Clinical Case Summary

Endoscopic full-thickness resection (eFTR) is an emerging technique that enables effective and safe management of complex colorectal (CR) lesions. In recent years, eFTR has been described as an alternative to surgery in selected patients, namely for scars aiming to exclude residual tumors after non-curative endoscopic resection. We present a case of eFTR due to imaging suspicion of intraparietal colorectal recurrence without endoscopic findings.
A 41-year-old woman with Lynch syndrome (dMLH1) and a history of rectal adenocarcinoma underwent anterior resection of the rectum and adjuvant chemoradiotherapy at the age of 20. Afterwards endoscopic surveillance was initiated. At the age of 39, she presented with a suspicious lesion (Paris 0-Is+IIa, NICE 2, JNET2B), 16mm, in the hepatic angle, and underwent enbloc endoscopic mucosal resection. Histopathological analysis revealed a low-grade invasive colorectal carcinoma (CRC) with deep invasion of the submucosa (vertical R1). After a multidisciplinary meeting, complementary surgery was proposed but the patient refused, maintaining close surveillance. Two subsequent endoscopic revisions and two computed tomography (CT) scans showed no signs of macro or microscopic recurrence, even after extensive biopsies of the colonic scar. However, a CT scan 20months post-resection showed a 2cm parietal thickening in the hepatic angle. Suspecting parietal tumor recurrence without superficial endoscopic findings, a transmural endoscopic resection using FTRD® of the scar was performed. Histology revealed no tumor recurrence.
Transmural evaluation of the scar after noncurative endoscopic resection of T1 CRC, whether for excluding residual tumor or during surveillance to exclude recurrence, represents a promising indication for eFTR. This technique has demonstrated to be a safe and effective therapeutic alternative for this new indication, avoiding surgery and its associated morbidity and mortality.

References

Aslanian HR, Sethi A, Bhutani MS, Goodman AJ, Krishnan K, Lichtenstein DR, et al. ASGE guideline for endoscopic full-thickness resection and submucosal tunnel endoscopic resection. VideoGIE 2019;4:343–50. https://doi.org/10.1016/j.vgie.2019.03.010.
Gijsbers K, Laclé M, Elias SG, Backes Y, Bosman J, van Berkel A. Full-Thickness Scar Resection After R1 / Rx Excised T1 Colorectal Cancers as an Alternative to Completion Surgery : Official journal of the American College of Gastroenterology | ACG. Am J Gastroenterol 2022;117:647–53. https://doi.org/10.14309/ajg.0000000000001621.
Pimentel-Nunes P, Libânio D, Bastiaansen BAJ, Bhandari P, Bisschops R, Bourke MJ, et al. Endoscopic submucosal dissection for superficial gastrointestinal lesions: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2022. Endoscopy 2022;54:591–622. https://doi.org/10.1055/a-1811-7025.

Introduction

Screening programmes for gastric cancer are currently being researched in Europe as part of the TOwards GAstric Cancer Screening Implementation (TOGAS) project (1). A ‘screen & treat’ approach for Helicobacter pylori (H. pylori), is one such strategy being assessed as part of a primary preventative measure. In order for such a programme to be viable, the availability of an effective treatment is paramount. Given the rising rates of antimicrobial resistance worldwide, careful consideration must be given to prescribing first-line treatment with the highest efficacy. This interim report evaluates key performance measures in the treatment of H. pylori within the Irish arm – representing the Western European cohort - of the TOGAS pilot screening programme.

Aims & Methods

This interim data evaluates the efficacy of 10-day treatment with single capsule combination therapy: Bismuth subcitrate 140mg/Metronidazole 125mg/Tetracycline 125mg, three tablets, four times daily (PYLERA, Juvise pharmaceuticals) with a high-dose proton pump inhibitor (Esomeprazole 40mg twice daily).
Secondary outcome measures include;

1. Treatment acceptance rate
2. Side-effect profile
3. Adverse events

3030 individuals aged 30-34 years were invited to undergo screening for H. pylori through their general practitioner or workplace in the period January 24-March 25. Those who tested positive on both serology (BIOHIT H. pylori IgG antibody) and 13-C urea breath test (IR Force 200, Richen Medical) were offered treatment. Treatment consisted of 10-day combination therapy (PYLERA) and a high-dose proton pump inhibitor (PPI). Eradication confirmation with a 13-C UBT was offered a minimum of 6 weeks post-treatment. Demographics, risk factors for infection, treatment effectiveness and side effect profile were recorded. Stata was used for statistical analysis. χ² test was used for comparison of categorical variables (significance level p<0.05).

Results

464 asymptomatic individuals were enrolled. The median age was 32; 48%(n=223) were male. 11%(n=50) tested positive on both serology and 13-C UBT. Those who tested positive were more likely to be male [64%] (p < 0.02), a history of current or previous smoking was found to be nonsignificant (34%, p <0.9). 96%(n=48) of positive participants consented to treatment; 2 were excluded from receiving treatment due to pregnancy. Among those treated, 96% (44/46) reported adherence rates of >90%. In those reporting compliance rates <90 %, side effect profile was the leading cause of non-compliance. Side effects were reported by 24% (11/46) of participants. These were predominantly gastrointestinal side effects and reported as mild-moderate in severity, 6% discontinued treatment on account of them (n=3). All symptoms resolved after cessation. No serious adverse events occurred. Post-treatment, a 13-C UBT was completed in 80% (n=37) of treated individuals. Eradication rates were 97% (36/37) in the per-protocol group and 89% (33/37) in the intention-to-treat group. Treatment discontinuation due to side effects was the leading cause of treatment ‘failure’. In those requiring 2^nd line therapy (n=4), levofloxacin-based quadruple therapy was found to be successful in 66%(2/3) of those who completed eradication follow-up.

Conclusion

Single capsule combination therapy and high-dose PPI achieved eradication rates of >90% in the per-protocol group. No serious adverse events occurred secondary to treatment. These interim results indicate that 10-day combination therapy serves as an effective first-line therapy for future population-based screening programmes in a European population.

References

1. Commission E. TOGAS - Towards Gastric Cancer Screening Implementation in the European Union: European Commission; 2023 [Available from: https://health.ec.europa.eu/non-communicable-diseases/cancer/europes-beating-cancer-plan-eu4health-financed-projects/projects/togas_en.

Disclosure

Dr. Deane reports receipt of research funding support from EU4 Health grant GA number: 101101252. Juvise pharmaceuticals provided PYLERA for this branch of the study.

Introduction

The urea breath test (UBT) is the clinic's most popular and accurate non-invasive diagnostic method for H. pylori infection. Yet, it is time-consuming and unavailable to some individuals. The oral rapid urease test (RUT) is an emerging non-invasive convenience method but lacks clinical data support.

Aims & Methods

A double-center, double-blind, methodological comparative design experiment is invited to evaluate the consistency of the oral RUT with UBT. 247 participants were enrolled. Their Dental plaque and tongue coating samples were collected, blind and tested with RUT.

Results

The significant association between the RUT and UBT was analyzed.A total of 247 participants were included in the study. The oral RUT showed a high level of agreement with the UBT. The sensitivity of the test reagent was 98.63% (95% CI: 92.64%, 99.76%), and the specificity was 96.34% (95% CI: 92.25%, 98.31%). The overall conformity rate was 97.05% (95% CI: 94.03%, 98.56%). The positive predictive value was 92.31%, and the negative predictive value was 99.37%. The positive likelihood ratio was 26.96, and the negative likelihood ratio was 0.01. The Kappa value was 0.97.

Conclusion

The efficacy of oral RUT for Helicobacter pylori infection diagnosis is extremely consistent with the UBT.

Introduction

Helicobacter pylori (H.pylori) infection is the main risk factor for gastric cancer. Infection leads to chronic inflammation and gastric gland hyperplasia. We found that infection induces alterations in the stromal niche, such as inhibited secretion of BMP ligands and increased expression of BMP inhibitors. BMP signaling is known to be involved in differentiation of base progenitor cells into pit secretory cells. However, whether it plays a role in regulating mucosal antimicrobial defense is still unknown and we now investigate how the downregulation of BMP signaling affects mucosal inflammatory responses.

Aims & Methods

Exploiting in vivo murine models as well as in vitro assays, we aim to investigate how the downregulation of epithelial BMP signaling affects mucosal homeostasis.
3D gastric organoids were used to explore the role of BMP in epithelial responses to microbial proteins (qPCR, Western Blotting). The effects of epithelial BMP downregulation and stromal Il1r1 signaling were investigated by exploiting conditional knockout mice (Axin2CreERT2-Bmpr1afl/fl or Bmpr1a KO; Col1a2CreERT2-Il1r1fl/fl or Il1r1 KO) either uninfected or infected with H.pylori PMSS1. Tissue samples were analyzed via immunofluorescence, RNA-in situ hybridization and gene expression analysis (qPCR, whole transcriptome). 2D primary murine stromal cell culture were exploited to investigate stromal responses to inflammatory triggers.

Results

Exploiting 3D organoids, we demonstrate that epithelial cells activate NF-κB signaling in response to microbe-derived proteins, while this effect is inhibited upon BMP signaling activation. In vivo, inhibition of BMP signaling in the epithelium via knockout of Bmpr1a (Bmpr1a KO) not only causes gland hyperplasia but also strongly enhances inflammation at the pit of gastric glands, where it is absent in mice with functional BMP signaling. We explore the consequences of increased inflammation upon epithelial Bmpr1a KO, demonstrating via whole transcriptome analysis that this is linked to enhanced antimicrobial tissue responses and that KO mice show reduced H.pylori colonization. Moreover, we discover that the influx of IL-1β producing cells observed upon BMP signaling downregulation has an impact on stromal cells, which in turn produce pro-regenerative factors causing epithelial reprogramming into a highly proliferative fetal-like regenerative state. We demonstrate that Il1r1 KO mice, where stromal cells lack the ability to respond to IL-1β, do not show fetal-like reprogramming and are more colonized by H.pylori.

Conclusion

Chronic H.pylori infection causes tissue reprogramming into a fetal-like state via a crosstalk between epithelial, stromal and immune cells. This state is linked to an enhanced proinflammatory response, increased proliferation and boosters antimicrobial defense. We propose that long-term activation of this state may enhance the risk for malignant transformation.

Introduction

Europe’s Beating Cancer Plan identified the urgent need for a gastric cancer screening strategy. In response, the TOGAS consortium (TOwards GAstric cancer Screening in the European Union) was established to evaluate different methods for gastric cancer prevention and detection within Europe(1). One such approach involves population-based screening of young adults for Helicobacter pylori (H.pylori) as a primary preventative strategy.

Aims & Methods

The pilot study aimed to assess the feasibility of screening asymptomatic 30-34 year olds for H.pylori. Key outcome measures included:
1) Response rate
2) Seropositivity
3) Treatment acceptance rate
4) Treatment effectiveness
Methods: Individuals aged 30-34 years were invited to participate in free screening via GP practices or occupational-based screening programmes in the period January 2024- March 2025. Invitations were distributed through email or text message at the discretion of the recruitment stream. Exclusion criteria included prior history of treatment of H. pylori or gastrectomy. Those who tested positive on serology (BIOHIT H. pylori IgG antibody, antibody titer >30 IU/ml) were offered confirmatory 13-C urea breath testing (Richen IR Force 200). Positive participants were offered treatment with a 10-day regimen of single capsule combination therapy (Bismuth subcitrate 140mg/Metronidazole 125mg/Tetracycline 125mg, three tablets, QDS; PYLERA, Juvise pharmaceuticals) + Esomeprazole 40mg BD. Eradication confirmation was offered a minimum of 6 weeks post-treatment. Demographics, risk factors, and treatment effectiveness were recorded.
The calculated sample size for statistical significance at a 95% confidence interval with a presumed prevalence rate of 30% was 323. The Mann-Whitney U-test was used for comparison of continuous variables, and the Chi² test for categorical variables (significance set at p<0.05).

Results

3030 invites were distributed (80% GP practices, 20% occupation-based). 20%(n=604) of recipients expressed interest in participating. Among these; 5%(n=31) were excluded and 18%(n=109) refused or ceased responding. 464 consented to and completed the study. The median age of participants was 32, 48%(n=223) were male. 15% (n=75) of those who underwent serology testing were seropositive. 97% agreed to have a confirmatory 13-C UBT, of which 50/73 (66%) tested positive. The median titre in this dual positivity group was 109 IU/mL [range 40-142], compared to 37 IU/mL [range 32-148 IU/ml] in the 13-C UT negative group. Overall, the true ‘positivity’ rate among those who agreed to screening was 11%. 96%(48/50) of positive participants agreed to treatment, a further 2 were excluded due to pregnancy. Among those treated, 96% (44/46) reported >90% adherence. 1^st line eradication rates, confirmed by a 13-C UBT, were 97%(36/37) in the per-protocol group and 89%(33/37) in the intention-to-treat group. Side effects were reported by 24%, the majority of which were GI. 4 patients required 2^nd line therapy due to early discontinuation or poor compliance, 1 failed 2^nd line therapy on follow-up eradication confirmation.

Conclusion

These interim results indicate that a population-based H.pylori screening approach is feasible within an Irish population. Despite a decreasing worldwide prevalence, infection remains a persistent issue. Although initial response rates to screening are modest, this is a novel pilot programme and reflects trends seen in the early phases of other national screening programmes, such as the colorectal cancer screening. As public awareness increases, higher engagement rates are anticipated.

References

1. Commission E. TOGAS - Towards Gastric Cancer Screening Implementation in the European Union: European Commission; 2023 [Available from: https://health.ec.europa.eu/non-communicable-diseases/cancer/europes-beating-cancer-plan-eu4health-financed-projects/projects/togas_en.

Disclosure

Dr. Deane reports receipt of research funding support from EU4 Health grant GA number: 101101252

Introduction

The gut microbiota plays a crucial role in the pathogenesis and progression of Crohn’s Disease (CD) by maintaining intestinal homeostasis, supporting metabolic and immune functions, and influencing overall health. An imbalance in the gut microbiota is associated with CD, as disruptions in microbial composition can be further impacted by dietary factors, highlighting the connection between nutrition and gut health.

Aims & Methods

This study aimed to evaluate the gut microbiota composition and its interactions with dietary factors to identify potential opportunities for targeted probiotic interventions in CD management. The study included 53 participants, of whom 20 had CD in remission, 18 had active disease, and 15 were healthy controls. CD activity was evaluated by colonoscopy assessment or by nuclear magnetic resonance scan enterography. All participants aged between 18 and 60 years were assessed using 24-hour dietary recall and gut microbiome profiling through 16S rRNA gene sequencing. Patients had confirmed diagnoses of CD with ileal and/or colonic involvement. The local ethics committee approved this study.

Results

Microbial composition analyses (beta diversity) revealed significant differences between groups. At the Operational Taxonomic Unit (OTU) level, healthy microbiome differed significantly from both remission and active CD patients, with healthy controls showing a more similar microbial composition compared to remission (p = 0.001) and active disease (p = 0.001). In addition, Shannon diversity analyses demonstrated that healthy individuals exhibited significantly higher OTU diversity compared to CD patients, further highlighting the microbial imbalance associated with the disease. Among specific taxa, Eubacterium hallii, a key butyrate producer, was significantly reduced in patients with active CD. This microorganism is integral to intestinal metabolic balance, playing essential roles in energy homeostasis, colonic motility, immunomodulation, and inflammation suppression. Furthermore, E. hallii plays a critical role in bile acid and cholesterol metabolism, highlighting its importance in gut health. Disease severity was associated with changes in microbial abundance, with specific taxa colonizing the gut at higher levels as disease activity increased, including Escherichia coli, Escherichia-Shigella, and taxa from the Enterobacteriaceae, Lachnospirales, and Bacteroides. This growth may be linked to inflammatory processes and intestinal dysbiosis, suggesting a potentially pathogenic role. Furthermore, dietary components such as saccharin, an artificial sweetener, were significantly associated with alterations in microbial composition.

Conclusion

These findings underline the potential for probiotics targeting specific taxa, such as E. hallii, to restore microbial balance and improve clinical outcomes in CD. The study also highlights the impact of dietary components, such as saccharin, in disrupting the gut microbiome, suggesting that certain dietary factors may contribute to microbial imbalance and inflammation in CD. Future research should focus on integrating dietary patterns with probiotic development to optimize gut health and mitigate inflammation in CD patients.

References

1. BOLTE, L. A. et al. Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome. Gut, p. gutjnl-2020-322670, 2 abr. 2021.
2. FAN, Y.; PEDERSEN, O. Gut microbiota in human metabolic health and disease. Nature Reviews Microbiology, v. 19, n. 1, p. 55–71, 4 jan. 2021.
3. GILL, P. A. et al. The Role of Diet and Gut Microbiota in Regulating Gastrointestinal and Inflammatory Disease. Frontiers in Immunology, v. 13, n. April, p. 1–22, 5 abr. 2022.