 0) (n=8) and non-complete MH (n=6) at week 14. Results Serum LRG concentrations were significantly lower in CR group compared to the non-CR group at week 0 (19.0 vs. 29.0 ug/mL, p=0.027) and week 6 (13.4 vs. 19.6 ug/mL, p=0.034) and significantly lower in MH group compared to the non-MH group at week 6 (13.7 vs. 21.6 ug/mL, p=0.033). In contrast, there were no significant differences in serum CRP and fecal calprotectin levels at any time point for either CR or MH. Serum MCP-1 levels showed significant differences between CR and non-CR at week 0 (609.0 vs 403.4 pg/mL, p=0.0018), between MH and non-MH at week 0 (587.2 vs 358.9 pg/mL, p<0. 001), week 6 (606.9 vs 451.6 pg/mL, p=0.015). DEGs extracted from colon tissue included LRG1 and LRG-related cytokines, MCP-1, reflecting the effect of vedolizumab treatment. Conclusion Both serum LRG (lower in CR/ MH group) and serum MCP-1 (higher in CR/MH group) were suggested to be promising predictive biomarkers of vedolizumab treatment response in patients with UC. Further studies are needed to assess their reliability and validity as indicators of treatment effectiveness.

Introduction: Budesonide, with its high topical steroidal activity, effectively prevents strictures following esophageal endoscopic treatment. However, its effectiveness in preventing restenosis after endoscopic balloon dilation (EBD) in patients with Crohn’s disease (CD) remains unclear. We aimed to evaluate the safety and effectiveness of oral budesonide after EBD in patients with CD. Methods: We conducted a multicenter prospective study of patients with CD who underwent EBD at the University of Osaka and its affiliated hospitals between March 2018 and March 2023 (UMIN000031839, jRCT1051190043). Oral budesonide was administered for 4 weeks after EBD, and patients were followed up for 52 weeks. Safety and effectiveness within 12 and 52 weeks of the procedure were evaluated, with endoscopic evaluation of restenosis at week 52. The stenosis diameter and length were estimated endoscopically and radiographically, respectively. In the historical control study, consecutive patients with CD who underwent EBD between February 2016 and July 2018 were included. The incidence rates of obstructive symptoms and hospitalization at 52 weeks after EBD were retrospectively investigated from the medical records. Results: Overall, 15 patients were analyzed (male, 14 [93.3%]; median age, 44 years [37–49]; disease type, L1, 8 [53.3%]/L3, 7 [46.7%]; stenosis location, jejunum, 1 [6.7%]/ileum, 8 [53.3%]/ileocolonic, 6 [40.0%]; median stenosis diameter, 5 mm [5–6]). No serious complications were observed within 12 or 52 weeks. Twelve (80%) patients showed no symptoms of stenosis within 52 weeks. Of the 14 patients who underwent an endoscopy at week 52, re-EBD was not required in 3 patients (21.4%). The stenosis diameter at week 52 improved significantly compared to the pre-dilation measurements (p = 0.004). Furthermore, the 15 patients treated with budesonide had a significantly lower incidence rates of obstructive symptoms and hospitalization compared to the 19 historical control patients (p = 0.020 and 0.035, respectively). Conclusion: Budesonide administration after EBD can be safely performed in patients with CD and may be effective in preventing restenosis and avoiding hospitalization and intestinal surgery.

There is insufficient evidence comparing the outcomes of tacrolimus-based remission induction therapy with infliximab in refractory ulcerative colitis (UC) and evidence regarding optimal strategies after tacrolimus-based remission induction therapy. We conducted a multi-institutional retrospective study of patients with UC treated with tacrolimus or infliximab between January 2010 and March 2019. The proportion of clinical remission at week 8 and cumulative colectomy-free rate were examined using propensity score matching analysis. The predictors for colectomy after tacrolimus induction were also investigated. Ninety patients in the tacrolimus group and 151 in the infliximab group were enrolled. The proportion of patients in clinical remission at week 8 was 65.2% in the matched tacrolimus group and 37.3% in the matched infliximab group (P = 0.0016), and the long-term colectomy-free rate was lower in the matched tacrolimus group than in the matched infliximab group (P = 0.0003). After clinical remission with tacrolimus, a serum albumin level of ≤ 3.5 g/dL at week 8 was extracted as a factor predicting colectomy (area under the curve: 0.94). Tacrolimus showed a higher remission induction effect for UC compared to infliximab. However, a high rate of colectomy after transition to maintenance treatment was found to be a concern for tacrolimus therapy.

Objectives The high rate of delayed bleeding after colorectal endoscopic submucosal dissection (ESD) in patients undergoing anticoagulant therapy remains a problem. Whether prophylactic clip closure reduces the rate of delayed bleeding in these patients is unclear. This study aimed to evaluate the efficacy of prophylactic clip closure in patients receiving anticoagulants. Methods This multicenter prospective interventional trial was conducted at nine referral centers in Japan. Patients regularly taking anticoagulants, including warfarin potassium or direct oral anticoagulants, and undergoing ESD for colorectal neoplasms were enrolled. The discontinuation of anticoagulants was minimized according to recent guidelines. After the ESD, post‐ESD ulcers were prophylactically closed using endoclips. The primary end‐point was the incidence of delayed bleeding. The sample size was 45 lesions, and prophylactic clip closure was considered effective when the upper limit of the 90% confidence interval (CI) for delayed bleeding did not exceed 20%. Results Forty‐five lesions were used, and three were excluded. Complete closure was achieved in 41/42 lesions (97.6%). The overall delayed bleeding rate was low, at 4.9% (2/41; 90% [CI] 0.8–14.5), which was significantly lower than that at the prespecified threshold of 20% ( P = 0.007). The median closure procedure time was 17 min, and the median number of clips was nine. No massive delayed bleeding requiring transfusion, interventional radiology, or surgery was observed, and no thromboembolic events were observed. Conclusion Prophylactic clip closure may reduce the risk of delayed bleeding following colorectal ESD in patients receiving anticoagulants. Trial registration UMIN Clinical Trial Registry (UMIN000036734).

Background and aimVarious techniques for direct biopsy from gastrointestinal subepithelial tumors (SETs) have been reported, although no standard method has been established. A common feature of these techniques is the removal of overlaying mucosa to enable direct biopsies from the SETs. These methods have been synthesized under the collective term "unroofing technique". We conducted a multicenter retrospective study to assess its efficacy and identify potential complications.MethodsThis study was conducted in 10 hospitals and involved all eligible patients who underwent unroofing techniques to obtain biopsies for gastrointestinal SETs between April 2015 and March 2021. The primary endpoint was the diagnostic accuracy of the unroofing technique, and the secondary endpoints were the incidence of adverse events and the factors contributing to the accurate diagnosis.ResultsThe study included 61 patients with 61 gastrointestinal SETs. The median tumor size was 20 mm, and the median procedure time was 38 min, with 82% successful tumor exposure. The rate of pathological diagnosis was 72.1%. In 44 patients with a pathological diagnosis, two showed discrepancies with the postresection pathological diagnosis. No factors, including facility experience, organ, tumor size, or tumor exposure, significantly affected the diagnostic accuracy. There was one case of delayed bleeding and two cases of perforation.ConclusionThe diagnostic yield of the unroofing technique was acceptable. The unroofing technique was beneficial regardless of institutional experience, organ, tumor size, or actual tumor exposure.

Serum leucine-rich alpha-2 glycoprotein (LRG) can monitor disease activities during biologics treatment in patients with inflammatory bowel disease (IBD). It is unclear whether the pretreatment serum LRG level can predict clinical effectiveness including serum trough levels of ustekinumab in patients with IBD. This multicenter prospective cohort study included 184 patients (Crohn's disease, 104; ulcerative colitis, 80) who received ustekinumab (n=119) or anti-tumor necrosis factor (n=65) between January 2019 and March 2023. Multivariate logistic regression analysis revealed serum LRG level at week 0 (0w-LRG, odds ratio 0.12, 95% confidence interval 0.02-0.68) as one of significant factors for clinical remission at week 8. We divided patients into the low- and the high-LRG groups by the median 0w-LRG (18.2 mu g/mL) and compared the effectiveness. In patients who received ustekinumab, the proportion of clinical remission at week 8 was significantly different between in the low- (76.9%) and in the high-LRG group (59.3%, P=0.038), and median serum trough level at week 8 was significantly different between in the low- (10.9 mu g/mL, interquartile range 6.7-13.4) and the high-LRG group (5.3 mu g/mL, interquartile range 2.4-8.3, P<0.001). The 0w-LRG can predict the effectiveness including serum trough levels of ustekinumab during induction treatment for patients with IBD.

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), predominantly affects young patients and leads to intestinal complications. Amyloidosis, which involves abnormal protein deposition, is a serious complication of IBD, with a low incidence. Early detection of subclinical amyloid deposits is crucial for preventing fatal outcomes; however, routine investigations are lacking. We aimed to retrospectively examine subclinical amyloid deposition in adult patients with IBD. Surgical specimens from 249 patients with IBD were collected from the databases of two hospitals. The specimens were subjected to staining and immunohistochemistry, and clinical information was collected simultaneously. The amyloid positivity rate was 0.8 % in CD (1/131) and 0 % in UC (0/118) based on Congo red staining. The patient with amyloid deposits was a female in her 80 s who lacked a family history of amyloidosis. The subtype was amyloid A. Clinical history revealed intestinal resection in her 30 s and subsequent abdominal symptoms. To the best of our knowledge, this is the first study to collect >100 surgically examined specimens from adults with CD or UC. In older patients with a long and complex clinical course, aggressive analysis of amyloids would be better.

Abstract Background Serum leucine-rich alpha-2 glycoprotein (LRG) is a biomarker reflecting endoscopic activity in patients with inflammatory bowel disease (IBD). However, it remains unclear whether serum LRG can predict the effectiveness of anti-cytokine biologics (biologics) in patients with IBD. This study aimed to evaluate whether serum LRG could predict the effectiveness and serum trough concentrations of biologics in patients with IBD. Methods This was a multicentre prospective cohort study including patients with IBD (including ulcerative colitis [UC] or Crohn’s disease [CD]) who received the biologics [ustekinumab (UST), anti-tumor necrosis factor (anti-TNF)] from January 2019 to March 2023 at 15 hospitals participating in the Osaka Gut Forum. The effectiveness of biologics was evaluated by clinical remission (CR) at week 8. We defined CR as a partial Mayo score of 2 or lower, with each subscore of 0 or 1 for UC and a CD activity index of < 150 for CD. Factors associated with CR at week 8 such as backgrounds, disease activities and concomitant medications at week 0 were analyzed by Cox proportional hazards model. For each biologic, we compared the effectiveness of biologics in the high LRG group with that in the low LRG group divided by the median serum LRG levels at week 0 (cut-off = 18.2 μg/mL). Results A total of 184 patients with IBD (UC, 80; CD, 104) were enrolled (UST/ anti-TNF, 119/ 65; biologic exposure, 31.5%; median disease duration, 6 years [Interquartile range (IQR) 1-14]). Median serum LRG levels at week 0 and serum C-reactive protein levels at week 0 were 18.2 μg/mL [IQR 12.5-28.1] and 0.19 mg/dL [IQR 0.03-0.77], respectively. At week 0, 63 (34.2%) and 64 (34.8%) patients concomitantly received corticosteroids and immunomodulators, respectively. In 184 patients with IBD, multivariate analysis revealed that serum LRG level at week 0 < 18.2 μg/mL was extracted as a significant factor for CR at week 8 (Odds ratio: OR 2.70, 95% confidence interval: CI 1.22-5.96). In patients who received UST, the proportion of CR at week 8 in the low-LRG group (76.9%) was significantly higher than that in the high-LRG group (59.3%, P = 0.038). In patients who received anti-TNF, however, the proportion of CR in the low-LRG group (84.6%) was not differ from that in the high-LRG group (82.1%, P = 0.781). Median serum trough concentrations of UST at week 8 in the low-LRG group (10.9 μg/mL, IQR 6.7-13.4) was significantly higher than that in the high-LRG group (5.3 μg/mL, IQR 2.4-8.3, P < 0.001). Conclusion Serum LRG could predict the effectiveness and serum trough concentrations of UST and be a biomarker for selecting biologics in patients with IBD.

INTRODUCTION: We aimed to evaluate the natural course of sporadic nonampullary duodenal adenomas (SNDAs) and determine the risk factors of progression. METHODS: We retrospectively analyzed the follow-up outcomes of patients with biopsy-diagnosed SNDA between April 2010 and March 2016 at 13 institutions. All initial biopsy specimens were centrally evaluated. Only those diagnosed with adenomas were included. Mucinous phenotypes were classified into pure intestinal and non–pure intestinal phenotypes. Cumulative incidence rates of carcinoma and tumor enlargement were evaluated. Tumor enlargement was defined as a ≥25% or 5-mm increase in tumor size. RESULTS: Overall, 121 lesions were analyzed. Within a median observation period of 32.7 months, 5 lesions were diagnosed as carcinomas; the cumulative 5-year incidence of carcinoma was 9.5%. Male sex ( P = 0.046), initial lesion size ≥10 mm ( P = 0.044), and non–pure intestinal phenotype ( P = 0.019) were significantly associated with progression to carcinoma. Tumor enlargement was observed in 22 lesions, with a cumulative 5-year incidence of 33.9%. Initial lesion size ≥10 mm ( P < 0.001), erythematous lesion ( P = 0.002), high-grade adenoma ( P = 0.002), Ki67 negative ( P = 0.007), and non–pure intestinal phenotype ( P = 0.001) were risk factors of tumor enlargement. In a multivariate analysis, an initial lesion size ≥10 mm ( P = 0.010) and non–pure intestinal phenotype ( P = 0.046) were independent and significant risk factors of tumor enlargement. DISCUSSION: Lesion size ≥10 mm and non–pure intestinal phenotype on initial biopsy are risk factors of cancer progression and tumor enlargement in cases with SNDA. Thus, management effectiveness may be improved by focusing on lesion size and the mucinous phenotype.