Introduction

Currently, the only management option for patients with celiac disease (CeD) is lifelong adherence to a gluten-free diet (GFD). Here, we report the results of a phase 2 study of the computationally designed glutenase TAK-062 (zamaglutenase) for the treatment of CeD in patients on a GFD (NCT05353985).

Aims & Methods

Eligible patients were aged >18 years with ongoing CeD-related gastrointestinal (GI) symptoms and villous height to crypt depth ratio (Vh:Cd) <2.5, despite maintenance of a GFD for ≥1 year. Study phases were: (1) a 4-week screening period to confirm symptoms and perform endoscopy; (2) a 4-week single-blind placebo run-in, including 2 weeks receiving placebo simulated inadvertent gluten exposure (SIGE) bars (Weeks −4 to −2) and 2 weeks receiving SIGE bars containing approximately 500 mg of gluten 3× per week (TIW; Week −2 to Day 1); and (3) a 24-week treatment period with patients randomized to receive TAK-062 600 mg or placebo with meals 3× per day (TID), plus gluten-containing SIGE TIW, followed by an endoscopy. Symptoms were assessed daily using the 5-item Celiac Disease Symptom Diary v2.1 (CDSD), that evaluates the severity of CeD symptoms on a 5-point Likert scale.

The primary endpoint was change from baseline to Week 12 in mean weekly CDSD GI symptom severity scores, and the secondary endpoint was change from baseline to Week 24 in Vh:Cd. Safety was assessed throughout the study. Differences between groups were assessed using a mixed model for repeated measures (primary endpoint) and ANCOVA (secondary endpoint) at a 2-sided significance level of 0.05.

Results

A total of 153 patients were randomized (placebo: n = 76; TAK-062: n = 77); one patient in the TAK-062 arm did not receive treatment. Mean age was 46.0 years, 75.2% of patients were female, mean time since diagnosis was 8.7 years, and 24.2% were seropositive. Mean baseline Vh:Cd was 1.78 and mean baseline weekly CDSD GI symptom severity score was 0.93. There were no appreciable differences between groups in baseline characteristics.

There was no significant improvement in weekly CDSD GI symptom severity score from baseline to Week 12 in either arm, and no significant difference between groups; non-significant improvements of approximately 0.1 were observed in both arms (Table). Vh:Cd remained stable to Week 24 in the placebo arm, but significantly decreased by 0.34 (95% confidence interval: −0.53, −0.14) in the TAK-062 arm, with a significant difference between groups (Table). Similar results were observed in all subgroups assessed.

TAK-062 was clinically well tolerated despite the significant decrease in Vh:Cd, with comparable proportions of patients in both arms experiencing an adverse event (AE) (placebo: 64.5%; TAK-062: 73.7%) or serious AE (placebo: 5.3%; TAK-062: 1.3%). The most frequent AEs were GI-related and occurred at a similar frequency in both arms, with the exception of diarrhea (placebo: 2.6%; TAK-062: 17.1%).

Conclusion

TAK-062 did not demonstrate efficacy for improving symptoms or histology in patients with ongoing active CeD on a GFD. Vh:Cd significantly worsened in the TAK-062 arm, with a significant difference between groups; possible reasons for this are under investigation. Stable Vh:Cd in the placebo arm indicates that SIGE successfully mitigates trial-related disease improvements previously observed in similar cohorts.

Disclosure

LE has nothing to disclose. ML reports receiving consulting fees from Anokion, EllaOla, and Takeda, and research funding from Moderna (institution) and Takeda (institution). PR has nothing to disclose. CC has nothing to disclose. JS reports receiving consulting fees from Chugai, GIG, and Takeda, and research funding from Takeda. JAM reports grants from ImmusanT, National Institutes of Health, Department of Defense, Immunogenix, Takeda Pharmaceuticals, Allakos, Provention Bio, Oberkotter Foundation, and 9 Meters Biopharma; a contract (to institution) from Kanyos Bio (a wholly owned subsidiary of Anokion); consultancy fees from Johnson and Johnson, Bristol Myers Squibb, Intrexon Corporation, Dren Bio, Neoleukin Therapeutics, Reistone Biopharma, Immunic Therapeutics, Senda Biosciences, Brightseed Bio, Chugai Pharma, Alimentiv, Equillium, Interlude Biopharma, Ukko Inc., argenx; has received royalties from Torax Medical and Evelo Biosciences; and holds shares in Entero Healthcare and Minnesota Medical Technologies. DSS reports receiving honoraria and research funding from Takeda. HL, JRM, MZ, SG, and DAL are employees and shareholders of Takeda.

Introduction

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the U.S., with persistent disparities across racial and ethnic groups. Current uniform screening guidelines overlook population differences in risk. Polygenic risk scores (PRS) offer a pathway to personalized, risk-stratified screening, but their cost-effectiveness across diverse populations is unclear.

Aims & Methods

In this study, we estimated the cost-effectiveness of PRS-based, risk-stratified screening across four major U.S. racial and ethnic groups (White, Black, Asian and Hispanic), modelling lifetime costs, quality-adjusted life-years gained (QALYGs), and colonoscopy use to assess both overall and subgroup-specific outcomes.
PRS data from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) were used to stratify individuals into risk 40 groups. The microsimulation model MISCAN-Colon was used to determine the optimal colonoscopy screening strategy for each risk group within the racial and ethnic groups. Investigated strategies varied in terms of starting age (40–60 years), stopping age (70–85 years), and screening interval (5–15 years). Within each racial and ethnic group, the cost-effectiveness of the optimal strategies of the 40 risk groups was compared with uniform colonoscopy screening (ages 45–75, every 10 years).

Results

Risk-stratified screening produced different recommendations across risk levels and populations. For low-risk groups, strategies ranged from no screening in Whites and Blacks to a one-time colonoscopy at age 55 for Asians and at age 60 for Hispanics. In contrast, for high-risk groups, all populations benefited most from intensive screening with colonoscopy every 5 years from ages 40–85. Across all racial and ethnic groups, PRS-guided screening outperformed uniform strategies, preventing more CRC cases and deaths but at the cost of higher colonoscopy use and costs. In constrained analyses, when QALYGs were fixed to the level of uniform screening, risk-stratified screening reduced costs by 6–27% and when costs were fixed to the level of uniform screening QALYGs increased by 8–29% These efficiency gains were most pronounced in Hispanics (–27% costs; +29% QALYGs) and Asians (–14% costs; +13% QALYGs), with smaller but consistent improvements in Whites (-9% costs; +12% QALYGs) and Blacks (-6% costs; +8%QALYGs).

Table 1. Lifetime Effects and Costs per 1,000 40-Year-Old Individuals for No Screening, Uniform Screening, and PRS-Guided Risk-Stratified Screening at a $100,000/QALYG Threshold, With QALYGs- and Cost-Constrained Analyses, Stratified by Racial and Ethnic Group (Results only for Hispanics and Asians)
Asians

Conclusion

PRS-guided screening may offer a pathway to more tailored CRC prevention, with modest overall gains but potentially greater cost savings and health benefits in Hispanics and Asians.

References

1. Carethers JM. Racial and ethnic disparities in colorectal cancer incidence and mortality. Adv Cancer Res. 2021;151:197-229.
2. May FP, Yang L, Corona E, Glenn BA, Bastani R. Disparities in Colorectal Cancer Screening in the United States Before and After Implementation of the Affordable Care Act. Clin Gastroenterol Hepatol. 2020;18(8):1796-804 e2.
3. Dixon P, Keeney E, Taylor JC, Wordsworth S, Martin RM. Can polygenic risk scores contribute to cost-effective cancer screening? A systematic review. Genet Med. 2022;24(8):1604-17.
4. Tamlander M, Jermy B, Seppälä TT, Färkkilä M, FinnGen, Widén E, et al. Genome-wide polygenic risk scores for colorectal cancer have implications for risk-based screening. Br J Cancer. 2024;130(4):651-9.

Disclosure

No conflicts of interest.

Introduction

Corpus atrophic gastritis (CAG) requires endoscopic-histological surveillance due to the risk of developing gastric neoplastic lesions (GNL). This study aimed to identify variables associated with GNL development at long-term follow-up using a feature ranking method based on a novel One-Class Support Vector Machine (SVM) model.

Aims & Methods

A dataset containing clinical, endoscopic, and histological variables from consecutive CAG patients (2001-2023) adhering to a surveillance program was considered. GNL presence at the longest available follow-up was recorded. Gastric biopsies and histological evaluations were conducted according to the updated Sydney system. CAG patients with any missing data or a GNL diagnosis at the baseline gastroscopy were excluded from the final analysis. A Fisher score-based feature ranking method and One-Class SVM were used to select the optimal subset of baseline variables associated with GNL development, aiming to achieve average sensitivity (Se) and specificity (Sp) above 80%.

Results

Overall, 355 CAG patients were initially considered. Of these, 36 were excluded due to the presence of GNL at baseline gastroscopy, and 216 for missing data. Thus, a total of 103 patients were considered and grouped into: CAG patients with [22 patients (F 68.1%), median age 68 (35-83) years] and without GNL at follow-up [81 patients (F 72.8%), median age 59(26-84) years]. After a median follow-up of 60 (12-192) months, 13 epithelial GNL (gastric adenocarcinoma or high/low-grade dysplasia) and nine type-1 gastric-neuroendocrine-tumors (T1gNET) were recorded. Parietal-cell-antibodies and pepsinogen-I < 30 μg/l were associated with both epithelial GNL and T1gNET. Antral inflammation and age > 60 were linked to epithelial GNL, while anti-thyroperoxidase-antibodies, smoking, and dyspeptic symptoms at CAG diagnosis were linked to T1gNET. Low-dose aspirin and H. pylori eradication therapy showed inverse associations with epithelial GNL and T1gNET, respectively.

Conclusion

This is the first study in which an AI model simultaneously considers clinical, endoscopic, and histological characteristics from a dataset of CAG patients, showing good sensitivity and specificity in identifying those variables associated with developing GNL. Nonetheless, we acknowledge the need for improved variable standardization and data balancing between groups to enhance model performance further.

Introduction

The European Union has signalled gastric cancer screening and prevention as a major health priority. The TOGAS consortium (TOwards GAstric cancer Screening in the European Union; togas.lu.lv), funded in response to this call, investigates different strategies for primary and secondary prevention of gastric cancer in Europe. One pilot study aims at determining the yield of having an oesophagogastroduodenoscopy (OGD) on the same day of a colonoscopy for colorectal cancer screening or polyp surveillance.

Aims & Methods

This is the first interim data on n=602 individuals recruited in 8 centres across Europe (France, Germany, Ireland, Latvia, Lithuania, the Netherlands, Portugal, and Spain). Individuals of the age of 50-74 years, attending for screening or surveillance colonoscopy, were invited to participate if they did not have a past diagnosis of gastric preneoplastic conditions requiring surveillance. Standardization of endoscopic procedures was assured by a rigorous protocol including all quality parameters defined by ESGE. This included standards for image documentation and biopsy sampling. Demographics, comorbidities, medication and the previous surgical and family history were recorded. Patients with marked preneoplastic changes (i.e. glandular atrophy or intestinal metaplasia [IM] at OLGA/OLGIM stage 3 or 4, and/or EGGIM score >5) were registered as requiring further endoscopic surveillance. Mann-Whitney U-test was applied for comparison of age between groups and Chi2 test for comparison of categorical variables (significance for p<0.05).

Results

The mean age of participants was 62 years (SD +/- 8.0), with 55.8% being male. Of 245 individuals who underwent an OGD prior to inclusion, 93.1% of these procedures were done >3years before and 60.4% were done at a tertiary centre. We identified 6 (1.0%) malignant/neoplastic lesions, 4 gastric cancers/dysplastic lesions and 2 oesophageal carcinomas. A positive H. pylori status was diagnosed in 34.2%. Endoscopically, a diagnosis of preneoplastic conditions was made in 217 participants (36.0%). Of these, 84 (14.0%) showed gastric atrophy, 45 (7.5%) gastric IM and 75 (12.5%) both conditions combined. Of those with gastric atrophy, this was classified as multifocal in 44 (27.6%) individuals, of those with IM in 45 (37.5%). OLGA stages 3 and 4 were confirmed for 1.9% and 0.8%, OLGIM stages 3 and 4 for 2.3% and 0.4%. Benign ulcers were diagnosed in 28 (4.7%) participants. The majority being gastric ulcers in 19 (3.2%) individuals, duodenal ulcers in 9 (1.5%), and oesophageal ulcers in 2 (0.3%). An additional 13 (2%) participants were diagnosed with Barrett’s oesophagus. It is of note that also 12 (2.0%) colorectal cancers were identified in the cohort. A positive H. pylori status was associated with the need for gastric surveillance (p=0.031).

Conclusion

This interim analysis of the first European pilot study on a combined screening for upper and lower GI tumours shows that this approach is feasible. Regarding the detection of upper GI malignancy and preneoplastic conditions, our findings are in line with previous systematic reviews, but we also demonstrate a reasonable rate of non-malignant findings that are also of relevance when defining the best screening strategy in Europe.

Disclosure

JB: Advisory fee from Flynn Pharma Ltd, Juvise Pharmaceuticals.
MCWS: Research Support from Sysmex, Norgine, Sentinel
OK: Speakers fee, advisory fee from Abbvie, Pfizer, Takeda, Janssen, Shire.

Introduction

Pathological esophageal acid exposure may persist in patients with Barrett’s esophagus (BE) despite standard proton pump inhibitor (PPI) therapy and symptom control, although current guidelines recommend at least standard-dose PPI for all patients with BE.¹

Aims & Methods

Aim was to evaluate the role of esophageal function testing in assessing acid exposure in BE patients on PPI therapy and in predicting neoplastic progression. We conducted a multicenter retrospective study including asymptomatic BE patients (defined by GerdQ total score <8 and a score of 0 on the first GerdQ item) who underwent high-resolution manometry and 24-hour pH impedance monitoring while on various PPI regimens. Maximal PPI therapy included esomeprazole 40 mg, pantoprazole 40 mg, rabeprazole 20 mg, or lansoprazole 30 mg, all administered twice daily. All other regimens were considered standard dosing. Index upper endoscopy with biopsies was performed under the same therapeutic regimen. Histologically, presence and degree of neoplasia (all confirmed by a second pathologist) was recorded. Acid exposure time (AET) <4% was defined as adequate acid control; AET >6% as pathological reflux. Predictors of pathological reflux and neoplasia were assessed using logistic regression analysis.

Results

A total of 135 patients (2016-2025) were included (mean age 58 ± 15 years; 73% male). Median BE length was C1 (range 0–3 cm) and M2 (range 1–5 cm), with 41% (n=56) classified as having long-segment BE. Sixty-seven patients (50%) were on standard-dose PPI. Pathological reflux was identified in 37 patients (27%), of whom 25 (67%) were on standard-dose therapy. Fourteen patients (10%) had borderline AET values (4–6%). Among the 84 patients (62%) with adequate acid control, 33 (39%) were taking standard-dose PPI. On multivariable analysis, standard-dose PPI (OR 3.04; 95% CI 1.34–6.89; p=0.008) and type III esophagogastric junction morphology (OR 2.52; 95% CI 1.01–5.01; p=0.047), consistent with manometric hiatal hernia, were independently associated with pathological reflux. Non-dysplastic BE was found in 112 patients, while 13 (10%) had neoplasia at index endoscopy (8 low-grade dysplasia, 3 high-grade dysplasia, 2 intramucosal adenocarcinoma). Pathological reflux was the only independent predictor of neoplasia (OR 10.41; 95% CI 2.65–41.26; p<0.001).

Table 1. Logistic regression analysis for factors associated with neoplasia on index endoscopy.

Conclusion

Nearly one-third of asymptomatic BE patients exhibit pathological reflux on pH-monitoring despite PPI treatment, predominantly among those on standard-dose and with manometric hiatal hernia. Nonetheless, adequate acid control is achieved in over one-third of patients on standard PPI therapy. Pathological reflux is associated with a 10-fold increased risk of neoplasia.

References

1. Shaheen NJ, Falk GW, Iyer PG, et al. Diagnosis and Management of Barrett's Esophagus: An Updated ACG Guideline. Am J Gastroenterol. 2022;117(4):559-587.

Introduction

Few studies have examined esophageal motility disorders in patients with type 2 diabetes operated with sleeve gastrectomy (SG) or gastric bypass (RYGB).

Aims & Methods

We have recently reported overall prevalence of gastroesophageal reflux disease (GERD) in this group of patients (1) and now aimed to investigate potential differences between the two surgical methods regarding the prevalence of dysmotility 5 years after surgery. Furthermore, we also aimed to analyse and report on the available GERD-data in detail.
In the Oseberg study (January 2013 – December 2022), 125 patients with BMI ≥ 35 kg/m² and type 2 diabetes were screened, sixteen patients were excluded or withdrew consent, leaving 109 patients allocated to SG (n=55) or RYGB (n=54). To assess reflux symptoms, GerdQ (Gastroesophageal reflux disease questionnaire) was completed. Gastroscopy and 24-hour pH monitoring were used to examine GERD. High-resolution manometry with the Chicago classification v3.0 was used to assess esophageal motility.

Results

At inclusion the average age was 47.7 years (SD 9.6), BMI was 42.3 kg/m2 (5.3), and 66% were women. At the 5-year follow-up, 29 (53%) patients in SG-group and 32 (59%) in RYGB-group underwent gastroscopy, 22 (40%) vs. 25 (46%) underwent 24-hour pH monitoring, 23 (42%) vs. 26 (48%) underwent manometry, and 42 (76%) vs. 42 (78%) completed GerdQ. The proportion of patients with GERD symptoms (GerdQ ≥8) was low in both groups, with a slightly lower prevalence after RYGB (2%) than after SG (14%). There was no difference in the prevalence of erosive esophagitis between the groups (38% in SG and 41% in RYGB), all findings with less advanced esophagitis (Los Angeles grades A and B), but one patient in each group had new onset Barrett's esophagus. The proportion of patients with pH<4 for more than 6% of the recording (Acid exposure time, AET) was significantly higher after SG compared with RYGB (59% versus 8%, p < 0.0001). Esophageal dysmotility was diagnosed in 14 (61%) after SG compared with 19 (73%) patients after RYGB. Most of these patients (n=22) had hypertensive or hypotensive lower esophageal sphincter (LES), with no difference between groups. The remaining 11 patients had ineffective esophageal motility (IEM) or elevated distal contractile integral (DCI). None of the patients with dysmotility reported swallowing difficulties or chest pain with food intake.

Conclusion

The Oseberg study demonstrates a high prevalence of asymptomatic esophageal dysmotility after SG or RYGB with uncertain clinical relevance. Furthermore, a seven times higher prevalence of pathological acid reflux after SG compared with RYGB was demonstrated, but the prevalences of erosive esophagitis and esophageal dysmotility were approximately similar between groups. Few of the examined patients reported GERD symptoms, hence objective assessment of GERD should be included in long-term follow-up after SG to detect and prevent the development of Barrett's esophagus, dysplasia, and adenocarcinoma.

References

1. Hauge JW et al., Effect of gastric bypass versus sleeve gastrectomy on the remission of type 2 diabetes, weight loss, and cardiovascular risk factors at 5 years (Oseberg): secondary outcomes of a single-centre, triple-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2025 Apr 1:S2213-8587(24)00396-6