Introduction

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by inflammation, influx of eosinophils and esophageal remodeling. Therapy for EoE includes swallowed/topical corticosteroids, dupilumab, proton pump inhibitors, and dietary elimination; but these are not always effective.
EP-104GI is an extended-release fluticasone propionate (FP) intra-esophageal injection being developed as a novel treatment for EoE. It consists of polymer-coated FP crystals that release drug locally via diffusion at a pre-defined rate to reduce peak concentrations and prolong the therapeutic window. Preclinical work in pigs has demonstrated that EP-104GI remains at injection sites for at least 6 weeks (duration of the study), with FP spreading 2-4 cm into the surrounding tissue.

Aims & Methods

RESOLVE (NCT05608681) is a Phase 1b, multicenter, open-label, 3+3 design dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of EP-104GI in patients with EoE. The starting dose of EP-104GI consisted of 1 mg injected at each of 4 sites in 4 quadrants over 2 circumferential areas in the esophagus (4 mg total dose). Dose escalations increase the dose per site and/or number of sites; the second and third cohorts received 1 mg and 2.5 mg respectively at each of 8 sites; the fourth cohort received 2.5 mg at 12 sites (8, 20, and 30 mg total doses). After a single administration of EP-104GI in these cohorts, participants are assessed for up to 24 weeks. Additional cohorts are planned to evaluate greater dose per injection site and/or increased number of injections with a longer duration of follow-up.
Assessments include Peak Eosinophil Count (PEC) from esophageal biopsies at 16 sites, patient-reported symptom outcomes including the Straumann Dysphagia Index (SDI) and Likert scales for dysphagia and odynophagia, and plasma concentrations of FP. Adverse events (AEs) and laboratory tests including serum glucose and cortisol are assessed.

Results

Cohort 1-3 safety observations include mild-moderate AEs; the majority not related to EP-104GI. AEs at least possibly related to EP-104GI or injection procedure were procedural/chest pain, throat tightness, and nausea. Glucose levels post-dose have remained stable. Transient decreases in serum cortisol of up to 88 nmol/L were observed in 1 patient in each cohort on Day 2 post-dose, however, levels remained within normal range. There have been no symptoms of adrenal insufficiency.
Response data from Cohorts 1 and 2 (Table 1) demonstrate a decrease from baseline in symptom scores at Weeks 12 and 24. Reduction in mean PEC has been observed in all patients in Cohort 2, with a trend indicating that increasing the total dose of EP-104GI results in a more consistent reduction in PEC at the 16 biopsy sites assessed.

Table 1: Patient-reported symptom outcomes, peak eosinophil count (PEC), and plasma fluticasone propionate (FP) after a single dose of EP-104GI	Cohort 1 (1 mg × 4 sites, total 4 mg)	Cohort 2 (1 mg × 8 sites, total 8 mg)
Mean change from baseline (CFB) in Straumann Dysphagia Index (0-9) at Weeks 12 and 24	-4.0, -4.0	-2.7, -3.3
Mean CFB in Dysphagia (0-10) at Weeks 12 and 24	-4.0, -5.0	-4.3, -4.0
Mean CFB in Odynophagia (0-10) at Weeks 12 and 24	-2.0, -3.0	-5.7, -4.3
Mean CFB in PEC at Weeks 4 and 12 (cells/hpf from 16 sites)	No reduction observed	-26%, -44%
Mean plasma concentration of FP at 2 hours post-dose (pg/mL)	4.3	11.2

Conclusion

A novel diffusion-based localized delivery of FP via EP-104GI injection into the esophagus is feasible and safe in patients with EoE in this initial escalating dose cohort study. Initial efficacy data show improvement in symptom outcomes and histological findings which may increase with dose. These findings support the potential for extended intervals of at least 6 months between injections. Recruitment is ongoing.

Disclosure

JH, AM, MMK, CD, AL, VP and MW: employees of Eupraxia Pharmaceuticals
ED: Research funding: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda Consultant: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, 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, Upstream Bio Educational grant: Allakos, Aqilion, Holoclara, Invea
HHK: advisory board and speaker's bureau for Sanofi.
AJB: received research funding from Nutricia, Thelial, Sanofi/Regeneron, SST, and Dr. Falk Pharma and received speaker and/or consulting fees from Laborie, Medtronic, BMS, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Reckitt and AstraZeneca
NG: nothing to declare

Introduction

Endoscopic sleeve gastroplasty (ESG) is a less invasive alternative to surgery for patients with obesity. The post procedure recovery is quicker and patients can be discharged one day after procedure.

Aims & Methods

We aimed to determine the outcome after ESG in patients with obesity and benefit of adding GLP1 agonist after ESG. All patients undergoing ESG at our center from 2017 up to 2020 were retrospectively recruited. Patients with BMI ranging from 30 to 40 kg/m² were eligible for ESG. The baseline demographic and clinical profile and reports of investigations were recorded. The date of procedure and follow up details including weight at various time points were noted. The procedure was done by Apollo^TM overstitch device. The primary outcome was loss of at least 10% weight from baseline after ESG. The secondary outcome was loss of >20% weight after surgery. Multivariate analysis was performed using logistic regression to asses the predictors of weight loss after ESG including use of GLP1 agonist.

Results

	Weight loss >10% (n=28)	Weight loss <10% (n=13)	p
Age (Years)	39.9+9	37.4+9.2	0.3
Gender (Female)	25 (89.3%)	12 (92.3%)	0.98
Weight before ESG (Kg)	90.4+12.8	88.9+8.6	0.76
Use of GLP1 agonist after ESG	11 (39.3%)	8 (61.5%)	0.2

Forty-six patients underwent ESG during the study period. Their mean age was 39.9+8.8 years and 91.3% were females. The mean BMI before ESG was 35.1+2.9 kg/m² and mean weight was 90.2+11.5 kg. Follow-up data was available for 41 patients: the mean duration of follow-up was 29.4+14.8months. The primary outcome (weight loss >10%) was achieved in 68.3% patients. Weight loss >20% was noted in 19.5% subjects. The mean weight 6-12 months after ESG was 80.8+11.2 Kg and after 2 years was 87.6+12.6 Kg. Multivariate analysis was done using age, gender, baseline weight and use of GLP1 agonist as variables for predicting weight loss after ESG (Table 1). We did not find any significant predictors including use of GLP1 agonist (p=0.2).

Conclusion

ESG leads to weight loss in about two-third of patients although the effect is not sustained after 2 years. Use of GLP1 agonist does not have additional impact on weight loss.

Introduction

In recent years, there has been a surge in the development of artificial intelligence (AI) systems for endoscopic applications, such as Barrett’s neoplasia detection and polyp characterization. While these systems have shown promising results, the vast majority is trained and validated on small, retrospective, single-center or expert-acquired data sets. Current AI systems are particularly prone to a so-called domain-shift: a system only performs well on data it has been trained on. As real-world scenarios in the endoscopy suite can be complex and diverse, the risk of poor generalization of AI should not be underestimated.

Aims & Methods

In this study we aim to provide a quantitative analysis of this domain shift and propose several strategies to improve generalization to clinical practice. We trained three AI systems for commonly used applications in gastrointestinal endoscopy, using publicly available data sets with high quality standards. In order to identify the limitations of these systems, all test sets were artificially degraded in a stepwise manner with clinically prevalent artifacts: blur, inadequate exposure and color variability. These degradations represent the heterogeneity of image quality in daily clinical practice. Severity of degradation was clinically calibrated by a panel of expert endoscopists. Two levels of degradation were identified: 1) mild degradation, still considered as high quality data; 2) moderate degradation, considered as image quality that could still be encountered in daily clinical practice. The trained models were subsequently evaluated for their appropriate performance metrics on the gradually degraded test sets. After implementation of several training strategies to mitigate potential performance loss, the models were re-evaluated on the same test sets.

Results

All three models display a considerable decrease in performance when exposed to various types of clinically relevant image degradation. Mean loss was 7.4% and 16.6% for respective mild and moderate degradation. Implementation of specific training strategies to improve robustness resulted in substantial reduction of performance loss on all degraded test sets.

Conclusion

This study highlights the potential limitations of current AI systems in endoscopic applications which may lead to poor generalization. Specific training strategies can mitigate this risk and improve robustness of these systems. Development of robust and reliable AI systems that deliver consistent and accurate performance is crucial to ensure safe implementation into daily clinical practice.

Introduction

There are no established treatments for esophageal anastomotic stricture refractory to endoscopic balloon dilation (EBD). Patients experience a reduced quality of life and suffer a financial burden after surgery until the strictures are relieved. New treatments for refractory anastomotic stricture are clearly needed. Local steroid injection is reported to improve the effects of EBD. In addition, EBD with local steroid injection is a current community standard treatment for patients with refractory anastomotic stricture after esophagectomy, although the effect is limited. A new endoscopic treatment for such strictures is radial incision and cutting (RIC), which improves strictures by cutting through scar tissue at the stricture site with an electrocautery knife and removing any fibrous tissue that may cause re-stricture. However, the evidence for its effectiveness is limited to retrospective studies and small case series.

Aims & Methods

The aim of this multicenter, randomized, open-label, phaseⅡ/Ⅲ trial was to investigate the safety and the superiority of RIC with steroid injection compared with EBD with steroid injection for patients with refractory anastomotic stricture after esophagectomy for thoracic esophageal cancer. This is the first randomized controlled trial in the world for patients with refractory esophageal anastomotic strictures. Patients with Dysphagia Score ≥2 (able to swallow only semisolid foods or liquids) who had strictures through which a conventional endoscope (diameter, 9.6–10.4 mm) did not pass despite three or more EBDs or bougienage dilations were eligible for this trial. The primary endpoint in the phase II part was proportion of hemorrhages, post-operative esophageal perforations, esophageal hemorrhages, pneumothorax, lung or mediastinum infections or other unexpected adverse events. Co-primary endpoints in the phase III part were re-stricture-free survival and number of dilations for 24 weeks after treatment. This study was registered with the Japan Registry of Clinical Trials jRCTs031180177.

Results

From May 2014 to March 2022, 130 patients were enrolled from 32 institutions participating Gastrointestinal Endoscopy Study Group of the Japan Clinical Oncology Group and 65 patients each were randomized to EBD arm and RIC arm. The median number of dilations before registration was five in each arm. Dysphagia Score represented grade 2 (able to swallow semisolid foods) in 104 (80.0%) patients, grade 3 (able to swallow liquids only) in 25 (19.2%) patients, and grade 4 (unable to swallow liquids) in 1 (0.8%) patient in whole of study. Grade 3/4 pre-defined adverse events occurred in 1 (1.5%) patient in each arm. Median re-stricture-free survival in EBD arm was 10.6 weeks (95% CI: 6.9-20.1 weeks) and 8.7 weeks (95% CI: 7.1-10.9 weeks) in RIC arm (hazard ratio 1.22, 90% CI 0.85-1.74, one-sided p=0.82). The median number of dilations for 24 weeks after initial treatment was once (IQR: 0-2) in EBD arm and twice (IQR: 0-4) in RIC arm (one-sided p=0.99). The proportion of patients with anastomotic diameter >10 mm at 8 weeks after treatment was 27.7% (95% CI: 17.3-40.2%) in EBD arm and 24.6% (95% CI: 14.8-36.9%) in RIC arm.

Conclusion

RIC with steroid injection was not superior to repeated EBD with steroid injection for refractory anastomotic stricture after esophagectomy. EBD combined with steroid injection remains the standard of care for refractory anastomotic stricture after esophagectomy.

Introduction

Irritable bowel syndrome (IBS) is a highly prevalent disorder. According to Rome IV, the diagnosis relies on the presence of abdominal pain in association with a change in stool consistency or frequency. Guidelines recommend minimal testing to exclude other diseases, while advising on therapeutic options. However, the actual application of these guidelines into practice needs confirmation.

Aims & Methods

This study aims to assess the management of IBS by general practitioners (GP) and gastro-enterologists (GE) in their daily practice. Methods: Belgian GP and GE completed an online vignette-based survey between January and July 2022. Apart from data about years of experience, participants indicated their preferred diagnostic modality or therapeutic option for eight cases of diarrhoea-predominant IBS. Cases varied in age (25, 48 and 65 years), cardinal symptom (pain, discomfort, or diarrhoea) and availability of test results (none, limited to biochemistry and ultrasound, or extensive including endoscopy), while stressing out the prolonged duration of the symptoms and the absence of red flags. Frequencies were compared by Chi-square. The main determinants to the diagnosis of IBS were assessed by logistic regression.

Results

Sixty-four gastroenterologists and 31 general practitioners completed the survey. When considering pain and discomfort as cardinal symptoms in a young patient, 87.4% and 84.1% of participants diagnosed IBS, which decreased to 58.3% with diarrhoea. The diagnosis of IBS dropped to 26.8% for a patient of 65 years. In those cases, GP less frequently diagnosed IBS (all p<0.05), except with diarrhoea as cardinal symptom (p=0.78). According to logistic regression, diagnosing IBS was related to patient age, cardinal symptom, availability of prior test results and specialty, and only borderline related to the experience of the practitioner (p<.001, R²=.293). Even when diagnosing IBS, 89.5% ordered one or more additional tests (77.9% biochemistry, 59.3% stool culture and parasites, 60.5% faecal occult blood testing, 17.4% breath testing, 12.8% imaging, 9.3% endoscopy). Upon normal results, 57% would not order further investigations. Both GP and GE opted for spasmolytics (62.3%) and dietary interventions (28.3%) as the preferred first-line treatment for IBS. Second-line treatment consisted of referral to a specialist or colleague (19.4%), dietary intervention (22.6%), neuromodulators (19.4%) and spasmolytics (14.5%). In second-line, GP favoured referral (61.1%) and dietary intervention (22.2%), while GE preferred neuromodulators (27.3%) and spasmolytics (18.2%). No GP initiated modulators. Similar figures were obtained in third-line.

Conclusion

In Belgium, abdominal pain or discomfort are equivalent cardinal symptoms when diagnosing IBS. Diarrhoea as cardinal symptom, older age and absence of prior testing lowered the preference for IBS, especially in GPs. Even when diagnosing IBS, healthcare providers order a large variety of tests. Spasmolytics and dietary interventions are favoured in first-line. Upon failure, only GE prescribe neuromodulators, while GP opt for referral. Future education of GP and GE should focus on harmonising the diagnostic approach and medical treatment of IBS with existing guidelines.

Disclosure

Consultancy for Truvion Healthcare

Introduction

Thiopurines are one of the major drugs for inflammatory bowel disease. In Asian individuals, the SNP p.Arg139Cys in exon 3 of NUDT15 is associated with leucopenia and hair loss.

Aims & Methods

The aims of this study are to evaluate the long-term effects of NUDT15 on clinical outcomes.
The patients (ulcerative colitis130, Crohn’s disease 55 cases) were divided into the mutant and the wild group of NUDT15, and the daily dosage of thiopurines and the effect of the mutation on hospitalization and surgery were investigated.

Results

Compared to the mutant group (n = 48), the daily thiopurine dosage increased in the wild group (n = 137)(p = 0.024). The time to dose reduction and discontinuation of thiopurine was significantly shorter in the mutant group, respectively (p < 0.001, p = 0.039). The mutant group tended to have more hospitalizations (p = 0.067), and surgeries were significantly more frequent (p = 0.028). In ulcerative colitis, thiopurine discontinuation was associated with hospitalization and surgery, respectively (p = 0.003, HR 2.87, 95% CI 1.44 - 5.71, p = 0.036, HR 5.45, 95% CI 1.12 - 26.5). In Crohn's disease, the presence of SNPs was associated with hospitalization (p = 0.019, HR 3.68, 95% CI 1.24-10.97) and surgery (p = 0.036, HR 6.81, 95% CI 1.14 - 40.86).

Conclusion

In ulcerative colitis, it is important to continue thiopurine with fine-tuning of the dosage to avoid hospitalization and surgery. In Crohn's disease, a direct association between the NUDT15 SNP and hospitalization and surgery was demonstrated.

References

1. Yang, S. K. et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 46, 1017-1020, doi:10.1038/ng.3060 (2014).
2. Kojima, Y. et al. Influence of NUDT15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines. World J Gastroenterol 24, 511-518, doi:10.3748/wjg.v24.i4.511 (2018).
3. Coenen, M. J. H. et al. Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology 149, 907-917.e907, doi:10.1053/j.gastro.2015.06.002 (2015).
4. Hirotsu, Y. et al. Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next-generation sequencing. Mol Genet Genomic Med 3, 121-129, doi:10.1002/mgg3.120 (2015).
5. Sakamoto, I. et al. BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer. Cancer 122, 84-90, doi:10.1002/cncr.29707 (2016).
6. Hirotsu, Y. et al. Intrinsic HER2 V777L mutation mediates resistance to trastuzumab in a breast cancer patient. Med Oncol 34, 3 (2017).
7. Hirotsu, Y. et al. Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer. Mol Genet Genomic Med 3, 459-466 (2015).

Disclosure

The authors have no conflict of interest to declare. All co-authors have seen and agree with the contents of the manuscript, and there is no financial interest to declare.

Introduction

Recently, the number of ESD cases of early gastric cancer detected after Helicobacter pylori eradication (GCAE) has been increasing. As the number of years since eradication increases, the management of metachronous carcinomas after ESD for GCAE has also become an issue. Serum gastrin level has been reported to be useful in identifying groups at high-risk of developing gastric cancer. In this study, we investigated the clinicopathological characteristics of patients with early-stage GCAE who underwent ESD at our department. Furthermore, we determined the risk of metachronous GCAE after ESD and the correlation between serum gastrin level and metachronous GCAE.

Aims & Methods

We retrospectively analyzed a total of 300 lesions in 245 patients who underwent ESD for GCAE with known period after eradication at Hiroshima University Hospital between April 2010 and December 2019 and examined their clinicopathology. We divided 220 lesions in 194 patients with initial GCAE who had no history of gastric endoscopic resection before successful eradication into the " metachronous gastric cancer (MGC) groups " and " no metachronous gastric cancer (NGC) groups ". Then, we examined the clinicopathological characteristics of metachronous gastric cancer cases. We classified 74 lesions in 63 patients of male and differentiated type cancers who have not been using PPIs into two groups: 37 lesions in 32 patients with gastrin level of less than 80 pg/ml and 37 lesions in 31 patients with gastrin level higher than 80 pg/ml.

Results

At a median follow-up of 4.0 years, 16 patients (8.2%) developed metachronous gastric cancers. Males were more predominant in the MGC group than in the NGC group (male / female; 16/0 vs. 223/74，p=0.02), which included increased cases of severe atrophy of the background gastric mucosa (mild to moderate / severe; 3/13 vs. 94/84, p=0.01), more lesions in the U and M regions of stomach (U･M / L; 19/4 vs 121/76, p=0.05), and a higher proportion of synchronous multiple lesions (synchronous tumor/ no synchronous tumor; 11/12 vs. 160/37, p=0.01). The relationship between gastrin levels and metachronous gastric cancer was examined, revealing that gastrin levels were higher in the MGC group. The group with a gastrin level of 80 pg/ml or higher had a significantly higher incidence of metachronous lesions than the group with that of less than 80 pg/ml (OR 6.88; 95% CI, 1.61–29.3; p=0.01).

Conclusion

These results that male patient with severe atrophy, the rates of localization to the U and M regions of stomach and the incidence of synchronous multiple lesions before ESD indicate should be noted and surveyed more strictly for metachronous gastric cancers developing after ESD of GCAE. Patients with gastrin 80 pg/ml or higher had increased risk of MGC, indicating that gastrin level may be a serological marker for MGC.