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

Eosinophilic esophagitis (EoE) is a chronic, progressive, immune-mediated inflammatory disease characterized by esophageal inflammation with infiltration of eosinophils (eos) and symptoms of esophageal dysfunction. Interleukin (IL)-13, a type 2 inflammatory cytokine, plays a key role in the pathophysiology of EoE. Cendakimab (CEN) is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody targeting IL-13, inhibiting binding to both its receptors, IL-13Rα1 and IL-13Rα2. CEN reduced mean esophageal eos counts and improved symptoms and endoscopic features of EoE in a phase 2 study. We report results from a pivotal phase 3 trial (NCT04753697) of CEN in adult and adolescent patients (pts) with EoE after 24 wk of treatment.

Aims & Methods

This multicenter, multinational, randomized, double-blind, placebo (PBO)-controlled study enrolled pts aged 12–75 y with active EoE (peak esophageal eos count [PEC] ≥ 15 eos/high power field [hpf] at any 2 levels of the esophagus), ≥ 4 dysphagia days (DD) over the 14-day period prior to day 1 evaluated using the modified Daily Symptom Diary (mDSD), and lack of complete response to ≥ 8 wk proton pump inhibitor treatment. The study planned to enroll ~70% of pts who were steroid inadequate responders or intolerant (steroid IR/I). Pts were randomized 1:1:1 to receive subcutaneous CEN 360 mg weekly for 48 wk (QW/QW), CEN 360 mg QW for 24 wk followed by CEN 360 mg every other wk for 24 wk (QW/Q2W), or PBO QW for 48 wk. Coprimary endpoints were mean change from baseline (BL) to wk 24 in DD and proportion of pts with eos histologic response, defined as PEC ≤ 6/hpf at wk 24. Key secondary endpoints included eos histologic response < 15/hpf at wk 24, endoscopic response (mean change in Endoscopic Reference Score [EREFS] total score), mean change in EoE Histology Scoring System (EoEHSS) grade/stage score, and mean change in mDSD composite score, from BL to wk 24. Safety was also evaluated.

Results

Overall, 430 pts (~66% steroid IR/I) were randomized to CEN (n = 286; QW/QW, n = 143, QW/Q2W, n = 143), or PBO (n = 144). In pts treated with CEN 360 mg QW, there was a statistically significant reduction from BL to wk 24 in DD vs PBO (−6.1 vs −4.2 days; difference [95% CI] vs PBO: −1.9 [−3.0 to −0.8]; P = 0.0005) and a statistically significantly higher proportion of pts with eos histologic response at wk 24 vs PBO (28.6% vs 2.2%; difference [95% CI] vs PBO: 26.4 [20.6 to 32.2]; P < 0.0001) (Table). Statistically significant improvements in all key secondary endpoints were observed for CEN-treated vs PBO-treated pts (Table). At wk 24, adverse events (AE) related to study drug occurred in 30.3% and 18.9% of pts in the CEN and PBO arms, with AEs leading to discontinuation in 1.4% and 0.7% of pts, respectively. No deaths occurred.

Table. Efficacy results at wk 24

Conclusion

Treatment with CEN demonstrated statistically significant improvement in symptoms and histologic and endoscopic features of EoE vs PBO. CEN was generally safe and well-tolerated through wk 24.

Disclosure

AS has served a consultant for Adare/Ellodi, AbbVie, AstraZeneca, Celgene/Receptos/Bristol Myers Squibb, Dr. Falk Pharma, Gossamer Bio, GSK, Janssen, MSD, Pfizer, Regeneron/Sanofi, Takeda, and Vifor; and has received grant/research support from Adare/Ellodi, Celgene/Receptos/Bristol Myers Squibb, GSK, and Regeneron/Sanofi. CMC, SZ, KL, AV, AY, and YSO are employees and shareholders of Bristol Myers Squibb. CLZ is a contractor to Bristol Myers Squibb. ESD has served as a consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Bryn, Calypso, Celgene/Receptos/Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; has received grant/research support from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Revolov, and Shire/Takeda; and has received educational grants from Allakos, Aqilion, Holoclara, and Invea. GF has served as a consultant for Adare/Ellodi, Allakos, Celgene/Receptos/Bristol Myers Squibb, LucidDx, Nexstone Immunology/Uniquity, Phathom, Regeneron/Sanofi, Shire/Takeda, and Upstream Bio; has received grant/research support from Adare/Ellodi, Allakos, Arena/Pfizer, Celldex, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Sanofi, Revolov, and Shire/Takeda. CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Ferring, Pfizer. HP has served as a consultant for Dr. Falk Pharma, Arena/Pfizer, GSK and Abbott. TV is a speaker for Dr. Falk Pharma and Bristol Myers Squibb; consultancy for Dr. Falk Pharma, Bristol Myers Squibb; research grant from Dr. Falk Pharma. SO has served a consultant for Dr. Falk Pharma, Medtronic, Regeneron/Sanofi, Celgene/Receptos/Bristol Myers Squibb; and has received grant/research support from Medtronic, Regeneron/Sanofi, Alfasigma.

Introduction

State of the art Barrett’s esophagus (BE) surveillance while-light endoscopy (WLE) is challenged by low detection rates due to the poor contrast offered by early neoplastic lesions. To improve detection, random biopsies are taken according to the Seattle protocol, however this comes with high sampling errors. ^1–4

Aims & Methods

With this phase II study we aim to validate the improvement in lesion detection seen in the phase I study, as well as compare bevacizumab-800CW with another targeted tracer, cetuximab-800CW, as well as an untargeted fluorescent dye, indocyanine green (ICG).
In a Phase II clinical study of 60 BE patients, fluorescence molecular imaging with topical administration of the fluorescent tracer bevacizumab-800CW targeting vascular endothelial growth factor A (VEGF) was evaluated for the detection of dysplasia and early-stage esophageal adenocarcinoma (EAC). Furthermore, we compared bevacizumab-800CW head-to-head with cetuximab-800CW, targeting epidermal growth factor receptor (EGFR), and a non-targeting fluorescent dye, ICG, in groups of 10 patients. Patients underwent a normal endoscopy procedure, in addition the tracers were topically administered and after 5-minute incubation time, fluorescent imaging was done. Target to background ratios (TBR) of both tracers and ICG were calculated by selecting regions of interest (ROI) for EC lesion and background and measuring fluorescent intensity in these RIOs.

Results

We found that FME with bevacizumab-800CW improved real-time dysplastic esophageal lesion detection by a tremendous 112% (70 vs. 33 lesions) compared to the referring general endoscopists and 27% (70 vs. 55 lesions) compared to an expert BE endoscopist. Compared to the fluorescent tracer cetuximab-800CW and fluorescent dye ICG, bevacizumab-800CW showed superior detection ability in each paired 10 patients. Bevacizumab-800CW showed TBR superiority over cetuximab-800CW (median TBR 3.39 versus 2.68 (p=0.0214) and ICG (median TBR 3.72 versus 1.15 (p<0.0001)).

Conclusion

Real-time early EAC and dysplasia detection can be improved by 27% for BE expert endoscopist and by 112% for general endoscopists by using fluorescence endoscopy in combination with bevacizumab-800CW. Bevacizumab-800CW is a superior tracer compared to cetuximab-800CW and compared to an untargeted fluorescent dye, ICG. Furthermore, we show how, besides the obvious and critical improvement of early esophageal cancer detection, FME couldimprove standardizing the quality of BE surveillance endoscopy by enabling community endoscopists to perform similarly to Barrett experts.

References

1. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):1084-1091. doi:10.1053/J.GASTRO.2011.01.030
2. Spechler SJ, Fitzgerald RC, Prasad GA, Wang KK. History, Molecular Mechanisms, and Endoscopic Treatment of Barrett’s Esophagus. Gastroenterology. 2010;138(3):854. doi:10.1053/J.GASTRO.2010.01.002
3. Fitzgerald RC, Di Pietro M, Ragunath K, et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut. 2014;63(1):7-42. doi:10.1136/GUTJNL-2013-305372
4. Vieth M, Ell C, Gossner L, May A, Stolte M. Histological analysis of endoscopic resection specimens from 326 patients with Barrett’s esophagus and early neoplasia. Endoscopy. 2004;36(9):776-781. doi:10.1055/S-2004-825802/ID/18

Introduction

Crohn's disease is characterized by patchy, transmural inflammation predominantly affecting the ileum and colon. Ileo-colonoscopy remains the gold standard for assessing mucosal inflammatory activity in clinical trials, and can be quantified using the Simple Endoscopic Score for Crohn’s Disease (SES-CD). However, ileo-colonoscopy is invasive, therefore there has been growing interest in non-invasive imaging modalities such as magnetic resonance imaging (MRI). The Simplified Magnetic Resonance Index of Activity (sMaRIA) is an MRI-based score which provides a standardised approach for evaluating disease activity. Most previous studies investigating the correlation between sMaRIA and SES-CD have been single centre studies with limited numbers of readers and performed only in patients with longstanding disease. While MRI is superior to colonoscopy for assessment of transmural penetrating and stricturing disease, the performance of sMaRIA for assessment of mucosal activity in the post-treatment setting remains unanswered.

Aims & Methods

To evaluate the performance of sMaRIA for detection of mucosal inflammation in patients with recently diagnosed Crohn’s disease using ileo-colonoscopy and SES-CD as the reference standard. We conducted a post-hoc analysis of the PROFILE trial, in which patients had undergone paired ileo-colonoscopy and small bowel MRI at end of trial (week 48). Central reading was performed by validated pools of consultant radiologists (MRI) and gastroenterologists (ileo-colonoscopy), blinded to clinical data. Correlations between SES-CD and sMaRIA scores were assessed, alongside classification performance and remission rates by treatment arm. For this study endoscopic and MRI remission were respectively defined as SES-CD ulcer subscore <1 and sMaRIA ulcer subscore of 0.

Results

253 patients had paired ileo-colonoscopy and MRI at end of trial with a median time gap of 22 days between investigations and no treatment change over this period. The overall correlation between SES-CD and sMaRIA scores at week 48 was poor (Spearman’s rank=0.196). [KS(UHNFT1] Overall sMaRIA had low sensitivity (27%) [NN2] for identifying active inflammation evident on ileo-colonoscopy. On segmental analysis MRI detected only 4/146 ulcerated segments (SES-CD ulcer subscore >0). Focusing on patients with ileal involvement, terminal ileal ulcer subscores also showed low correlation (Spearman’s rank=0.11). When using the mucosal component of MRI / sMaRIA to assess ulcer-free remission, no difference in end of trial outcomes was observed for “top-down” vs “accelerated step-up” treatment groups (95% vs 96% remission, p=0.728). Rates of ulcer-free remission assessed by SES-CD were different between treatment groups (86% vs 71% remission, p=0.004).

Conclusion

In this cohort of recently-diagnosed patients with Crohn’s disease and predominantly inflammatory disease phenotype, sMaRIA showed low sensitivity for detecting mucosal inflammation / ulceration. Had sMaRIA been used instead of SES-CD in the PROFILE trial it would have failed to identify the benefit of the “top-down” treatment strategy. These findings suggest that sMaRIA on MRI should not replace SES-CD scoring on ileo-colonoscopy for assessing mucosal inflammatory activity in Crohn’s disease.

References

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trialNoor, Nurulamin MNoor, Nurulamin et al.
The Lancet Gastroenterology & Hepatology, Volume 9, Issue 5, 415 - 427