Introduction

Metachronous recurrence frequently develop in patients with superficial esophageal squamous cell carcinomas (ESCCs) after curative endoscopic submucosal dissection (ESD), especially in those with multiple (>10) small lugol-voiding lesions (LVLs) over the esophageal background mucosa (i.e. speckled pattern) [1-2]. Therefore, the speckled-type lugol background mucosa should be seen as a precancerous lesion of ESCC, that requires early intervention and close surveillance. Radiofrequency ablation (RFA) is an effective and safe modality to eradicate the dysplasia or intestinal metaplasia in Barrett’s esophagus as well as the squamous moderate-grade (MGIN) or high-grade intraepithelial neoplasia (HGIN) [3-5]. Hybrid therapy is currently the preferred strategy for management of Barrett’s neoplasia, using ESD for visible lesions, followed by RFA for the residual Barrett’s epithelium to achieve the goal of total Barrett’s eradication [6].

Aims & Methods

Based on this concept and the safety profiles of RFA, we proposed a randomized controlled trial to investigate whether endoscopic RFA for esophageal background mucosal resurfacing (EBMR) could decrease the rate of metachronous neoplasia.Patients who received a curative ESD, and the lugol staining showed speckled pattern over the background mucosa, were randomly assigned in a 1:1 ratio to either RFA (EBMR) or endoscopic surveillance alone (control). The procedure of EBMR with RFA was performed with balloon device for circumferential ablation of the total esophageal mucosa at the 2-3 months after ESD. The primary outcome was the metachronous recurrence of squamous neoplasia during a 5-year follow-up since randomization. The secondary outcomes were the adverse events.

Results

Of 112 patients screened, thirty patients were randomized to receive EBMR (n=15) or control (n=15). The mean procedure time of EBMR was 30.7minutes (range, 25-40 minutes). One patient developed post-RFA stenosis and was resolved after 3 sessions of endoscopic dilation. EBMR reduced the risk of metachronous recurrence (0% EBMR vs. 53% control, P=0.001) with a number needed to treat (NNT) of 1.9. Reverse of the lugol staining speckled pattern to few LVLs occurred in all patients and persisted for at least 5-year in the ablation group, compared with a total of 13 metachronous recurrences in 8 patients (53%) of control group.

Table 1. Primary and secondary outcomes

Conclusion

In this randomized trial of patients with multiple small LVLs over the esophageal background after curative ESD, EBMR with balloon-type RFA is a promising and safe procedure to prevent the metachronous recurrence over 5 years of follow-up. (Clinical trial registration number: NCT03183115)

References

1. Shimizu Y, Tukagoshi H, Fujita M et al. Metachronous squamous cell carcinoma of the esophagus arising after endoscopic mucosal resection. Gastrointestinal endoscopy 2001; 54: 190-194
2. Urabe Y, Hiyama T, Tanaka S et al. Metachronous multiple esophageal squamous cell carcinomas and Lugol-voiding lesions after endoscopic mucosal resection. Endoscopy 2009; 41: 304-309
3. Shaheen NJ, Sharma P, Overholt BF et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. The New England journal of medicine 2009; 360: 2277-2288
4. Yu X, van Munster SN, Zhang Y et al. Durability of radiofrequency ablation for treatment of esophageal squamous cell neoplasia: 5-year follow-up of a treated cohort in China. Gastrointestinal endoscopy 2019; 89: 736-748 e732
5. Wang WL, Chang IW, Chen CC et al. Lessons from pathological analysis of recurrent early esophageal squamous cell neoplasia after complete endoscopic radiofrequency ablation. Endoscopy 2018; 50: 743-750
6. Desai M, Saligram S, Gupta N et al. Efficacy and safety outcomes of multimodal endoscopic eradication therapy in Barrett's esophagus-related neoplasia: a systematic review and pooled analysis. Gastrointestinal endoscopy 2017; 85: 482-495

Disclosure

There was no any conflict of interest

Introduction

Spasmolytic polypeptide expressing metaplasia (SPEM) is a cell repair lineage and is a very important phenotype of gastric mucosal injury and precancerous lesion.
Previously, parietal cells loss is considered as the first step and followed with chief cells transdiffernation to induce SPEM. But whether chief cells initial loss cause SPEM
needs to be further investigation. Acidic mammalian chitinase (CHIA) belongs to the 18 glycosidase family and is highly expressed in the chief cells. Our previous study showed that CHIA deficiency in the chief cells is the key event to induce SPME to progress to gastric cancer (Liu et al., DDW 2023 and 2024). However, the molecular role of CHIA in the development of SPEM is need further investigated.

Aims & Methods

Electron microscopy, qRT-PCR and single-cell sequencing (scRNA-seq) technology, as well as histopathological and immunofluorescence (IF) stainning with specific markers were performed in chief cells specific CHIA knockout mouse model (CHIA^rox/rox-GIF-Dre) and wild-type mice(CHIA^rox/rox), and in CHIA over - expression mice (CHIA ^rox/rox - GIF - Dre + rAAv - CHIA) and the control group (CHIA ^rox/rox - GIF - Dre + rAAv - control).

Results

Compared with CHIA^rox/rox mice, histological analysis and scRNA-seq technology data showed that loss of chief cells with increased M2 macrophage infiltration and final SPEM formation, but remaining of parietal cells in CHIA^rox/rox-GIF-Dre mice. Electron microscopy showed CHIA deficiency in mice resulted in endoplasmic reticulum was dilated and swollen, as well as the mitochondrial membrane was discontinuous of chief cells, followed with the accumulation of endoplasmic reticulum stress marker, including PERK, XBP-1, eIF2α/P-eIF2α, and GRP78, together with upregulation of pyroptosis-related marker, including NLRP3, ACS, GSDMD, NEK7, Caspase1, Caspase11, IL-1β, and IL-18, which was detected by qRT-PCR. These data indicating that target CHIA deletion caused chief cells pyroptosis. Furthermore, qRT-PCR analysis showed that CHIA deficiency caused the activation of IL33/IL-13 circuit in the mucosa of mice. Moreover, double immunofluorescence staining confirmed that upregulation and colocalization of IL-33 induced M2 macrophage polarization markers, including F4/80 and CD163⁺ with NLRP3 in the base of gastric mucosal of CHIA^rox/rox-GIF-Dre mice when compared with CHIA^rox/rox mice.Notably, CHIA ^rox/rox - GIF - Dre + rAvv - CHIA mice reversed the above process compared with controls.

Conclusion

Chief cells specific CHIA deficiency resulted in endoplasmic reticulum stress mediate NLRP3 inflammasome activation to induce chief cells proptosis.
Chief cells initial loss is sufficient and the key step to activate IL-33/ST2-M2 macrophage polarization axis to induce SPEM, which is independent of parietal cells loss.

Introduction

Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in patients (pts) with an inadequate response to UDCA or as monotherapy in pts unable to tolerate UDCA. RESPONSE was a Phase 3, randomised, placebo-controlled clinical trial of seladelpar in pts with inadequate response/intolerance to UDCA. Pts completing RESPONSE were eligible to roll over into ASSURE (NCT03301506), an ongoing, open-label, long-term, Phase 3 safety trial. Here, we describe data from month 18 (month 6 of ASSURE) in pts with or without prior use of fibrates or obeticholic acid (OCA) who rolled over from RESPONSE into ASSURE.

Aims & Methods

Pts received 10 mg seladelpar orally daily or placebo in RESPONSE; pts received open-label 10 mg seladelpar in ASSURE. Fibrates and OCA were prohibited during the study period and a 6-week washout was required prior to entry in RESPONSE. Data were described for pts in ASSURE with or without prior use of fibrates/OCA and based on whether they received seladelpar (continuous seladelpar pts) or placebo (crossover pts) in RESPONSE. Efficacy included the percentage of pts achieving a composite biochemical response (CBR; alkaline phosphatase [ALP] < 1.67 × upper limit of normal [ULN], ALP decrease ≥ 15%, and total bilirubin ≤ ULN). Safety assessments included adverse events (AEs) and laboratory parameters.

Results

Among pts who continued into ASSURE from RESPONSE (158), 16 continuous seladelpar and 11 crossover pts reported prior use of fibrates/OCA (total, n=27; 17%); 88 continuous seladelpar and 43 crossover pts reported no prior use of fibrates/OCA (total, n=131; 83%). At month 18, among continuous seladelpar pts, 9/15 (60%) pts with prior fibrate/OCA use achieved a CBR vs 54/87 (62%) pts without prior fibrate/OCA use. Among crossover pts, 7/11 (64%) pts with prior fibrate/OCA use vs 32/41 (78%) pts without prior fibrate/OCA use achieved a CBR at month 6 of ASSURE. From ASSURE initiation to month 6, incidence of AEs was similar across continuous seladelpar and crossover pts, regardless of prior OCA/fibrate use; no treatment-related serious AEs were reported.

Conclusion

In this interim analysis of continuous seladelpar and crossover pts from ASSURE, pts who reported prior use of fibrates/OCA achieved a similar sustained biochemical response with seladelpar compared with pts who reported no prior use. Seladelpar appeared safe and well tolerated in this subgroup.

Disclosure

AV reports receiving speaker fees from Intercept Pharmaceuticals and participation on an advisory board with Novartis. DP reports receiving consulting fees from Mediar Therapeutics. AEK reports receiving grants or contracts from Gilead Sciences, Inc., Intercept Pharmaceuticals and Roche; consulting fees from AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; Astellas; AstraZeneca; Attovia Therapeutics; Avior Bio; Bayer; Bristol Myers Squibb; Böhringer-Ingelheim; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Rectify Pharma; Roche; and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie; Advanz Pharma; AOP Orphan Pharmaceuticals; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Falk; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Johnson & Johnson; Medscape; Merck Sharp & Dohme; Mirum Pharma; NewBridge Pharmaceuticals; Novartis; Roche; Vertex Pharmaceuticals; and Viofor; support for attending meetings and/or travel from Gilead Sciences, Inc.; participation on a data safety monitoring board with AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; AstraZeneca; Avior Bio; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Roche; and Takeda; and a leadership or fiduciary role in other board, society, committee, or advocacy groups (paid or unpaid) with PBC Foundation, Swiss Association for the Study of the Liver (SASL), Swiss Gastroenterology Society (SGG), Swiss Hepa, and Swiss Transplant Society (STS). VC reports receiving speaker fees from AbbVie; Advanz Pharma; Echosens; Gilead Sciences, Inc.; Ipsen; and Roche; and participation on an advisory board with Advanz Pharma; Gilead Sciences, Inc.; Ipsen; and Roche. EGD reports receiving consulting fees from Ipsen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen; support for attending meetings and/or travel from Advanz Pharma; and participation on a data safety monitoring board or advisory board for GSK. CH, XQ, SP, WTB, and TRW are employees of Gilead Sciences, Inc., and may own stock in Gilead Sciences, Inc. SCG reports receiving grants or contracts from AbbVie, Arbutus Biopharma, CymaBay Therapeutics, GSK, Ipsen, and Mirum Pharma; and participation on a data safety monitoring board or advisory board with CymaBay Therapeutics, GSK, and Ipsen.