Introduction

Loss of parietal cells causes the development of spasmolytic polypeptide-expressing metaplasia (SPEM) through transdifferentiation of chief cells. However, whether initial chief cell loss cause SPEM needs to be further investigated. Acidic mammalian chitinase (CHIA) belongs to the 18 glycosidase family and is expressed in epithelial cells in various organ, which can degrade chitin-containing pathogens, participate in Th2-mediated inflammation. CHIA is highly expressed in the chief cells, and our previous study showed that CHIA deficiency in the chief cells is the key event to induces SPEM and progress to gastric cancer, which is independent of parietal cell loss (Zhao et al., DDW 2023; Hu et al., KDDW 2021). However, the molecular role and mechanism of CHIA in the development of SPEM is need further investigated.

Aims & Methods

Aims: Explore new cellular origins and specific molecular mechanisms of SPEM occurrence.
Methods: PCR and single-cell sequencing (scRNA-seq) technology, histopathological and immunofluorescence (IF) with specific markers were performed in CHIA wild type (WT) mice and knockout (KO) mice. Multiple endoplasmic reticulum stress markers, macrophage polarization markers and cytokine-related markers were detected by qPCR in CHIA WT and KO.

Results

PCR and scRNA-seq technology data showed that increased M2 macrophage infiltration and SPEM formation, but remaining of parietal cells in CHIA KO mice, when compared to CHIA WT mice. Furthermore, deletion of CHIA in mice resulted in release of endoplasmic reticulum stress-triggered, including upregulation of endoplasmic reticulum stress markers (PERK, XBP-1, eIF2α/P- eIF2α, and GRP78), followed with upregulation of pyroptosis-related marker, including NLRP3, ACS, GSDMD, NEK7, Caspase1, Caspase11, IL-1β, and IL-18, as well as significantly increasement of IL33/IL-13 release. Moreover, Double immunofluorescence staining showed that upregulation and colocalization of NLRP3 and IL-33 induced M2 macrophage polarization markers, including F4/80 and CD163in the gastric mucosal of CHIA KO mice. Notably, IF showed that CHIA deficiency caused the mucous neck cell marker SOX9 shifted from the cervical isthmus into the SPEM cells, and co-localized with the SPEM markers CD44v, TFF2 and MUC6, suggesting that the origin of SPEM cells may transdifferentiate from mucous neck cell after CHIA gene deletion.^​

Conclusion

CHIA deficiency in the chief cells promotes SPEM through the pyroptosis mediated M2 macrophage polarization. The origin of CHIA deficiency promotes injury may origin from the transdifferentiation of mucous neck mucus cells into SPEM cells.

Disclosure

The authors declare that they have no conflicts of interest.

Introduction

Biologic and small-molecule therapies are widely used for ulcerative colitis (UC), but their comparative effectiveness in TNF-exposed patients remains unclear.

Aims & Methods

This study evaluates the clinical and biomarker responses to Vedolizumab, Tofacitinib, and Ustekinumab over 12 months, adjusting for baseline differences using Inverse Probability of Treatment Weighting (IPTW). A multicenter retrospective cohort of TNF-exposed UC patients treated with Vedolizumab (n = 260), Tofacitinib (n = 149), or Ustekinumab (n = 193) was analyzed. Clinical outcomes, including Partial Mayo Score (pMayo), clinical remission, and biomarker response (CRP, ESR, fecal calprotectin), were assessed at baseline (T0), 8 weeks (T1), 24 weeks (T2), and 52 weeks (T3). IPTW balanced baseline characteristics, and longitudinal changes were analyzed using a repeated-measures general linear model (GLM) with post-hoc corrections for multiple comparisons.

Results

Before IPTW, significant baseline differences existed, with Tofacitinib patients being younger (p < 0.001), more frequently female (p = 0.003), and having higher fecal calprotectin levels (p = 0.005). After IPTW, covariate balance was achieved (SMD < 0.10). pMayo scores significantly declined in all treatment groups over time (p < 0.001, η² = 0.469), with no significant main effect of therapy (p = 0.329). A minor time-by-therapy interaction (p = 0.036, η² = 0.026) indicated slight response variations but lacked clinical significance. Before IPTW, Tofacitinib showed superior pMayo improvement versus Ustekinumab (p = 0.008), but this difference lost significance post-IPTW, suggesting baseline confounding. At 52 weeks, clinical remission was highest with Tofacitinib (57%), followed by Vedolizumab (40%) and Ustekinumab (22%) (p = 0.003). Biomarker remission favored Vedolizumab (48.8%) over Tofacitinib (19.5%) and Ustekinumab (21.2%) (p = 0.002). Adverse events were rare but more frequent with Vedolizumab (p < 0.001).

Conclusion

Over 12 months, all therapies significantly improved clinical and biomarker outcomes, with no significant differences in overall pMayo reduction post-IPTW. Tofacitinib achieved the highest clinical remission, while Vedolizumab demonstrated superior biomarker response. These findings highlight the need for individualized treatment selection in TNF-exposed UC patients.

Introduction

Pancreatic cancer is a highly lethal disease, commonly characterized by aggressiveness and a unique tumor microenvironment, where mutant KRAS signaling stands as a hallmark event in its pathophysiology.

Aims & Methods

To deepen our understanding of KRAS-dependent signaling, stem cell-derived pancreatic ductal-like organoids (PDLOs) were induced by oncogenic KRAS expression, followed by time-resolved single-cell RNA- and bulk ATAC-sequencing. This unique precancerous state model facilitated a comprehensive characterization of early oncogenic events at cellular resolution.

Results

Specifically, mutated KRAS triggers two distinct gene signature programs: extracellular matrix remodeling and inflammation-related signaling. Correlation with published datasets underscored relevance of these distinct gene signatures in advanced cancer states within human patients. Various co-culture systems showed that KRAS^G12D-expressing PDLOs could induce cancer-associated fibroblast (CAF) activation while simultaneously shielding KRAS-activated, yet non-cancerous, organoids from T cell infiltration in vitro. Furthermore, in silico approaches were employed to reconstruct a virtual pancreatic cancer space, demonstrating that our PDLOs transcriptomically bridge healthy and malignant duct, while also unveiling the KRAS driven pathways mediating CAF reprogramming and T cell shielding preceding cancer onset.

Conclusion

In summary, our human PDLO model enables us to explore the transition from normal to cancerous states, overcoming gaps in our understanding of tumor development and tumor niche preparation.

Introduction

Colectomy is the primary treatment for dysplastic lesions in inflammatory bowel disease (IBD). Since the development of advanced endoscopic techniques, the management of dysplasia is evolving. Endoscopic submucosal resection (ESD) could be used in selected cases at referral centres as an alternative to colectomy. However, the feasibility and safety in IBD remains limited.

Aims & Methods

To evaluate en-bloc resection rate and the need of colectomy due to ESD failure in IBD.
Secondary aims: to assess the complications of ESD, the local recurrence of dysplastic lesions, the presence of synchronous and metachronous lesions and the risk of IBD relapse following the procedure.
Multicentre, retrospective study of IBD patients who underwent ESD for suspected colonic dysplastic lesions at least one month before the inclusion date. Patients with total colectomy before ESD, invisible dysplasia at the time of ESD, or pregnancy were excluded. En-bloc resection rate and colectomy due to ESD failure at the short term were evaluated by logistic regression analysis. The risk of IBD relapse was evaluated by Cox regression analysis.

Results

Sixty patients from 22 centres were included: 47 with ulcerative colitis, 11 with Crohn’s disease and 2 with IBD-unclassified. The mean age at ESD was 64 years (SD 13). The majority of the lesions (n=33, 55%) were located in rectum. Fifty lesions (83%) were located in areas previously inflamed. En-bloc and R0 were achieved in 58 (97%) and 50 patients (83%), respectively. Colectomy due to ESD failure was required in 5 patients (8.3%), all of them occurred within 6 months after ESD. No risk factors were associated with colectomy in multivariable analysis, including inflammatory activity, IBD treatments or characteristics of the lesions. Complications occurred in 17 patients (28%): 3 did not required any treatment, 6 required pharmacologic therapy, 6 needed endoscopic or radiologic intervention, and 2 underwent surgery (Table 1). No deaths were reported.
At least one surveillance colonoscopy after ESD was performed in 42 patients (70%). Local recurrence was observed in 2 patients (4.7%) while other dysplastic lesions were detected in 11 (26%) during the follow-up (median 1.5 years, IQR 0.5-3.4). All these lesions were removed endoscopically. Synchronous and metachronous lesions were identified in 4 (20%) and 9 patients (19%), respectively. IBD relapse occurred in 8 patients during the follow-up, with an incidence rate of 7% person-year (CI 95%:3-13). The occurrence of relapses was gradually throughout the follow-up period.

Table 1. Complications of endoscopic submucosal dissection

Conclusion

ESD avoids colectomy in 90% of IBD patients with dysplastic lesions. One-third of the patients experienced complications, all of them resolved with no sequelae. Given the risk of new dysplastic lesions, ongoing monitoring with surveillance colonoscopies is recommended.

Disclosure

María José García has received financial support for travelling and educational activities from Janssen, Pfizer, AbbVie, Takeda, Kern Pharma, Faes Farma and Ferring.
Edoardo Vincenzo Savarino has served as speaker for Abbvie, Abivax, Agave, AGPharma, Alfasigma, Apoteca, Biosline, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Galapagos, Johnson&Johnson,consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Dr. Falk, Eli Lilly, Fenix Pharma, Ferring, Giuliani, Grunenthal, Johnson&Johnson, JB Pharmaceuticals, Merck & Co, Nestlè, Pfizer, Reckitt Benckiser, Sanofi/Regeneron, SILA, Sofar, Takeda, Unifarco; he received research support from Bonollo, Difass, Pfizer, Reckitt Benckiser, Sanofi/Regeneron, SILA, Sofar, Unifarco, Zeta Farmaceutici.
Irene González-Partida has received support for conference attendance and speaker fees from AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Janssen, MSD, Kern, Pfizer, Shire, Takeda, Teva and Tillotts Pharma AG.
Alicia López has served as speaker for Chiesi, Takeda, ABBVIE, Lilly. I have received support for conference attendance from Pfizer, Lilly, Kern Pharma, Falk, Ferring, and Janssen
Jordina Llao has received educacional suport from Abbvie, Tillots, Ferring and Lilly.