Introduction

The vacuum-assisted closure stent (VAC-stent) is a novel approach for managing esophageal defects, combining endoscopic vacuum therapy (EVT) and metal stent support to promote effective tissue healing [1].
We present a case of esophageal perforation following circumferential Endoscopic Submucosal Dissection (ESD), successfully managed with a VAC-Stent (video 1).

Aims & Methods

We report a case of a 59-year-old man with a 40mm lesion involving 75% of the esophageal circumference (Paris 0-IIa + Is), arising in Barrett’s esophagus (Prague C4M5) and consistent with adenocarcinoma, who was referred to our unit. CT scans excluded metastatic disease, and after multidisciplinary consultation, ESD was planned.

Results

Circumferential ESD was performed using a triple-tunnel approach. After the resection, muscular tears were closed with through-the-scope (TTS) clips, and pre-emptive Endoscopic Vacuum Therapy (EVT) was applied to enhance granulation and healing.
Due to rising inflammatory markers and fever onset, an esophagogastroduodenoscopy (EGD) was performed on the 3rd Post-Operative Day (POD). The EGD revealed two <5mm perforations 4cm apart, and a VAC-stent was placed to bridge the defects. At the follow-up EGD on the 9th POD, a single defect remained, and a new VAC-Stent was placed. The patient showed progressive clinical improvement and successfully resumed a liquid diet. By the 15th POD, the perforations had healed.
The patient was discharged in good clinical condition on the 18th POD.
At the EGD on the 30th POD, homogeneous healing tissue was observed, with no stricture detected at the resection site.
Histological analysis of the ESD specimen revealed moderately differentiated adenocarcinoma with submucosal invasion: pT1b (sm1) pNX G2, with R0 resection achieved and no high-risk pathological features. An oncological and endoscopic follow-up was planned.

Conclusion

Our case demonstrates that the VAC-Stent is a safe and effective method for treating perforations following esophageal ESD. In cases of circumferential ESD, VAC-stent use may also help prevent strictures.

References

[1]. Dell’Anna G, Fanti L, Fanizza J, et al. VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New “Kid on the Block” Who Marries the Best of Old Techniques—A Review. Journal of Clinical Medicine 2024; 13: 3805. doi:10.3390/jcm13133805

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

Crohn’s disease (CD) is associated both (i) with polymorphisms in the card15 gene, coding for the cytosolic NOD2 innate immunity receptor, recognizing bacterial peptidoglycan (PG), and (ii) with a decrease in Faecalibacterium, an anti-inflammatory intestinal bacterium¹. Oral administration of Faecalibacterium could represent a novel therapeutic strategy for CD patients, which is currently under investigation with F. prausnitzii EXL01 strain (human clinical trial #NCT05542355). Indeed, Faecalibacterium exhibits anti-inflammatory effects both in vitro and in vivo in colitis models^1-6 and we recently discovered that it directly induced the production of Interleukin-10 (IL-10) in CD14+ human monocytes⁷. However, the bacterial molecules, the host receptors and signaling pathways involved are still poorly understood. Therefore, the aim of the current study was to decipher the role of the interaction between Faecalibacterium, its PG and NOD2 in health and CD.

Aims & Methods

The PG structure of F. prausnitzii EXL01 was determined by ultra high-performance liquid chromatography and mass spectrometry. NOD2 activation was evaluated using HEK-human NOD2 reporter cell line. Following stimulation with either bacteria or PG, secretion of IL-10 and TNF-a by i) WT and NOD2 KO THP1 human monocytic cell line and ii) by dendritic cells (DC) from WT and NOD2^-/- mice and from human patients with CD harboring 0 or 2 NOD2 loss-of-function frameshift mutations were evaluated by ELISA.

Results

Faecalibacterium PG presents an amino acid substitution in the minimal motif recognized by NOD2 (data patented). PG of F. prausnitzii activates NOD2, but not NOD1, in a dose-dependent manner and has a higher ability to activate NOD2 than the one from other Gram positive bacteria. We showed that the production of IL-10 by THP1 monocytes and murine DC upon stimulation either with F. prausnitzii or its PG was decreased in absence of NOD2, indicating that secretion of IL-10 by human and murine immune cells upon Faecalibacterium stimulation is dependent on NOD2. Interestingly, no significant effect was observed for TNF-a secretion, leading to a significant decrease of the IL-10/TNF- a ratio in NOD2 KO cells. In addition, secretion of IL-10 upon stimulation with F. prausnitzii or its PG was lower in DC from CD patients with 2 NOD2 loss-of-function frameshift mutations compared to DC from CD patients without NOD2 mutation. Levels of secreted TNF-a were higher in DC from CD patients with 2 NOD2 loss-of-function frameshift mutations compared to DC from CD patients without NOD2 mutation, leading to decreased IL-10/TNF- a ratio in absence of functional NOD2. The pathways downstream of NOD2 as well as the effects of Faecalibacterium and its PG on NOD2 in vivo are currently under investigation.

Conclusion

Our study showed that Faecalibacterium and its PG activate NOD2, and therefore the production of IL-10, in a different way than other Gram-positive bacteria. These results provide new insight into the molecular pathways underlying the immunomodulatory effects of F. prausnitzii, and highlight NOD engagement as a key immunological feature. Identification of PG as a molecule responsible for the therapeutic effects paves the way for the next generation of Faecalibacterium-based drugs, whether whole-cell or component-driven, in inflammatory diseases such as CD.

References

1. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008; 105: 16731-6.
2. Lenoir M, Martin R, Torres-Maravilla E, et al. Butyrate mediates anti-inflammatory effects of Faecalibacterium prausnitzii in intestinal epithelial cells through Dact3. Gut Microbes. 2020; 12: 1-16.
3. Quevrain E, Maubert MA, Michon C, et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease. Gut. 2016; 65: 415-25.
4. Rossi O, van Berkel LA, Chain F, et al. Faecalibacterium prausnitzii A2-165 has a high capacity to induce IL-10 in human and murine dendritic cells and modulates T cell responses. Sci Rep. 2016; 6: 18507.
5. Sarrabayrouse G, Bossard C, Chauvin JM, et al. CD4CD8 lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria and deficient in patients with inflammatory bowel disease. PLoS Biol. 2014; 12: e1001833.
6. Touch S, Godefroy E, Rolhion N, et al. Human CD4+CD8alpha+ Tregs induced by Faecalibacterium prausnitzii protect against intestinal inflammation. JCI Insight. 2022; 7.
7. https://www.biorxiv.org/content/10.1101/2024.10.06.616495v1

Disclosure

HS reports lecture fees, board membership, or consultancy from Carenity, AbbVie, Astellas, Danone, Ferring, Mayoly Spindler, MSD, Novartis, Roche, Tillots, Enterome, BiomX, Takeda, Biocodex, has stocks from Enterome and is co-founder of Exeliom Biosciences. PL report lecture fee, board membership, or consultancy from Biose, Biostime, Boiron, Bonduelle, BMS, Bromatech, IPSEN, iTaK, Lallemand, Lesaffre, L’Oréal, Mayoli, Merck, Procter and Gamble, Second Genome, Therascience and URGO and is co-founder of Exeliom Biosciences. Other authors declare no competing interests. DS, LH, PR and BH are employees of Exeliom Biosciences.